Science.gov

Sample records for glucagon-like peptide-1 analogue

  1. The glucagon-like peptide 1 analogue Exendin-4 attenuates alcohol mediated behaviors in rodents.

    PubMed

    Egecioglu, Emil; Steensland, Pia; Fredriksson, Ida; Feltmann, Kristin; Engel, Jörgen A; Jerlhag, Elisabet

    2013-08-01

    Development of alcohol use disorders largely depends on the effects of alcohol on the brain reward systems. Emerging evidence indicate that common mechanisms regulate food and alcohol intake and raise the possibility that endocrine signals from the gut may play an important role for alcohol consumption, alcohol-induced reward and the motivation to consume alcohol. Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide regulating food intake and glucose homeostasis, has recently been shown to target central brain areas involved in reward and motivation, including the ventral tegmental area and nucleus accumbens. Herein we investigated the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4), on various measures of alcohol-induced reward as well as on alcohol intake and alcohol seeking behavior in rodents. Treatment with Ex4, at a dose with no effect per se, attenuated alcohol-induced locomotor stimulation and accumbal dopamine release in mice. Furthermore, conditioned place preference for alcohol was abolished by both acute and chronic treatment with Ex4 in mice. Finally we found that Ex4 treatment decreased alcohol intake, using the intermittent access 20% alcohol two-bottle-choice model, as well as alcohol seeking behavior, using the progressive ratio test in the operant self-administration model, in rats. These novel findings indicate that GLP-1 signaling attenuates the reinforcing properties of alcohol implying that the physiological role of GLP-1 extends beyond glucose homeostasis and food intake regulation. Collectively these findings implicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for alcohol use disorders.

  2. Glucagon-like peptide 1 and the cardiovascular system.

    PubMed

    Fava, Stephen

    2014-01-01

    Glucagon-like peptide 1 (GLP1) is a major incretin hormone. This means that it is secreted by the gut in response to food and helps in reducing post-prandial glucose exertion. It achieves this through a number of mechanisms, including stimulating insulin release by pancreatic β-cells in a glucose-dependent manner; inhibition of glucagon release by pancreatic α-cells (also in a glucose-dependent manner); induction of central appetite suppression and by delaying gastric empting thereby inducing satiety and also reducing the rate of absorption of nutrients. However, GLP1 receptors have been described in a number of extra-pancreatic tissues, including the endothelium and the myocardium. This suggests that the physiological effects of GLP1 extend beyond post-prandial glucose control and raises the possibility that GLP1 might have cardiovascular effects. This is of importance in our understanding of incretin hormone physiology and especially because of the possible implications that it might have with regard to cardiovascular effects of incretin-based therapies, namely DPP-IV inhibitors (gliptins) and GLP1 analogues. This review analyzes the animal and human data on the effects of GLP1 on the cardiovascular system in health and in disease and the currently available data on cardiovascular effects of incretin-based therapies. It is the author's view that the physiological role of GLP1 is not only to minimize postprandial hypoglycaemia, but also protect against it.

  3. Glucagon-like peptide 1 (GLP-1) and eating.

    PubMed

    Gutzwiller, Jean-Pierre; Degen, Lukas; Heuss, Ludwig; Beglinger, Christoph

    2004-08-01

    New information regarding gastrointestinal mechanisms that participate in the control of food intake has extended our understanding of appetite control. Although each new signaling pathway discovered in the gut is a potential target for drug development in the treatment of obesity, the growing number of such signaling molecules indicates that a highly complex process controls food intake. The present summary focuses on the role of glucagon-like peptide 1 (GLP-1) in this regulatory process. The different biological effects of GLP-1 (glucose-lowering properties, inhibition of appetite and food intake) provide a powerful impetus for development of GLP-1-based new drugs.

  4. The discovery of glucagon-like peptide 1.

    PubMed

    Lund, P Kay

    2005-06-15

    The discovery of glucagon-like peptide 1 (GLP-1) began more than two decades ago with the observations that anglerfish islet proglucagon messenger RNAs (mRNAs) contained coding sequences for two glucagon-related peptides arranged in tandem. Subsequent analyses revealed that mammalian proglucagon mRNAs encoded a precursor containing the sequence of pancreatic glucagon, intestinal glicentin and two glucagon-related peptides termed GLP-1 and GLP-2. Multidisciplinary approaches were then required to define the structure of biologically active GLP-1 7-36 amide and its role as an incretin, satiety hormone and, most recently, a neuroprotective peptide. This historial perspective outlines the use of traditional recombinant DNA approaches to derive the GLP-1 sequence and highlights the challenges and combination of clinical and basic science approaches required to define the physiology and pathophysiology of bioactive peptides discovered through genomics. PMID:15780428

  5. Multiple Factors Related to the Secretion of Glucagon-Like Peptide-1

    PubMed Central

    Wang, XingChun; Liu, Huan; Chen, Jiaqi; Li, Yan; Qu, Shen

    2015-01-01

    The glucagon-like peptide-1 is secreted by intestinal L cells in response to nutrient ingestion. It regulates the secretion and sensitivity of insulin while suppressing glucagon secretion and decreasing postprandial glucose levels. It also improves beta-cell proliferation and prevents beta-cell apoptosis induced by cytotoxic agents. Additionally, glucagon-like peptide-1 delays gastric emptying and suppresses appetite. The impaired secretion of glucagon-like peptide-1 has negative influence on diabetes, hyperlipidemia, and insulin resistance related diseases. Thus, glucagon-like peptide-1-based therapies (glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) are now well accepted in the management of type 2 diabetes. The levels of glucagon-like peptide-1 are influenced by multiple factors including a variety of nutrients. The component of a meal acts as potent stimulants of glucagon-like peptide-1 secretion. The levels of its secretion change with the intake of different nutrients. Some drugs also have influence on GLP-1 secretion. Bariatric surgery may improve metabolism through the action on GLP-1 levels. In recent years, there has been a great interest in developing effective methods to regulate glucagon-like peptide-1 secretion. This review summarizes the literature on glucagon-like peptide-1 and related factors affecting its levels. PMID:26366173

  6. Glucagon-like peptide-1 binding to rat skeletal muscle.

    PubMed

    Delgado, E; Luque, M A; Alcántara, A; Trapote, M A; Clemente, F; Galera, C; Valverde, I; Villanueva-Peñacarrillo, M L

    1995-01-01

    We have found [125I]glucagon-like peptide-1(7-36)-amide-specific binding activity in rat skeletal muscle plasma membranes, with an estimated M(r) of 63,000 by cross-linking and SDS-PAGE. The specific binding was time and membrane protein concentration dependent, and displaceable by unlabeled GLP-1(7-36)-amide with an ID50 of 3 x 10(-9) M of the peptide; GLP-1(1-36)-amide also competed, whereas glucagon and insulin did not. GLP-1(7-36)-amide did not modify the basal adenylate cyclase activity in skeletal muscle plasma membranes. These data, together with our previous finding of a potent glycogenic effect of GLP-1(7-36)-amide in rat soleus muscle, and also in isolated hepatocytes, which was not accompanied by a rise in the cell cyclic AMP content, lead use to believe that the insulin-like effects of this peptide on glucose metabolism in the muscle could be mediated by a type of receptor somehow different to that described for GLP-1 in pancreatic B cells, where GLP-1 action is mediated by the cyclic AMP-adenylate cyclase system.

  7. Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists

    PubMed Central

    Kang, Yu Mi

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP-1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP-1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes. PMID:27118277

  8. Glucagon-like peptide-1: The missing link in the metabolic clock?

    PubMed

    Brubaker, Patricia L; Gil-Lozano, Manuel

    2016-04-01

    Circadian expression of clock genes in peripheral tissues is critical to the coordinated regulation of intestinal digestive and absorptive functions, insulin secretion, and peripheral tissue nutrient deposition during periods of nutrient ingestion, thereby preventing metabolic dysregulation. As glucagon-like peptide-1 is a key incretin hormone that regulates glucose-dependent insulin secretion, we hypothesized that this intestinal hormone is a player in the peripheral metabolic clock, linking nutrient ingestion to insulin secretion. We have now established that secretion of glucagon-like peptide-1 from the intestinal L cell shows a rhythmic pattern in rats and humans in vivo that is altered by circadian disruptors, such as constant light exposure, consumption of a Western diet and feeding at inappropriate times (i.e., during the light period in rodents). Interestingly, the alterations in the rhythm of the glucagon-like peptide-1 secretory responses were found to parallel the changes in the pattern of insulin responses in association with significant impairments in glucose tolerance. Furthermore, we have detected circadian clock gene expression, and showed circadian secretion of glucagon-like peptide-1 from both the murine and human L cell in vitro. These findings demonstrate that glucagon-like peptide-1 is a functional component of the peripheral metabolic clock, and suggest that altered release of glucagon-like peptide-1 might play a role in the metabolic perturbations that result from circadian disruption. PMID:27186359

  9. Glucagon-like peptide-1 binding to rat hepatic membranes.

    PubMed

    Villanueva-Peñacarrillo, M L; Delgado, E; Trapote, M A; Alcántara, A; Clemente, F; Luque, M A; Perea, A; Valverde, I

    1995-07-01

    We have found [125I]glucagon-like peptide (GLP)-1(7-36)amide specific binding activity in rat liver and isolated hepatocyte plasma membranes, with an M(r) of approximately 63,000, estimated by cross-linking and SDS-PAGE. The specific binding was time- and membrane protein concentration-dependent, and equally displaced by unlabelled GLP-1(7-36)amide and by GLP-1(1-36)amide, achieving its ID50 at 3 x 10(-9) M of the peptides. GLP-1(7-36)amide did not modify the basal or the glucagon (10(-8) M)-stimulated adenylate cyclase in the hepatocyte plasma membranes. These data, together with our previous findings of a potent glycogenic effect of GLP-1(7-36)amide in isolated rat hepatocytes, led us to postulate that the insulin-like effects of this peptide on glucose liver metabolism could be mediated by a type of receptor probably different from that described for GLP-1 in pancreatic B-cells or, alternatively, by the same receptor which, in this tissue as well as in muscle, uses a different transduction system.

  10. The mechanism of glucagon-like peptide-1 participation in the osmotic homeostasis.

    PubMed

    Natochin, Yu V; Marina, A S; Kutina, A V; Balbotkina, E V; Karavashkina, T A

    2016-07-01

    We have found the physiological mechanism of intensification of the excessive fluid removal from the body under the action of glucagon-like peptide-1 and its analog exenatide. Under the water load in rats, exenatide significantly increased the clearance of lithium, reduced fluid reabsorption in the proximal tubule of the nephron and intensified reabsorption of sodium ions in the distal parts, which contributed to the formation of sodium-free water and faster recovery of osmotic homeostasis. Blocking this pathway with a selective antagonist of glucagon-like peptide-1 receptors slowed down the elimination of excessive water from the body. PMID:27595820

  11. Medicinal Plants Qua Glucagon-Like Peptide-1 Secretagogue via Intestinal Nutrient Sensors

    PubMed Central

    Kim, Ki-Suk; Jang, Hyeung-Jin

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) participates in glucose homeostasis and feeding behavior. Because GLP-1 is rapidly inactivated by the enzymatic cleavage of dipeptidyl peptidase-4 (DPP4) long-acting GLP-1 analogues, for example, exenatide and DPP4 inhibitors, for example, liraglutide, have been developed as therapeutics for type 2 diabetes mellitus (T2DM). However, the inefficient clinical performance and the incidence of side effects reported on the existing therapeutics for T2DM have led to the development of a novel therapeutic strategy to stimulate endogenous GLP-1 secretion from enteroendocrine L cells. Since the GLP-1 secretion of enteroendocrine L cells depends on the luminal nutrient constituents, the intestinal nutrient sensors involved in GLP-1 secretion have been investigated. In particular, nutrient sensors for tastants, cannabinoids, and bile acids are able to recognize the nonnutritional chemical compounds, which are abundant in medicinal plants. These GLP-1 secretagogues derived from medicinal plants are easy to find in our surroundings, and their effectiveness has been demonstrated through traditional remedies. The finding of GLP-1 secretagogues is directly linked to understanding of the role of intestinal nutrient sensors and their recognizable nutrients. Concurrently, this study demonstrates the possibility of developing novel therapeutics for metabolic disorders such as T2DM and obesity using nutrients that are readily accessible in our surroundings. PMID:26788106

  12. Oral Delivery of Pentameric Glucagon-Like Peptide-1 by Recombinant Lactobacillus in Diabetic Rats

    PubMed Central

    Krogh-Andersen, Kasper; Pelletier, Julien; Marcotte, Harold; Östenson, Claes-Göran; Hammarström, Lennart

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced by intestinal cells and stimulates insulin secretion from the pancreas in a glucose-dependent manner. Exogenously supplied GLP-1 analogues are used in the treatment of type 2 diabetes. An anti-diabetic effect of Lactobacillus in lowering plasma glucose levels and its use as a vehicle for delivery of protein and antibody fragments has been shown previously. The aim of this study was to employ lactobacilli as a vehicle for in situ production and delivery of GLP-1 analogue to normalize blood glucose level in diabetic GK (Goto-Kakizaki) rats. In this study, we designed pentameric GLP-1 (5×GLP-1) analogues which were both expressed in a secreted form and anchored to the surface of lactobacilli. Intestinal trypsin sites were introduced within 5×GLP-1, leading to digestion of the pentamer into an active monomeric form. The E. coli-produced 5×GLP-1 peptides delivered by intestinal intubation to GK rats resulted in a significant improvement of glycemic control demonstrated by an intraperitoneal glucose tolerance test. Meanwhile, the purified 5×GLP-1 (trypsin-digested) from the Lactobacillus cultures stimulated insulin secretion from HIT-T15 cells, similar to the E. coli-produced 5×GLP-1 peptides. When delivered by gavage to GK rats, non-expressor L. paracasei significantly lowered the blood glucose level but 5×GLP-1 expression did not provide an additional anti-diabetic effect, possibly due to the low levels produced. Our results indicate that lactobacilli themselves might be used as an alternative treatment method for type 2 diabetes, but further work is needed to increase the expression level of GLP-1 by lactobacilli in order to obtain a significant insulinotropic effect in vivo. PMID:27610615

  13. Oral Delivery of Pentameric Glucagon-Like Peptide-1 by Recombinant Lactobacillus in Diabetic Rats.

    PubMed

    Lin, Yin; Krogh-Andersen, Kasper; Pelletier, Julien; Marcotte, Harold; Östenson, Claes-Göran; Hammarström, Lennart

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced by intestinal cells and stimulates insulin secretion from the pancreas in a glucose-dependent manner. Exogenously supplied GLP-1 analogues are used in the treatment of type 2 diabetes. An anti-diabetic effect of Lactobacillus in lowering plasma glucose levels and its use as a vehicle for delivery of protein and antibody fragments has been shown previously. The aim of this study was to employ lactobacilli as a vehicle for in situ production and delivery of GLP-1 analogue to normalize blood glucose level in diabetic GK (Goto-Kakizaki) rats. In this study, we designed pentameric GLP-1 (5×GLP-1) analogues which were both expressed in a secreted form and anchored to the surface of lactobacilli. Intestinal trypsin sites were introduced within 5×GLP-1, leading to digestion of the pentamer into an active monomeric form. The E. coli-produced 5×GLP-1 peptides delivered by intestinal intubation to GK rats resulted in a significant improvement of glycemic control demonstrated by an intraperitoneal glucose tolerance test. Meanwhile, the purified 5×GLP-1 (trypsin-digested) from the Lactobacillus cultures stimulated insulin secretion from HIT-T15 cells, similar to the E. coli-produced 5×GLP-1 peptides. When delivered by gavage to GK rats, non-expressor L. paracasei significantly lowered the blood glucose level but 5×GLP-1 expression did not provide an additional anti-diabetic effect, possibly due to the low levels produced. Our results indicate that lactobacilli themselves might be used as an alternative treatment method for type 2 diabetes, but further work is needed to increase the expression level of GLP-1 by lactobacilli in order to obtain a significant insulinotropic effect in vivo. PMID:27610615

  14. Efficacy and safety of liraglutide, a once-daily human glucagon-like peptide-1 analogue, in Latino/Hispanic patients with type 2 diabetes: post hoc analysis of data from four phase III trials.

    PubMed

    Davidson, J A; Ørsted, D D; Campos, C

    2016-07-01

    The aim of the present analysis was to evaluate the efficacy of the glucagon-like peptide-1 receptor agonist liraglutide in Latino/Hispanic individuals with type 2 diabetes, in addition to comparing its treatment effects with those observed in non-Latino/Hispanic individuals. Analyses were performed on patient-level data from a subset of individuals self-defined as Latino/Hispanic from four phase III studies, the LEAD-3, LEAD-4, LEAD-6 and 1860-LIRA-DPP-4 trials. Endpoints included change in glycated haemoglobin (HbA1c) and body weight from baseline. In Latino/Hispanic patients (n = 505; 323 treated with liraglutide) after 26 weeks, mean HbA1c reductions were significantly greater with both liraglutide 1.2 and 1.8 mg versus comparator or placebo in the LEAD-3 and LEAD-4 studies, and with 1.8 mg liraglutide in the 1860-LIRA-DPP-4 trial. In LEAD-3 both doses led to significant differences in body weight change among Latino/Hispanic patients versus the comparator. With 1.8 mg liraglutide, difference in weight change was significant only in the 1860-LIRA-DPP-4 trial versus sitagliptin. For both endpoints Latino/Hispanic and non-Latino/Hispanic patients responded to liraglutide similarly. In summary, liraglutide is efficacious for treatment of type 2 diabetes in Latino/Hispanic patients, with a similar efficacy to that seen in non-Latino/Hispanic patients. PMID:26936426

  15. Mechanisms underlying glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 secretion.

    PubMed

    Reimann, Frank; Gribble, Fiona M

    2016-04-01

    The incretin hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1, are secreted from intestinal K- and L cells, respectively, with the former being most abundant in the proximal small intestine, whereas the latter increase in number towards the distal gut. Although an overlap between K- and L cells can be observed immunohistochemically or in murine models expressing fluorescent markers under the control of the two hormone promoters, the majority (>80%) of labeled cells seems to produce only one of these hormones. Transcriptomic analysis showed a close relationship between small intestinal K- and L cells, and glucose sensing mechanisms appear similar in both cell types with a predominant role of electrogenic glucose uptake through sodium-coupled glucose transporter 1. Similarly, both cell types produce the long-chain fatty acid sensing G-protein-coupled receptors, FFAR1 (GPR40) and FFAR4 (GPR120), but differ in the expression/functionality of other lipid sensing receptors. GPR119 and FFAR2/3, for example, have clearly documented roles in glucagon-like peptide-1 secretion, whereas agonists for the endocannabinoid receptor type 1 have been found to show largely selective inhibition of glucose-dependent insulinotropic peptide secretion. In conclusion, although K- and L cell populations overlap and share key molecular nutrient-sensing mechanisms, subtle differences between the responsiveness of the different cell types might be exploited to differentially modulate glucose-dependent insulinotropic peptide or glucagon-like peptide-1 secretion. PMID:27186350

  16. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury

    SciTech Connect

    Goto, Hiromasa; Nomiyama, Takashi; Mita, Tomoya; Yasunari, Eisuke; Azuma, Kosuke; Komiya, Koji; Arakawa, Masayuki; Jin, Wen Long; Kanazawa, Akio; Kawamori, Ryuzo; Fujitani, Yoshio; Hirose, Takahisa; Watada, Hirotaka

    2011-02-04

    Research highlights: {yields} Exendin-4 reduces neointimal formation after vascular injury in a mouse model. {yields} Exendin-4 dose not alter metabolic parameters in non-diabetic, non-obese mouse model. {yields} Exendin-4 reduces PDGF-induced cell proliferation in cultured SMCs. {yields} Exendin-4 may reduces neointimal formation after vascular injury at least in part through its direct action on SMCs. -- Abstract: Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4 weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10 nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.

  17. Glucagon-like peptide-1, diabetes, and cognitive decline: possible pathophysiological links and therapeutic opportunities.

    PubMed

    Mossello, Enrico; Ballini, Elena; Boncinelli, Marta; Monami, Matteo; Lonetto, Giuseppe; Mello, Anna Maria; Tarantini, Francesca; Baldasseroni, Samuele; Mannucci, Edoardo; Marchionni, Niccolò

    2011-01-01

    Metabolic and neurodegenerative disorders have a growing prevalence in Western countries. Available epidemiologic and neurobiological evidences support the existence of a pathophysiological link between these conditions. Glucagon-like peptide 1 (GLP-1), whose activity is reduced in insulin resistance, has been implicated in central nervous system function, including cognition, synaptic plasticity, and neurogenesis. We review the experimental researches suggesting that GLP-1 dysfunction might be a mediating factor between Type 2 diabetes mellitus (T2DM) and neurodegeneration. Drug treatments enhancing GLP-1 activity hold out hope for treatment and prevention of Alzheimer's disease (AD) and cognitive decline.

  18. Oral Delivery of Glucagon-Like Peptide-1 and Analogs: Alternatives for Diabetes Control?

    PubMed Central

    Araújo, Francisca; Fonte, Pedro; Santos, Hélder A.; Sarmento, Bruno

    2012-01-01

    Type 2 diabetes mellitus (T2DM) is one of the most prevalent diseases worldwide. Current treatments are often associated with off-target effects and do not significantly impact disease progression. New therapies are therefore urgently needed to overcome this social burden. Glucagon-like peptide-1 (GLP-1), an incretin hormone, has been used to control T2DM symptomatology. However, the administration of peptide or proteins drugs is still a huge challenge in the pharmaceutical field, requiring administration by parenteral routes. This article reviews the main hurdles in oral administration of GLP-1 and focuses on the strategies utilized to overcome them. PMID:23294796

  19. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis

    PubMed Central

    Armstrong, Matthew J.; Hull, Diana; Guo, Kathy; Barton, Darren; Hazlehurst, Jonathan M.; Gathercole, Laura L.; Nasiri, Maryam; Yu, Jinglei; Gough, Stephen C.; Newsome, Philip N.; Tomlinson, Jeremy W.

    2016-01-01

    Background & Aims Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH. Methods Fourteen patients were randomised to 1.8 mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes. Results Liraglutide reduced BMI (−1.9 vs. +0.04 kg/m2; p <0.001), HbA1c (−0.3 vs. +0.3%; p <0.01), cholesterol-LDL (−0.7 vs. +0.05 mmol/L; p <0.01), ALT (−54 vs. −4.0 IU/L; p <0.01) and serum leptin, adiponectin, and CCL-2 (all p <0.05). Liraglutide increased hepatic insulin sensitivity (−9.36 vs. −2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p <0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (−24.9 vs. +54.8 pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p <0.05), and specifically within subcutaneous adipose tissue (p <0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (−1.26 vs. +1.30%; p <0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p <0.01). Conclusions Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of

  20. The complexity of signalling mediated by the glucagon-like peptide-1 receptor.

    PubMed

    Fletcher, Madeleine M; Halls, Michelle L; Christopoulos, Arthur; Sexton, Patrick M; Wootten, Denise

    2016-04-15

    The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR that is a major therapeutic target for the treatment of type 2 diabetes. The receptor is activated by the incretin peptide GLP-1 promoting a broad range of physiological effects including glucose-dependent insulin secretion and biosynthesis, improved insulin sensitivity of peripheral tissues, preservation of β-cell mass and weight loss, all of which are beneficial in the treatment of type 2 diabetes. Despite this, existing knowledge surrounding the underlying signalling mechanisms responsible for the physiological actions downstream of GLP-1R activation is limited. Here, we review the current understanding around GLP-1R-mediated signalling, in particular highlighting recent contributions to the field on biased agonism, the spatial and temporal aspects for the control of signalling and how these concepts may influence future drug development. PMID:27068973

  1. Glucagon-Like Peptide 1 Analogs and their Effects on Pancreatic Islets.

    PubMed

    Tudurí, Eva; López, Miguel; Diéguez, Carlos; Nadal, Angel; Nogueiras, Rubén

    2016-05-01

    Glucagon-like peptide 1 (GLP-1) exerts many actions that improve glycemic control. GLP-1 stimulates glucose-stimulated insulin secretion and protects β cells, while its extrapancreatic effects include cardioprotection, reduction of hepatic glucose production, and regulation of satiety. Although an appealing antidiabetic drug candidate, the rapid degradation of GLP-1 by dipeptidyl peptidase 4 (DPP-4) means that its therapeutic use is unfeasible, and this prompted the development of two main GLP-1 therapies: long-acting GLP-1 analogs and DPP-4 inhibitors. In this review, we focus on the pancreatic effects exerted by current GLP-1 derivatives used to treat diabetes. Based on the results from in vitro and in vivo studies in humans and animal models, we describe the specific actions of GLP-1 analogs on the synthesis, processing, and secretion of insulin, islet morphology, and β cell proliferation and apoptosis. PMID:27062006

  2. Pharmacological Actions of Glucagon-Like Peptide-1, Gastric Inhibitory Polypeptide, and Glucagon.

    PubMed

    Sekar, R; Singh, K; Arokiaraj, A W R; Chow, B K C

    2016-01-01

    Glucagon family of peptide hormones is a group of structurally related brain-gut peptides that exert their pleiotropic actions through interactions with unique members of class B1 G protein-coupled receptors (GPCRs). They are key regulators of hormonal homeostasis and are important drug targets for metabolic disorders such as type-2 diabetes mellitus (T2DM), obesity, and dysregulations of the nervous systems such as migraine, anxiety, depression, neurodegeneration, psychiatric disorders, and cardiovascular diseases. The current review aims to provide a detailed overview of the current understanding of the pharmacological actions and therapeutic advances of three members within this family including glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon. PMID:27572131

  3. Glucagon-like Peptide-1 (GLP-1) Analogs: Recent Advances, New Possibilities, and Therapeutic Implications

    PubMed Central

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin that plays important physiological roles in glucose homeostasis. Produced from intestine upon food intake, it stimulates insulin secretion and keeps pancreatic β-cells healthy and proliferating. Because of these beneficial effects, it has attracted a great deal of attention in the past decade, and an entirely new line of diabetic therapeutics has emerged based on the peptide. In addition to the therapeutic applications, GLP-1 analogs have demonstrated a potential in molecular imaging of pancreatic β-cells; this may be useful in early detection of the disease and evaluation of therapeutic interventions, including islet transplantation. In this Perspective, we focus on GLP-1 analogs for their studies on improvement of biological activities, enhancement of metabolic stability, investigation of receptor interaction, and visualization of the pancreatic islets. PMID:25349901

  4. Pharmacokinetics and pharmacodynamics of the glucagon-like peptide-1 analog liraglutide in healthy cats.

    PubMed

    Hall, M J; Adin, C A; Borin-Crivellenti, S; Rudinsky, A J; Rajala-Schultz, P; Lakritz, J; Gilor, C

    2015-04-01

    Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that induces glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion. Glucagon-like peptide-1 also increases beta cell mass and satiation while decelerating gastric emptying. Liraglutide is a fatty-acid derivative of GLP-1 with a protracted pharmacokinetic profile that is used in people for treatment of type II diabetes mellitus and obesity. The aim of this study was to determine the pharmacokinetics and pharmacodynamics of liraglutide in healthy cats. Hyperglycemic clamps were performed on days 0 (HGC) and 14 (LgHGC) in 7 healthy cats. Liraglutide was administered subcutaneously (0.6 mg/cat) once daily on days 8 through 14. Compared with the HGC (mean ± standard deviation; 455.5 ± 115.8 ng/L), insulin concentrations during LgHGC were increased (760.8 ± 350.7 ng/L; P = 0.0022), glucagon concentrations decreased (0.66 ± 0.4 pmol/L during HGC vs 0.5 ± 0.4 pmol/L during LgHGC; P = 0.0089), and there was a trend toward an increased total glucose infused (median [range] = 1.61 (1.11-2.54) g/kg and 2.25 (1.64-3.10) g/kg, respectively; P = 0.087). Appetite reduction and decreased body weight (9% ± 3%; P = 0.006) were observed in all cats. Liraglutide has similar effects and pharmacokinetics profile in cats to those reported in people. With a half-life of approximately 12 h, once daily dosing might be feasible; however, significant effects on appetite and weight loss may necessitate dosage or dosing frequency reductions. Further investigation of liraglutide in diabetic cats and overweight cats is warranted.

  5. Successful Pregnancy after Improving Insulin Resistance with the Glucagon-Like Peptide-1 Analogue in a Woman with Polycystic Ovary Syndrome: A Case Report and Review of the Literature.

    PubMed

    Yang, Qianying; Wang, Fang

    2016-01-01

    The polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility. It is diagnosed by the presence of hyperandrogenemia, insulin resistance (IR), obesity and other endocrine or metabolic disorders. Exenatide (EX) is a kind of glucagon-like peptide, which is a new option for patients with diabetes mellitus. We present a patient with infertility for PCOS. She was overweight and her medical history included IR, right-sided ovarian mucinous cystadenomas, and left-sided teratoma. Although she had been treated with ovarian surgery, clomiphene citrate and gonadotropins, weight loss and metformin, which have been effective for dominant follicle development, she still failed to conceive. Then EX was initiated to intervene for 2 months. EX treatment was successful to improve IR; after that the infertile woman with PCOS became pregnant. EX improves IR and reproduction capacity in PCOS patients, reducing insulin level and ameliorating endocrine disorders, thereby improving ovarian function, promoting follicle development, and providing new avenues for the treatment of infertility with PCOS. PMID:27300746

  6. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice.

    PubMed

    Sørensen, Gunnar; Reddy, India A; Weikop, Pia; Graham, Devon L; Stanwood, Gregg D; Wortwein, Gitta; Galli, Aurelio; Fink-Jensen, Anders

    2015-10-01

    Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic neurons in the VTA project to the NAc, and these neurons play a pivotal role in the rewarding effects of drugs of abuse. Based on the anatomical distribution of GLP-1 receptors in the brain and the well-established effects of GLP-1 on food reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction.

  7. Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation.

    PubMed

    Torres, Gloria; Morales, Pablo E; García-Miguel, Marina; Norambuena-Soto, Ignacio; Cartes-Saavedra, Benjamín; Vidal-Peña, Gonzalo; Moncada-Ruff, David; Sanhueza-Olivares, Fernanda; San Martín, Alejandra; Chiong, Mario

    2016-03-15

    Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone produced by gastrointestinal tract in response to food ingestion. GLP-1 plays a very important role in the glucose homeostasis by stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting gastric emptying, reducing appetite and food intake. Because of these actions, the GLP-1 peptide-mimetic exenatide is one of the most promising new medicines for the treatment of type 2 diabetes. In vivo treatments with GLP-1 or exenatide prevent neo-intima layer formation in response to endothelial damage and atherosclerotic lesion formation in aortic tissue. Whether GLP-1 modulates vascular smooth muscle cell (VSMC) migration and proliferation by controlling mitochondrial dynamics is unknown. In this report, we showed that GLP-1 increased mitochondrial fusion and activity in a PKA-dependent manner in the VSMC cell line A7r5. GLP-1 induced a Ser-637 phosphorylation in the mitochondrial fission protein Drp1, and decreased Drp1 mitochondrial localization. GLP-1 inhibited PDGF-BB-induced VSMC migration and proliferation, actions inhibited by overexpressing wild type Drp1 and mimicked by the Drp1 inhibitor Mdivi-1 and by overexpressing dominant negative Drp1. These results show that GLP-1 stimulates mitochondrial fusion, increases mitochondrial activity and decreases PDGF-BB-induced VSMC dedifferentiation by a PKA/Drp1 signaling pathway. Our data suggest that GLP-1 inhibits vascular remodeling through a mitochondrial dynamics-dependent mechanism.

  8. Glucagon-Like Peptide-1 Receptor Agonist Treatment for Pediatric Obesity.

    PubMed

    Kelly, Aaron S

    2016-01-01

    Obesity is a complex and retractable disease for which effective and durable treatments are elusive. Successful treatment of severe obesity with lifestyle modification therapy alone is highly unlikely, particularly for adolescents. Pharmacotherapy, if appropriately prescribed, can be an effective tool to use in conjunction with lifestyle modification therapy to achieve better weight loss outcomes. Only a few obesity medications have been evaluated in children and adolescents with results suggesting modest efficacy. However, a new pipeline of obesity drugs has been recently approved for use among adults. Among these, glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment appears to have reasonable weight loss efficacy along with other beneficial pleiotropic effects. Although larger trials will be required to confirm the results, two small pediatric clinical trials have suggested that GLP-1RA treatment may be useful in adolescents with severe obesity. Once sufficient evidence is generated supporting the safety and efficacy of GLP-1RAs and other obesity medications in youth, the pediatric medical community needs to become less resistant to the use of pharmacotherapy. Otherwise, poor outcomes will continue to be the norm.

  9. Glucagon-like peptide-1 is specifically involved in sweet taste transmission.

    PubMed

    Takai, Shingo; Yasumatsu, Keiko; Inoue, Mayuko; Iwata, Shusuke; Yoshida, Ryusuke; Shigemura, Noriatsu; Yanagawa, Yuchio; Drucker, Daniel J; Margolskee, Robert F; Ninomiya, Yuzo

    2015-06-01

    Five fundamental taste qualities (sweet, bitter, salty, sour, umami) are sensed by dedicated taste cells (TCs) that relay quality information to gustatory nerve fibers. In peripheral taste signaling pathways, ATP has been identified as a functional neurotransmitter, but it remains to be determined how specificity of different taste qualities is maintained across synapses. Recent studies demonstrated that some gut peptides are released from taste buds by prolonged application of particular taste stimuli, suggesting their potential involvement in taste information coding. In this study, we focused on the function of glucagon-like peptide-1 (GLP-1) in initial responses to taste stimulation. GLP-1 receptor (GLP-1R) null mice had reduced neural and behavioral responses specifically to sweet compounds compared to wild-type (WT) mice. Some sweet responsive TCs expressed GLP-1 and its receptors were expressed in gustatory neurons. GLP-1 was released immediately from taste bud cells in response to sweet compounds but not to other taste stimuli. Intravenous administration of GLP-1 elicited transient responses in a subset of sweet-sensitive gustatory nerve fibers but did not affect other types of fibers, and this response was suppressed by pre-administration of the GLP-1R antagonist Exendin-4(3-39). Thus GLP-1 may be involved in normal sweet taste signal transmission in mice.

  10. Glucagon-like peptide 1 (GLP-1) in the gastrointestinal tract of the pheasant (Phasianus colchicus).

    PubMed

    Pirone, Andrea; Ding, Bao An; Giannessi, Elisabetta; Coli, Alessandra; Stornelli, Maria Rita; di Cossato, Margherita Marzoni Fecia; Piano, Ilaria; Lenzi, Carla

    2012-10-01

    The distribution of Glucagon-like peptide 1 (GLP-1) was investigated in the gastrointestinal tract of the pheasant using immunohistochemistry. GLP-1 immunoreactive cells were common in the small intestine, in the proventriculus and in the pancreas. Immunostained cells were not seen in the crop, in the gizzard and in the large intestine. Double labelling demonstrated that GLP-1 and pituitary adenylate cyclase-activating polypeptide (PACAP) were occasionally co-localized only in the duodenal villi. In contrast to what was previously described in the chicken and ostrich, we noted GLP-1 positive cells in the duodenum. These data were consistent with the presence of proglucagon mRNA in the chicken duodenum. Our findings indicate that GLP-1 might have an inhibitory effect on gastric and crop emptying and on acid secretion also in the pheasant. Moreover, the results of the present research regarding the initial region of the small intestine suggest a further direct mechanism of the GLP-1 release during the early digestion phase and an enhancement of its incretin role.

  11. Activation of spinal glucagon-like peptide-1 receptors specifically suppresses pain hypersensitivity.

    PubMed

    Gong, Nian; Xiao, Qi; Zhu, Bin; Zhang, Chang-Yue; Wang, Yan-Chao; Fan, Hui; Ma, Ai-Niu; Wang, Yong-Xiang

    2014-04-01

    This study aims to identify the inhibitory role of the spinal glucagon like peptide-1 receptor (GLP-1R) signaling in pain hypersensitivity and its mechanism of action in rats and mice. First, GLP-1Rs were identified to be specifically expressed on microglial cells in the spinal dorsal horn, and profoundly upregulated after peripheral nerve injury. In addition, intrathecal GLP-1R agonists GLP-1(7-36) and exenatide potently alleviated formalin-, peripheral nerve injury-, bone cancer-, and diabetes-induced hypersensitivity states by 60-90%, without affecting acute nociceptive responses. The antihypersensitive effects of exenatide and GLP-1 were completely prevented by GLP-1R antagonism and GLP-1R gene knockdown. Furthermore, exenatide evoked β-endorphin release from both the spinal cord and cultured microglia. Exenatide antiallodynia was completely prevented by the microglial inhibitor minocycline, β-endorphin antiserum, and opioid receptor antagonist naloxone. Our results illustrate a novel spinal dorsal horn microglial GLP-1R/β-endorphin inhibitory pathway in a variety of pain hypersensitivity states. PMID:24719110

  12. [Glucagon-like peptide-1 (GLP-1) mimetics: a new treatment for Alzheimer's disease?].

    PubMed

    García-Casares, Natalia; García-Arnés, Juan Antonio; Gómez-Huelgas, Ricardo; Valdivielso-Felices, Pedro; García-Arias, Carlota; González-Santos, Pedro

    2014-12-01

    Introduccion. Los analogos del glucagon-like peptide-1 (GLP-1) son una opcion terapeutica establecida en los pacientes con diabetes tipo 2. Sin embargo, las propiedades de los analogos del GLP-1 van mas alla del control estrictamente metabolico del paciente diabetico. Los efectos neuroprotectores de los analogos del GLP-1 se han puesto de manifiesto en estudios recientes y han abierto nuevos campos de investigacion en trastornos neurodegenerativos como la enfermedad de Alzheimer (EA), entre otros. Objetivo. Revision sistematica de los estudios experimentales y ensayos clinicos en humanos que demuestran las propiedades neuroprotectoras de los analogos del GLP-1 en la EA. Desarrollo. Los estudios experimentales que se han llevado a cabo en modelos de roedores con EA demuestran las propiedades neuroprotectoras de los analogos del GLP-1 sobre el sistema nervioso central que reducen las placas de beta-amiloide, el estres oxidativo y la respuesta inflamatoria cerebral. Recientemente se han puesto en marcha estudios con analogos del GLP-1 en humanos con deterioro cognitivo y EA. Conclusiones. Los analogos del GLP-1 presentan propiedades neuroprotectoras. Al considerarse la diabetes tipo 2 un factor de riesgo para el deterioro cognitivo y la demencia, deben considerarse los beneficios de los analogos del GLP-1 sobre la cognicion. Del mismo modo, los analogos del GLP-1 suponen un tratamiento prometedor en la EA.

  13. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells.

    PubMed

    Trabelsi, Mohamed-Sami; Daoudi, Mehdi; Prawitt, Janne; Ducastel, Sarah; Touche, Véronique; Sayin, Sama I; Perino, Alessia; Brighton, Cheryl A; Sebti, Yasmine; Kluza, Jérôme; Briand, Olivier; Dehondt, Hélène; Vallez, Emmanuelle; Dorchies, Emilie; Baud, Grégory; Spinelli, Valeria; Hennuyer, Nathalie; Caron, Sandrine; Bantubungi, Kadiombo; Caiazzo, Robert; Reimann, Frank; Marchetti, Philippe; Lefebvre, Philippe; Bäckhed, Fredrik; Gribble, Fiona M; Schoonjans, Kristina; Pattou, François; Tailleux, Anne; Staels, Bart; Lestavel, Sophie

    2015-01-01

    Bile acids are signalling molecules, which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex bile acids in the intestinal lumen and decrease intestinal FXR activity. The BAS-BA complex also induces glucagon-like peptide-1 (GLP-1) production by L cells which potentiates β-cell glucose-induced insulin secretion. Whether FXR is expressed in L cells and controls GLP-1 production is unknown. Here, we show that FXR activation in L cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycaemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes. PMID:26134028

  14. Male fertility and obesity: are ghrelin, leptin and glucagon-like peptide-1 pharmacologically relevant?

    PubMed

    Alves, Marco G; Jesus, Tito T; Sousa, Mário; Goldberg, Erwin; Silva, Branca M; Oliveira, Pedro F

    2016-01-01

    Obesity is rising to unprecedented numbers, affecting a growing number of children, adolescents and young adult men. These individuals face innumerous health problems, including subfertility or even infertility. Overweight and obese men present severe alterations in their body composition and hormonal profile, particularly in ghrelin, leptin and glucagon-like peptide-1 (GLP-1) levels. It is well known that male reproductive health is under the control of the individual's nutritional status and also of a tight network of regulatory signals, particularly hormonal signaling. However, few studies have been focused on the effects of ghrelin, leptin and GLP-1 in male reproduction and how energy homeostasis and male reproductive function are linked. These hormones regulate body glucose homeostasis and several studies suggest that they can serve as targets for anti-obesity drugs. In recent years, our understanding of the mechanisms of action of these hormones has grown significantly. Curiously, their effect on male reproductive potential, that is highly dependent of the metabolic cooperation established between testicular cells, remains a matter of debate. Herein, we review general concepts of male fertility and obesity, with a special focus on the effects of ghrelin, leptin and GLP-1 on male reproductive health. We also discuss the possible pharmacological relevance of these hormones to counteract the fertility problems that overweight and obese men face.

  15. [Albiglutide (Eperzan): a new once-weekly agonist of glucagon-like peptide-1 receptors].

    PubMed

    Scheen, A J

    2015-04-01

    Albiglutide (Eperzan) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors that is indicated in the treatment of type 2 diabetes. Two doses are available, 30 mg and 50 mg, to be injected subcutaneously once a week. It has been extensively evaluated in the HARMONY programme of eight large randomised controlled trials that were performed at different stages of type 2 diabetes, in comparison with placebo or an active comparator. The endocrine and metabolic effects of albiglutide are similar to those of other GLP-1 receptor agonists: stimulation of insulin secretion (incretin effect) and inhibition of glucagon secretion, both in a glucose-dependent manner, retardation of gastric emptying and increase of satiety. These effects lead to a reduction in glycated haemoglobin (HbA(1c)) levels, combined with a weight reduction. The overall tolerance profile is good. Albiglutide is currently reimbursed in Belgium after failure (HbA(1c) > 7.5%) of and in combination with a dual therapy with metformin and a sulfonylurea as well as in combination with a basal insulin (with or without oral antidiabetic drugs). To avoid hypoglycaemia, a reduction in the dose of sulfonylurea or insulin may be recommended. A once-weekly administration should increase patient's acceptance of injectable therapy and improve compliance.

  16. Glucagon-like peptide 1 and dysglycemia: Conflict in incretin science.

    PubMed

    Singh, Awadhesh Kumar

    2015-01-01

    Although GLP-1 (glucagon like peptide-1) based therapies (GLP-1 agonists and dipeptidyl peptidase-4 inhibitors) is currently playing a cornerstone role in the treatment of type 2 diabetes, dilemma does exist about some of its basic physiology. So far, we know that GLP-1 is secreted by the direct actions of luminal contents on the L cells in distal jejunum and proximal ileum. However, there is growing evidence now, which suggest that other mechanism via "neural" or "upper gut" signals may be playing a second fiddle and could stimulate GLP-1 secretion even before the luminal contents have reached into the proximities of L cells. Therefore, the contribution of direct and indirect mechanism to GLP-1 secretion remains elusive. Furthermore, no clear consensus exists about the pattern of GLP-1 secretion, although many believe it is monophasic. One of the most exciting issues in incretin science is GLP-1 level and GLP-1 responsiveness. It is not exactly known as to what happens to endogenous GLP-1 with progressive worsening of dysglycemia from normal glucose tolerance to impaired glucose to frank diabetes and furthermore with increasing duration of diabetes. Although, conventional wisdom suggests that there may be a decrease in endogenous GLP-1 level with the worsening of dysglycemia, literature showed discordant results. Furthermore, there is emerging evidence to suggest that GLP-1 response can vary with ethnicity. This mini review is an attempt to put a brief perspective on all these issues. PMID:25593851

  17. Farnesoid X Receptor Inhibits Glucagon-Like Peptide-1 Production by Enteroendocrine L-cells

    PubMed Central

    TRABELSI, Mohamed-Sami; DAOUDI, Mehdi; PRAWITT, Janne; DUCASTEL, Sarah; TOUCHE, Véronique; SAYIN, Sama I.; PERINO, Alessia; BRIGHTON, Cheryl A.; SEBTI, Yasmine; KLUZA, Jérôme; BRIAND, Olivier; DEHONDT, Hélène; VALLEZ, Emmanuelle; DORCHIES, Emilie; BAUD, Grégory; SPINELLI, Valeria; HENNUYER, Nathalie; CARON, Sandrine; BANTUBUNGI, Kadiombo; CAIAZZO, Robert; REIMANN, Frank; MARCHETTI, Philippe; LEFEBVRE, Philippe; BÄCKHED, Fredrik; GRIBBLE, Fiona M.; SCHOONJANS, Kristina; PATTOU, François; TAILLEUX, Anne; STAELS, Bart; LESTAVEL, Sophie

    2015-01-01

    Bile acids (BA) are signalling molecules which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex BA in the intestinal lumen and decrease intestinal FXR activity. The BAS-BA complex also induces Glucagon-Like Peptide-1 (GLP-1) production by L-cells which potentiates β-cell glucose-induced insulin secretion. Whether FXR is expressed in L-cells and controls GLP-1 production is unknown. Here we show that FXR activation in L-cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR-deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes. PMID:26134028

  18. Glucagon-like peptide-1 receptor agonists favorably address all components of metabolic syndrome

    PubMed Central

    Chatterjee, Sanjay; Ghosal, Samit; Chatterjee, Saurav

    2016-01-01

    Cardiovascular death is the leading cause of mortality for patients with type 2 diabetes mellitus. The etiology of cardiovascular disease in diabetes may be divided into hyperglycemia per se and factors operating through components of metabolic syndrome (MetS). Hyperglycemia causes direct injury to vascular endothelium and possibly on cardiac myocytes. MetS is a cluster of risk factors like obesity, hyperglycemia, hypertension and dyslipidemia. The incidence of this syndrome is rising globally. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are a group of drugs, which address all components of this syndrome favorably. Experimental evidence suggests that they have favorable actions on myocardium as well. Several compounds belonging to GLP-1RA class are in market now and a large number awaiting their entry. Although, originally this class of drugs emerged as a treatment for type 2 diabetes mellitus, more recent data generated revealed beneficial effects on multiple metabolic parameters. We have studied literature published between 2000 and 2016 to look into effects of GLP-1RA on components of MetS. Results from recently concluded clinical trials suggest that some of the molecules in this class may have favorable effects on cardiovascular outcome. PMID:27795818

  19. Oligomerization of a Glucagon-like Peptide 1 Analog: Bridging Experiment and Simulations

    PubMed Central

    Frederiksen, Tine M.; Sønderby, Pernille; Ryberg, Line A.; Harris, Pernille; Bukrinski, Jens T.; Scharff-Poulsen, Anne M.; Elf-Lind, Maria N.; Peters, Günther H.

    2015-01-01

    The glucagon-like peptide 1 (GLP-1) analog, liraglutide, is a GLP-1 agonist and is used in the treatment of type-2 diabetes mellitus and obesity. From a pharmaceutical perspective, it is important to know the oligomerization state of liraglutide with respect to stability. Compared to GLP-1, liraglutide has an added fatty acid (FA) moiety that causes oligomerization of liraglutide as suggested by small-angle x-ray scattering (SAXS) and multiangle static light scattering (MALS) results. SAXS data suggested a global shape of a hollow elliptical cylinder of size hexa-, hepta-, or octamer, whereas MALS data indicate a hexamer. To elaborate further on the stability of these oligomers and the role of the FA chains, a series of molecular-dynamics simulations were carried out on 11 different hexa-, hepta-, and octameric systems. Our results indicate that interactions of the fatty acid chains contribute noticeably to the stabilization. The simulation results indicate that the heptamer with paired FA chains is the most stable oligomer when compared to the 10 other investigated structures. Theoretical SAXS curves extracted from the simulations qualitatively agree with the experimentally determined SAXS curves supporting the view that liraglutide forms heptamers in solution. In agreement with the SAXS data, the heptamer forms a water-filled oligomer of elliptical cylindrical shape. PMID:26340816

  20. Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis.

    PubMed

    Koehler, Jacqueline A; Baggio, Laurie L; Cao, Xiemin; Abdulla, Tahmid; Campbell, Jonathan E; Secher, Thomas; Jelsing, Jacob; Larsen, Brett; Drucker, Daniel J

    2015-03-01

    Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67(+) cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R-dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP-1R-dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice.

  1. Diabetes and cardiovascular disease: focus on glucagon-like peptide-1 based therapies

    PubMed Central

    Stranges, Paul

    2012-01-01

    Type 2 diabetes is a well known risk factor for cardiovascular disease (CVD). While glycemic control has consistently been shown to prevent microvascular complications, large randomized trials have not demonstrated the same consistent beneficial effects of intensive glycemic control in improving cardiovascular (CV) outcomes. Thus, optimal glucose control alone is not sufficient to reduce CV risk. Aggressive management of CV risk factors such as blood pressure, lipids, and body weight is also necessary. A growing body of evidence suggests that the recently available glucagon-like peptide 1 receptor (GLP-1R) agonists have beneficial CV effects beyond glucose control. Studies have demonstrated beneficial effects in the myocardium, endothelium, vasculature and various markers of cardiovascular risk such as body weight, blood pressure and dyslipidemia. Despite the growing evidence, large, randomized, blinded clinical trials with hard CV endpoints have not been performed. Most human studies have been small, and have focused on surrogate endpoints. The findings need to be confirmed by prospective, randomized cardiovascular outcomes trials. In this review we examine the GLP-1R agonist data on weight reduction, blood pressure lowering, beneficial changes in dyslipidemia, and improvements in myocardial and endothelial function. The safety as well as potential role of these agents in treatment regimens for type 2 diabetes is also addressed. PMID:25083236

  2. Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation.

    PubMed

    Torres, Gloria; Morales, Pablo E; García-Miguel, Marina; Norambuena-Soto, Ignacio; Cartes-Saavedra, Benjamín; Vidal-Peña, Gonzalo; Moncada-Ruff, David; Sanhueza-Olivares, Fernanda; San Martín, Alejandra; Chiong, Mario

    2016-03-15

    Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone produced by gastrointestinal tract in response to food ingestion. GLP-1 plays a very important role in the glucose homeostasis by stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting gastric emptying, reducing appetite and food intake. Because of these actions, the GLP-1 peptide-mimetic exenatide is one of the most promising new medicines for the treatment of type 2 diabetes. In vivo treatments with GLP-1 or exenatide prevent neo-intima layer formation in response to endothelial damage and atherosclerotic lesion formation in aortic tissue. Whether GLP-1 modulates vascular smooth muscle cell (VSMC) migration and proliferation by controlling mitochondrial dynamics is unknown. In this report, we showed that GLP-1 increased mitochondrial fusion and activity in a PKA-dependent manner in the VSMC cell line A7r5. GLP-1 induced a Ser-637 phosphorylation in the mitochondrial fission protein Drp1, and decreased Drp1 mitochondrial localization. GLP-1 inhibited PDGF-BB-induced VSMC migration and proliferation, actions inhibited by overexpressing wild type Drp1 and mimicked by the Drp1 inhibitor Mdivi-1 and by overexpressing dominant negative Drp1. These results show that GLP-1 stimulates mitochondrial fusion, increases mitochondrial activity and decreases PDGF-BB-induced VSMC dedifferentiation by a PKA/Drp1 signaling pathway. Our data suggest that GLP-1 inhibits vascular remodeling through a mitochondrial dynamics-dependent mechanism. PMID:26807480

  3. Functional Consequences of Glucagon-like Peptide-1 Receptor Cross-talk and Trafficking*

    PubMed Central

    Roed, Sarah Noerklit; Nøhr, Anne Cathrine; Wismann, Pernille; Iversen, Helle; Bräuner-Osborne, Hans; Knudsen, Sanne Moeller; Waldhoer, Maria

    2015-01-01

    The signaling capacity of seven-transmembrane/G-protein-coupled receptors (7TM/GPCRs) can be regulated through ligand-mediated receptor trafficking. Classically, the recycling of internalized receptors is associated with resensitization, whereas receptor degradation terminates signaling. We have shown previously that the incretin glucagon-like peptide-1 receptor (GLP-1R) internalizes fast and is primarily resensitized through recycling back to the cell surface. GLP-1R is expressed in pancreatic islets together with the closely related glucose-dependent insulinotropic polypeptide (GIPR) and glucagon (GCGR) receptors. The interaction and cross-talk between coexpressed receptors is a wide phenomenon of the 7TM/GPCR superfamily. Numerous reports show functional consequences for signaling and trafficking of the involved receptors. On the basis of the high structural similarity and tissue coexpression, we here investigated the potential cross-talk between GLP-1R and GIPR or GCGR in both trafficking and signaling pathways. Using a real-time time-resolved FRET-based internalization assay, we show that GLP-1R, GIPR, and GCGR internalize with differential properties. Remarkably, upon coexpression of the internalizing GLP-1R and the non-internalizing GIPR, GLP-1-mediated GLP-1R internalization was impaired in a GIPR concentration-dependent manner. As a functional consequence of such impaired internalization capability, GLP-1-mediated GLP-1R signaling was abrogated. A similar compromised signaling was found when GLP-1R internalization was abrogated by a dominant-negative version of dynamin (dynamin-1 K44E), which provides a mechanistic link between GLP-1R trafficking and signaling. This study highlights the importance of receptor internalization for full functionality of GLP-1R. Moreover, cross-talk between the two incretin receptors GLP-1R and GIPR is shown to alter receptor trafficking with functional consequences for GLP-1R signaling. PMID:25451942

  4. Role of lateral septum glucagon-like peptide 1 receptors in food intake.

    PubMed

    Terrill, Sarah J; Jackson, Christine M; Greene, Hayden E; Lilly, Nicole; Maske, Calyn B; Vallejo, Samantha; Williams, Diana L

    2016-07-01

    Hindbrain glucagon-like peptide 1 (GLP-1) neurons project to numerous forebrain areas, including the lateral septum (LS). Using a fluorescently labeled GLP-1 receptor (GLP-1R) agonist, Exendin 4 (Ex4), we demonstrated GLP-1 receptor binding throughout the rat LS. We examined the feeding effects of Ex4 and the GLP-1R antagonist Exendin (9-39) (Ex9) at doses subthreshold for effect when delivered to the lateral ventricle. Intra-LS Ex4 suppressed overnight chow and high-fat diet (HFD) intake, and Ex9 increased chow and HFD intake relative to vehicle. During 2-h tests, intra-LS Ex9 significantly increased 0.25 M sucrose and 4% corn oil. Ex4 can cause nausea, but intra-LS administration of Ex4 did not induce pica. Furthermore, intra-LS Ex4 had no effect on anxiety-like behavior in the elevated plus maze. We investigated the role of LS GLP-1R in motivation for food by examining operant responding for sucrose on a progressive ratio (PR) schedule, with and without a nutrient preload to maximize GLP-1 neuron activation. The preload strongly suppressed PR responding, but blockade of GLP-1R in the intermediate subdivision of the LS did not affect motivation for sucrose under either load condition. The ability of the nutrient load to suppress subsequent chow intake was significantly attenuated by intermediate LS Ex9 treatment. By contrast, blockade of GLP-1R in the dorsal subdivision of the LS increased both PR responding and overnight chow intake. Together, these studies suggest that endogenous activity of GLP-1R in the LS influence feeding, and dLS GLP-1Rs, in particular, play a role in motivation. PMID:27194565

  5. Effects of glucagon-like peptide-1 in diabetic rat small resistance arteries.

    PubMed

    Bayram, Zeliha; Nacitarhan, Cahit; Ozdem, Sadi S

    2014-09-01

    We investigated the functional effects of glucagon-like peptide-1 [GLP-1(7-36)] and GLP-1(9-36) and the mechanism(s) playing a role in the effects of these agents in isolated small resistance arteries from control and diabetic rats. Cumulative concentrations of GLP-1(7-36) and GLP-1(9-36) produced concentration-dependent relaxations in endothelium-intact but not endothelium-denuded arteries that were significantly decreased in diabetic rats. GLP-1 receptor antagonist exendin(9-39) significantly inhibited responses to GLP-1 analogs. Nitric oxide/cyclic guanosine monophosphate pathway blockers, but not indomethacin, significantly decreased responses to GLP-1(7-36) or GLP-1(9-36) in control and diabetic rats. 4-Aminopyridine or glibenclamide incubation did not alter relaxations to GLP-1 analogs. GLP-1(7-36)- and GLP-1(9-36)-induced relaxations were blunted significantly and to similar extends by charybdotoxin and apamin combination in control and diabetic rats. Catalase did not affect, whereas superoxide dismutase (SOD) caused a significant increase in relaxations to GLP-1 analogs only in diabetic rats. We provided evidence about the relaxant effects of GLP-1(7-36) and GLP-1(9-36) in resistance arteries that were reduced in diabetic rats. Both calcium-activated potassium channels and endothelium played a major role in relaxations. Increment in certain reactive oxygen species and/or reduction in superoxide dismutase function might play a role in reduced relaxant responses of resistance arteries to GLP-1(7-36) and GLP-1(9-36) in diabetic rats.

  6. Parabrachial Nucleus Contributions to Glucagon-Like Peptide-1 Receptor Agonist-Induced Hypophagia

    PubMed Central

    Swick, Jennifer C; Alhadeff, Amber L; Grill, Harvey J; Urrea, Paula; Lee, Stephanie M; Roh, Hyunsun; Baird, John-Paul

    2015-01-01

    Exendin-4 (Ex4), a glucagon-like peptide-1 receptor (GLP-1R) agonist approved to treat type 2 diabetes mellitus, is well known to induce hypophagia in human and animal models. We evaluated the contributions of the hindbrain parabrachial nucleus (PBN) to systemic Ex4-induced hypophagia, as the PBN receives gustatory and visceral afferent relays and descending input from several brain nuclei associated with feeding. Rats with ibotenic-acid lesions targeted to the lateral PBN (PBNx) and sham controls received Ex4 (1 μg/kg) before 24 h home cage chow or 90 min 0.3 M sucrose access tests, and licking microstructure was analyzed to identify components of feeding behavior affected by Ex4. PBN lesion efficacy was confirmed using conditioned taste aversion (CTA) tests. As expected, sham control but not PBNx rats developed a CTA. In sham-lesioned rats, Ex4 reduced chow intake within 4 h of injection and sucrose intake within 90 min. PBNx rats did not show reduced chow or sucrose intake after Ex4 treatment, indicating that the PBN is necessary for Ex4 effects under the conditions tested. In sham-treated rats, Ex4 affected licking microstructure measures associated with hedonic taste evaluation, appetitive behavior, oromotor coordination, and inhibitory postingestive feedback. Licking microstructure responses in PBNx rats after Ex4 treatment were similar to sham-treated rats with the exception of inhibitory postingestive feedback measures. Together, the results suggest that the PBN critically contributes to the hypophagic effects of systemically delivered GLP-1R agonists by enhancing visceral feedback. PMID:25703200

  7. Glucagon-Like Peptide-1 Regulates Cholecystokinin Production in β-Cells to Protect From Apoptosis

    PubMed Central

    Linnemann, Amelia K.; Neuman, Joshua C.; Battiola, Therese J.; Wisinski, Jaclyn A.; Kimple, Michelle E.

    2015-01-01

    Cholecystokinin (CCK) is a classic gut hormone that is also expressed in the pancreatic islet, where it is highly up-regulated with obesity. Loss of CCK results in increased β-cell apoptosis in obese mice. Similarly, islet α-cells produce increased amounts of another gut peptide, glucagon-like peptide 1 (GLP-1), in response to cytokine and nutrient stimulation. GLP-1 also protects β-cells from apoptosis via cAMP-mediated mechanisms. Therefore, we hypothesized that the activation of islet-derived CCK and GLP-1 may be linked. We show here that both human and mouse islets secrete active GLP-1 as a function of body mass index/obesity. Furthermore, GLP-1 can rapidly stimulate β-cell CCK production and secretion through direct targeting by the cAMP-modulated transcription factor, cAMP response element binding protein (CREB). We find that cAMP-mediated signaling is required for Cck expression, but CCK regulation by cAMP does not require stimulatory levels of glucose or insulin secretion. We also show that CREB directly targets the Cck promoter in islets from obese (Leptinob/ob) mice. Finally, we demonstrate that the ability of GLP-1 to protect β-cells from cytokine-induced apoptosis is partially dependent on CCK receptor signaling. Taken together, our work suggests that in obesity, active GLP-1 produced in the islet stimulates CCK production and secretion in a paracrine manner via cAMP and CREB. This intraislet incretin loop may be one mechanism whereby GLP-1 protects β-cells from apoptosis. PMID:25984632

  8. Septal Glucagon-Like Peptide 1 Receptor Expression Determines Suppression of Cocaine-Induced Behavior

    PubMed Central

    Harasta, Anne E; Power, John M; von Jonquieres, Georg; Karl, Tim; Drucker, Daniel J; Housley, Gary D; Schneider, Miriam; Klugmann, Matthias

    2015-01-01

    Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are a key component of the satiety signaling system, and long-acting GLP-1 analogs have been approved for the treatment of type-2 diabetes mellitus. Previous reports demonstrate that GLP-1 regulates glucose homeostasis alongside the rewarding effects of food. Both palatable food and illicit drugs activate brain reward circuitries, and pharmacological studies suggest that central nervous system GLP-1 signaling holds potential for the treatment of addiction. However, the role of endogenous GLP-1 in the attenuation of reward-oriented behavior, and the essential domains of the mesolimbic system mediating these beneficial effects, are largely unknown. We hypothesized that the central regions of highest Glp-1r gene activity are essential in mediating responses to drugs of abuse. Here, we show that Glp-1r-deficient (Glp-1r−/−) mice have greatly augmented cocaine-induced locomotor responses and enhanced conditional place preference compared with wild-type (Glp-1r+/+) controls. Employing mRNA in situ hybridization we located peak Glp-1r mRNA expression in GABAergic neurons of the dorsal lateral septum, an anatomical site with a crucial function in reward perception. Whole-cell patch-clamp recordings of dorsal lateral septum neurons revealed that genetic Glp-1r ablation leads to increased excitability of these cells. Viral vector-mediated Glp-1r gene delivery to the dorsal lateral septum of Glp-1r−/− animals reduced cocaine-induced locomotion and conditional place preference to wild-type levels. This site-specific genetic complementation did not affect the anxiogenic phenotype observed in Glp-1r−/− controls. These data reveal a novel role of GLP-1R in dorsal lateral septum function driving behavioral responses to cocaine. PMID:25669605

  9. Investigating G protein signalling bias at the glucagon-like peptide-1 receptor in yeast

    PubMed Central

    Weston, C; Poyner, D; Patel, V; Dowell, S; Ladds, G

    2014-01-01

    BACKGROUND AND PURPOSE The glucagon-like peptide 1 (GLP-1) receptor performs an important role in glycaemic control, stimulating the release of insulin. It is an attractive target for treating type 2 diabetes. Recently, several reports of adverse side effects following prolonged use of GLP-1 receptor therapies have emerged: most likely due to an incomplete understanding of signalling complexities. EXPERIMENTAL APPROACH We describe the expression of the GLP-1 receptor in a panel of modified yeast strains that couple receptor activation to cell growth via single Gα/yeast chimeras. This assay enables the study of individual ligand–receptor G protein coupling preferences and the quantification of the effect of GLP-1 receptor ligands on G protein selectivity. KEY RESULTS The GLP-1 receptor functionally coupled to the chimeras representing the human Gαs, Gαi and Gαq subunits. Calculation of the dissociation constant for a receptor antagonist, exendin-3 revealed no significant difference between the two systems. We obtained previously unobserved differences in G protein signalling bias for clinically relevant therapeutic agents, liraglutide and exenatide; the latter displaying significant bias for the Gαi pathway. We extended the use of the system to investigate small-molecule allosteric compounds and the closely related glucagon receptor. CONCLUSIONS AND IMPLICATIONS These results provide a better understanding of the molecular events involved in GLP-1 receptor pleiotropic signalling and establish the yeast platform as a robust tool to screen for more selective, efficacious compounds acting at this important class of receptors in the future. PMID:24712679

  10. Expression, purification, and C-terminal amidation of recombinant human glucagon-like peptide-1.

    PubMed

    Zhang, Zhi-Zhen; Yang, Sheng-Sheng; Dou, Hong; Mao, Ji-Fang; Li, Kang-Sheng

    2004-08-01

    Human glucagon-like peptide-1 (hGLP-1) (7-36) amide, a gastrointestinal hormone with a pharmaceutical potential in treating type 2 diabetes mellitus, is composed of 30 amino acid residues as a mature protein. We report here the development of a method for high-level expression and purification of recombinant hGLP-1 (7-36) amide (rhGLP-1) through glutathione S-transferase (GST) fusion expression system. The cDNA of hGLP-1-Leu, the 31st-residue leucine-extended precursor peptide, was prepared by annealing and ligating of artificially synthetic oligonucleotide fragments, inserted into pBluescript SK (+/-) plasmid, and then cloned into pGEX-4T-3 GST fusion vector. The fusion protein GST-hGLP-1-Leu, expressed in Escherichia coli strain BL21 (DE3), was purified by affinity chromatography after high-level culture and sonication of bacteria. Following cleavage of GST-hGLP-1-Leu by cyanogen bromide, the recombinant hGLP-1-Leu was released from fusion protein, and purified using QAE Sepharose ion exchange and RP C(18) chromatography. After purification, the precursor hGLP-1-Leu was transacylated by carboxypeptidase Y, Arg-NH(2) as a nucleophile, to produce rhGLP-1. Electrospray ionization mass spectrometry showed the molecular weight was as expected. The biological activity of rhGLP-1 in a rat model demonstrated that plasma glucose concentrations were significantly lower and insulin concentrations higher after intraperitoneal injection of rhGLP-1 together with glucose compared with glucose alone (P < 0.001). PMID:15249052

  11. Nutrient-induced glucagon like peptide-1 release is modulated by serotonin.

    PubMed

    Ripken, Dina; van der Wielen, Nikkie; Wortelboer, Heleen M; Meijerink, Jocelijn; Witkamp, Renger F; Hendriks, Henk F J

    2016-06-01

    Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects of serotonin reuptake inhibition by fluoxetine on nutrient-induced GLP-1, PYY and CCK release from isolated pig intestinal segments. Next, serotonin-induced GLP-1 release was studied in enteroendocrine STC-1 cells, where effects of serotonin receptor inhibition were studied using specific and non-specific antagonists. Casein (1% w/v), safflower oil (3.35% w/v), sucrose (50mM) and rebaudioside A (12.5mM) stimulated GLP-1 release from intestinal segments, whereas casein only stimulated PYY and CCK release. Combining nutrients with fluoxetine further increased nutrient-induced GLP-1, PYY and CCK release. Serotonin release from intestinal tissue segments was stimulated by casein and safflower oil while sucrose and rebaudioside A had no effect. The combination with fluoxetine (0.155μM) further enhanced casein and safflower oil induced-serotonin release. Exposure of ileal tissue segments to serotonin (30μM) stimulated GLP-1 release whereas it did not induce PYY and CCK release. Serotonin (30 and 100μM) also stimulated GLP-1 release from STC-1 cells, which was inhibited by the non-specific 5HT receptor antagonist asenapine (1 and 10μM). These data suggest that nutrient-induced GLP-1 release is modulated by serotonin through a receptor mediated process. PMID:27142747

  12. Protective Role of Glucagon-Like Peptide-1 Against High-Glucose-Induced Endothelial Oxidative Damage

    PubMed Central

    Guo, Lixin; Qiao, Yue; Zhang, Lina; Pan, Qi

    2015-01-01

    Abstract To investigate the protective effect of glucagon-like peptide-1 (GLP-1) against cell damage induced by high glucose. Human umbilical vein endothelial cells (HUVECs) were divided into control group (5.5 mmol/L) and high glucose groups (19, 33, or 47 mmol/L), which were cultured with different concentrations of glucose for 48 hours, respectively. Cell viability was measured with MTT assay. Levels of intracellular reactive oxygen species (ROS) were monitored by flow cytometry and apoptotic cell death was measured by staining with Annexin V-FITC and propidium iodide. Cultured cells were detected with intercellular adhesion molecule 1 (ICAM-1), VCAM-1, and JNK on protein. Compared with the control group, cell viability was decreased by 20% and 37%, respectively, when cultured under 33 and 47 mM, while increased in different GLP-1-treated groups (0.01 L, 0.1, 1, and 10 nmol/L). The GLP-1 treatment significantly reduced the ROS level of high glucose treatment group but not impact on the control group. Meanwhile, the level of apoptosis was elevated in the high glucose treatment group. Early apoptosis was significantly reversed in the GLP-1-treated group (0.1, 1, and 10 nmol/L). Late apoptosis was uniquely decreased in the GLP-1 concentrations of 10 nmol/L. Furthermore, GLP-1 could also reduce the protein levels of ICAM-1, VCAM-1, and phospho JNK in the endothelial cells with high glucose treatment. GLP-1 could inhibit cell apoptosis and reduce ROS generation and JNK-Bax signaling pathway activation, which were induced by high glucose treatment. PMID:26632709

  13. Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion.

    PubMed

    Mizokami, Akiko; Yasutake, Yu; Higashi, Sen; Kawakubo-Yasukochi, Tomoyo; Chishaki, Sakura; Takahashi, Ichiro; Takeuchi, Hiroshi; Hirata, Masato

    2014-12-01

    Uncarboxylated osteocalcin (GluOC), a bone-derived hormone, regulates energy metabolism by stimulating insulin secretion and pancreatic β-cell proliferation. We previously showed that the effect of GluOC on insulin secretion is mediated largely by glucagon-like peptide-1 (GLP-1) secreted from the intestine in response to GluOC exposure. We have now examined the effect of oral administration of GluOC on glucose utilization as well as the fate of such administered GluOC in mice. Long-term intermittent or daily oral administration of GluOC reduced the fasting blood glucose level and improved glucose tolerance in mice without affecting insulin sensitivity. It also increased the fasting serum insulin concentration as well as the β-cell area in the pancreas. A small proportion of orally administered GluOC reached the small intestine and remained there for at least 24h. GluOC also entered the general circulation, and the serum GLP-1 concentration was increased in association with the presence of GluOC in the intestine and systemic circulation. The putative GluOC receptor, GPRC6A was detected in intestinal cells, and was colocalized with GLP-1 in some of these cells. Our results suggest that orally administered GluOC improved glucose handling likely by acting from both the intestinal lumen and the general circulation, with this effect being mediated in part by stimulation of GLP-1 secretion. Oral administration of GluOC warrants further study as a safe and convenient option for the treatment or prevention of metabolic disorders. PMID:25230237

  14. Glucagon-like peptide-1 receptor agonist administration suppresses both water and saline intake in rats.

    PubMed

    McKay, N J; Daniels, D

    2013-10-01

    Glucagon-like peptide-1 (GLP-1) plays an important role in energy homeostasis. Injections of GLP-1 receptor (GLP-1R) agonists suppress food intake, and endogenous GLP-1 is released when nutrients enter the gut. There is also growing evidence that the GLP-1 system is involved in the regulation of body fluid homeostasis. GLP-1R agonists suppress water intake independent of their effects on food intake. It is unknown, however, whether this suppressive effect of GLP-1R agonists extends to saline intake. Accordingly, we tested the effect of the GLP-1R agonists liraglutide (0.05 μg) and exendin-4 (0.05 μg) on water and saline intake, as stimulated either by angiotensin II (AngII) or by water deprivation with partial rehydration (WD-PR). Each agonist suppressed AngII-induced water intake; however, only exendin-4 suppressed saline intake. WD-PR-induced water and saline intakes were both attenuated by each agonist. Analysis of drinking microstructure after WD-PR found a reliable effect of the agonists on burst number. Furthermore, exendin-4 conditioned a robust taste avoidance to saccharine; however, there was no similar effect of liraglutide. To evaluate the relevance of the conditioned taste avoidance, we tested whether inducing visceral malaise by injection of lithium chloride (LiCl) suppressed fluid intake. Injection of LiCl did not suppress water or saline intakes. Overall, these results indicate that the fluid intake suppression by GLP-1R activation is not selective to water intake, is a function of post-ingestive feedback, and is not secondary to visceral malaise.

  15. Glucagon-like peptide-1 receptor agonists suppress water intake independent of effects on food intake.

    PubMed

    McKay, Naomi J; Kanoski, Scott E; Hayes, Matthew R; Daniels, Derek

    2011-12-01

    Glucagon-like peptide-1 (GLP-1) is produced by and released from the small intestine following ingestion of nutrients. GLP-1 receptor (GLP-1R) agonists applied peripherally or centrally decrease food intake and increase glucose-stimulated insulin secretion. These effects make the GLP-1 system an attractive target for the treatment of type 2 diabetes mellitus and obesity. In addition to these more frequently studied effects of GLP-1R stimulation, previous reports indicate that GLP-1R agonists suppress water intake. The present experiments were designed to provide greater temporal resolution and site specificity for the effect of GLP-1 and the long-acting GLP-1R agonists, exendin-4 and liraglutide, on unstimulated water intake when food was and was not available. All three GLP-1R ligands suppressed water intake after peripheral intraperitoneal administration, both in the presence of and the absence of food; however, the magnitude and time frame of water intake suppression varied by drug. GLP-1 had an immediate, but transient, hypodipsic effect when administered peripherally, whereas the water intake suppression by IP exendin-4 and liraglutide was much more persistent. Additionally, intracerebroventricular administration of GLP-1R agonists suppressed water intake when food was absent, but the suppression of intake showed modest differences depending on whether the drug was administered to the lateral or fourth ventricle. To the best of our knowledge, this is the first demonstration of GLP-1 receptor agonists affecting unstimulated, overnight intake in the absence of food, the first test for antidipsogenic effects of hindbrain application of GLP-1 receptor agonists, and the first test of a central effect (forebrain or hindbrain) of liraglutide on water intake. Overall, these results show that GLP-1R agonists have a hypodipsic effect that is independent of GLP-1R-mediated effects on food intake, and this occurs, in part, through central nervous system GLP-1R activation.

  16. The role of apolipoprotein A-IV in regulating glucagon-like peptide-1 secretion.

    PubMed

    Wang, Fei; Yang, Qing; Huesman, Sarah; Xu, Min; Li, Xiaoming; Lou, Danwen; Woods, Stephen C; Marziano, Corina; Tso, Patrick

    2015-10-15

    Both glucagon-like peptide-1 (GLP-1) and apolipoprotein A-IV (apoA-IV) are produced from the gut and enhance postprandial insulin secretion. This study investigated whether apoA-IV regulates nutrient-induced GLP-1 secretion and whether apoA-IV knockout causes compensatory GLP-1 release. Using lymph-fistula-mice, we first determined lymphatic GLP-1 secretion by administering apoA-IV before an intraduodenal Ensure infusion. apoA-IV changed neither basal nor Ensure-induced GLP-1 secretion relative to saline administration. We then assessed GLP-1 in apoA-IV-/- and wild-type (WT) mice administered intraduodenal Ensure. apoA-IV-/- mice had comparable lymph flow, lymphatic triglyceride, glucose, and protein outputs as WT mice. Intriguingly, apoA-IV-/- mice had higher lymphatic GLP-1 concentration and output than WT mice 30 min after Ensure administration. Increased GLP-1 was also observed in plasma of apoA-IV-/- mice at 30 min. apoA-IV-/- mice had comparable total gut GLP-1 content relative to WT mice under fasting, but a lower GLP-1 content 30 min after Ensure administration, suggesting that more GLP-1 was secreted. Moreover, an injection of apoA-IV protein did not reverse the increased GLP-1 secretion in apoA-IV-/- mice. Finally, we assessed gene expression of GLUT-2 and the lipid receptors, including G protein-coupled receptor (GPR) 40, GPR119, and GPR120 in intestinal segments. GLUT-2, GPR40 and GPR120 mRNAs were unaltered by apoA-IV knockout. However, ileal GPR119 mRNA was significantly increased in apoA-IV-/- mice. GPR119 colocalizes with GLP-1 in ileum and stimulates GLP-1 secretion by sensing OEA, lysophosphatidylcholine, and 2-monoacylglycerols. We suggest that increased ileal GPR119 is a potential mechanism by which GLP-1 secretion is enhanced in apoA-IV-/- mice. PMID:26294669

  17. Positive Allosteric Modulation of the Glucagon-like Peptide-1 Receptor by Diverse Electrophiles.

    PubMed

    Bueno, Ana B; Showalter, Aaron D; Wainscott, David B; Stutsman, Cynthia; Marín, Aranzazu; Ficorilli, James; Cabrera, Over; Willard, Francis S; Sloop, Kyle W

    2016-05-13

    Therapeutic intervention to activate the glucagon-like peptide-1 receptor (GLP-1R) enhances glucose-dependent insulin secretion and improves energy balance in patients with type 2 diabetes mellitus. Studies investigating mechanisms whereby peptide ligands activate GLP-1R have utilized mutagenesis, receptor chimeras, photo-affinity labeling, hydrogen-deuterium exchange, and crystallography of the ligand-binding ectodomain to establish receptor homology models. However, this has not enabled the design or discovery of drug-like non-peptide GLP-1R activators. Recently, studies investigating 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), a GLP-1R-positive allosteric modulator, determined that Cys-347 in the GLP-1R is required for positive allosteric modulator activity via covalent modification. To advance small molecule activation of the GLP-1R, we characterized the insulinotropic mechanism of BETP. In guanosine 5'-3-O-(thio)triphosphate binding and INS1 832-3 insulinoma cell cAMP assays, BETP enhanced GLP-1(9-36)-NH2-stimulated cAMP signaling. Using isolated pancreatic islets, BETP potentiated insulin secretion in a glucose-dependent manner that requires both the peptide ligand and GLP-1R. In studies of the covalent mechanism, PAGE fluorography showed labeling of GLP-1R in immunoprecipitation experiments from GLP-1R-expressing cells incubated with [(3)H]BETP. Furthermore, we investigated whether other reported GLP-1R activators and compounds identified from screening campaigns modulate GLP-1R by covalent modification. Similar to BETP, several molecules were found to enhance GLP-1R signaling in a Cys-347-dependent manner. These chemotypes are electrophiles that react with GSH, and LC/MS determined the cysteine adducts formed upon conjugation. Together, our results suggest covalent modification may be used to stabilize the GLP-1R in an active conformation. Moreover, the findings provide pharmacological guidance for the discovery and

  18. Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes.

    PubMed

    Luque, M A; González, N; Márquez, L; Acitores, A; Redondo, A; Morales, M; Valverde, I; Villanueva-Peñacarrillo, M L

    2002-06-01

    Glucagon-like peptide-1 (GLP-1) has been shown to have insulin-like effects upon the metabolism of glucose in rat liver, muscle and fat, and on that of lipids in rat and human adipocytes. These actions seem to be exerted through specific receptors which, unlike that of the pancreas, are not - at least in liver and muscle - cAMP-associated. Here we have investigated the effect, its characteristics, and possible second messengers of GLP-1 on the glucose metabolism of human skeletal muscle, in tissue strips and primary cultured myocytes. In muscle strips, GLP-1, like insulin, stimulated glycogen synthesis, glycogen synthase a activity, and glucose oxidation and utilization, and inhibited glycogen phosphorylase a activity, all of this at physiological concentrations of the peptide. In cultured myotubes, GLP-1 exerted, from 10(-13) mol/l, a dose-related increase of the D-[U-(14)C]glucose incorporation into glycogen, with the same potency as insulin, together with an activation of glycogen synthase a; the effect of 10(-11) mol/l GLP-1 on both parameters was additive to that induced by the equimolar amount of insulin. Synthase a was still activated in cells after 2 days of exposure to GLP-1, as compared with myotubes maintained in the absence of peptide. In human muscle cells, exendin-4 and its truncated form 9-39 amide (Ex-9) are both agonists of the GLP-1 effect on glycogen synthesis and synthase a activity; but while neither GLP-1 nor exendin-4 affected the cellular cAMP content after 5-min incubation in the absence of 3-isobutyl-1-methylxantine (IBMX), an increase was detected with Ex-9. GLP-1, exendin-4, Ex-9 and insulin all induced the prompt hydrolysis of glycosylphosphatidylinositols (GPIs). This work shows a potent stimulatory effect of GLP-1 on the glucose metabolism of human skeletal muscle, and supports the long-term therapeutic value of the peptide. Further evidence for a GLP-1 receptor in this tissue, different from that of the pancreas, is also illustrated

  19. Positive Allosteric Modulation of the Glucagon-like Peptide-1 Receptor by Diverse Electrophiles*

    PubMed Central

    Showalter, Aaron D.; Wainscott, David B.; Stutsman, Cynthia; Marín, Aranzazu; Ficorilli, James; Cabrera, Over

    2016-01-01

    Therapeutic intervention to activate the glucagon-like peptide-1 receptor (GLP-1R) enhances glucose-dependent insulin secretion and improves energy balance in patients with type 2 diabetes mellitus. Studies investigating mechanisms whereby peptide ligands activate GLP-1R have utilized mutagenesis, receptor chimeras, photo-affinity labeling, hydrogen-deuterium exchange, and crystallography of the ligand-binding ectodomain to establish receptor homology models. However, this has not enabled the design or discovery of drug-like non-peptide GLP-1R activators. Recently, studies investigating 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), a GLP-1R-positive allosteric modulator, determined that Cys-347 in the GLP-1R is required for positive allosteric modulator activity via covalent modification. To advance small molecule activation of the GLP-1R, we characterized the insulinotropic mechanism of BETP. In guanosine 5′-3-O-(thio)triphosphate binding and INS1 832-3 insulinoma cell cAMP assays, BETP enhanced GLP-1(9–36)-NH2-stimulated cAMP signaling. Using isolated pancreatic islets, BETP potentiated insulin secretion in a glucose-dependent manner that requires both the peptide ligand and GLP-1R. In studies of the covalent mechanism, PAGE fluorography showed labeling of GLP-1R in immunoprecipitation experiments from GLP-1R-expressing cells incubated with [3H]BETP. Furthermore, we investigated whether other reported GLP-1R activators and compounds identified from screening campaigns modulate GLP-1R by covalent modification. Similar to BETP, several molecules were found to enhance GLP-1R signaling in a Cys-347-dependent manner. These chemotypes are electrophiles that react with GSH, and LC/MS determined the cysteine adducts formed upon conjugation. Together, our results suggest covalent modification may be used to stabilize the GLP-1R in an active conformation. Moreover, the findings provide pharmacological guidance for the discovery and

  20. [Protective effects of glucagon-like peptide-1 on beta-cells: preclinical and clinical data].

    PubMed

    Consoli, Agostino; Di Biagio, Rosamaria

    2011-12-01

    Dipartimento di Medicina Interna e Scienze dell'Invecchiamento, Università degli Studi "G. d'Annunzio", Chieti Continuing b-cell mass and function loss represents the key mechanism for the pathogenesis and the progression of type 2 diabetes mellitus. Drugs capable of arresting b-cell loss and eventually able to bring b-cell function close to be back to normal would then be a formidable help in type 2 diabetes mellitus treatment. The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide can stimulate in vitro neogenesis and prevent apoptosis in b-cell-like cell lines. Consistently, treatment with GLP-1 receptor agonists ameliorates glucose metabolism, preserves b-cell mass and improves b-cell function in several animal models of diabetes. For instance, in the db/db mice, liraglutide protects the b-cell from oxidative stress and endoplasmic reticulum stress-related damage. Data in humans, in vivo, are less definitive and often based on scarcely reliable indexes of b-cell function. However, short-term treatment (14 weeks) with liraglutide increased b-cell maximal response capacity in a dose-response fashion. A longer (1 year) exenatide treatment also was able to increase b-cell maximal response capacity, but the effect was no longer there after a 4-week washout period. However, a marginal, although significant as compared to glargine treatment, improvement in another b-cell function index (disposition index) was observed after a 4-week washout period following 3-year exenatide treatment. Finally, although no clinical trials with a long enough follow-up period are presently available, durable glucose control has been obtained during 2 years of liraglutide treatment in monotherapy. Since the durability of good control is strictly dependent upon a lack of further b-cell function deterioration, these clinical data may foster hope that GLP-1 receptor antagonist treatment might help preserving b-cell function also in individuals affected by type 2

  1. Dual-purpose linker for alpha helix stabilization and imaging agent conjugation to glucagon-like peptide-1 receptor ligands.

    PubMed

    Zhang, Liang; Navaratna, Tejas; Liao, Jianshan; Thurber, Greg M

    2015-02-18

    Peptides display many characteristics of efficient imaging agents such as rapid targeting, fast background clearance, and low non-specific cellular uptake. However, poor stability, low affinity, and loss of binding after labeling often preclude their use in vivo. Using glucagon-like peptide-1 receptor (GLP-1R) ligands exendin and GLP-1 as a model system, we designed a novel α-helix-stabilizing linker to simultaneously address these limitations. The stabilized and labeled peptides showed an increase in helicity, improved protease resistance, negligible loss or an improvement in binding affinity, and excellent in vivo targeting. The ease of incorporating azidohomoalanine in peptides and efficient reaction with the dialkyne linker enable this technique to potentially be used as a general method for labeling α helices. This strategy should be useful for imaging beta cells in diabetes research and in developing and testing other peptide targeting agents. PMID:25594741

  2. Multifunctional Antibody Agonists Targeting Glucagon-like Peptide-1, Glucagon, and Glucose-Dependent Insulinotropic Polypeptide Receptors.

    PubMed

    Wang, Ying; Du, Jintang; Zou, Huafei; Liu, Yan; Zhang, Yuhan; Gonzalez, Jose; Chao, Elizabeth; Lu, Lucy; Yang, Pengyu; Parker, Holly; Nguyen-Tran, Van; Shen, Weijun; Wang, Danling; Schultz, Peter G; Wang, Feng

    2016-09-26

    Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), glucagon (GCG) receptor (GCGR), and glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) receptor (GIPR), are three metabolically related peptide hormone receptors. A novel approach to the generation of multifunctional antibody agonists that activate these receptors has been developed. Native or engineered peptide agonists for GLP-1R, GCGR, and GIPR were fused to the N-terminus of the heavy chain or light chain of an antibody, either alone or in pairwise combinations. The fusion proteins have similar in vitro biological activities on the cognate receptors as the corresponding peptides, but circa 100-fold longer plasma half-lives. The GLP-1R mono agonist and GLP-1R/GCGR dual agonist antibodies both exhibit potent effects on glucose control and body weight reduction in mice, with the dual agonist antibody showing enhanced activity in the latter. PMID:27595986

  3. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    PubMed

    Escalada, Francisco Javier

    2014-09-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes.

  4. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    PubMed

    Escalada, Francisco Javier

    2014-01-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes.

  5. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    PubMed

    Escalada, Francisco Javier

    2014-01-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. PMID:25326836

  6. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    PubMed

    Escalada, Francisco Javier

    2014-09-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. PMID:25437458

  7. Molecular Characterisation of Small Molecule Agonists Effect on the Human Glucagon Like Peptide-1 Receptor Internalisation

    PubMed Central

    Thompson, Aiysha; Stephens, Jeffrey W.; Bain, Stephen C.

    2016-01-01

    The glucagon-like peptide receptor (GLP-1R), which is a G-protein coupled receptor (GPCR), signals through both Gαs and Gαq coupled pathways and ERK phosphorylation to stimulate insulin secretion. The aim of this study was to determine molecular details of the effect of small molecule agonists, compounds 2 and B, on GLP-1R mediated cAMP production, intracellular Ca2+ accumulation, ERK phosphorylation and its internalisation. In human GLP-1R (hGLP-1R) expressing cells, compounds 2 and B induced cAMP production but caused no intracellular Ca2+ accumulation, ERK phosphorylation or hGLP-1R internalisation. GLP-1 antagonists Ex(9–39) and JANT-4 and the orthosteric binding site mutation (V36A) in hGLP-1R failed to inhibit compounds 2 and B induced cAMP production, confirming that their binding site distinct from the GLP-1 binding site on GLP-1R. However, K334A mutation of hGLP-1R, which affects Gαs coupling, inhibited GLP-1 as well as compounds 2 and B induced cAMP production, indicating that GLP-1, compounds 2 and B binding induce similar conformational changes in the GLP-1R for Gαs coupling. Additionally, compound 2 or B binding to the hGLP-1R had significantly reduced GLP-1 induced intracellular Ca2+ accumulation, ERK phosphorylation and hGLP-1R internalisation. This study illustrates pharmacology of differential activation of GLP-1R by GLP-1 and compounds 2 and B. PMID:27100083

  8. The insulinotropic effect of exogenous glucagon-like peptide-1 is not affected by acute vagotomy in anaesthetized pigs.

    PubMed

    Veedfald, Simon; Hansen, Marie; Christensen, Louise Wulff; Larsen, Sara Agnete Hjort; Hjøllund, Karina Rahr; Plamboeck, Astrid; Hartmann, Bolette; Deacon, Carolyn Fiona; Holst, Jens Juul

    2016-07-01

    What is the central question of this study? We investigated whether intestinal vagal afferents are necessary for the insulinotropic effect of glucagon-like peptide-1 (GLP-1) infused into a mesenteric artery or a peripheral vein before and after acute truncal vagotomy. What is the main finding and its importance? We found no effect of truncal vagotomy on the insulinotropic effect of exogenous GLP-1 and speculate that high circulating concentrations of GLP-1 after i.v. and i.a. infusion might have overshadowed any neural signalling component. We propose that further investigations into the possible vagal afferent signalling of GLP-1 would best be pursued using enteral stimuli to provide high subepithelial levels of endogenous GLP-1. Glucagon-like peptide 1 (GLP-1) is secreted from the gut in response to luminal stimuli and stimulates insulin secretion in a glucose-dependent manner. As a result of rapid enzymatic degradation of GLP-1 by dipeptidyl peptidase-4, a signalling pathway involving activation of intestinal vagal afferents has been proposed. We conducted two series of experiments in α-chloralose-anaesthetized pigs. In protocol I, pigs (n = 14) were allocated for either i.v. or i.a. (mesenteric) GLP-1 infusions (1 and 2 pmol kg(-1)  min(-1) , 30 min) while maintaining permissive glucose concentrations at 6 mmol l(-1) by i.v. glucose infusion. The GLP-1 infusions were repeated after acute truncal vagotomy. In protocol II, pigs (n = 27) were allocated into six groups. Glucagon-like peptide 1 was infused i.v. or i.a. (mesenteric) for 1 h at 3 or 30 pmol kg(-1)  min(-1) . During the steady state (21 min into the GLP-1 infusion), glucose (0.2 g kg(-1) , i.v.) was administered over 9 min to stimulate β-cell secretion. Thirty minutes after the glucose infusion, GLP-1 infusions were discontinued. Following a washout period, the vagal trunks were severed in four of six groups (vagal trunks were left intact in two of six groups), whereupon all

  9. The glucagon-like peptide 1 receptor agonist enhances intrinsic peroxisome proliferator-activated receptor γ activity in endothelial cells

    SciTech Connect

    Onuma, Hirohisa; Inukai, Kouichi Kitahara, Atsuko; Moriya, Rie; Nishida, Susumu; Tanaka, Toshiaki; Katsuta, Hidenori; Takahashi, Kazuto; Sumitani, Yoshikazu; Hosaka, Toshio; Ishida, Hitoshi

    2014-08-22

    Highlights: • PPARγ activation was involved in the GLP-1-mediated anti-inflammatory action. • Exendin-4 enhanced endogenous PPARγ transcriptional activity in HUVECs. • H89, a PKA inhibitor, abolished GLP-1-induced PPARγ enhancement. • The anti-inflammatory effects of GLP-1 may be explained by PPARγ activation. - Abstract: Recent studies have suggested glucagon-like peptide-1 (GLP-1) signaling to exert anti-inflammatory effects on endothelial cells, although the precise underlying mechanism remains to be elucidated. In the present study, we investigated whether PPARγ activation is involved in the GLP-1-mediated anti-inflammatory action on endothelial cells. When we treated HUVEC cells with 0.2 ng/ml exendin-4, a GLP-1 receptor agonist, endogenous PPARγ transcriptional activity was significantly elevated, by approximately 20%, as compared with control cells. The maximum PPARγ activity enhancing effect of exendin-4 was observed 12 h after the initiation of incubation with exendin-4. As H89, a PKA inhibitor, abolished GLP-1-induced PPARγ enhancement, the signaling downstream from GLP-1 cross-talk must have been involved in PPARγ activation. In conclusion, our results suggest that GLP-1 has the potential to induce PPARγ activity, partially explaining the anti-inflammatory effects of GLP-1 on endothelial cells. Cross-talk between GLP-1 signaling and PPARγ activation would have major impacts on treatments for patients at high risk for cardiovascular disease.

  10. Spergularia marina Induces Glucagon-Like Peptide-1 Secretion in NCI-H716 Cells Through Bile Acid Receptor Activation

    PubMed Central

    Kim, Kyong; Lee, Yu Mi; Rhyu, Mee-Ra

    2014-01-01

    Abstract Spergularia marina Griseb. (SM) is a halophyte that grows in mud flats. The aerial portions of SM have been eaten as vegetables and traditionally used to prevent chronic diseases in Korea. However, there has been no scientific report that demonstrates the pharmacological effects of SM. Glucagon-like peptide-1 (GLP-1) is important for the maintenance of glucose and energy homeostasis through acting as a signal in peripheral and neural systems. To discover a functional food for regulating glucose and energy homeostasis, we evaluated the effect of an aqueous ethanolic extract (AEE) of SM on GLP-1 release from enteroendocrine NCI-H716 cells. In addition, we explored the Takeda G-protein-coupled receptor 5 (TGR5) agonist activity of AEE-SM in Chinese hamster ovary (CHO)-K1 cells transiently transfected with human TGR5. As a result, treatment of NCI-H716 cells with AEE-SM increased GLP-1 secretion and intracellular Ca2+ and cyclic AMP (cAMP) levels in a dose-dependent manner. Transfection of NCI-H716 cells with TGR5-specific small interference RNA inhibited AEE-SM-induced GLP-1 secretion and the increase in Ca2+ and cAMP levels. Moreover, AEE-SM showed that the TGR5 agonist activity in CHO-K1 cells transiently transfected with TGR5. The results suggest that AEE-SM might be a candidate for a functional food to regulate glucose and energy homeostasis. PMID:25260089

  11. Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future

    PubMed Central

    Kalra, Sanjay; Baruah, Manash P.; Sahay, Rakesh K.; Unnikrishnan, Ambika Gopalakrishnan; Uppal, Shweta; Adetunji, Omolara

    2016-01-01

    Glucagon-like peptide-1 (GLP-1)–based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs) continue to become available, physicians will soon face the challenge of selecting the right option customized to their patient's needs. The following discussion, derived from an extensive literature search using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide, provides a comprehensive review of existing and upcoming molecules in the GLP-1 RA class in terms of their structure, pharmacological profiles, efficacy, safety, and convenience. Search Methodology: A literature search was conducted using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide. Relevant articles were those that discussed structural, pharmacokinetic and pharmacodynamic differences, classification, long-acting and short-acting GLP-1 RAs, phase 3 trials, and expert opinions. Additional targeted searches were conducted on diabetes treatment guidelines and reviews on safety, as well as the American Diabetes Association/European Society for Study of Diabetes (ADA/EASD) statement on pancreatic safety. PMID:27042424

  12. An Emerging Role of Glucagon-Like Peptide-1 in Preventing Advanced-Glycation-End-Product-Mediated Damages in Diabetes

    PubMed Central

    Puddu, Alessandra; Mach, François; Nencioni, Alessio; Viviani, Giorgio Luciano; Montecucco, Fabrizio

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake. These antidiabetic activities highlight GLP-1 as a potential therapeutic molecule in the clinical management of type 2 diabetes, (a disease characterized by progressive decline of beta-cell function and mass, increased insulin resistance, and final hyperglycemia). Since chronic hyperglycemia contributed to the acceleration of the formation of Advanced Glycation End-Products (AGEs, a heterogeneous group of compounds derived from the nonenzymatic reaction of reducing sugars with free amino groups of proteins implicated in vascular diabetic complications), the administration of GLP-1 might directly counteract diabetes pathophysiological processes (such as pancreatic β-cell dysfunction). This paper outlines evidence on the protective role of GLP-1 in preventing the deleterious effects mediated by AGEs in type 2 diabetes. PMID:23365488

  13. Neuroendocrine function and response to stress in mice with complete disruption of glucagon-like peptide-1 receptor signaling.

    PubMed

    MacLusky, N J; Cook, S; Scrocchi, L; Shin, J; Kim, J; Vaccarino, F; Asa, S L; Drucker, D J

    2000-02-01

    Glucagon-like peptide-1 (GLP-1), a potent regulator of glucose homeostasis, is also produced in the central nervous system, where GLP-1 has been implicated in the neuroendocrine control of hypothalamic-pituitary function, food intake, and the response to stress. The finding that intracerebroventricular GLP-1 stimulates LH, TSH, corticosterone, and vasopressin secretion in rats prompted us to assess the neuroendocrine consequences of disrupting GLP-1 signaling in mice in vivo. Male GLP-1 receptor knockout (GLP-1R-/-) mice exhibit reduced gonadal weights, and females exhibit a slight delay in the onset of puberty; however, male and female GLP-1R-/- animals reproduce successfully and respond appropriately to fluid restriction. Although adrenal weights are reduced in GLP-1R-/- mice, hypothalamic CRH gene expression and circulating levels of corticosterone, thyroid hormone, testosterone, estradiol, and progesterone are normal in the absence of GLP-1R-/- signaling. Intriguingly, GLP-1R-/- mice exhibit paradoxically increased corticosterone responses to stress as well as abnormal responses to acoustic startle that are corrected by glucocorticoid treatment. These findings suggest that although GLP-1R signaling is not essential for development and basal function of the murine hypothalamic-pituitary-adrenal axis, abrogation of GLP-1 signaling is associated with impairment of the behavioral and neuroendocrine responses to stress.

  14. Glucagon-like peptide-1 receptor agonist therapeutics for total diabetes management: assessment of composite end-points.

    PubMed

    Yabe, Daisuke; Kuwata, Hitoshi; Usui, Ryota; Kurose, Takeshi; Seino, Yutaka

    2015-01-01

    Assessment of the benefits of anti-diabetic drugs for type 2 diabetes requires analysis of composite end-points, taking HbA1c, bodyweight, hypoglycemia and other metabolic parameters into consideration; continuous, optimal glycemic control as well as bodyweight, blood pressure and lipid levels are critical to prevent micro- and macro-vascular complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now established as an important total treatment strategy for type 2 diabetes, exerting glucose-lowering effects with little hypoglycemia risk and also ameliorating bodyweight, blood pressure and lipid levels, which are therapeutic targets for prevention of complications of the disease. The available data strongly suggest only beneficial effects of GLP-1RAs; however, long-term evaluation of the relevant composite end-points including health-related quality of life and cost-effectiveness remain to be investigated in adequately powered, prospective, controlled clinical trials. In the meantime, healthcare professionals need to be scrupulously attentive for potential, rare adverse events in patients using GLP-1RAs. PMID:25916903

  15. Subthreshold α₂-adrenergic activation counteracts glucagon-like peptide-1 potentiation of glucose-stimulated insulin secretion.

    PubMed

    Pan, Minglin; Yang, Guang; Cui, Xiuli; Yang, Shao-Nian

    2011-01-01

    The pancreatic β cell harbors α₂-adrenergic and glucagon-like peptide-1 (GLP-1) receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α₂-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α₂-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX-) sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α₂-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

  16. Function and expression of sulfonylurea, adrenergic, and glucagon-like peptide 1 receptors in isolated porcine islets.

    PubMed

    Kelly, Amy C; Steyn, Leah V; Kitzmann, Jenna P; Anderson, Miranda J; Mueller, Kate R; Hart, Nathaniel J; Lynch, Ronald M; Papas, Klearchos K; Limesand, Sean W

    2014-01-01

    The scarcity of human cadaveric pancreata limits large-scale application of islet transplantation for patients with diabetes. Islets isolated from pathogen-free pigs provide an economical and abundant alternative source assuming immunologic barriers are appropriate. Membrane receptors involved in insulin secretion that also have potential as imaging targets were investigated in isolated porcine islets. Quantitative (q)PCR revealed that porcine islets express mRNA transcripts for sulfonylurea receptor 1 (Sur1), inward rectifying potassium channel (Kir6.2, associated with Sur1), glucagon-like peptide 1 receptor (GLP1R), and adrenergic receptor alpha 2A (ADRα2A). Receptor function was assessed in static incubations with stimulatory glucose concentrations, and in the presence of receptor agonists. Glibenclamide, an anti-diabetic sulfonylurea, and exendin-4, a GLP-1 mimetic, potentiated glucose-stimulated insulin secretion >2-fold. Conversely, epinephrine maximally reduced insulin secretion 72 ± 9% (P < 0.05) and had a half maximal inhibitory concentration of 60 nm in porcine islets (95% confidence interval of 45-830 nm). The epinephrine action was inhibited by the ADRα2A antagonist yohimbine. Our findings demonstrate that porcine islets express and are responsive to both stimulatory and inhibitory membrane localized receptors, which can be used as imaging targets after transplantation or to modify insulin secretion.

  17. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men.

    PubMed

    Gutzwiller, Jean-Pierre; Tschopp, Stefan; Bock, Andreas; Zehnder, Carlos E; Huber, Andreas R; Kreyenbuehl, Monika; Gutmann, Heike; Drewe, Jürgen; Henzen, Christoph; Goeke, Burkhard; Beglinger, Christoph

    2004-06-01

    Glucagon-like peptide-1-(7-36)-amide (GLP-1) is involved in satiety control and glucose homeostasis. Animal studies suggest a physiological role for GLP-1 in water and salt homeostasis. This study's aim was to define the effects of GLP-1 on water and sodium excretion in both healthy and obese men. Fifteen healthy subjects and 16 obese men (mean body mass index, 36 kg/m2) were examined in a double-blind, placebo-controlled, crossover study to demonstrate the effects of a 3-h infusion of GLP-1 on urinary sodium excretion, urinary output, and the glomerular filtration rate after an i.v. 9.9-g salt load. Infusion of GLP-1 evoked a dose-dependent increase in urinary sodium excretion in healthy subjects (from 74 +/- 8 to 143 +/- 18 mmol/180 min, P = 0.0013). In obese men, there was a significant increase in urinary sodium excretion (from 59 to 96 mmol/180 min, P = 0.015), a decrease in urinary H+ secretion (from 1.1 to 0.3 pmol/180 min, P = 0.013), and a 6% decrease in the glomerular filtration rate (from 151 +/- 8 to 142 +/- 8 ml/min, P = 0.022). Intravenous infusions of GLP-1 enhance sodium excretion, reduce H+ secretion, and reduce glomerular hyperfiltration in obese men. These findings suggest an action at the proximal renal tubule and a potential renoprotective effect.

  18. Glucagon-like peptide-1 inhibits angiotensin II-induced mesangial cell damage via protein kinase A.

    PubMed

    Ishibashi, Yuji; Matsui, Takanori; Ojima, Ayako; Nishino, Yuri; Nakashima, Sae; Maeda, Sayaka; Yamagishi, Sho-ichi

    2012-11-01

    There is a growing body of evidence that renin-angiotensin system plays a role in diabetic nephropathy. Recently, we have found that glucagon-like peptide-1 (GLP-1), one of the incretins, a gut hormone secreted from L cells in the intestine in response to food intake, inhibits advanced glycation end product-induced monocyte chemoattractant protein-1 gene expression in mesangial cells thorugh the interaction with the receptor of GLP-1. However, effects of GLP-1 on angiotensin II-exposed mesangial cells are unknown. This study investigated whether and how GLP-1 blocked the angiotensin II-induced mesangial cell damage in vitro. GLP-1 completely blocked the angiotensin II-induced superoxide generation, NF-κB activation, up-regulation of mRNA levels of intercellular adhesion molecule-1 and plasminogen activator inhibitor-1 in mesangial cells, all of which were prevented by the treatments with H-89, an inhibitor of protein kinase A. The present results demonstrated for the first time that GLP-1 blocked the angiotensin II-induced mesangial cell injury by inhibiting superoxide-mediated NF-κB activation via protein kinase C pathway. Our present study suggests that strategies to enhance the biological actions of GLP-1 may be a promising strategy for the treatment of diabetic nephropathy.

  19. Glucagon Like Peptide-1 Promotes Adipocyte Differentiation via the Wnt4 Mediated Sequestering of Beta-Catenin.

    PubMed

    Liu, Rui; Li, Na; Lin, Yi; Wang, Mei; Peng, Yongde; Lewi, Keidren; Wang, Qinghua

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) plays a role in the regulation of adipogenesis; however, the precise underlying molecular mechanism has not been fully defined. Wnt was recently identified as an important regulator of adipogenesis. This study aimed to investigate the involvement of the Wnt signaling pathway in the effects of GLP-1 on adipocyte differentiation. 3T3-L1 cells were induced to differentiate. The changes in the expression levels of adipogenic transcription factors and Wnts and the phosphorylation level and subcellular localization of β-catenin were quantified after GLP-1 treatment. GLP-1 stimulated adipocyte differentiation and lipid accumulation, which were accompanied by the expression of adipocyte marker genes. The expression of Wnt4 was upregulated in the process of adipocyte differentiation, which was further enhanced by treatment with GLP-1. β-catenin, an important mediator of the Wnt pathway, was immediately dephosphorylated and translocated from cytoplasm to nucleus when differentiation was induced. In the presence of GLP-1, however, β-catenin was redirected to the cell plasma membrane leading to its decreased accumulation in the nucleus. Knockdown of Wnt4 blocked the effect of GLP-1 on the cellular localization of β-catenin and expression level of adipogenic transcription factors. Our findings showed that GLP-1 promoted adipogenesis through the modulation of the Wnt4/β-catenin signaling pathway, suggesting that the GLP-1-Wntβ-catenin system might be a new target for the treatment of metabolic disease. PMID:27504979

  20. The inactivation of extracellular signal-regulated kinase by glucagon-like peptide-1 contributes to neuroprotection against oxidative stress.

    PubMed

    Nakajima, Shingo; Numakawa, Tadahiro; Adachi, Naoki; Yoon, Hyung Shin; Odaka, Haruki; Ooshima, Yoshiko; Kunugi, Hiroshi

    2016-03-11

    Glucagon-like peptide-1 (GLP-1), an insulinotropic peptide secreted from enteroendocrine cells, has been known to have a neuroprotective effect. However, it is not fully understood the intracellular mediator of GLP-1 signaling in neuronal cells. In the present study, we examined the change in intracellular signaling of cortical neurons after GLP-1 application and luminal glucose stimulation in vitro and in vivo. GLP-1 receptor was highly expressed in cultured cortical neurons and brain tissues including the prefrontal cortex and hippocampus. The activation of GLP-1 receptor (5min) significantly decreased levels of phosphorylated extracellular signal-regulated kinase (pERK), which is involved in neuronal cell survival and death, in cultured cortical neurons. Oral glucose administration also rapidly reduced pERK levels in the prefrontal cortex, while intraperitoneal glucose injection did not show such an effect. Further, GLP-1 attenuated hydrogen peroxide-induced cell death and hyperactivity of ERK in cultured cortical neurons. It is possible that increased GLP-1 by luminal glucose stimulation affects cortical system including the maintenance of neuronal cell survival. PMID:26827720

  1. Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes

    PubMed Central

    Tate, Mitchel; Chong, Aaron; Robinson, Emma; Green, Brian D; Grieve, David J

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the CVS where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting is limited, although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1-based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes. PMID:25231355

  2. Dietary Mannoheptulose Increases Fasting Serum Glucagon Like Peptide-1 and Post-Prandial Serum Ghrelin Concentrations in Adult Beagle Dogs.

    PubMed

    McKnight, Leslie L; Eyre, Ryan; Gooding, Margaret A; Davenport, Gary M; Shoveller, Anna Kate

    2015-01-01

    There is a growing interest in the use of nutraceuticals for weight management in companion animals. The purpose of this study was to determine the effects of mannoheptulose (MH), a sugar in avocados that inhibits glycolysis, on energy metabolism in adult Beagle dogs. The study was a double-blind, randomized controlled trial where dogs were allocated to a control (CON, n = 10, 10.1 ± 0.4 kg) or MH containing diet (168 mg/kg, n = 10, 10.3 ± 0.4 kg). Blood was collected after an overnight fast and 1 h post-feeding (week 12) to determine serum satiety related hormones and biochemistry. Resting and post-prandial energy expenditure and respiratory quotient were determined by indirect calorimetry (weeks 4 and 8). Physical activity was measured using an accelerometer (weeks 3, 7, 11). Body composition was assessed using dual X-ray absorptiometry (week 12). MH significantly (p < 0.05) increased fasting serum glucagon-like peptide-1 and post-prandial serum ghrelin. MH tended (p < 0.1) to increase fasting serum gastric inhibitory peptide and decrease physical activity. Together, these findings suggest that dietary MH has the ability to promote satiation and lowers daily energy expenditure. PMID:26479244

  3. Glucagon Like Peptide-1 Promotes Adipocyte Differentiation via the Wnt4 Mediated Sequestering of Beta-Catenin

    PubMed Central

    Liu, Rui; Li, Na; Lin, Yi; Wang, Mei; Peng, Yongde; Lewi, Keidren; Wang, Qinghua

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) plays a role in the regulation of adipogenesis; however, the precise underlying molecular mechanism has not been fully defined. Wnt was recently identified as an important regulator of adipogenesis. This study aimed to investigate the involvement of the Wnt signaling pathway in the effects of GLP-1 on adipocyte differentiation. 3T3-L1 cells were induced to differentiate. The changes in the expression levels of adipogenic transcription factors and Wnts and the phosphorylation level and subcellular localization of β-catenin were quantified after GLP-1 treatment. GLP-1 stimulated adipocyte differentiation and lipid accumulation, which were accompanied by the expression of adipocyte marker genes. The expression of Wnt4 was upregulated in the process of adipocyte differentiation, which was further enhanced by treatment with GLP-1. β-catenin, an important mediator of the Wnt pathway, was immediately dephosphorylated and translocated from cytoplasm to nucleus when differentiation was induced. In the presence of GLP-1, however, β-catenin was redirected to the cell plasma membrane leading to its decreased accumulation in the nucleus. Knockdown of Wnt4 blocked the effect of GLP-1 on the cellular localization of β-catenin and expression level of adipogenic transcription factors. Our findings showed that GLP-1 promoted adipogenesis through the modulation of the Wnt4/β-catenin signaling pathway, suggesting that the GLP-1-Wntβ-catenin system might be a new target for the treatment of metabolic disease. PMID:27504979

  4. Transient Receptor Potential Vanilloid 1 Activation Enhances Gut Glucagon-Like Peptide-1 Secretion and Improves Glucose Homeostasis

    PubMed Central

    Wang, Peijian; Yan, Zhencheng; Zhong, Jian; Chen, Jing; Ni, Yinxing; Li, Li; Ma, Liqun; Zhao, Zhigang; Liu, Daoyan; Zhu, Zhiming

    2012-01-01

    Type 2 diabetes mellitus (T2DM) is rapidly prevailing as a serious global health problem. Current treatments for T2DM may cause side effects, thus highlighting the need for newer and safer therapies. We tested the hypothesis that dietary capsaicin regulates glucose homeostasis through the activation of transient receptor potential vanilloid 1 (TRPV1)-mediated glucagon-like peptide-1 (GLP-1) secretion in the intestinal cells and tissues. Wild-type (WT) and TRPV1 knockout (TRPV1−/−) mice were fed dietary capsaicin for 24 weeks. TRPV1 was localized in secretin tumor cell-1 (STC-1) cells and ileum. Capsaicin stimulated GLP-1 secretion from STC-1 cells in a calcium-dependent manner through TRPV1 activation. Acute capsaicin administration by gastric gavage increased GLP-1 and insulin secretion in vivo in WT but not in TRPV1−/− mice. Furthermore, chronic dietary capsaicin not only improved glucose tolerance and increased insulin levels but also lowered daily blood glucose profiles and increased plasma GLP-1 levels in WT mice. However, this effect was absent in TRPV1−/− mice. In db/db mice, TRPV1 activation by dietary capsaicin ameliorated abnormal glucose homeostasis and increased GLP-1 levels in the plasma and ileum. The present findings suggest that TRPV1 activation–stimulated GLP-1 secretion could be a promising approach for the intervention of diabetes. PMID:22664955

  5. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons

    PubMed Central

    Yamamoto, Hiroshi; Lee, Charlotte E.; Marcus, Jacob N.; Williams, Todd D.; Overton, J. Michael; Lopez, Marisol E.; Hollenberg, Anthony N.; Baggio, Laurie; Saper, Clifford B.; Drucker, Daniel J.; Elmquist, Joel K.

    2002-01-01

    Glucagon-like peptide-1 (GLP-1) released from the gut functions as an incretin that stimulates insulin secretion. GLP-1 is also a brain neuropeptide that controls feeding and drinking behavior and gastric emptying and elicits neuroendocrine responses including development of conditioned taste aversion. Although GLP-1 receptor (GLP-1R) agonists are under development for the treatment of diabetes, GLP-1 administration may increase blood pressure and heart rate in vivo. We report here that centrally and peripherally administered GLP-1R agonists dose-dependently increased blood pressure and heart rate. GLP-1R activation induced c-fos expression in the adrenal medulla and neurons in autonomic control sites in the rat brain, including medullary catecholamine neurons providing input to sympathetic preganglionic neurons. Furthermore, GLP-1R agonists rapidly activated tyrosine hydroxylase transcription in brainstem catecholamine neurons. These findings suggest that the central GLP-1 system represents a regulator of sympathetic outflow leading to downstream activation of cardiovascular responses in vivo. PMID:12093887

  6. Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future.

    PubMed

    Kalra, Sanjay; Baruah, Manash P; Sahay, Rakesh K; Unnikrishnan, Ambika Gopalakrishnan; Uppal, Shweta; Adetunji, Omolara

    2016-01-01

    Glucagon-like peptide-1 (GLP-1)-based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs) continue to become available, physicians will soon face the challenge of selecting the right option customized to their patient's needs. The following discussion, derived from an extensive literature search using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide, provides a comprehensive review of existing and upcoming molecules in the GLP-1 RA class in terms of their structure, pharmacological profiles, efficacy, safety, and convenience. Search Methodology: A literature search was conducted using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide. Relevant articles were those that discussed structural, pharmacokinetic and pharmacodynamic differences, classification, long-acting and short-acting GLP-1 RAs, phase 3 trials, and expert opinions. Additional targeted searches were conducted on diabetes treatment guidelines and reviews on safety, as well as the American Diabetes Association/European Society for Study of Diabetes (ADA/EASD) statement on pancreatic safety.

  7. Glucagon-Like Peptide-1 as Predictor of Body Mass Index and Dentate Gyrus Neurogenesis: Neuroplasticity and the Metabolic Milieu

    PubMed Central

    Coplan, Jeremy D.; Perera, Tarique D.; Fulton, Sasha L.; Banerji, Mary Ann; Dwork, Andrew J.; Kral, John G.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1), and body mass index (BMI) in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge—high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues. PMID:25506432

  8. The influence of restricted feeding on glucagon-like peptide-1 (GLP-1)-containing cells in the chicken small intestine.

    PubMed

    Monir, M M; Hiramatsu, K; Yamasaki, A; Nishimura, K; Watanabe, T

    2014-04-01

    The influence of restricted feeding on the distribution of glucagon-like peptide-1 (GLP-1)-containing endocrine cells in the chicken small intestine was investigated using immunohistochemical and morphometrical techniques. This study demonstrated that the restricted feeding had an influence on the activity of GLP-1-immunoreactive cells in the chicken small intestine. There were differences in the localization and the frequency of occurrence of GLP-1-immunoreactive cells in the small intestine between control and restricted groups, especially 25% feed supply group provided with 25% of the intake during the adapting period. GLP-1-immunoreactive cells in the control chickens were mainly located in epithelium from crypts to the lower part of intestinal villi. Those in restricted groups, however, tended to be located from crypts to the middle part of intestinal villi. The frequency of occurrence of GLP-1-immunoreactive cells was lowest in the control group, medium in 50% feed supply group and highest in 25% feed supply group at each intestinal region examined in this study, that is, increased with the advancement of restricting the amount of feed supply. These data show that the quantity of food intake is one of signals that have an influence on the secretion of GLP-1 from L cells in the chicken small intestine.

  9. Albiglutide, an albumin-based fusion of glucagon-like peptide 1 for the potential treatment of type 2 diabetes.

    PubMed

    Tomkin, Gerald H

    2009-10-01

    Albiglutide, under development by GlaxoSmithKline plc for the treatment of type 2 diabetes mellitus (T2DM), is an albumin-fusion peptide. The compound is a mimetic of glucagon-like peptide 1 (GLP-1), a hormone that decreases glucose levels, but has a short half-life because of degradation by dipeptidyl peptidase (DPP)-4. Albiglutide has a longer half-life as a result of its fusion with albumin and its resistance to degradation by DPP-4, caused by an amino acid substitution (Ala to Glu) at the DPP-4-sensitive hydrolysis site. Data from phase II clinical trials in patients with T2DM revealed that albiglutide was well tolerated and that the drug significantly reduced HbA1c levels compared with placebo. At the time of publication, phase III trials assessing albiglutide alone and in combination with other antidiabetic drugs were recruiting patients with T2DM. Albiglutide represents a promising new drug for the treatment of patients with T2DM; the results of long-term trials are awaited with interest.

  10. Effects of glucagon-like peptide-1 and feeding on gastric volumes in diabetes mellitus with cardio-vagal dysfunction.

    PubMed

    Delgado-Aros, S; Vella, A; Camilleri, M; Low, P A; Burton, D D; Thomforde, G M; Stephens, D

    2003-08-01

    Glucagon-like peptide-1 (GLP-1) increases gastric volume in humans possibly through the vagus nerve. Gastric volume response to feeding is preserved after vagal denervation in animals. We evaluated gastric volume responses to GLP-1 and placebo in seven diabetic patients with vagal neuropathy in a crossover study. We also compared gastric volume response to feeding in diabetes with that in healthy controls. We measured gastric volume using SPECT imaging. Data are median (interquartile range). In diabetic patients, GLP-1 did not increase gastric volume during fasting [5 mL (-3; 30)] relative to placebo [4 mL (-14; 50) P = 0.5], or postprandially [Delta postprandial minus fasting volume 469 mL (383; 563) with GLP-1 and 452 mL (400; 493) with placebo P = 0.3]. Change in gastric volume over fasting in diabetic patients on placebo was comparable to that of healthy controls [452 mL (400; 493)], P = 0.5. In contrast to effects in health, GLP-1 did not increase gastric volume in diabetics with vagal neuropathy, suggesting GLP-1's effects on stomach volume are vagally mediated. Normal gastric volume response to feeding in diabetics with vagal neuropathy suggests that other mechanisms compensate for vagal denervation.

  11. REVIEW: Role of cyclic AMP signaling in the production and function of the incretin hormone glucagon-like peptide-1

    NASA Astrophysics Data System (ADS)

    Yu, Zhiwen; Jin, Tianru

    2008-01-01

    Pancreatic cells express the proglucagon gene (gcg) and thereby produce the peptide hormone glucagon, which stimulates hepatic glucose production and thereby increases blood glucose levels. The same gcg gene is also expressed in the intestinal endocrine L cells and certain neural cells in the brain. In the gut, gcg expression leads to the production of glucagon-like peptide-1 (GLP-1). This incretin hormone stimulates insulin secretion when blood glucose level is high. In addition, GLP-1 stimulates pancreatic cell proliferation, inhibits cell apoptosis, and has been utilized in the trans-differentiation of insulin producing cells. Today, a long-term effective GLP-1 receptor agonist has been developed as a drug in treating diabetes and potentially other metabolic disorders. Extensive investigations have shown that the expression of gcg and the production of GLP-1 can be activated by the elevation of the second messenger cyclic AMP (cAMP). Recent studies suggest that in addition to protein kinase A (PKA), exchange protein activated by cAMP (Epac), another effector of cAMP signaling, and the crosstalk between PKA and Wnt signaling pathway, are also involved in cAMP-stimulated gcg expression and GLP-1 production. Furthermore, functions of GLP-1 in pancreatic cells are mainly mediated by cAMP-PKA, cAMP-Epac and Wnt signaling pathways as well.

  12. Metformin ameliorates lipotoxicity-induced mesangial cell apoptosis partly via upregulation of glucagon like peptide-1 receptor (GLP-1R).

    PubMed

    Kim, Dong-il; Park, Min-jung; Heo, Young-ran; Park, Soo-hyun

    2015-10-15

    Glucagon like peptide-1 receptor (GLP-1R), known to be expressed in pancreatic beta cells, is also expressed in glomerular mesangial cells and its agonist has protective effects in diabetic nephropathy. However, its regulatory mechanisms by lipotoxicity in glomerular mesangial cells are not understood. We found that palmitate-mediated lipotoxicity increased apoptosis and decreased GLP-1R expression in a rat mesangial cell line. Silencing GLP-1R expression also increased mesangial cell apoptosis. Interestingly, metformin, one of the biguanide drugs that has anti-diabetic effects, attenuated lipotoxicity-induced mesangial cell apoptosis and restored GLP-1R expression. Moreover, this treatment alleviated GLP-1R knockdown-induced mesangial cell apoptosis. To further evaluate in vivo, diabetic obese db/db mice were administered metformin. Glomerular GLP-1R expression was diminished in db/db mice, as compared with db/m control mice. However, this decrease significantly recovered on metformin administration. Together, these data provide novel evidence that lipotoxicity decreases the mesangial GLP-1R expression in intact cells and in vivo. The decrease induced mesangial cell apoptosis. Furthermore, we provided the evidence that metformin treatment has a renal protective effect partly via increased mesangial GLP-1R expression. Our data suggested that regulation of GLP-1R expression could be a promising approach to treat diabetic nephropathy and the novel mechanism of metformin mediated GLP-1R regulation.

  13. Clinical Application of Glucagon-Like Peptide 1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus

    PubMed Central

    Cho, Young Min; Wideman, Rhonda D.

    2013-01-01

    Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L-cells in response to oral nutrient intake and elicits glucose-stimulated insulin secretion while suppressing glucagon secretion. It also slows gastric emptying, which contributes to decreased postprandial glycemic excursions. In the 1990s, chronic subcutaneous infusion of GLP-1 was found to lower blood glucose levels in patients with type 2 diabetes. However, GLP-1's very short half-life, arising from cleavage by the enzyme dipeptidyl peptidase 4 (DPP-4) and glomerular filtration by the kidneys, presented challenges for clinical use. Hence, DPP-4 inhibitors were developed, as well as several GLP-1 analogs engineered to circumvent DPP-4-mediated breakdown and/or rapid renal elimination. Three categories of GLP-1 analogs, are being developed and/or are in clinical use: short-acting, long-acting, and prolonged-acting GLP-1 analogs. Each class has different plasma half-lives, molecular size, and homology to native GLP-1, and consequently different characteristic effects on glucose metabolism. In this article, we review current clinical data derived from each class of GLP-1 analogs, and consider the clinical effects reported for each category in recent head to head comparison studies. Given the relatively brief clinical history of these compounds, we also highlight several important efficacy and safety issues which will require further investigation. PMID:24396690

  14. Glucagon-like peptide-1 receptor is present in pancreatic acinar cells and regulates amylase secretion through cAMP.

    PubMed

    Hou, Yanan; Ernst, Stephen A; Heidenreich, Kaeli; Williams, John A

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is a glucoincretin hormone that can act through its receptor (GLP-1R) on pancreatic β-cells and increase insulin secretion and production. GLP-1R agonists are used clinically to treat type 2 diabetes. GLP-1 may also regulate the exocrine pancreas at multiple levels, including inhibition through the central nervous system, stimulation indirectly through insulin, and stimulation directly on acinar cells. However, it has been unclear whether GLP-1R is present in pancreatic acini and what physiological functions these receptors regulate. In the current study we utilized GLP-1R knockout (KO) mice to study the role of GLP-1R in acinar cells. RNA expression of GLP-1R was detected in acutely isolated pancreatic acini. Acinar cell morphology and expression of digestive enzymes were not affected by loss of GLP-1R. GLP-1 induced amylase secretion in wild-type (WT) acini. In GLP-1R KO mice, this effect was abolished, whereas vasoactive intestinal peptide-induced amylase release in KO acini showed a pattern similar to that in WT acini. GLP-1 stimulated cAMP production and increased protein kinase A-mediated protein phosphorylation in WT acini, and these effects were absent in KO acini. These data show that GLP-1R is present in pancreatic acinar cells and that GLP-1 can regulate secretion through its receptor and cAMP signaling pathway.

  15. Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed.

    PubMed

    King, Klim; Lin, Nai-Pin; Cheng, Yu-Hong; Chen, Gao-Hui; Chein, Rong-Jie

    2015-10-23

    The glucagon-like peptide-1 receptor (GLP-1R) is expressed in many tissues and has been implicated in diverse physiological functions, such as energy homeostasis and cognition. GLP-1 analogs are approved for treatment of type 2 diabetes and are undergoing clinical trials for other disorders, including neurodegenerative diseases. GLP-1 analog therapies maintain chronically high plasma levels of the analog and can lead to loss of spatiotemporal control of GLP-1R activation. To avoid adverse effects associated with current therapies, we characterized positive modulators of GLP-1R signaling. We screened extracts from edible plants using an intracellular cAMP biosensor and GLP-1R endocytosis assays. Ethanol extracts from fenugreek seeds enhanced GLP-1 signaling. These seeds have previously been found to reduce glucose and glycated hemoglobin levels in humans. An active compound (N55) with a new N-linoleoyl-2-amino-γ-butyrolactone structure was purified from fenugreek seeds. N55 promoted GLP-1-dependent cAMP production and GLP-1R endocytosis in a dose-dependent and saturable manner. N55 specifically enhanced GLP-1 potency more than 40-fold, but not that of exendin 4, to stimulate cAMP production. In contrast to the current allosteric modulators that bind to GLP-1R, N55 binds to GLP-1 peptide and facilitates trypsin-mediated GLP-1 inactivation. These findings identify a new class of modulators of GLP-1R signaling and suggest that GLP-1 might be a viable target for drug discovery. Our results also highlight a feasible approach for screening bioactive activity of plant extracts. PMID:26336108

  16. Prediction of the effect on antihyperglycaemic action of sitagliptin by plasma active form glucagon-like peptide-1

    PubMed Central

    Kushiyama, Akifumi; Kikuchi, Takako; Tanaka, Kentaro; Tahara, Tazu; Takao, Toshiko; Onishi, Yukiko; Yoshida, Yoko; Kawazu, Shoji; Iwamoto, Yasuhiko

    2016-01-01

    AIM: To investigate whether active glucagon-like peptide-1 (GLP-1) is a prediction Factor of Effect of sitagliptin on patients with type 2 diabetes mellitus (GLP-1 FEST:UMIN000010645). METHODS: Seventy-six patients with type 2 diabetes, who had insufficient glycemic control [Hemoglobin A1c (HbA1c) ≥ 7%] in spite of treatment with metformin and/or sulfonylurea, were included in the investigation. Patients were divided into three groups by tertiles of fasting plasma active GLP-1 level, before the administration of 50 mg sitagliptin. RESULTS: At baseline, body mass index, serum UA, insulin and HOMA-IR were higher in the high active GLP-1 group than in the other two groups. The high active GLP-1 group did not show any decline of HbA1c (7.6% ± 1.4% to 7.5% ± 1.5%), whereas the middle and low groups indicated significant decline of HbA1c (7.4 ± 0.7 to 6.8 ± 0.6 and 7.4 ± 1.2 to 6.9 ± 1.3, respectively) during six months. Only the low and middle groups showed a significant increment of active GLP-1, C-peptide level, a decreased log and proinsulin/insulin ratio after administration. In logistic analysis, the low or middle group is a significant explanatory variable for an HbA1c decrease of ≥ 0.5%, and its odds ratio is 4.5 (1.40-17.6) (P = 0.01) against the high active GLP-1 group. This remains independent when adjusted for HbA1c level before administration, patients’ medical history, medications, insulin secretion and insulin resistance. CONCLUSION: Plasma fasting active GLP-1 is an independent predictive marker for the efficacy of dipeptidyl peptidase 4 inhibitor sitagliptin. PMID:27326345

  17. Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment

    PubMed Central

    Dong, Zhenhua; Chai, Weidong; Wang, Wenhui; Zhao, Lina; Fu, Zhuo; Cao, Wenhong

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) causes vasodilation and increases muscle glucose uptake independent of insulin. Recently, we have shown that GLP-1 recruits muscle microvasculature and increases muscle glucose use via a nitric oxide (NO)-dependent mechanism. Protein kinase A (PKA) is a major signaling intermediate downstream of GLP-1 receptors. To examine whether PKA mediates GLP-1's microvascular action in muscle, GLP-1 was infused to overnight-fasted male rats for 120 min in the presence or absence of H89, a PKA inhibitor. Hindleg muscle microvascular recruitment and glucose use were determined. GLP-1 infusion acutely increased muscle microvascular blood volume within 30 min without altering microvascular blood flow velocity or blood pressure. This effect persisted throughout the 120-min infusion period, leading to a significant increase in muscle microvascular blood flow. These changes were paralleled with an approximately twofold increase in plasma NO levels and hindleg glucose extraction. Systemic infusion of H89 completely blocked GLP-1-mediated muscle microvascular recruitment and increases in NO production and muscle glucose extraction. In cultured endothelial cells, GLP-1 acutely increased PKA activity and stimulated endothelial NO synthase phosphorylation at Ser1177 and NO production. PKA inhibition abolished these effects. In ex vivo studies, perfusion of the distal saphenous artery with GLP-1 induced significant vasorelaxation that was also abolished by pretreatment of the vessels with PKA inhibitor H89. We conclude that GLP-1 recruits muscle microvasculature by expanding microvascular volume and increases glucose extraction in muscle via a PKA/NO-dependent pathway in the vascular endothelium. This may contribute to postprandial glycemic control and complication prevention in diabetes. PMID:23193054

  18. Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism.

    PubMed

    Sassoon, Daniel J; Goodwill, Adam G; Noblet, Jillian N; Conteh, Abass M; Herring, B Paul; McClintick, Jeanette N; Tune, Johnathan D; Mather, Kieren J

    2016-07-01

    This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miRNA) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-minutes coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect the blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca(2+) binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion. PMID:27234258

  19. Dietary Mannoheptulose Increases Fasting Serum Glucagon Like Peptide-1 and Post-Prandial Serum Ghrelin Concentrations in Adult Beagle Dogs

    PubMed Central

    McKnight, Leslie L.; Eyre, Ryan; Gooding, Margaret A.; Davenport, Gary M.; Shoveller, Anna Kate

    2015-01-01

    Simple Summary There is increased interest in the use of nutraceuticals for weight management in companion animals. A nutraceutical can broadly be considered a food (or a part of) that provides a health benefit. Mannoheptulose (MH), a sugar found in avocados, is being investigated as a nutraceutical for dogs. In this study, dogs fed a diet containing MH had increased concentrations of blood biomarkers related to energy intake. In addition, dogs fed MH were less physically active than dogs fed a control diet. These findings suggest that dietary MH has the ability to alter energy intake and lower daily energy expenditure. Abstract There is a growing interest in the use of nutraceuticals for weight management in companion animals. The purpose of this study was to determine the effects of mannoheptulose (MH), a sugar in avocados that inhibits glycolysis, on energy metabolism in adult Beagle dogs. The study was a double-blind, randomized controlled trial where dogs were allocated to a control (CON, n = 10, 10.1 ± 0.4 kg) or MH containing diet (168 mg/kg, n = 10, 10.3 ± 0.4 kg). Blood was collected after an overnight fast and 1 h post-feeding (week 12) to determine serum satiety related hormones and biochemistry. Resting and post-prandial energy expenditure and respiratory quotient were determined by indirect calorimetry (weeks 4 and 8). Physical activity was measured using an accelerometer (weeks 3, 7, 11). Body composition was assessed using dual X-ray absorptiometry (week 12). MH significantly (p < 0.05) increased fasting serum glucagon-like peptide-1 and post-prandial serum ghrelin. MH tended (p < 0.1) to increase fasting serum gastric inhibitory peptide and decrease physical activity. Together, these findings suggest that dietary MH has the ability to promote satiation and lowers daily energy expenditure. PMID:26479244

  20. Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control?

    PubMed Central

    Grieve, David J; Cassidy, Roslyn S; Green, Brian D

    2009-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD. PMID:19681866

  1. Crosstalk between diabetes and brain: glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration.

    PubMed

    Duarte, A I; Candeias, E; Correia, S C; Santos, R X; Carvalho, C; Cardoso, S; Plácido, A; Santos, M S; Oliveira, C R; Moreira, P I

    2013-04-01

    According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.

  2. Endogenous glucagon-like peptide-1 reduces drinking behavior and is differentially engaged by water and food intakes in rats.

    PubMed

    McKay, Naomi J; Galante, Daniela L; Daniels, Derek

    2014-12-01

    Glucagon-like peptide-1 (GLP-1) is produced in the ileum and the nucleus of the solitary tract. It is well known that GLP-1 controls food intake, but there is a growing literature indicating that GLP-1 also is involved in fluid intake. It is not known, however, if the observed effects are pharmacological or if endogenous GLP-1 and its receptor contribute to physiological fluid intake control. Accordingly, we blocked endogenous GLP-1 by application of a receptor antagonist and measured subsequent drinking. Furthermore, we measured changes in GLP-1-associated gene expression after water intake, and compared the effects of fluid intake to those caused by food intake. Rats injected with the antagonist exendin-9 (Ex-9) drank more fluid in response to either subcutaneous hypertonic saline or water deprivation with partial rehydration than did vehicle-treated rats. Analysis of licking behavior showed that Ex-9 increased fluid intake by increasing the number of licking bursts, without having an effect on the number of licks per burst, suggesting that endogenous GLP-1 suppresses fluid intake by influencing satiety. Subsequent experiments showed that water intake had a selective effect on central GLP-1-related gene expression, unlike food intake, which affected both central and peripheral GLP-1. Although water and food intakes both affected central GLP-1-relevant gene expression, there were notable differences in the timing of the effect. These results show a novel role of the endogenous GLP-1 system in fluid intake, and indicate that elements of the GLP-1 system can be engaged separately by different forms of ingestive behavior.

  3. Enzymatic mono-pegylation of glucagon-like peptide 1 towards long lasting treatment of type 2 diabetes

    PubMed Central

    Selis, Fabio; Schrepfer, Rodolfo; Sanna, Riccardo; Scaramuzza, Silvia; Tonon, Giancarlo; Dedoni, Simona; Onali, Pierluigi; Orsini, Gaetano; Genovese, Stefano

    2012-01-01

    Human glucagon-like peptide-1 (GLP-1) is a physiological gastrointestinal peptide with glucose-dependent insulinotropic effects which is therefore considered an interesting antidiabetic agent. However, after in vivo administration, exogenous GLP-1 does not exert its physiological action due to the combination of rapid proteolytic degradation by ubiquitous dipeptidyldipeptidase IV (DPP IV) enzyme and renal clearance resulting in an extremely short circulating half-life. In this work we describe the conjugation of GLP-1-(7-36)-amide derivatives with polyethylene glycol (PEG) by enzymatic site-specific transglutamination reaction as an approach to reduce both the proteolysis and the renal clearance rates. The compound GLP-1-(7-36)-amide-Q23-PEG 20 kDa monopegylated on the single glutamine residue naturally present in position 23 maintained the ability to activate the GLP-1 receptor expressed in the rat β-cell line RIN-m5F with nanomolar potency along with an increased in vitro resistance to DDP IV and a circulating half-life of about 12 h after subcutaneous administration in rats. These properties enabled GLP-(7-36)-amide-Q23-PEG 20 kDa to exert a glucose-stabilizing effect for a period as long as 8 h, as demonstrated by a single subcutaneous injection to diabetic mice concomitantly challenged with an oral glucose load. The results reported in this work indicate that GLP-(7-36)-amide-Q23-PEG 20 kDa could be a lead compound for the development of long-lasting anti-diabetic agents useful in the treatment of type 2 diabetes affected patients. PMID:25755995

  4. Novel Glucagon-Like Peptide-1 Analog Delivered Orally Reduces Postprandial Glucose Excursions in Porcine and Canine Models

    PubMed Central

    Eldor, Roy; Kidron, Miriam; Greenberg-Shushlav, Yael; Arbit, Ehud

    2010-01-01

    Background Glucagon-like peptide-1 (GLP-1) and its analogs are associated with a gamut of physiological processes, including induction of insulin release, support of normoglycemia, β-cell function preservation, improved lipid profiles, and increased insulin sensitivity. Thus, GLP-1 harbors significant therapeutic potential for regulating type 2 diabetes mellitus, where its physiological impact is markedly impaired. To date, GLP-1 analogs are only available as injectable dosage forms, and its oral delivery is expected to provide physiological portal/peripheral concentration ratios while fostering patient compliance and adherence. Methods Healthy, fasting, enterically cannulated pigs and beagle canines were administered a single dose of the exenatide-based ORMD-0901 formulation 30 min before oral glucose challenges. Blood samples were collected every 15 min for evaluation of ORMD-0901 safety and efficacy in regulating postchallenge glucose excursions. Results Enterically delivered ORMD-0901 was well tolerated by all animals. ORMD-0901 formulations RG3 and AG2 led to reduced glucose excursions in pigs when delivered prior to a 5 g/kg glucose challenge, where area under the curve (AUC)0–120 values were up to 43% lower than in control sessions. All canines challenged with a glucose load with no prior exposure to exenatide, demonstrated higher AUC0–150 values than in their exenatide-treated sessions. Subcutaneous exenatide delivery amounted to a 51% reduction in mean glucose AUC0–150, while formulations AG4 and AG3 prompted 43% and 29% reductions, respectively. Conclusions When delivered enterically, GLP-1 (ORMD-0901) is absorbed from the canine and porcine gastrointestinal tracts and retains its biological activity. Further development of this drug class in an oral dosage form is expected to enhance diabetes control and patient compliance. PMID:21129350

  5. Glucagon-like peptide-1 improves beta-cell antioxidant capacity via extracellular regulated kinases pathway and Nrf2 translocation.

    PubMed

    Fernández-Millán, E; Martín, M A; Goya, L; Lizárraga-Mollinedo, E; Escrivá, F; Ramos, S; Álvarez, C

    2016-06-01

    Oxidative stress plays an important role in the development of beta-cell dysfunction and insulin resistance, two major pathophysiological abnormalities of type 2 diabetes. Expression levels of antioxidant enzymes in beta cells are very low, rendering them more susceptible to damage caused by reactive oxygen species (ROS). Although the antioxidant effects of glucagon-like peptide-1 (GLP-1) and its analogs have been previously reported, the exact mechanisms involved are still unclear. In this study, we demonstrated that GLP-1 was able to effectively inhibit oxidative stress and cell death of INS-1E beta cells induced by the pro-oxidant tert-butyl hydroperoxide (tert-BOOH). Incubation with GLP-1 enhanced cellular levels of glutathione and the activity of its related enzymes, glutathione-peroxidase (GPx) and -reductase (GR) in beta cells. However, inhibition of ERK, but not of the PI3K/AKT pathway abolished, at least in part, the antioxidant effect of GLP-1. Moreover, ERK activation seems to be protein kinase A (PKA)-dependent because inhibition of PKA with H-89 was sufficient to block the GLP-1-derived protective effect on beta cells. GLP-1 likewise increased the synthesis of GR and favored the translocation of the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Glucose-stimulated insulin secretion was also preserved in beta-cells challenged with tert-BOOH but pre-treated with GLP-1, probably through the down-regulation of the mitochondrial uncoupling-protein2 (UCP2). Thus, our results provide additional mechanisms of action of GLP-1 to prevent oxidative damage in beta cells through the modulation of signaling pathways involved in antioxidant enzyme regulation. PMID:26968794

  6. Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed*

    PubMed Central

    King, Klim; Lin, Nai-Pin; Cheng, Yu-Hong; Chen, Gao-Hui; Chein, Rong-Jie

    2015-01-01

    The glucagon-like peptide-1 receptor (GLP-1R) is expressed in many tissues and has been implicated in diverse physiological functions, such as energy homeostasis and cognition. GLP-1 analogs are approved for treatment of type 2 diabetes and are undergoing clinical trials for other disorders, including neurodegenerative diseases. GLP-1 analog therapies maintain chronically high plasma levels of the analog and can lead to loss of spatiotemporal control of GLP-1R activation. To avoid adverse effects associated with current therapies, we characterized positive modulators of GLP-1R signaling. We screened extracts from edible plants using an intracellular cAMP biosensor and GLP-1R endocytosis assays. Ethanol extracts from fenugreek seeds enhanced GLP-1 signaling. These seeds have previously been found to reduce glucose and glycated hemoglobin levels in humans. An active compound (N55) with a new N-linoleoyl-2-amino-γ-butyrolactone structure was purified from fenugreek seeds. N55 promoted GLP-1-dependent cAMP production and GLP-1R endocytosis in a dose-dependent and saturable manner. N55 specifically enhanced GLP-1 potency more than 40-fold, but not that of exendin 4, to stimulate cAMP production. In contrast to the current allosteric modulators that bind to GLP-1R, N55 binds to GLP-1 peptide and facilitates trypsin-mediated GLP-1 inactivation. These findings identify a new class of modulators of GLP-1R signaling and suggest that GLP-1 might be a viable target for drug discovery. Our results also highlight a feasible approach for screening bioactive activity of plant extracts. PMID:26336108

  7. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders

    PubMed Central

    Salcedo, Isidro; Tweedie, David; Li, Yazhou; Greig, Nigel H

    2012-01-01

    Like type-2 diabetes mellitus (T2DM), neurodegenerative disorders and stroke are an ever increasing, health, social and economic burden for developed Westernized countries. Age is an important risk factor in all of these; due to the rapidly increasing rise in the elderly population T2DM and neurodegenerative disorders, both represent a looming threat to healthcare systems. Whereas several efficacious drugs are currently available to ameliorate T2DM, effective treatments to counteract pathogenic processes of neurodegenerative disorders are lacking and represent a major scientific and pharmaceutical challenge. Epidemiological data indicate an association between T2DM and most major neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Likewise, there is an association between T2DM and stroke incidence. Studies have revealed that common pathophysiological features, including oxidative stress, insulin resistance, abnormal protein processing and cognitive decline, occur across these. Based on the presence of shared mechanisms and signalling pathways in these seemingly distinct diseases, one could hypothesize that an effective treatment for one disorder could prove beneficial in the others. Glucagon-like peptide-1 (GLP-1)-based anti-diabetic drugs have drawn particular attention as an effective new strategy to not only regulate blood glucose but also to reduce apoptotic cell death of pancreatic beta cells in T2DM. Evidence supports a neurotrophic and neuroprotective role of GLP-1 receptor (R) stimulation in an increasing array of cellular and animal neurodegeneration models as well as in neurogenesis. Herein, we review the physiological role of GLP-1 in the nervous system, focused towards the potential benefit of GLP-1R stimulation as an immediately translatable treatment strategy for acute and chronic neurological disorders. PMID:22519295

  8. The effect of glucagon-like peptide-1 in the management of diabetes mellitus: cellular and molecular mechanisms.

    PubMed

    Lotfy, Mohamed; Singh, Jaipaul; Rashed, Hameed; Tariq, Saeed; Zilahi, Erika; Adeghate, Ernest

    2014-11-01

    Incretins, such as glucagon-like peptide-1 (GLP)-1, have been shown to elevate plasma insulin concentration. The purpose of this study is to investigate the cellular and molecular basis of the beneficial effects of GLP-1. Normal and diabetic male Wistar rats were treated with GLP-1 (50 ng/kg body weight) for 10 weeks. At the end of the experiment, pancreatic tissues were taken for immunohistochemistry, immunoelectron microscopy and real-time polymerase chain reaction studies. Samples of blood were retrieved from the animals for the measurement of enzymes and insulin. The results show that treatment of diabetic rats with GLP-1 caused significant (P < 0.05) reduction in body weight gain and blood glucose level. GLP-1 (10(-12)-10(-6) M) induced significant (P < 0.01) dose-dependent increases in insulin release from the pancreas of normal and diabetic rats compared to basal. Diabetes-induced abnormal liver (aspartate aminotransferase and alanine aminotransferase) and kidney (blood urea nitrogen and uric acid) parameters were corrected in GLP-1-treated rats compared to controls. GLP-1 treatment induced significant (P < 0.05) elevation in the expression of pancreatic duodenal homeobox-1, heat shock protein-70, glutathione peroxidase, insulin receptor and GLP-1-receptor genes in diabetic animals compared to controls. GLP-1 is present in pancreatic beta cells and significantly (P < 0.05) increased the number of insulin-, glutathione reductase- and catalase-immunoreactive islet cells. The results of this study show that GLP-1 is co-localized with insulin and seems to exert its beneficial effects by increasing cellular concentrations of endogenous antioxidant genes and other genes involved in the maintenance of pancreatic beta cell structure and function.

  9. 64Cu Labeled Sarcophagine Exendin-4 for MicroPET Imaging of Glucagon like Peptide-1 Receptor Expression

    PubMed Central

    Wu, Zhanhong; Liu, Shuanglong; Nair, Indu; Omori, Keiko; Scott, Stephen; Todorov, Ivan; Shively, John E.; Conti, Peter S.; Li, Zibo; Kandeel, Fouad

    2014-01-01

    The Glucagon-like peptide 1 receptor (GLP-1R) has become an important target for imaging due to its elevated expression profile in pancreatic islets, insulinoma, and the cardiovascular system. Because native GLP-1 is degraded rapidly by dipeptidyl peptidase-IV (DPP-IV), several studies have conjugated different chelators to a more stable analog of GLP-1 (such as exendin-4) as PET or SPECT imaging agents with various advantages and disadvantages. Based on the recently developed Sarcophagin chelator, here, we describe the construction of GLP-1R targeted PET probes containing monomeric and dimeric exendin-4 subunit. The in vitro binding affinity of BarMalSar-exendin-4 and Mal2Sar-(exendin-4)2 was evaluated in INS-1 cells, which over-express GLP-1R. Mal2Sar-(exendin-4)2 demonstrated around 3 times higher binding affinity compared with BaMalSar-exendin-4. After 64Cu labeling, microPET imaging of 64Cu-BaMalSar-exendin-4 and 64Cu-Mal2Sar-(exendin-4)2 were performed on subcutaneous INS-1 tumors, which were clearly visualized with both probes. The tumor uptake of 64Cu-Mal2Sar-(exendin-4)2 was significantly higher than that of 64Cu-BaMaSarl-exendin-4, which could be caused by polyvalency effect. The receptor specificity of these probes was confirmed by effective blocking of the uptake in both tumor and normal positive organs with 20-fold excess of unlabeled exendin-4. In conclusion, sarcophagine cage conjugated exendin-4 demonstrated persistent and specific uptake in INS-1 insulinoma model. Dimerization of exendin-4 could successfully lead to increased tumor uptake in vivo. Both 64Cu-BaMalSar-exendin-4 and 64Cu-Mal2Sar-(exendin-4)2 hold a great potential for GLP-1R targeted imaging. PMID:24955138

  10. Dipeptidylpeptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) receptor agonists: yes.

    PubMed

    Scheen, André J

    2012-03-01

    The pharmacological treatment of type 2 diabetes (T2DM) is becoming increasingly complex, especially since the availability of incretin-based therapies. Compared with other glucose-lowering strategies, these novel drugs offer some advantages such as an absence of weight gain and a negligible risk of hypoglycaemia and, possibly, better cardiovascular and β-cell protection. The physician has now multiple choices to manage his/her patient after secondary failure of metformin, and the question whether it is preferable to add an oral dipeptidylpeptidase-4 (DPP-4) inhibitor (gliptin) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist will emerge. Obviously, DPP-4 inhibitors offer several advantages compared with GLP-1 receptor agonists, especially regarding easiness of use, tolerance profile and cost. However, because they can only increase endogenous GLP-1 concentrations to physiological (rather than pharmacological) levels, they are less potent to improve glucose control, promote weight reduction ("weight neutrality") and reduce blood pressure compared to GLP-1 receptor agonists. Of note, none of the two classes have proven long-term safety and positive impact on diabetic complications yet. The role of DPP-4 inhibitors and GLP-1 receptor agonists in the therapeutic armamentarium of T2DM is rapidly evolving, but their respective potential strengths and weaknesses should be better defined in long-term head-to-head comparative controlled trials. Instead of trying to answer the question whether DPP-4 inhibitors are favourable to GLP-1 receptor agonists (or vice versa), it is probably more clinically relevant to look at which T2DM patient will benefit more from one or the other therapy considering all his/her individual clinical characteristics ("personalized medicine").

  11. Resistant maltodextrin promotes fasting glucagon-like peptide-1 secretion and production together with glucose tolerance in rats.

    PubMed

    Hira, Tohru; Ikee, Asuka; Kishimoto, Yuka; Kanahori, Sumiko; Hara, Hiroshi

    2015-07-14

    Glucagon-like peptide-1 (GLP-1), which is produced and released from enteroendocrine L cells, plays pivotal roles in postprandial glycaemia. The ingestion of resistant maltodextrin (RMD), a water-soluble non-digestible saccharide, improves the glycaemic response. In the present study, we examined whether the continuous feeding of RMD to rats affected GLP-1 levels and glycaemic control. Male Sprague-Dawley rats (6 weeks of age) were fed an American Institute of Nutrition (AIN)-93G-based diet containing either cellulose (5 %) as a control, RMD (2.5 or 5 %), or fructo-oligosaccharides (FOS, 2.5 or 5 %) for 7 weeks. During the test period, an intraperitoneal glucose tolerance test (IPGTT) was performed after 6 weeks. Fasting GLP-1 levels were significantly higher in the 5 % RMD group than in the control group after 6 weeks. The IPGTT results showed that the glycaemic response was lower in the 5 % RMD group than in the control group. Lower caecal pH, higher caecal tissue and content weights were observed in the RMD and FOS groups. Proglucagon mRNA levels were increased in the caecum and colon of both RMD and FOS groups, whereas caecal GLP-1 content was increased in the 5 % RMD group. In addition, a 1 h RMD exposure induced GLP-1 secretion in an enteroendocrine L-cell model, and single oral administration of RMD increased plasma GLP-1 levels in conscious rats. The present study demonstrates that continuous ingestion of RMD increased GLP-1 secretion and production in normal rats, which could be stimulated by its direct and indirect (enhanced gut fermentation) effects on GLP-1-producing cells, and contribute to improving glucose tolerance.

  12. Neural effects of gut- and brain-derived glucagon-like peptide-1 and its receptor agonist.

    PubMed

    Katsurada, Kenichi; Yada, Toshihiko

    2016-04-01

    Glucagon-like peptide-1 (GLP-1) is derived from both the enteroendocrine L cells and preproglucagon-expressing neurons in the nucleus tractus solitarius (NTS) of the brain stem. As GLP-1 is cleaved by dipeptidyl peptidase-4 yielding a half-life of less than 2 min, it is plausible that the gut-derived GLP-1, released postprandially, exerts its effects on the brain mainly by interacting with vagal afferent neurons located at the intestinal or hepatic portal area. GLP-1 neurons in the NTS widely project in the central nervous system and act as a neurotransmitter. One of the physiological roles of brain-derived GLP-1 is restriction of feeding. GLP-1 receptor agonists have recently been used to treat type 2 diabetic patients, and have been shown to exhibit pleiotropic effects beyond incretin action, which involve brain functions. GLP-1 receptor agonist administered in the periphery is stable because of its resistance to dipeptidyl peptidase-4, and is highly likely to act on the brain by passing through the blood-brain barrier (BBB), as well as interacting with vagal afferent nerves. Central actions of GLP-1 have various roles including regulation of feeding, weight, glucose and lipid metabolism, cardiovascular functions, cognitive functions, and stress and emotional responses. In the present review, we focus on the source of GLP-1 and the pathway by which peripheral GLP-1 informs the brain, and then discuss recent findings on the central effects of GLP-1 and GLP-1 receptor agonists. PMID:27186358

  13. Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist Stimulates Insulin Secretion in Rodents and From Human Islets

    PubMed Central

    Sloop, Kyle W.; Willard, Francis S.; Brenner, Martin B.; Ficorilli, James; Valasek, Kathleen; Showalter, Aaron D.; Farb, Thomas B.; Cao, Julia X.C.; Cox, Amy L.; Michael, M. Dodson; Gutierrez Sanfeliciano, Sonia Maria; Tebbe, Mark J.; Coghlan, Michael J.

    2010-01-01

    OBJECTIVE The clinical effectiveness of parenterally-administered glucagon-like peptide-1 (GLP-1) mimetics to improve glucose control in patients suffering from type 2 diabetes strongly supports discovery pursuits aimed at identifying and developing orally active, small molecule GLP-1 receptor agonists. The purpose of these studies was to identify and characterize novel nonpeptide agonists of the GLP-1 receptor. RESEARCH DESIGN AND METHODS Screening using cells expressing the GLP-1 receptor and insulin secretion assays with rodent and human islets were used to identify novel molecules. The intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp characterized the insulinotropic effects of compounds in vivo. RESULTS Novel low molecular weight pyrimidine-based compounds that activate the GLP-1 receptor and stimulate glucose-dependent insulin secretion are described. These molecules induce GLP-1 receptor-mediated cAMP signaling in HEK293 cells expressing the GLP-1 receptor and increase insulin secretion from rodent islets in a dose-dependent manner. The compounds activate GLP-1 receptor signaling, both alone or in an additive fashion when combined with the endogenous GLP-1 peptide; however, these agonists do not compete with radiolabeled GLP-1 in receptor-binding assays. In vivo studies using the IVGTT and the hyperglycemic clamp in Sprague Dawley rats demonstrate increased insulin secretion in compound-treated animals. Further, perifusion assays with human islets isolated from a donor with type 2 diabetes show near-normalization of insulin secretion upon compound treatment. CONCLUSIONS These studies characterize the insulinotropic effects of an early-stage, small molecule GLP-1 receptor agonist and provide compelling evidence to support pharmaceutical optimization. PMID:20823098

  14. Glucagon-like peptide-1 improves beta-cell antioxidant capacity via extracellular regulated kinases pathway and Nrf2 translocation.

    PubMed

    Fernández-Millán, E; Martín, M A; Goya, L; Lizárraga-Mollinedo, E; Escrivá, F; Ramos, S; Álvarez, C

    2016-06-01

    Oxidative stress plays an important role in the development of beta-cell dysfunction and insulin resistance, two major pathophysiological abnormalities of type 2 diabetes. Expression levels of antioxidant enzymes in beta cells are very low, rendering them more susceptible to damage caused by reactive oxygen species (ROS). Although the antioxidant effects of glucagon-like peptide-1 (GLP-1) and its analogs have been previously reported, the exact mechanisms involved are still unclear. In this study, we demonstrated that GLP-1 was able to effectively inhibit oxidative stress and cell death of INS-1E beta cells induced by the pro-oxidant tert-butyl hydroperoxide (tert-BOOH). Incubation with GLP-1 enhanced cellular levels of glutathione and the activity of its related enzymes, glutathione-peroxidase (GPx) and -reductase (GR) in beta cells. However, inhibition of ERK, but not of the PI3K/AKT pathway abolished, at least in part, the antioxidant effect of GLP-1. Moreover, ERK activation seems to be protein kinase A (PKA)-dependent because inhibition of PKA with H-89 was sufficient to block the GLP-1-derived protective effect on beta cells. GLP-1 likewise increased the synthesis of GR and favored the translocation of the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Glucose-stimulated insulin secretion was also preserved in beta-cells challenged with tert-BOOH but pre-treated with GLP-1, probably through the down-regulation of the mitochondrial uncoupling-protein2 (UCP2). Thus, our results provide additional mechanisms of action of GLP-1 to prevent oxidative damage in beta cells through the modulation of signaling pathways involved in antioxidant enzyme regulation.

  15. Molecular Basis of Glucagon-like Peptide 1 Docking to Its Intact Receptor Studied with Carboxyl-terminal Photolabile Probes*

    PubMed Central

    Chen, Quan; Pinon, Delia I.; Miller, Laurence J.; Dong, Maoqing

    2009-01-01

    The glucagon-like peptide 1 (GLP1) receptor is a member of Family B G protein-coupled receptors and represents an important drug target for type 2 diabetes. Despite recent solution of the structure of the amino-terminal domain of this receptor and that of several close family members, understanding of the molecular basis of natural ligand GLP1 binding to its intact receptor remains limited. The goal of this study was to explore spatial approximations between specific receptor residues within the carboxyl terminus of GLP1 and its receptor as normally docked. Therefore, we developed and characterized two high affinity, full-agonist photolabile GLP1 probes having sites for covalent attachment in positions 24 and 35. Both probes labeled the receptor specifically and saturably. Subsequent peptide mapping using chemical and proteinase cleavages of purified wild-type and mutant GLP1 receptor identified that the Arg131–Lys136 segment at the juxtamembrane region of the receptor amino terminus contained the site of labeling for the position 24 probe, and the specific receptor residue labeled by this probe was identified as Glu133 by radiochemical sequencing. Similarly, nearby residue Glu125 within the same region of the receptor amino-terminal domain was identified as the site of labeling by the position 35 probe. These data represent the first direct demonstration of spatial approximation between GLP1 and its intact receptor as docked, providing two important constraints for the modeling of this interaction. This should expand our understanding of the molecular basis of natural agonist ligand binding to the GLP1 receptor and may be relevant to other family members. PMID:19815559

  16. Efficacy and tolerability of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus

    PubMed Central

    McCarty, Delilah J.

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) has been evaluated for use in the treatment of type 2 diabetes mellitus (T2DM) due to its role in glucose regulation. Four GLP-1 receptor agonists (RAs) are currently indicated for T2DM in the USA. Exenatide and liraglutide are short-acting and require twice-daily and daily dosing, respectively. Two longer acting agents, exenatide long-acting release (LAR) and albiglutide, were formulated to allow for once-weekly dosing. All four GLP-1 RAs have demonstrated reductions in hemoglobin A1c, fasting blood glucose, and body weight both as monotherapy and in combination with first- and second-line diabetes agents including metformin, sulfonylureas, thiazolidinediones, and insulin. Greater glycemic control was seen with liraglutide compared with the other GLP-1 treatment options; however, the two long-acting agents were superior to exenatide twice daily. All agents were well tolerated with most adverse events being mild or moderate in nature. The most common adverse event was transient nausea which typically resolved 4–8 weeks after treatment initiation. Long-acting agents had lower rates of nausea but an increased incidence of injection site reactions. Trials have suggested GLP-1 RAs may improve cardiovascular risk factors including blood pressure, lipid parameters and inflammatory markers. Future trials are needed to confirm the clinical outcomes of these agents. Overall, GLP-1 RAs will provide benefit for patients with T2DM intolerable to or not reaching glycemic goals with first-line agents, especially in patients in need of weight loss. PMID:25678952

  17. Glucagon-like peptide-1 modulates neurally evoked mucosal chloride secretion in guinea pig small intestine in vitro.

    PubMed

    Baldassano, Sara; Wang, Guo-Du; Mulè, Flavia; Wood, Jackie D

    2012-02-01

    Glucagon-like peptide-1 (GLP-1) acts at the G protein-coupled receptor, GLP-1R, to stimulate secretion of insulin and to inhibit secretion of glucagon and gastric acid. Involvement in mucosal secretory physiology has received negligible attention. We aimed to study involvement of GLP-1 in mucosal chloride secretion in the small intestine. Ussing chamber methods, in concert with transmural electrical field stimulation (EFS), were used to study actions on neurogenic chloride secretion. ELISA was used to study GLP-1R effects on neural release of acetylcholine (ACh). Intramural localization of GLP-1R was assessed with immunohistochemistry. Application of GLP-1 to serosal or mucosal sides of flat-sheet preparations in Ussing chambers did not change baseline short-circuit current (I(sc)), which served as a marker for chloride secretion. Transmural EFS evoked neurally mediated biphasic increases in I(sc) that had an initial spike-like rising phase followed by a sustained plateau-like phase. Blockade of the EFS-evoked responses by tetrodotoxin indicated that the responses were neurally mediated. Application of GLP-1 reduced the EFS-evoked biphasic responses in a concentration-dependent manner. The GLP-1 receptor antagonist exendin-(9-39) suppressed this action of GLP-1. The GLP-1 inhibitory action on EFS-evoked responses persisted in the presence of nicotinic or vasoactive intestinal peptide receptor antagonists but not in the presence of a muscarinic receptor antagonist. GLP-1 significantly reduced EFS-evoked ACh release. In the submucosal plexus, GLP-1R immunoreactivity (IR) was expressed by choline acetyltransferase-IR neurons, neuropeptide Y-IR neurons, somatostatin-IR neurons, and vasoactive intestinal peptide-IR neurons. Our results suggest that GLP-1R is expressed in guinea pig submucosal neurons and that its activation leads to a decrease in neurally evoked chloride secretion by suppressing release of ACh at neuroepithelial junctions in the enteric neural networks

  18. β-Cell Glucagon-Like Peptide-1 Receptor Contributes to Improved Glucose Tolerance After Vertical Sleeve Gastrectomy.

    PubMed

    Garibay, Darline; McGavigan, Anne K; Lee, Seon A; Ficorilli, James V; Cox, Amy L; Michael, M Dodson; Sloop, Kyle W; Cummings, Bethany P

    2016-09-01

    Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible for this remain incompletely defined. Glucagon-like peptide-1 (GLP-1) is a gut hormone that contributes to the maintenance of glucose homeostasis and is elevated after VSG. VSG-induced increases in postprandial GLP-1 secretion have been proposed to contribute to the glucoregulatory benefits of VSG; however, previous work has been equivocal. In order to test the contribution of enhanced β-cell GLP-1 receptor (GLP-1R) signaling we used a β-cell-specific tamoxifen-inducible GLP-1R knockout mouse model. Male β-cell-specific Glp-1r(β-cell+/+) wild type (WT) and Glp-1r(β-cell-/-) knockout (KO) littermates were placed on a high-fat diet for 6 weeks and then switched to high-fat diet supplemented with tamoxifen for the rest of the study. Mice underwent sham or VSG surgery after 2 weeks of tamoxifen diet and were fed ad libitum postoperatively. Mice underwent oral glucose tolerance testing at 3 weeks and were euthanized at 6 weeks after surgery. VSG reduced body weight and food intake independent of genotype. However, glucose tolerance was only improved in VSG WT compared with sham WT, whereas VSG KO had impaired glucose tolerance relative to VSG WT. Augmentation of glucose-stimulated insulin secretion during the oral glucose tolerance test was blunted in VSG KO compared with VSG WT. Therefore, our data suggest that enhanced β-cell GLP-1R signaling contributes to improved glucose regulation after VSG by promoting increased glucose-stimulated insulin secretion. PMID:27501183

  19. Evidence for glucagon-like peptide-1 receptor signaling to activate ATP-sensitive potassium channels in pancreatic beta cells.

    PubMed

    Kwon, Hye-Jung; Park, Hyun-Sun; Park, Sung-Hee; Park, Jae-Hyung; Shin, Su-Kyung; Song, Seung Eun; Hwang, Meeyul; Cho, Ho-Chan; Song, Dae-Kyu

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic beta cells. GLP-1 has been shown to confer glucose-insensitive beta cells with glucose sensitivity by modulation of the activity of the ATP-sensitive potassium (KATP) channel. The channel closing effect of GLP-1, interacting with corresponding G-protein-coupled receptors, has been well established; however, to our knowledge, no study has shown whether GLP-1 directly induces activation of beta-cell KATP channels. Here, we aimed to evaluate whether the activation of beta-cell KATP channels by GLP-1 exists and affects intracellular Ca(2+) levels ([Ca(2+)]i). KATP channel activity was measured in isolated rat pancreatic beta cells by whole-cell perforated patch-clamp recordings with a diazoxide-containing pipette solution. Changes in [Ca(2+)]i and the subcellular localization of KATP channels were observed using the calcium-sensitive dye fura-4/AM and anti-Kir6.2 antibodies in INS-1 beta cells, respectively. To eliminate the well-known inhibitory effects of GLP-1 on KATP channel activity, channels were fully inhibited by pretreatment with methyl pyruvate and epigallocatechin-3-gallate. In the pretreated beta cells, GLP-1 and exendin-4 promptly activated the channels, reducing [Ca(2+)]i. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 blocked the effects of GLP-1 on channel activity. Moreover, phosphatidylinositol-3,4,5-trisphosphate mimicked the effects of GLP-1. These results suggested that beta-cell GLP-1 receptor signaling involved activation of KATP channels via a PI3K-dependent pathway. This alternative mechanism of GLP-1 function may act as a negative feedback pathway, modulating the glucose-dependent GLP-1 inhibition on KATP channel activity. PMID:26655814

  20. Importance of Large Intestine in Regulating Bile Acids and Glucagon-Like Peptide-1 in Germ-Free Mice.

    PubMed

    Selwyn, Felcy Pavithra; Csanaky, Iván L; Zhang, Youcai; Klaassen, Curtis D

    2015-10-01

    It is known that 1) elevated serum bile acids (BAs) are associated with decreased body weight, 2) elevated glucagon-like peptide-1 (GLP-1) levels can decrease body weight, and 3) germ-free (GF) mice are resistant to diet-induced obesity. The purpose of this study was to test the hypothesis that a lack of intestinal microbiota results in more BAs in the body, resulting in increased BA-mediated transmembrane G protein-coupled receptor 5 (TGR5) signaling and increased serum GLP-1 as a mechanism of resistance of GF mice to diet-induced obesity. GF mice had 2- to 4-fold increased total BAs in the serum, liver, bile, and ileum. Fecal excretion of BAs was 63% less in GF mice. GF mice had decreased secondary BAs and increased taurine-conjugated BAs, as anticipated. Surprisingly, there was an increase in non-12α-OH BAs, namely, β-muricholic acid, ursodeoxycholic acid (UDCA), and their taurine conjugates, in GF mice. Further, in vitro experiments confirmed that UDCA is a primary BA in mice. There were minimal changes in the mRNA of farnesoid X receptor target genes in the ileum (Fibroblast growth factor 15, small heterodimer protein, and ileal bile acid-binding protein), in the liver (small heterodimer protein, liver receptor homolog-1, and cytochrome P450 7a1), and BA transporters (apical sodium dependent bile acid transporter, organic solute transporter α, and organic solute transporter β) in the ileum of GF mice. Surprisingly, there were marked increases in BA transporters in the large intestine. Increased GLP-1 levels and gallbladder size were observed in GF mice, suggesting activation of TGR5 signaling. In summary, the GF condition results in increased expression of BA transporters in the colon, resulting in 1) an increase in total BA concentrations in tissues, 2) a change in BA composition to favor an increase in non-12α-OH BAs, and 3) activation of TGR5 signaling with increased gallbladder size and GLP-1.

  1. Importance of Large Intestine in Regulating Bile Acids and Glucagon-Like Peptide-1 in Germ-Free Mice

    PubMed Central

    Selwyn, Felcy Pavithra; Csanaky, Iván L.; Zhang, Youcai

    2015-01-01

    It is known that 1) elevated serum bile acids (BAs) are associated with decreased body weight, 2) elevated glucagon-like peptide-1 (GLP-1) levels can decrease body weight, and 3) germ-free (GF) mice are resistant to diet-induced obesity. The purpose of this study was to test the hypothesis that a lack of intestinal microbiota results in more BAs in the body, resulting in increased BA-mediated transmembrane G protein–coupled receptor 5 (TGR5) signaling and increased serum GLP-1 as a mechanism of resistance of GF mice to diet-induced obesity. GF mice had 2- to 4-fold increased total BAs in the serum, liver, bile, and ileum. Fecal excretion of BAs was 63% less in GF mice. GF mice had decreased secondary BAs and increased taurine-conjugated BAs, as anticipated. Surprisingly, there was an increase in non–12α-OH BAs, namely, β-muricholic acid, ursodeoxycholic acid (UDCA), and their taurine conjugates, in GF mice. Further, in vitro experiments confirmed that UDCA is a primary BA in mice. There were minimal changes in the mRNA of farnesoid X receptor target genes in the ileum (Fibroblast growth factor 15, small heterodimer protein, and ileal bile acid–binding protein), in the liver (small heterodimer protein, liver receptor homolog-1, and cytochrome P450 7a1), and BA transporters (apical sodium dependent bile acid transporter, organic solute transporter α, and organic solute transporter β) in the ileum of GF mice. Surprisingly, there were marked increases in BA transporters in the large intestine. Increased GLP-1 levels and gallbladder size were observed in GF mice, suggesting activation of TGR5 signaling. In summary, the GF condition results in increased expression of BA transporters in the colon, resulting in 1) an increase in total BA concentrations in tissues, 2) a change in BA composition to favor an increase in non–12α-OH BAs, and 3) activation of TGR5 signaling with increased gallbladder size and GLP-1. PMID:26199423

  2. Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line

    SciTech Connect

    Zhang, Leshuai W.; McMahon Tobin, Grainne A.; Rouse, Rodney L.

    2012-10-15

    The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in “on-target” RIN-5mF (islet) cells as well as in “off-target” AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4 mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA-treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-L-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose-stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment. -- Highlights: ► Exenatide did not inhibit islet, acinar or ductal cell proliferation. ► GLP1R protein decreased after glucose stimulation in oleic acid-treated ductal cells. ► Oleic acid treatment altered localization of GLP1R with early and recycling

  3. GLP-1(28-36)amide, the Glucagon-like peptide-1 metabolite: friend, foe, or pharmacological folly?

    PubMed

    Taing, Meng-Wong; Rose, Felicity J; Whitehead, Jonathan P

    2014-01-01

    The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes. GLP-1 mediates its key insulinotropic effects via a G-protein coupled receptor expressed on β-cells and other pancreatic cell types. The insulinotropic activity of GLP-1 is terminated via enzymatic cleavage by dipeptidyl peptidase-4. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive; however, accumulating evidence indicates some have biological activity that may contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor. Recent reports describing the putative effects of one such metabolite, the GLP-1-derived nonapeptide GLP-1(28-36) amide, are the focus of this review. Administration of the nonapeptide elevates cyclic adenosine monophosphate (cAMP) and activates protein kinase A, β-catenin, and cAMP response-element binding protein in pancreatic β-cells and hepatocytes. In stressed cells, the nonapeptide targets the mitochondria and, via poorly defined mechanisms, helps to maintain mitochondrial membrane potential and cellular adenosine triphosphate levels and to reduce cytotoxicity and apoptosis. In mouse models of diet-induced obesity, treatment with the nonapeptide reduces weight gain and ameliorates associated pathophysiology, including hyperglycemia, hyperinsulinemia, and hepatic steatosis. Nonapeptide administration in a streptozotocin-induced model of type 1 diabetes also improves glucose disposal concomitant with elevated insulin levels and increased β-cell mass and proliferation. Collectively, these results suggest some of the beneficial effects of GLP-1 receptor analogs may be mediated by the nonapeptide. However, the concentrations required to elicit some of these effects are in the micromolar range, leading to reservations about potentially related therapeutic benefits. Moreover, although controversial, concerns have been raised about the potential for incretin

  4. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

    PubMed Central

    Harkavyi, Alexander; Abuirmeileh, Amjad; Lever, Rebecca; Kingsbury, Ann E; Biggs, Christopher S; Whitton, Peter S

    2008-01-01

    Background It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD. Methods Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of EX-4. Rats were then investigated in vivo and ex vivo with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system. Results EX-4 (0.1 and 0.5 μg/kg) was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats. Conclusion The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models of PD, EX-4 is in

  5. Postprandial glucose, insulin, and glucagon-like peptide-1 responses of different equine breeds adapted to meals containing micronized maize.

    PubMed

    Bamford, N J; Baskerville, C L; Harris, P A; Bailey, S R

    2015-07-01

    The enteroinsular axis is a complex system that includes the release of incretin hormones from the gut to promote the absorption and utilization of glucose after a meal. The insulinogenic effect of incretin hormones such as glucagon-like peptide-1 (GLP-1) remains poorly characterized in the horse. The aim of this study was to compare postprandial glucose, insulin, and GLP-1 responses of different equine breeds adapted to twice-daily meals containing micronized maize. Four Standardbred horses, 4 mixed-breed ponies, and 4 Andalusian cross horses in moderate BCS (5.5 ± 0.2 out of 9) were fed meals at 0800 and 1600 h each day. The meals contained micronized maize (mixed with soaked soybean hulls and lucerne chaff), with the amount of maize gradually increased over 12 wk to reach a final quantity of 1.7 g/kg BW (1.1 g/kg BW starch) in each meal. Animals had ad libitum access to the same hay throughout. After 12 wk of acclimation, serial blood samples were collected from all animals over a 14-h period to measure concentrations of glucose, insulin, and GLP-1, with meals fed immediately after the 0 and 8 h samples. Glucose area under the curve (AUC) values were similar between breed groups (P = 0.41); however, ponies and Andalusian horses exhibited significantly higher insulin AUC values after both meals compared with Standardbred horses (both P < 0.005). Postprandial GLP-1 AUC values were also significantly higher in ponies and Andalusian horses compared with Standardbred horses (breed × time interaction; P < 0.001). Correlation analysis demonstrated a strong positive association between concentrations of insulin and GLP-1 over time (rs = 0.752; P < 0.001). The increased insulin concentrations in ponies and Andalusian horses may partly reflect lower insulin sensitivity but could also be attributed to increased GLP-1 release. Given that hyperinsulinemia is a recognized risk factor for the development of laminitis in domestic equids, this study provides evidence that the

  6. Taspoglutide, an analog of human glucagon-like Peptide-1 with enhanced stability and in vivo potency.

    PubMed

    Sebokova, Elena; Christ, Andreas D; Wang, Haiyan; Sewing, Sabine; Dong, Jesse Z; Taylor, John; Cawthorne, Michael A; Culler, Michael D

    2010-06-01

    Taspoglutide is a novel analog of human glucagon-like peptide-1 [hGLP-1(7-36)NH2] in clinical development for the treatment of type 2 diabetes. Taspoglutide contains alpha-aminoisobutyric acid substitutions replacing Ala(8) and Gly(35) of hGLP-1(7-36)NH2. The binding affinity [radioligand binding assay using [(125)I]hGLP-1(7-36)NH2], potency (cAMP production in CHO cells stably overexpressing hGLP-1 receptor), and in vitro plasma stability of taspoglutide compared with hGLP-1(7-36)NH2 have been evaluated. Effects on basal and glucose-stimulated insulin secretion were determined in vitro in INS-1E cells and in vivo in normal rats. Taspoglutide has comparable affinity (affinity constant 1.1 +/- 0.2 nm) to the natural ligand (affinity constant 1.5 +/- 0.3 nm) for the hGLP-1 receptor and exhibits comparable potency in stimulating cAMP production (EC(50) Taspo 0.06 nm and EC(50) hGLP-1(7-36)NH2 0.08 nm). Taspoglutide exerts insulinotropic action in vitro and in vivo and retains the glucoincretin property of hGLP-1(7-36)NH2. Stimulation of insulin secretion is concentration dependent and evident in the presence of high-glucose concentrations (16.7 mm) with a taspoglutide concentration as low as 0.001 nm. Taspoglutide is fully resistant to dipeptidyl peptidase-4 cleavage (during 1 h incubation at room temperature with purified enzyme) and has an extended in vitro plasma half-life relative to hGLP-1(7-36)NH2 (9.8 h vs. 50 min). In vitro, taspoglutide does not inhibit dipeptidyl peptidase-4 activity. This study provides the biochemical and pharmacological basis for the sustained plasma drug levels and prolonged therapeutic activity seen in early clinical trials of taspoglutide. Excellent stability and potency with substantial glucoincretin effects position taspoglutide as a promising new agent for treatment of type 2 diabetes.

  7. The peptide agonist-binding site of the glucagon-like peptide-1 (GLP-1) receptor based on site-directed mutagenesis and knowledge-based modelling

    PubMed Central

    Dods, Rachel L.; Donnelly, Dan

    2015-01-01

    Glucagon-like peptide-1 (7–36)amide (GLP-1) plays a central role in regulating blood sugar levels and its receptor, GLP-1R, is a target for anti-diabetic agents such as the peptide agonist drugs exenatide and liraglutide. In order to understand the molecular nature of the peptide–receptor interaction, we used site-directed mutagenesis and pharmacological profiling to highlight nine sites as being important for peptide agonist binding and/or activation. Using a knowledge-based approach, we constructed a 3D model of agonist-bound GLP-1R, basing the conformation of the N-terminal region on that of the receptor-bound NMR structure of the related peptide pituitary adenylate cyclase-activating protein (PACAP21). The relative position of the extracellular to the transmembrane (TM) domain, as well as the molecular details of the agonist-binding site itself, were found to be different from the model that was published alongside the crystal structure of the TM domain of the glucagon receptor, but were nevertheless more compatible with published mutagenesis data. Furthermore, the NMR-determined structure of a high-potency cyclic conformationally-constrained 11-residue analogue of GLP-1 was also docked into the receptor-binding site. Despite having a different main chain conformation to that seen in the PACAP21 structure, four conserved residues (equivalent to His-7, Glu-9, Ser-14 and Asp-15 in GLP-1) could be structurally aligned and made similar interactions with the receptor as their equivalents in the GLP-1-docked model, suggesting the basis of a pharmacophore for GLP-1R peptide agonists. In this way, the model not only explains current mutagenesis and molecular pharmacological data but also provides a basis for further experimental design. PMID:26598711

  8. Effects of prepartum fat supplementation on plasma concentrations of glucagon-like peptide-1, peptide YY, adropin, insulin, and leptin in periparturient dairy cows.

    PubMed

    Zapata, Rizaldy C; Salehi, Reza; Ambrose, Divakar J; Chelikani, Prasanth K

    2015-10-01

    Dietary fat supplementation during the periparturient period is one strategy to increase energy intake and attenuate the degree of negative energy balance during early lactation; however, little is known of the underlying hormonal and metabolic adaptations. We evaluated the effects of prepartum fat supplementation on energy-balance parameters and plasma concentrations of glucagon-like peptide-1, peptide tyrosine-tyrosine (PYY), adropin, insulin, leptin, glucose, nonesterified fatty acid, and β-hydroxybutyric acid in dairy cows. Twenty-four pregnant dairy cows were randomized to diets containing either rolled canola or sunflower seed at 8% of dry matter, or no oilseed supplementation, during the last 5 wk of gestation and then assigned to a common lactation diet postpartum. Blood samples were collected at -2, +2, and +14 h relative to feeding, at 2 wk after the initiation of the diets, and at 2 wk postpartum. Dietary canola and sunflower supplementation alone did not affect energy balance, body weight, and plasma concentrations of glucagon-like peptide-1, PYY, adropin, insulin, leptin, nonesterified fatty acid, and β-hydroxybutyric acid; however, canola decreased and sunflower tended to decrease dry matter intake. We also observed that the physiological stage had a significant, but divergent, effect on circulating hormones and metabolite concentrations. Plasma glucagon-like peptide-1, PYY, adropin, nonesterified fatty acid, and β-hydroxybutyric acid concentrations were greater postpartum than prepartum, whereas glucose, insulin, leptin, body weight, and energy balance were greater prepartum than postpartum. Furthermore, the interaction of treatment and stage was significant for leptin and adropin, and tended toward significance for PYY and insulin; only insulin exhibited an apparent postprandial increase. Postpartum PYY concentrations exhibited a strong negative correlation with body weight, suggesting that PYY may be associated with body weight regulation during

  9. Exploration of structure-activity relationships at the two C-terminal residues of potent 11mer Glucagon-Like Peptide-1 receptor agonist peptides via parallel synthesis.

    PubMed

    Haque, Tasir S; Martinez, Rogelio L; Lee, Ving G; Riexinger, Douglas G; Lei, Ming; Feng, Ming; Koplowitz, Barry; Mapelli, Claudio; Cooper, Christopher B; Zhang, Ge; Huang, Christine; Ewing, William R; Krupinski, John

    2010-07-01

    We report the identification of potent agonists of the Glucagon-Like Peptide-1 receptor (GLP-1R) via evaluation of two positional scanning libraries and a two-dimensional focused library, synthesized in part on SynPhase Lanterns. These compounds are 11 amino acid peptides containing several unnatural amino acids, including (in particular) analogs of biphenylalanine (Bip) at the two C-terminal positions. Typical activities of the most potent peptides in this class are in the picomolar range in an in vitro functional assay using human GLP-1 receptor.

  10. Identification of potent 11mer glucagon-like peptide-1 receptor agonist peptides with novel C-terminal amino acids: Homohomophenylalanine analogs.

    PubMed

    Haque, Tasir S; Lee, Ving G; Riexinger, Douglas; Lei, Ming; Malmstrom, Sarah; Xin, Li; Han, Songping; Mapelli, Claudio; Cooper, Christopher B; Zhang, Ge; Ewing, William R; Krupinski, John

    2010-05-01

    We report the identification of potent agonists of the Glucagon-Like Peptide-1 Receptor (GLP-1R). These compounds are short, 11 amino acid peptides containing several unnatural amino acids, including (in particular) analogs of homohomophenylalanine (hhPhe) at the C-terminal position. Typically the functional activity of the more potent peptides in this class is in the low picomolar range in an in vitro cAMP assay, with one example demonstrating excellent in vivo activity in an ob/ob mouse model of diabetes.

  11. Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis

    PubMed Central

    2010-01-01

    Background Glucagon-like peptide (GLP-1) analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs. Methods MEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events. Results Studies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 μg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily. Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg) than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists have some effect on beta

  12. The putative signal peptide of glucagon-like peptide-1 receptor is not required for receptor synthesis but promotes receptor expression

    PubMed Central

    Ge, Yunjun; Yang, Dehua; Dai, Antao; Zhou, Caihong; Zhu, Yue; Wang, Ming-Wei

    2014-01-01

    GLP-1R (glucagon-like peptide-1 receptor) mediates the ‘incretin effect’ and many other anti-diabetic actions of its cognate ligand, GLP-1 (glucagon-like peptide-1). It belongs to the class B family of GPCRs (G protein-coupled receptors) and possesses an N-terminal putative SP (signal peptide). It has been reported that this sequence is required for the synthesis of GLP-1R and is cleaved after receptor synthesis. In the present study, we conducted an in-depth exploration towards the role of the putative SP in GLP-1R synthesis. A mutant GLP-1R without this sequence was expressed in HEK293 cells (human embryonic kidney 293 cells) and displayed normal functionality with respect to ligand binding and activation of adenylate cyclase. Thus the putative SP does not seem to be required for receptor synthesis. Immunoblotting analysis shows that the amount of GLP-1R synthesized in HEK293 cells is low when the putative SP is absent. This indicates that the role of the sequence is to promote the expression of GLP-1R. Furthermore, epitopes tagged at the N-terminal of GLP-1R are detectable by immunofluorescence and immunoblotting in our experiments. In conclusion, the present study points to different roles of SP in GLP-1R expression which broadens our understanding of the functionality of this putative SP of GLP-1R and possibly other Class B GPCRs. PMID:25330813

  13. A Dual-Purpose Linker for Alpha Helix Stabilization and Imaging Agent Conjugation to Glucagon-Like Peptide-1 Receptor Ligands

    PubMed Central

    Zhang, Liang; Navaratna, Tejas; Liao, Jianshan; Thurber, Greg M.

    2016-01-01

    Peptides display many characteristics of efficient imaging agents such as rapid targeting, fast background clearance, and low non-specific cellular uptake. However, poor stability, low affinity, and loss of binding after labeling often preclude their use in vivo. Using the glucagon-like peptide-1 receptor (GLP-1R) ligands exendin and GLP-1 as a model system, we designed a novel alpha helix stabilizing linker to simultaneously address these limitations. The stabilized and labeled peptides showed an increase in helicity, improved protease resistance, negligible loss or an improvement in binding affinity, and excellent in vivo targeting. The ease of incorporating azidohomoalanine in peptides and efficient reaction with the dialkyne linker enables this technique to potentially be used as a general method for labeling alpha helices. This strategy should be useful for imaging beta cells in diabetes research and in developing and testing other peptide targeting agents. PMID:25594741

  14. [Dulaglutide (Trulicity®), a new once-weekly agonist of glucagon-like peptide-1 receptors for type 2 diabetes].

    PubMed

    Scheen, A J

    2016-03-01

    Dulaglutide (Trulicity®) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors indicated in the treatment of type 2 diabetes. Phase III clinical trials in AWARD programme demonstrated the efficacy and safety of dulaglutide in patients with type 2 diabetes treated by diet and exercise, metformin, a combination of metformin and a sulfonylurea or metformin and pioglitazone or even by supplements of prandial insulin. In the AWARD programme, dulaglutide (subcutaneous 0.75 or 1.5 mg once weekly) exerted a greater glucose-lowering activity than metformin, sitagliptin, exenatide or insulin glargine, and was non-inferior to liraglutide 1.8 mg once daily. Dulaglutide is currently reimbursed in Belgium after failure of and in combination with a dual oral therapy with metformin and a sulfonylurea or metformin and pioglitazone.

  15. [Impact of anti-diabetic therapy based on glucagon-like peptide-1 receptor agonists on the cardiovascular risk of patients with type 2 diabetes mellitus].

    PubMed

    Camafort-Babkowski, Miguel

    2013-08-17

    Anti-diabetic drugs have, in addition to their well-known glucose lowering-effect, different effects in the rest of cardiovascular factors that are associated with diabetes mellitus. Glucagon-like peptide-1 (GLP-1) receptor agonists have recently been incorporated to the therapeutic arsenal of type 2 diabetes mellitus. The objective of this review is to summarize the available evidence on the effect of the GLP-1 receptor agonists on different cardiovascular risk factors, mediated by the effect of GLP-1 receptor agonists on the control of hyperglycaemia and the GLP-1 receptor agonists effect on other cardiovascular risk factors (weight control, blood pressure control, lipid profile and all other cardiovascular risk biomarkers). In addition, we present the emerging evidence with regards to the impact that GLP-1 receptor agonists therapy could have in the reduction of cardiovascular events and the currently ongoing studies addressing this issue.

  16. [Dulaglutide (Trulicity®), a new once-weekly agonist of glucagon-like peptide-1 receptors for type 2 diabetes].

    PubMed

    Scheen, A J

    2016-03-01

    Dulaglutide (Trulicity®) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors indicated in the treatment of type 2 diabetes. Phase III clinical trials in AWARD programme demonstrated the efficacy and safety of dulaglutide in patients with type 2 diabetes treated by diet and exercise, metformin, a combination of metformin and a sulfonylurea or metformin and pioglitazone or even by supplements of prandial insulin. In the AWARD programme, dulaglutide (subcutaneous 0.75 or 1.5 mg once weekly) exerted a greater glucose-lowering activity than metformin, sitagliptin, exenatide or insulin glargine, and was non-inferior to liraglutide 1.8 mg once daily. Dulaglutide is currently reimbursed in Belgium after failure of and in combination with a dual oral therapy with metformin and a sulfonylurea or metformin and pioglitazone. PMID:27311248

  17. [Impact of anti-diabetic therapy based on glucagon-like peptide-1 receptor agonists on the cardiovascular risk of patients with type 2 diabetes mellitus].

    PubMed

    Camafort-Babkowski, Miguel

    2013-08-17

    Anti-diabetic drugs have, in addition to their well-known glucose lowering-effect, different effects in the rest of cardiovascular factors that are associated with diabetes mellitus. Glucagon-like peptide-1 (GLP-1) receptor agonists have recently been incorporated to the therapeutic arsenal of type 2 diabetes mellitus. The objective of this review is to summarize the available evidence on the effect of the GLP-1 receptor agonists on different cardiovascular risk factors, mediated by the effect of GLP-1 receptor agonists on the control of hyperglycaemia and the GLP-1 receptor agonists effect on other cardiovascular risk factors (weight control, blood pressure control, lipid profile and all other cardiovascular risk biomarkers). In addition, we present the emerging evidence with regards to the impact that GLP-1 receptor agonists therapy could have in the reduction of cardiovascular events and the currently ongoing studies addressing this issue. PMID:23332622

  18. Imaging exocytosis of single glucagon-like peptide-1 containing granules in a murine enteroendocrine cell line with total internal reflection fluorescent microscopy

    SciTech Connect

    Ohara-Imaizumi, Mica; Aoyagi, Kyota; Akimoto, Yoshihiro; Nakamichi, Yoko; Nishiwaki, Chiyono; Kawakami, Hayato; Nagamatsu, Shinya

    2009-12-04

    To analyze the exocytosis of glucagon-like peptide-1 (GLP-1) granules, we imaged the motion of GLP-1 granules labeled with enhanced yellow fluorescent protein (Venus) fused to human growth hormone (hGH-Venus) in an enteroendocrine cell line, STC-1 cells, by total internal reflection fluorescent (TIRF) microscopy. We found glucose stimulation caused biphasic GLP-1 granule exocytosis: during the first phase, fusion events occurred from two types of granules (previously docked granules and newcomers), and thereafter continuous fusion was observed mostly from newcomers during the second phase. Closely similar to the insulin granule fusion from pancreatic {beta} cells, the regulated biphasic exocytosis from two types of granules may be a common mechanism in glucose-evoked hormone release from endocrine cells.

  19. Imaging exocytosis of single glucagon-like peptide-1 containing granules in a murine enteroendocrine cell line with total internal reflection fluorescent microscopy.

    PubMed

    Ohara-Imaizumi, Mica; Aoyagi, Kyota; Akimoto, Yoshihiro; Nakamichi, Yoko; Nishiwaki, Chiyono; Kawakami, Hayato; Nagamatsu, Shinya

    2009-12-01

    To analyze the exocytosis of glucagon-like peptide-1 (GLP-1) granules, we imaged the motion of GLP-1 granules labeled with enhanced yellow fluorescent protein (Venus) fused to human growth hormone (hGH-Venus) in an enteroendocrine cell line, STC-1 cells, by total internal reflection fluorescent (TIRF) microscopy. We found glucose stimulation caused biphasic GLP-1 granule exocytosis: during the first phase, fusion events occurred from two types of granules (previously docked granules and newcomers), and thereafter continuous fusion was observed mostly from newcomers during the second phase. Closely similar to the insulin granule fusion from pancreatic beta cells, the regulated biphasic exocytosis from two types of granules may be a common mechanism in glucose-evoked hormone release from endocrine cells.

  20. Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.

    PubMed

    Graaf, Chris de; Donnelly, Dan; Wootten, Denise; Lau, Jesper; Sexton, Patrick M; Miller, Laurence J; Ahn, Jung-Mo; Liao, Jiayu; Fletcher, Madeleine M; Yang, Dehua; Brown, Alastair J H; Zhou, Caihong; Deng, Jiejie; Wang, Ming-Wei

    2016-10-01

    The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain-binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders. PMID:27630114

  1. Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes

    PubMed Central

    de Graaf, Chris; Donnelly, Dan; Wootten, Denise; Lau, Jesper; Sexton, Patrick M.; Miller, Laurence J.; Ahn, Jung-Mo; Liao, Jiayu; Fletcher, Madeleine M.; Brown, Alastair J. H.; Zhou, Caihong; Deng, Jiejie; Wang, Ming-Wei

    2016-01-01

    The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein–coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain–binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders. PMID:27630114

  2. Renal extraction and acute effects of glucagon-like peptide-1 on central and renal hemodynamics in healthy men.

    PubMed

    Asmar, Ali; Simonsen, Lene; Asmar, Meena; Madsbad, Sten; Holst, Jens J; Frandsen, Erik; Moro, Cedric; Jonassen, Thomas; Bülow, Jens

    2015-04-15

    The present experiments were performed to elucidate the acute effects of intravenous infusion of glucagon-like peptide (GLP)-1 on central and renal hemodynamics in healthy men. Seven healthy middle-aged men were examined on two different occasions in random order. During a 3-h infusion of either GLP-1 (1.5 pmol·kg⁻¹·min⁻¹) or saline, cardiac output was estimated noninvasively, and intraarterial blood pressure and heart rate were measured continuously. Renal plasma flow, glomerular filtration rate, and uptake/release of hormones and ions were measured by Fick's Principle after catheterization of a renal vein. Subjects remained supine during the experiments. During GLP-1 infusion, both systolic blood pressure and arterial pulse pressure increased by 5±1 mmHg (P=0.015 and P=0.002, respectively). Heart rate increased by 5±1 beats/min (P=0.005), and cardiac output increased by 18% (P=0.016). Renal plasma flow and glomerular filtration rate as well as the clearance of Na⁺ and Li⁺ were not affected by GLP-1. However, plasma renin activity decreased (P=0.037), whereas plasma levels of atrial natriuretic peptide were unaffected. Renal extraction of intact GLP-1 was 43% (P<0.001), whereas 60% of the primary metabolite GLP-1 9-36amide was extracted (P=0.017). In humans, an acute intravenous administration of GLP-1 leads to increased cardiac output due to a simultaneous increase in stroke volume and heart rate, whereas no effect on renal hemodynamics could be demonstrated despite significant extraction of both the intact hormone and its primary metabolite. PMID:25670826

  3. Differential effects of glucagon-like peptide-1 on microvascular recruitment and glucose metabolism in short- and long-term insulin resistance

    PubMed Central

    Sjøberg, Kim A; Rattigan, Stephen; Jeppesen, Jacob F; Lundsgaard, Anne-Marie; Holst, Jens J; Kiens, Bente

    2015-01-01

    Abstract Acute infusion of glucagon-like peptide-1 (GLP-1) has potent effects on blood flow distribution through the microcirculation in healthy humans and rats. A high fat diet induces impairments in insulin-mediated microvascular recruitment (MVR) and muscle glucose uptake, and here we examined whether this could be reversed by GLP-1. Using contrast-enhanced ultrasound, microvascular recruitment was assessed by continuous real-time imaging of gas-filled microbubbles in the microcirculation after acute (5 days) and prolonged (8 weeks) high fat diet (HF)-induced insulin resistance in rats. A euglycaemic hyperinsulinaemic clamp (3 mU min−1 kg−1), with or without a co-infusion of GLP-1 (100 pmol l−1), was performed in anaesthetized rats. Consumption of HF attenuated the insulin-mediated MVR in both 5 day and 8 week HF interventions which was associated with a 50% reduction in insulin-mediated glucose uptake compared to controls. Acute administration of GLP-1 restored the normal microvascular response by increasing the MVR after both 5 days and 8 weeks of HF intervention (P < 0.05). This effect of GLP-1 was associated with a restoration of both whole body insulin sensitivity and increased insulin-mediated glucose uptake in skeletal muscle by 90% (P < 0.05) after 5 days of HF but not after 8 weeks of HF. The present study demonstrates that GLP-1 increases MVR in rat skeletal muscle and can reverse early stages of high fat diet-induced insulin resistance in vivo. Key points Acute glucagon-like peptide-1 (GLP-1) infusion reversed the high fat diet-induced microvascular insulin resistance that occurred after both 5 days and 8 weeks of a high fat diet intervention. When GLP-1 was co-infused with insulin it had overt effects on whole body insulin sensitivity as well as insulin-mediated skeletal muscle glucose uptake after 5 days of a high fat diet, but not after 8 weeks of high fat diet intervention. Acute GLP-1 infusion did not have an additive

  4. Evaluating preferences for profiles of glucagon-like peptide-1 receptor agonists among injection-naive type 2 diabetes patients in Japan

    PubMed Central

    Gelhorn, Heather L; Bacci, Elizabeth D; Poon, Jiat Ling; Boye, Kristina S; Suzuki, Shuichi; Babineaux, Steven M

    2016-01-01

    Objective The objective of this study was to use a discrete choice experiment (DCE) to estimate patients’ preferences for the treatment features, safety, and efficacy of two specific glucagon-like peptide-1 receptor agonists, dulaglutide and liraglutide, among patients with type 2 diabetes mellitus (T2DM) in Japan. Methods In Japan, patients with self-reported T2DM and naive to treatment with self-injectable medications were administered a DCE through an in-person interview. The DCE examined the following six attributes of T2DM treatment, each described by two levels: “dosing frequency”, “hemoglobin A1c change”, “weight change”, “type of delivery system”, “frequency of nausea”, and “frequency of hypoglycemia”. Part-worth utilities were estimated using logit models and were used to calculate the relative importance (RI) of each attribute. A chi-square test was used to determine the differences in preferences for the dulaglutide versus liraglutide profiles. Results The final evaluable sample consisted of 182 participants (mean age: 58.9 [standard deviation =10.0] years; 64.3% male; mean body mass index: 26.1 [standard deviation =5.0] kg/m2). The RI values for the attributes in rank order were dosing frequency (44.1%), type of delivery system (26.3%), frequency of nausea (15.1%), frequency of hypoglycemia (7.4%), weight change (6.2%), and hemoglobin A1c change (1.0%). Significantly more participants preferred the dulaglutide profile (94.5%) compared to the liraglutide profile (5.5%; P<0.0001). Conclusion This study elicited the preferences of Japanese T2DM patients for attributes and levels representing the actual characteristics of two existing glucagon-like peptide-1 receptor agonists. In this comparison, dosing frequency and type of delivery system were the two most important characteristics, accounting for >70% of the RI. These findings are similar to those of a previous UK study, providing information about patients’ preferences that

  5. Involvement of glucagon-like peptide 1 in the glucose homeostasis regulation in obese and pituitary-dependent hyperadrenocorticism affected dogs.

    PubMed

    Miceli, D D; Cabrera Blatter, M F; Gallelli, M F; Pignataro, O P; Castillo, V A

    2014-10-01

    The incretin glucagon-like peptide 1 (GLP-1) enhances insulin secretion. The aim of this study was to assess GLP-1, glucose and insulin concentrations, Homeostatic Model Assessment (HOMA insulin sensitivity and HOMA β-cell function) in dogs with pituitary-dependent hyperadrenocorticism (PDH), and compare these values with those in normal and obese dogs. The Oral Glucose Tolerance Test was performed and the glucose, GLP-1 and insulin concentrations were evaluated at baseline, and after 15, 30, 60 and 120 minutes. Both basal concentration and those corresponding to the subsequent times, for glucose, GLP-1 and insulin, were statistically elevated in PDH dogs compared to the other groups. Insulin followed a similar behaviour together with variations of GLP-1. HOMA insulin sensitivity was statistically decreased and HOMA β-cell function increased in dogs with PDH. The higher concentrations of GLP-1 in PDH could play an important role in the impairment of pancreatic β-cells thus predisposing to diabetes mellitus.

  6. Changes in the concentrations of glucagon-like peptide-1(7-36)amide and gastric inhibitory polypeptide during the lactation cycle in goats.

    PubMed

    Faulkner, A; Martin, P A

    1998-08-01

    Plasma concentrations of glucagon-like peptide-1(7-36)amide (GLP) and gastric inhibitory polypeptide (GIP) were determined at fortnightly intervals for over a year throughout the pregnancy-lactation cycle of goats. Both GIP and GLP concentrations were elevated during lactation and fell rapidly when milk secretion was terminated. At the onset of lactation GLP concentrations rose rapidly whereas GIP concentrations showed a delayed response. GLP concentrations remained high throughout lactation but those of GIP declined linearly as milk yields fell. Serum insulin concentrations correlated positively with plasma glucose concentrations but not with either GIP or GLP concentrations. Negative correlations were found between serum insulin concentrations and milk yield and plasma non-esterified fatty acid concentrations. The results are consistent with plasma GIP and GLP concentrations being determined by other factors in addition to nutrient intake and absorption. Changes in GIP concentrations mirrored reported changes in the hypertrophy and atrophy of the intestine in ruminants while GLP concentrations may be more dependent on the neural and endocrine factors associated with lactation. The elevated concentrations of both peptides indicated a specific role in lactation independent of their normal anabolic and insulinotropic effects.

  7. GSK2374697, a long duration glucagon-like peptide-1 (GLP-1) receptor agonist, reduces postprandial circulating endogenous total GLP-1 and peptide YY in healthy subjects.

    PubMed

    Lin, J; Hodge, R J; O'Connor-Semmes, R L; Nunez, D J

    2015-10-01

    We investigated the effects of a long-duration glucagon-like peptide-1 (GLP-1) receptor agonist, GSK2374697, on postprandial endogenous total GLP-1 and peptide YY (PYY). Two cohorts of healthy subjects, one normal/overweight and one obese, were randomized to receive GSK2374697 2 mg (n = 8 each) or placebo (n = 4 and n = 2) subcutaneously on days 1, 4 and 7. Samples for plasma endogenous GLP-1 and PYY were collected after breakfast on days -1 and 12. Weighted mean area under the curve (0-4 h) of total GLP-1 and PYY in treated subjects was reduced compared with placebo. The least squares mean difference for change from baseline was -1.24 pmol/l [95% confidence interval (CI) -2.33, -0.16] and -4.47 pmol/l (95% CI -8.74, -0.20) for total GLP-1 and PYY, respectively, in normal/overweight subjects (p < 0.05 for both), and -1.56 (95% CI -2.95, -0.16) and -3.02 (95% CI -8.58, 2.55), respectively, in obese subjects (p < 0.05 for GLP-1). In healthy subjects, GSK2374697 reduced postprandial total GLP-1 and PYY levels, suggesting feedback suppression of enteroendocrine L-cell secretion of these peptides.

  8. Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists' treatment: a meta-analysis of randomized controlled trials.

    PubMed

    Su, Bin; Sheng, Hui; Zhang, Manna; Bu, Le; Yang, Peng; Li, Liang; Li, Fei; Sheng, Chunjun; Han, Yuqi; Qu, Shen; Wang, Jiying

    2015-02-01

    Traditional anti-diabetic drugs may have negative or positive effects on risk of bone fractures. Yet the relationship between the new class glucagon-like peptide-1 receptor agonists (GLP-1 RA) and risk of bone fractures has not been established. We performed a meta-analysis including randomized controlled trials (RCT) to study the risk of bone fractures associated with liraglutide or exenatide, compared to placebo or other active drugs. We searched MEDLINE, EMBASE, and clinical trial registration websites for published or unpublished RCTs comparing the effects of liraglutide or exenatide with comparators. Only studies with disclosed bone fracture data were included. Separate pooled analysis was performed for liraglutide or exenatide, respectively, by calculating Mantel-Haenszel odds ratio (MH-OR). 16 RCTs were identified including a total of 11,206 patients. Liraglutide treatment was associated with a significant reduced risk of incident bone fractures (MH-OR=0.38, 95% CI 0.17-0.87); however, exenatide treatment was associated with an elevated risk of incident bone fractures (MH-OR=2.09, 95% CI 1.03-4.21). Publication bias and heterogeneity between studies were not observed. Our study demonstrated a divergent risk of bone fractures associated with different GLP-1 RA treatments. The current findings need to be confirmed by future well-designed prospective or RCT studies.

  9. Low incidence of anti-drug antibodies in patients with type 2 diabetes treated with once-weekly glucagon-like peptide-1 receptor agonist dulaglutide.

    PubMed

    Milicevic, Z; Anglin, G; Harper, K; Konrad, R J; Skrivanek, Z; Glaesner, W; Karanikas, C A; Mace, K

    2016-05-01

    Therapeutic administration of peptides may result in anti-drug antibody (ADA) formation, hypersensitivity adverse events (AEs) and reduced efficacy. As a large peptide, the immunogenicity of once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide is of considerable interest. The present study assessed the incidence of treatment-emergent dulaglutide ADAs, hypersensitivity AEs, injection site reactions (ISRs), and glycaemic control in ADA-positive patients in nine phase II and phase III trials (dulaglutide, N = 4006; exenatide, N = 276; non-GLP-1 comparators, N = 1141). Treatment-emergent dulaglutide ADAs were detected using a solid-phase extraction acid dissociation binding assay. Neutralizing ADAs were detected using a cell-based assay derived from human endothelial kidney cells (HEK293). A total of 64 dulaglutide-treated patients (1.6% of the population) tested ADA-positive versus eight (0.7%) from the non-GLP-1 comparator group. Of these 64 patients, 34 (0.9%) had dulaglutide-neutralizing ADAs, 36 (0.9%) had native-sequence GLP-1 (nsGLP-1) cross-reactive ADAs and four (0.1%) had nsGLP-1 neutralization ADAs. The incidence of hypersensitivity AEs and ISRs was similar in the dulaglutide versus placebo groups. No dulaglutide ADA-positive patient reported hypersensitivity AEs. Because of the low incidence of ADAs, it was not possible to establish their effect on glycaemic control. PMID:26847401

  10. Glucagon-like Peptide-1 receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake and motivation to feed.

    PubMed

    Alhadeff, Amber L; Baird, John-Paul; Swick, Jennifer C; Hayes, Matthew R; Grill, Harvey J

    2014-08-01

    Central glucagon-like peptide-1 receptor (GLP-1R) activation reduces food intake and the motivation to work for food, but the neurons and circuits mediating these effects are not fully understood. Although lateral parabrachial nucleus (lPBN) neurons are implicated in the control of food intake and reward, the specific role of GLP-1R-expressing lPBN neurons is unexplored. Here, neuroanatomical tracing, immunohistochemical, and behavioral/pharmacological techniques are used to test the hypothesis that lPBN neurons contribute to the anorexic effect of central GLP-1R activation. Results indicate that GLP-1-producing neurons in the nucleus tractus solitarius project monosynaptically to the lPBN, providing a potential endogenous mechanism by which lPBN GLP-1R signaling may exert effects on food intake control. Pharmacological activation of GLP-1R in the lPBN reduced food intake, and conversely, antagonism of GLP-1R in the lPBN increased food intake. In addition, lPBN GLP-1R activation reduced the motivation to work for food under a progressive ratio schedule of reinforcement. Taken together, these data establish the lPBN as a novel site of action for GLP-1R-mediated control of food intake and reward. PMID:24681814

  11. The aglycone of ginsenoside Rg3 enables glucagon-like peptide-1 secretion in enteroendocrine cells and alleviates hyperglycemia in type 2 diabetic mice

    PubMed Central

    Kim, Ki-Suk; Jung Yang, Hea; Lee, In-Seung; Kim, Kang-Hoon; Park, Jiyoung; Jeong, Hyeon-Soo; Kim, Yoomi; Seok Ahn, Kwang; Na, Yun-Cheol; Jang, Hyeung-Jin

    2015-01-01

    Ginsenosides can be classified on the basis of the skeleton of their aglycones. Here, we hypothesized that the sugar moieties attached to the dammarane backbone enable binding of the ginsenosides to the sweet taste receptor, eliciting glucagon-like peptide-1 (GLP-1) secretion in the enteroendocrine L cells. Using the human enteroendocrine NCI-H716 cells, we demonstrated that 15 ginsenosides stimulate GLP-1 secretion according to the position of their sugar moieties. Through a pharmacological approach and RNA interference technique to inhibit the cellular signal cascade and using the Gαgust−/− mice, we elucidated that GLP-1 secreting effect of Rg3 mediated by the sweet taste receptor mediated the signaling pathway. Rg3, a ginsenoside metabolite that transformed the structure through a steaming process, showed the strongest GLP-1 secreting effects in NCI-H716 cells and also showed an anti-hyperglycemic effect on a type 2 diabetic mouse model through increased plasma GLP-1 and plasma insulin levels during an oral glucose tolerance test. Our study reveals a novel mechanism where the sugar moieties of ginsenosides Rg3 stimulates GLP-1 secretion in enteroendocrine L cells through a sweet taste receptor-mediated signal transduction pathway and thus has an anti-hyperglycemic effect on the type 2 diabetic mouse model. PMID:26675132

  12. Application of Adaptive Design Methodology in Development of a Long-Acting Glucagon-Like Peptide-1 Analog (Dulaglutide): Statistical Design and Simulations

    PubMed Central

    Skrivanek, Zachary; Berry, Scott; Berry, Don; Chien, Jenny; Geiger, Mary Jane; Anderson, James H.; Gaydos, Brenda

    2012-01-01

    Background Dulaglutide (dula, LY2189265), a long-acting glucagon-like peptide-1 analog, is being developed to treat type 2 diabetes mellitus. Methods To foster the development of dula, we designed a two-stage adaptive, dose-finding, inferentially seamless phase 2/3 study. The Bayesian theoretical framework is used to adaptively randomize patients in stage 1 to 7 dula doses and, at the decision point, to either stop for futility or to select up to 2 dula doses for stage 2. After dose selection, patients continue to be randomized to the selected dula doses or comparator arms. Data from patients assigned the selected doses will be pooled across both stages and analyzed with an analysis of covariance model, using baseline hemoglobin A1c and country as covariates. The operating characteristics of the trial were assessed by extensive simulation studies. Results Simulations demonstrated that the adaptive design would identify the correct doses 88% of the time, compared to as low as 6% for a fixed-dose design (the latter value based on frequentist decision rules analogous to the Bayesian decision rules for adaptive design). Conclusions This article discusses the decision rules used to select the dula dose(s); the mathematical details of the adaptive algorithm—including a description of the clinical utility index used to mathematically quantify the desirability of a dose based on safety and efficacy measurements; and a description of the simulation process and results that quantify the operating characteristics of the design. PMID:23294775

  13. Inositolphosphoglycans possibly mediate the effects of glucagon-like peptide-1(7-36)amide on rat liver and adipose tissue.

    PubMed

    Márquez, L; Trapote, M A; Luque, M A; Valverde, I; Villanueva-Peñacarrillo, M L

    1998-03-01

    Insulin-like effects of glucagon-like peptide-1(7-36)amide (GLP-1) in rat liver, skeletal muscle and fat, and also the presence of GLP-1 receptors in these extrapancreatic tissues, have been documented. In skeletal muscle and liver, the action of GLP-1 is not associated with an activation of adenylate cyclase, and in cultured murine myocytes and hepatoma cell lines, it was found that GLP-1 provokes the generation of inositolphosphoglycan molecules (IPGs), which are considered second messengers of insulin action. In the present work, we document in isolated normal rat adipocytes and hepatocytes that GLP-1 exerts a rapid decrease of the radiolabelled glycosylphosphatidylinositols (GPIs)--precursors of IPGs--in the same manner as insulin, indicating their hydrolysis and the immediate short-lived generation of IPGs. Thus, IPGs could be mediators in the GLP-1 actions in adipose tissue and liver, as well as in skeletal muscle, through GLP-1 receptors which are, at least functionally, different from that of the pancreatic B-cell.

  14. Presence and characterization of glucagon-like peptide-1(7-36) amide receptors in solubilized membranes of rat adipose tissue.

    PubMed

    Valverde, I; Mérida, E; Delgado, E; Trapote, M A; Villanueva-Peñacarrillo, M L

    1993-01-01

    Specific binding of [125I]glucagon-like peptide-1(7-36)amide ([125I]GLP-1(7-36)amide) to solubilized rat adipose tissue membranes was found to be dependent on temperature, time, and membrane protein concentration and readily dissociated. GLP-1(1-36)amide, GLP-2, or glucagon (10(-6) M) did not compete with [125I]GLP-1(7-36)amide binding. Half-maximal binding was achieved with 8 x 10(-10) M unlabeled GLP-1(7-36)amide, and the Scatchard plot revealed the presence of high and low affinity binding sites with Kd values of approximately 0.6 and 20 nM, respectively. The binding capacity of [125I]GLP-1(7-36)amide was about 3 times higher than that of [125I]glucagon, while the high affinity Kd and the half-maximal binding of the two peptides were similar. The presence and abundance of GLP-1(7-36)amide receptors in fat tissue together with the previous findings that the peptide stimulates glycerol and cAMP production in rat adipocytes and stimulates fatty acid synthesis in explants of rat adipose tissue open the possibility that this insulinotropic intestinal peptide may also be involved in the regulation of lipid metabolism in health and disease.

  15. The cytoplasmic domain close to the transmembrane region of the glucagon-like peptide-1 receptor contains sequence elements that regulate agonist-dependent internalisation.

    PubMed

    Vázquez, Patricia; Roncero, Isabel; Blázquez, Enrique; Alvarez, Elvira

    2005-07-01

    In order to gain better insight into the molecular events involved in the signal transduction generated through glucagon-like peptide-1 (GLP-1) receptors, we tested the effect of deletions and point mutations within the cytoplasmic tail of this receptor with a view to establishing relationships between signal transduction desensitisation and receptor internalisation. Wild-type and truncated (deletion of the last 27 amino acids (GLPR 435R) and deletion of 44 amino acids (GLPR 418R)) GLP-1 receptors bound the agonist with similar affinity. Deletion of the last 27 amino acids decreased the internalisation rate by 78%, while deletion of 44 amino acids containing all the phosphorylation sites hitherto described in this receptor decreased the internalisation rate by only 47%. Binding of the ligand to both receptors stimulated adenylyl cyclase. In contrast, deletion of the region containing amino acids 419 to 435 (GLPR 419delta435) increased the internalisation rate by 268%, and the replacement of EVQ(408-410) by alanine (GLPR A(408-410)) increased this process to 296%. In both receptors, the efficacy in stimulating adenylate cyclase was decreased. All the receptors studied were internalised by coated pits, except for the receptor with a deletion of the last 44 amino acids, which also had a faster resensitisation rate. Our findings indicate that the neighbouring trans-membrane domain of the carboxyl-terminal tail of the GLP-1 receptor contains sequence elements that regulate agonist-dependent internalisation and transmembrane signalling.

  16. The aglycone of ginsenoside Rg3 enables glucagon-like peptide-1 secretion in enteroendocrine cells and alleviates hyperglycemia in type 2 diabetic mice.

    PubMed

    Kim, Ki-Suk; Jung Yang, Hea; Lee, In-Seung; Kim, Kang-Hoon; Park, Jiyoung; Jeong, Hyeon-Soo; Kim, Yoomi; Ahn, Kwang Seok; Na, Yun-Cheol; Jang, Hyeung-Jin

    2015-01-01

    Ginsenosides can be classified on the basis of the skeleton of their aglycones. Here, we hypothesized that the sugar moieties attached to the dammarane backbone enable binding of the ginsenosides to the sweet taste receptor, eliciting glucagon-like peptide-1 (GLP-1) secretion in the enteroendocrine L cells. Using the human enteroendocrine NCI-H716 cells, we demonstrated that 15 ginsenosides stimulate GLP-1 secretion according to the position of their sugar moieties. Through a pharmacological approach and RNA interference technique to inhibit the cellular signal cascade and using the Gαgust(-/-) mice, we elucidated that GLP-1 secreting effect of Rg3 mediated by the sweet taste receptor mediated the signaling pathway. Rg3, a ginsenoside metabolite that transformed the structure through a steaming process, showed the strongest GLP-1 secreting effects in NCI-H716 cells and also showed an anti-hyperglycemic effect on a type 2 diabetic mouse model through increased plasma GLP-1 and plasma insulin levels during an oral glucose tolerance test. Our study reveals a novel mechanism where the sugar moieties of ginsenosides Rg3 stimulates GLP-1 secretion in enteroendocrine L cells through a sweet taste receptor-mediated signal transduction pathway and thus has an anti-hyperglycemic effect on the type 2 diabetic mouse model. PMID:26675132

  17. The Role of Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes: Understanding How Data Can Inform Clinical Practice in Korea

    PubMed Central

    Chon, Suk; Ahn, Kyu Jeong; Jeong, In-Kyung; Kim, Byung-Joon; Kang, Jun Goo

    2015-01-01

    Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce glycosylated hemoglobin (HbA1c, 0.5% to 1.0%), and are associated with moderate weight loss and a relatively low risk of hypoglycemia. There are differences between Asian and non-Asian populations. We reviewed available data on GLP-1RAs, focusing on Korean patients, to better understand their risk/benefit profile and help inform local clinical practice. Control of postprandial hyperglycemia is important in Asians in whom the prevalence of post-challenge hyperglycemia is higher (vs. non-Asians). The weight lowering effects of GLP-1RAs are becoming more salient as the prevalence of overweight and obesity among Korean patients increases. The higher rate of gastrointestinal adverse events amongst Asian patients in clinical trials may be caused by higher drug exposure due to the lower body mass index of the participants (vs. non-Asian studies). Data on the durability of weight loss, clinically important health outcomes, safety and optimal dosing in Korean patients are lacking. Use of GLP-1RAs is appropriate in several patient groups, including patients whose HbA1c is uncontrolled, especially if this is due to postprandial glucose excursions and patients who are overweight or obese due to dietary problems (e.g., appetite control). The potential for gastrointestinal adverse events should be explained to patients at treatment initiation to facilitate the promotion of better compliance. PMID:26124987

  18. A depot-forming glucagon-like peptide-1 fusion protein reduces blood glucose for five days with a single injection

    PubMed Central

    Amiram, M.; Luginbuhl, K. M.; Li, X.; Feinglos, M. N.; Chilkoti, A.

    2013-01-01

    Peptide drugs are an exciting class of pharmaceuticals for the treatment of a variety of diseases; however, their short half-life dictates multiple and frequent injections causing undesirable side-effects. Herein, we describe a novel peptide delivery system that seeks to combine the attractive features of prolonged circulation time with a prolonged release formulation. This system consists of glucagon-like peptide-1, a type-2 diabetes drug fused to a thermally responsive, elastin-like-polypeptide (ELP) that undergoes a soluble-insoluble phase transition between room temperature and body temperature, thereby forming an injectable depot. We synthesized a set of GLP-1-ELP fusions and verified their proteolytic stability and potency in vitro. Significantly, a single injection of depot forming GLP-1-ELP fusions reduced blood glucose levels in mice for up to 5 days, 120 times longer than an injection of the native peptide. These findings demonstrate the unique advantages of using ELPs to release peptide-ELP fusions from a depot combined with enhanced systemic circulation to create a tunable peptide delivery system. PMID:23928357

  19. The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test.

    PubMed

    Isacson, Ruben; Nielsen, Elisabet; Dannaeus, Karin; Bertilsson, Göran; Patrone, Cesare; Zachrisson, Olof; Wikström, Lilian

    2011-01-10

    We have earlier shown that the glucagon-like peptide 1 receptor agonist exendin-4 stimulates neurogenesis in the subventricular zone and excerts anti-parkinsonian behavior. The aim of this study was to assess the effects of exendin-4 treatment on hippocampus-associated cognitive and mood-related behavior in adult rodents. To investigate potential effects of exendin-4 on hippocampal function, radial maze and forced swim test were employed. The time necessary to solve a radial maze task and the duration of immobility in the forced swim test were significantly reduced compared to respective vehicle groups if the animals had received exendin-4 during 1-2weeks before testing. In contrast to the positive control imipramine, single administration of exendin-4 1h before the challenge in the forced swim test had no effect. Immunohistochemical analysis showed that the incorporation of bromodeoxyuridine, a marker for DNA synthesis, as well as doublecortin expression was increased in the hippocampal dentate gyrus following chronic treatment with exendin-4 compared to vehicle-treated controls. The neurogenic effect of exendin-4 on hippocampus was confirmed by quantitative PCR showing an upregulation of mRNA expression for Ki-67, doublecortin and Mash-1. Since exendin-4 significantly improves hippocampus-associated behavior in adult rodents, it may be a candidate for alleviation of mood and cognitive disorders.

  20. Ingestion of coffee polyphenols increases postprandial release of the active glucagon-like peptide-1 (GLP-1(7-36)) amide in C57BL/6J mice.

    PubMed

    Fujii, Yoshie; Osaki, Noriko; Hase, Tadashi; Shimotoyodome, Akira

    2015-01-01

    The widespread prevalence of diabetes, caused by impaired insulin secretion and insulin resistance, is now a worldwide health problem. Glucagon-like peptide 1 (GLP-1) is a major intestinal hormone that stimulates glucose-induced insulin secretion from β cells. Prolonged activation of the GLP-1 signal has been shown to attenuate diabetes in animals and human subjects. Therefore, GLP-1 secretagogues are attractive targets for the treatment of diabetes. Recent epidemiological studies have reported that an increase in daily coffee consumption lowers diabetes risk. The present study examined the hypothesis that the reduction in diabetes risk associated with coffee consumption may be mediated by the stimulation of GLP-1 release by coffee polyphenol extract (CPE). GLP-1 secretion by human enteroendocrine NCI-H716 cells was augmented in a dose-dependent manner by the addition of CPE, and was compatible with the increase in observed active GLP-1(7-36) amide levels in the portal blood after administration with CPE alone in mice. CPE increased intracellular cyclic AMP (cAMP) levels in a dose-dependent manner, but this was not mediated by G protein-coupled receptor 119 (GPR119). The oral administration of CPE increased diet (starch and glyceryl trioleate)-induced active GLP-1 secretion and decreased glucose-dependent insulinotropic polypeptide release. Although CPE administration did not affect diet-induced insulin secretion, it decreased postprandial hyperglycaemia, which indicates that higher GLP-1 levels after the ingestion of CPE may improve insulin sensitivity. We conclude that dietary coffee polyphenols augment gut-derived active GLP-1 secretion via the cAMP-dependent pathway, which may contribute to the reduced risk of type 2 diabetes associated with daily coffee consumption.

  1. Correlation of Glypican-4 Level with Basal Active Glucagon-Like Peptide 1 Level in Patients with Type 2 Diabetes Mellitus

    PubMed Central

    Koh, Gwanpyo; Cho, Suk Ju; Yoo, So-Yeon; Chin, Sang Ouk

    2016-01-01

    Background Previous studies have reported that glypican-4 (GPC4) regulates insulin signaling by interacting with insulin receptor and through adipocyte differentiation. However, GPC4 has not been studied with regard to its effects on clinical factors in patients with type 2 diabetes mellitus (T2DM). We aimed to identify factors associated with GPC4 level in T2DM. Methods Between January 2010 and December 2013, we selected 152 subjects with T2DM and collected serum and plasma into tubes pretreated with aprotinin and dipeptidyl peptidase-4 inhibitor to preserve active gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). GPC4, active GLP-1, active GIP, and other factors were measured in these plasma samples. We performed a linear regression analysis to identify factors associated with GPC4 level. Results The subjects had a mean age of 58.1 years, were mildly obese (mean body mass index [BMI], 26.1 kg/m2), had T2DM of long-duration (mean, 101.3 months), glycated hemoglobin 7.5%, low insulin secretion, and low insulin resistance (mean homeostatic model assessment of insulin resistance [HOMA-IR], 1.2). Their mean GPC4 was 2.0±0.2 ng/mL. In multivariate analysis, GPC4 was independently associated with age (β=0.224, P=0.009), and levels of active GLP-1 (β=0.171, P=0.049) and aspartate aminotransferase (AST; β=–0.176, P=0.043) after being adjusted for other clinical factors. Conclusion GPC4 was independently associated with age, active GLP-1, and AST in T2DM patients, but was not associated with HOMA-IR and BMI, which are well known factors related to GPC4. Further study is needed to identify the mechanisms of the association between GPC4 and basal active GLP-1 levels. PMID:27704740

  2. Expression and Distribution of Glucagon-Like Peptide-1 Receptor mRNA, Protein and Binding in the Male Nonhuman Primate (Macaca mulatta) Brain

    PubMed Central

    Heppner, Kristy M.; Kirigiti, Melissa; Secher, Anna; Paulsen, Sarah Juel; Buckingham, Rikley; Pyke, Charles; Knudsen, Lotte B.

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) is released from endocrine L-cells lining the gut in response to food ingestion. However, GLP-1 is also produced in the nucleus of the solitary tract, where it acts as an anorectic neurotransmitter and key regulator of many autonomic and neuroendocrine functions. The expression and projections of GLP-1-producing neurons is highly conserved between rodent and primate brain, although a few key differences have been identified. The GLP-1 receptor (GLP-1R) has been mapped in the rodent brain, but no studies have described the distribution of GLP-1Rs in the nonhuman primate central nervous system. Here, we characterized the distribution of GLP-1R mRNA and protein in the adult macaque brain using in situ hybridization, radioligand receptor autoradiography, and immunohistochemistry with a primate specific GLP-1R antibody. Immunohistochemistry demonstrated that the GLP-1R is localized to cell bodies and fiber terminals in a very selective distribution throughout the brain. Consistent with the functional role of the GLP-1R system, we find the highest concentration of GLP-1R-immunoreactivity present in select hypothalamic and brainstem regions that regulate feeding, including the paraventricular and arcuate hypothalamic nuclei, as well as the area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus. Together, our data demonstrate that GLP-1R distribution is highly conserved between rodent and primate, although a few key species differences were identified, including the amygdala, where GLP-1R expression is much higher in primate than in rodent. PMID:25380238

  3. Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.

    PubMed

    Reddy, I A; Pino, J A; Weikop, P; Osses, N; Sørensen, G; Bering, T; Valle, C; Bluett, R J; Erreger, K; Wortwein, G; Reyes, J G; Graham, D; Stanwood, G D; Hackett, T A; Patel, S; Fink-Jensen, A; Torres, G E; Galli, A

    2016-01-01

    Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA. PMID:27187231

  4. Glucagon-Like Peptide 1 Protects against Hyperglycemic-Induced Endothelial-to-Mesenchymal Transition and Improves Myocardial Dysfunction by Suppressing Poly(ADP-Ribose) Polymerase 1 Activity

    PubMed Central

    Yan, Fei; Zhang, Guang-hao; Feng, Min; Zhang, Wei; Zhang, Jia-ning; Dong, Wen-qian; Zhang, Cheng; Zhang, Yun; Chen, Li; Zhang, Ming-Xiang

    2015-01-01

    Under high glucose conditions, endothelial cells respond by acquiring fibroblast characteristics, that is, endothelial-to-mesenchymal transition (EndMT), contributing to diabetic cardiac fibrosis. Glucagon-like peptide-1 (GLP-1) has cardioprotective properties independent of its glucose-lowering effect. However, the potential mechanism has not been fully clarified. Here we investigated whether GLP-1 inhibits myocardial EndMT in diabetic mice and whether this is mediated by suppressing poly(ADP-ribose) polymerase 1 (PARP-1). Streptozotocin diabetic C57BL/6 mice were treated with or without GLP-1 analog (24 nmol/kg daily) for 24 wks. Transthoracic echocardiography was performed to assess cardiac function. Human aortic endothelial cells (HAECs) were cultured in normal glucose (NG) (5.5 mmol/L) or high glucose (HG) (30 mmol/L) medium with or without GLP-1analog. Immunofluorescent staining and Western blot were performed to evaluate EndMT and PARP-1 activity. Diabetes mellitus attenuated cardiac function and increased cardiac fibrosis. Treatment with the GLP-1 analog improved diabetes mellitus–related cardiac dysfunction and cardiac fibrosis. Immunofluorescence staining revealed that hyperglycemia markedly increased the percentage of von Willebrand factor (vWF)+/alpha smooth muscle actin (α-SMA)+ cells in total α-SMA+ cells in diabetic hearts compared with controls, which was attenuated by GLP-1 analog treatment. In cultured HAECs, immunofluorescent staining and Western blot also showed that both GLP-1 analog and PARP-1 gene silencing could inhibit the HG-induced EndMT. In addition, GLP-1 analog could attenuate PARP-1 activation by decreasing the level of reactive oxygen species (ROS). Therefore, GLP-1 treatment could protect against the hyperglycemia-induced EndMT and myocardial dysfunction. This effect is mediated, at least partially, by suppressing PARP-1 activation. PMID:25715248

  5. Progesterone receptor membrane component 1 is a functional part of the glucagon-like peptide-1 (GLP-1) receptor complex in pancreatic β cells.

    PubMed

    Zhang, Ming; Robitaille, Mélanie; Showalter, Aaron D; Huang, Xinyi; Liu, Ying; Bhattacharjee, Alpana; Willard, Francis S; Han, Junfeng; Froese, Sean; Wei, Li; Gaisano, Herbert Y; Angers, Stéphane; Sloop, Kyle W; Dai, Feihan F; Wheeler, Michael B

    2014-11-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates glucose homeostasis. Because of their direct stimulation of insulin secretion from pancreatic β cells, GLP-1 receptor (GLP-1R) agonists are now important therapeutic options for the treatment of type 2 diabetes. To better understand the mechanisms that control the insulinotropic actions of GLP-1, affinity purification and mass spectrometry (AP-MS) were employed to uncover potential proteins that functionally interact with the GLP-1R. AP-MS performed on Chinese hamster ovary cells or MIN6 β cells, both expressing the human GLP-1R, revealed 99 proteins potentially associated with the GLP-1R. Three novel GLP-1R interactors (PGRMC1, Rab5b, and Rab5c) were further validated through co-immunoprecipitation/immunoblotting, fluorescence resonance energy transfer, and immunofluorescence. Functional studies revealed that overexpression of PGRMC1, a novel cell surface receptor that associated with liganded GLP-1R, enhanced GLP-1-induced insulin secretion (GIIS) with the most robust effect. Knockdown of PGRMC1 in β cells decreased GIIS, indicative of positive interaction with GLP-1R. To gain insight mechanistically, we demonstrated that the cell surface PGRMC1 ligand P4-BSA increased GIIS, whereas its antagonist AG-205 decreased GIIS. It was then found that PGRMC1 increased GLP-1-induced cAMP accumulation. PGRMC1 activation and GIIS induced by P4-BSA could be blocked by inhibition of adenylyl cyclase/EPAC signaling or the EGF receptor-PI3K signal transduction pathway. These data reveal a dual mechanism for PGRMC1-increased GIIS mediated through cAMP and EGF receptor signaling. In conclusion, we identified several novel GLP-1R interacting proteins. PGRMC1 expressed on the cell surface of β cells was shown to interact with the activated GLP-1R to enhance the insulinotropic actions of GLP-1.

  6. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.

    PubMed

    Nauck, M

    2016-03-01

    Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1), which is partly responsible for augmenting glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). In patients with T2D, pharmacological doses/concentrations of GLP-1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose-dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin-based glucose-lowering medications. Two classes of incretin-based therapies are available: GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs promote GLP-1 receptor (GLP-1R) signalling by providing GLP-1R stimulation through 'incretin mimetics' circulating at pharmacological concentrations, whereas DPP-4 inhibitors prevent the degradation of endogenously released GLP-1. Both agents produce reductions in plasma glucose and, as a result of their glucose-dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non-glycaemic benefits such as weight loss, improvements in β-cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin-based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.

  7. Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells.

    PubMed Central

    Tsuboi, Takashi; da Silva Xavier, Gabriela; Holz, George G; Jouaville, Laurence S; Thomas, Andrew P; Rutter, Guy A

    2003-01-01

    Glucagon-like peptide-1 (GLP-1) is a potent regulator of glucose-stimulated insulin secretion whose mechanisms of action are only partly understood. In the present paper, we show that at low (3 mM) glucose concentrations, GLP-1 increases the free intramitochondrial concentrations of both Ca(2+) ([Ca(2+)](m)), and ATP ([ATP](m)) in clonal MIN6 beta-cells. Suggesting that cAMP-mediated release of Ca(2+) from intracellular stores is responsible for these effects, increases in [ATP](m) that were induced by GLP-1 were completely blocked by the Rp isomer of adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS), or by chelation of intracellular Ca(2+). Furthermore, inhibition of Ins(1,4,5) P (3) (IP(3)) receptors with xestospongin C, or application of ryanodine, partially inhibited GLP-1-induced [ATP](m) increases, and the simultaneous blockade of both IP(3) and ryanodine receptors (RyR) completely eliminated the rise in [ATP](m). GLP-1 appeared to prompt Ca(2+)-induced Ca(2+) release through IP(3) receptors via a protein kinase A (PKA)-mediated phosphorylation event, since ryanodine-insensitive [ATP](m) increases were abrogated with the PKA inhibitor, H89. In contrast, the effects of GLP-1 on RyR-mediated [ATP](m) increases were apparently mediated by the cAMP-regulated guanine nucleotide exchange factor cAMP-GEFII, since xestospongin C-insensitive [ATP](m) increases were blocked by a dominant-negative form of cAMP-GEFII (G114E,G422D). Taken together, these results demonstrate that GLP-1 potentiates glucose-stimulated insulin release in part via the mobilization of intracellular Ca(2+), and the stimulation of mitochondrial ATP synthesis. PMID:12410638

  8. Glucagon-like peptide-1 attenuates advanced oxidation protein product-mediated damage in islet microvascular endothelial cells partly through the RAGE pathway

    PubMed Central

    Zhang, Zhen; Yang, Lei; Lei, Lei; Chen, Rongping; Chen, Hong; Zhang, Hua

    2016-01-01

    Advanced oxidation protein products (AOPPs) are knownt to play a role in the pathogenesis of diseases and related complications. However, whether AOPPs affect the survival of islet microvascular endothelial cells (IMECs) has not been reported to date, at least to the best of our knowledge. In this study, we aimed to investigate the mechanisms underlying AOPP-mediated damage in IMECs and the protective role of glucagon-like peptide-1 (GLP-1), which has been suggested to exert beneficial effects on the cardiovascular system. IMECs were treated with AOPPs (0–200 µg/ml) for 0–72 h in the presence or absence of GLP-1 (100 nmol/l). Apoptosis, cell viability and reactive oxygen species (ROS) production were examined, the expression levels of p53, Bax, receptor for advanced glycation end-products (RAGE) and NAD(P)H oxidase subunit were determined, and the activity of NAD(P)H oxidase, caspase-9 and caspase-3 was also determined. The results revealed that AOPPs increased the expression of RAGE, p47phox and p22phox; induced NAD(P)H oxidase-dependent ROS generation, increased p53 and Bax expression, enhanced the activity of caspase-9 and caspase-3, and induced cell apoptosis. Treatment with GLP-1 decreased the expression of RAGE, inhibited NAD(P)H oxidase activity, decreased cell apoptosis and increased cell viability. On the whole, our findings indicate that AOPPs induce the apoptosis of IMECs via the RAGE-NAD(P) H oxidase-dependent pathway and that treatment with GLP-1 effectively reverses these detrimental effects by decreasing AOPP-induced RAGE expression and restoring the redox balance. Our data may indicate that GLP-1 may prove to be beneficial in attenuating the progression of diabetes mellitus. PMID:27574116

  9. Plasma Free Amino Acid Responses to Intraduodenal Whey Protein, and Relationships with Insulin, Glucagon-Like Peptide-1 and Energy Intake in Lean Healthy Men.

    PubMed

    Luscombe-Marsh, Natalie D; Hutchison, Amy T; Soenen, Stijn; Steinert, Robert E; Clifton, Peter M; Horowitz, Michael; Feinle-Bisset, Christine

    2016-01-04

    This study determined the effects of increasing loads of intraduodenal (ID) dairy protein on plasma amino acid (AA) concentrations, and their relationships with serum insulin, plasma glucagon-like peptide-1 (GLP-1) and energy intake. Sixteen healthy men had concentrations of AAs, GLP-1 and insulin measured in response to 60-min ID infusions of hydrolysed whey protein administered, in double-blinded and randomised order, at 2.1 (P2.1), 6.3 (P6.3) or 12.5 (P12.5) kJ/min (encompassing the range of nutrient emptying from the stomach), or saline control (C). Energy intake was quantified immediately afterwards. Compared with C, the concentrations of 19/20 AAs, the exception being cysteine, were increased, and this was dependent on the protein load. The relationship between AA concentrations in the infusions and the area under the curve from 0 to 60 min (AUC0-60 min) of each AA profile was strong for essential AAs (R² range, 0.61-0.67), but more variable for non-essential (0.02-0.54) and conditional (0.006-0.64) AAs. The AUC0-60 min for each AA was correlated directly with the AUC0-60 min of insulin (R² range 0.3-0.6), GLP-1 (0.2-0.6) and energy intake (0.09-0.3) (p < 0.05, for all), with the strongest correlations being for branched-chain AAs, lysine, methionine and tyrosine. These findings indicate that ID whey protein infused at loads encompassing the normal range of gastric emptying increases plasma concentrations of 19/20 AAs in a load-dependent manner, and provide novel information on the close relationships between the essential AAs, leucine, valine, isoleucine, lysine, methionine, and the conditionally-essential AA, tyrosine, with energy intake, insulin and GLP-1.

  10. Exendin-4, a glucagon-like peptide 1 receptor agonist, protects against amyloid-β peptide-induced impairment of spatial learning and memory in rats.

    PubMed

    Jia, Xiao-Tao; Ye-Tian; Yuan-Li; Zhang, Ge-Juan; Liu, Zhi-Qin; Di, Zheng-Li; Ying, Xiao-Ping; Fang, Yan; Song, Er-Fei; Qi, Jin-Shun; Pan, Yan-Fang

    2016-05-15

    Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share specific molecular mechanisms, and agents with proven efficacy in one may be useful against the other. The glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has similar properties to GLP-1 and is currently in clinical use for T2DM treatment. Thus, this study was designed to characterize the effects of exendin-4 on the impairment of learning and memory induced by amyloid protein (Aβ) and its probable molecular underlying mechanisms. The results showed that (1) intracerebroventricular (i.c.v.) injection of Aβ1-42 resulted in a significant decline of spatial learning and memory of rats in water maze tests; (2) pretreatment with exendin-4 effectively and dose-dependently protected against the Aβ1-42-induced impairment of spatial learning and memory; (3) exendin-4 treatment significantly decreased the expression of Bax and cleaved caspase-3 and increased the expression of Bcl2 in Aβ1-42-induced Alzheimer's rats. The vision and swimming speed of the rats among all groups in the visible platform tests did not show any difference. These findings indicate that systemic pretreatment with exendin-4 can effectively prevent the behavioral impairment induced by neurotoxic Aβ1-42, and the underlying protective mechanism of exendin-4 may be involved in the Bcl2, Bax and caspase-3 pathways. Thus, the application of exendin-4 or the activation of its signaling pathways may be a promising strategy to ameliorate the degenerative processes observed in AD. PMID:26992957

  11. Cardioprotection Resulting from Glucagon-Like Peptide-1 Administration Involves Shifting Metabolic Substrate Utilization to Increase Energy Efficiency in the Rat Heart

    PubMed Central

    Aravindhan, Karpagam; Bao, Weike; Harpel, Mark R.; Willette, Robert N.; Lepore, John J.; Jucker, Beat M.

    2015-01-01

    Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mechanism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxidation levels were measured in both normal and ischemic hearts using a 1-13C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitoring pH and O2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake (↑64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohydrate versus fat oxidation (↑14%, p<0.01) in the LV area not at risk, without affecting cAMP levels. Interestingly, no substrate switching occurred in the LV area at risk, despite an increase in cAMP (↑106%, p<0.05) and lactate (↑121%, p<0.01) levels. Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding. Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury. In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner. PMID:26098939

  12. Cardioprotection Resulting from Glucagon-Like Peptide-1 Administration Involves Shifting Metabolic Substrate Utilization to Increase Energy Efficiency in the Rat Heart.

    PubMed

    Aravindhan, Karpagam; Bao, Weike; Harpel, Mark R; Willette, Robert N; Lepore, John J; Jucker, Beat M

    2015-01-01

    Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mechanism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxidation levels were measured in both normal and ischemic hearts using a 1-13C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitoring pH and O2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake (↑64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohydrate versus fat oxidation (↑14%, p<0.01) in the LV area not at risk, without affecting cAMP levels. Interestingly, no substrate switching occurred in the LV area at risk, despite an increase in cAMP (↑106%, p<0.05) and lactate (↑121%, p<0.01) levels. Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding. Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury. In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.

  13. Postprandial glucagon-like peptide-1 secretion is increased during the progression of glucose intolerance and obesity in high-fat/high-sucrose diet-fed rats.

    PubMed

    Nakajima, Shingo; Hira, Tohru; Hara, Hiroshi

    2015-05-14

    Glucagon-like peptide-1 (GLP-1) is secreted by distal enteroendocrine cells in response to luminal nutrients, and exerts insulinotropic and anorexigenic effects. Although GLP-1 secretory responses under established obese or diabetic conditions have been studied, it has not been investigated whether or how postprandial GLP-1 responses were affected during the progression of diet-induced obesity. In the present study, a meal tolerance test was performed every week in rats fed a high-fat and high-sucrose (HF/HS) diet to evaluate postprandial glycaemic, insulin and GLP-1 responses. In addition, gastric emptying was assessed by the acetaminophen method. After 8 weeks of HF/HS treatment, portal vein and intestinal mucosa were collected to examine GLP-1 production. Postprandial glucose in response to normal meal ingestion was increased in the HF/HS group within 2 weeks, and its elevation gradually returned close to that of the control group until day 50. Slower postprandial gastric emptying was observed in the HF/HS group on days 6, 13 and 34. Postprandial GLP-1 and insulin responses were increased in the HF/HS group at 7 weeks. Higher portal GLP-1 and insulin levels were observed in the HF/HS group, but mucosal gut hormone mRNA levels were unchanged. These results revealed that the postprandial GLP-1 response to meal ingestion is enhanced during the progression of diet-induced glucose intolerance and obesity in rats. The boosted postprandial GLP-1 secretion by chronic HF/HS diet treatment suggests increased sensitivity to luminal nutrients in the gut, and this may slow the establishment of glucose intolerance and obesity. PMID:25827219

  14. In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

    NASA Astrophysics Data System (ADS)

    Araújo, F.; Shrestha, N.; Gomes, M. J.; Herranz-Blanco, B.; Liu, D.; Hirvonen, J. J.; Granja, P. L.; Santos, H. A.; Sarmento, B.

    2016-05-01

    Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.

  15. Postprandial glucagon-like peptide-1 secretion is increased during the progression of glucose intolerance and obesity in high-fat/high-sucrose diet-fed rats.

    PubMed

    Nakajima, Shingo; Hira, Tohru; Hara, Hiroshi

    2015-05-14

    Glucagon-like peptide-1 (GLP-1) is secreted by distal enteroendocrine cells in response to luminal nutrients, and exerts insulinotropic and anorexigenic effects. Although GLP-1 secretory responses under established obese or diabetic conditions have been studied, it has not been investigated whether or how postprandial GLP-1 responses were affected during the progression of diet-induced obesity. In the present study, a meal tolerance test was performed every week in rats fed a high-fat and high-sucrose (HF/HS) diet to evaluate postprandial glycaemic, insulin and GLP-1 responses. In addition, gastric emptying was assessed by the acetaminophen method. After 8 weeks of HF/HS treatment, portal vein and intestinal mucosa were collected to examine GLP-1 production. Postprandial glucose in response to normal meal ingestion was increased in the HF/HS group within 2 weeks, and its elevation gradually returned close to that of the control group until day 50. Slower postprandial gastric emptying was observed in the HF/HS group on days 6, 13 and 34. Postprandial GLP-1 and insulin responses were increased in the HF/HS group at 7 weeks. Higher portal GLP-1 and insulin levels were observed in the HF/HS group, but mucosal gut hormone mRNA levels were unchanged. These results revealed that the postprandial GLP-1 response to meal ingestion is enhanced during the progression of diet-induced glucose intolerance and obesity in rats. The boosted postprandial GLP-1 secretion by chronic HF/HS diet treatment suggests increased sensitivity to luminal nutrients in the gut, and this may slow the establishment of glucose intolerance and obesity.

  16. In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

    PubMed Central

    Araújo, F.; Shrestha, N.; Gomes, M. J.; Herranz-Blanco, B.; Liu, D.; Hirvonen, J. J.; Granja, P. L.; Santos, H. A.

    2016-01-01

    Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study. PMID:27150301

  17. Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels

    PubMed Central

    Reddy, I A; Pino, J A; Weikop, P; Osses, N; Sørensen, G; Bering, T; Valle, C; Bluett, R J; Erreger, K; Wortwein, G; Reyes, J G; Graham, D; Stanwood, G D; Hackett, T A; Patel, S; Fink-Jensen, A; Torres, G E; Galli, A

    2016-01-01

    Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA. PMID:27187231

  18. Spatial Approximations between Residues 6 and 12 in the Amino-terminal Region of Glucagon-like Peptide 1 and Its Receptor

    PubMed Central

    Chen, Quan; Pinon, Delia I.; Miller, Laurence J.; Dong, Maoqing

    2010-01-01

    Understanding the molecular basis of natural ligand binding and activation of the glucagon-like peptide 1 (GLP1) receptor may facilitate the development of agonist drugs useful for the management of type 2 diabetes mellitus. We previously reported molecular approximations between carboxyl-terminal residues 24 and 35 within GLP1 and its receptor. In this work, we have focused on the amino-terminal region of GLP1, known to be critical for receptor activation. We developed two high-affinity, full agonist photolabile GLP1 probes having sites of covalent attachment in positions 6 and 12 of the 30-residue peptide (GLP1(7–36)). Both probes bound to the receptor specifically and covalently labeled single distinct sites. Chemical and protease cleavage of the labeled receptor identified the juxtamembrane region of its amino-terminal domain as the region of covalent attachment of the position 12 probe, whereas the region of labeling by the position 6 probe was localized to the first extracellular loop. Radiochemical sequencing identified receptor residue Tyr145, adjacent to the first transmembrane segment, as the site of labeling by the position 12 probe, and receptor residue Tyr205, within the first extracellular loop, as the site of labeling by the position 6 probe. These data provide support for a common mechanism for natural ligand binding and activation of family B G protein-coupled receptors. This region of interaction of peptide amino-terminal domains with the receptor may provide a pocket that can be targeted by small molecule agonists. PMID:20529866

  19. Refinement of Glucagon-like Peptide 1 Docking to Its Intact Receptor Using Mid-region Photolabile Probes and Molecular Modeling*

    PubMed Central

    Miller, Laurence J.; Chen, Quan; Lam, Polo C.-H.; Pinon, Delia I.; Sexton, Patrick M.; Abagyan, Ruben; Dong, Maoqing

    2011-01-01

    The glucagon-like peptide 1 (GLP1) receptor is an important drug target within the B family of G protein-coupled receptors. Its natural agonist ligand, GLP1, has incretin-like actions and the receptor is a recognized target for management of type 2 diabetes mellitus. Despite recent solution of the structure of the amino terminus of the GLP1 receptor and several close family members, the molecular basis for GLP1 binding to and activation of the intact receptor remains unclear. We previously demonstrated molecular approximations between amino- and carboxyl-terminal residues of GLP1 and its receptor. In this work, we study spatial approximations with the mid-region of this peptide to gain insights into the orientation of the intact receptor and the ligand-receptor complex. We have prepared two new photolabile probes incorporating a p-benzoyl-l-phenylalanine into positions 16 and 20 of GLP1(7–36). Both probes bound to the GLP1 receptor specifically and with high affinity. These were each fully efficacious agonists, stimulating cAMP accumulation in receptor-bearing CHO cells in a concentration-dependent manner. Each probe specifically labeled a single receptor site. Protease cleavage and radiochemical sequencing identified receptor residue Leu141 above transmembrane segment one as its site of labeling for the position 16 probe, whereas the position 20 probe labeled receptor residue Trp297 within the second extracellular loop. Establishing ligand residue approximation with this loop region is unique among family members and may help to orient the receptor amino-terminal domain relative to its helical bundle region. PMID:21454562

  20. Split Ssp DnaB mini-intein-mediated production of recombinant human glucagon-like peptide-1/7-36.

    PubMed

    Jiang, Aiqin; Jin, Wenbo; Zhao, Feng; Tang, Yanchun; Sun, Ziyong; Liu, Jian-Ning

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) plays an important role in the regulation of postprandial insulin release. Here, we used the split DnaB mini-intein system to produce recombinant human GLP-1/7-36 (rhGLP-1) in Escherichia coli. The C-terminal domain of DnaB mini-intein (IntC) was genetically fused at the N-terminus of rhGLP-1 to produce IntC-GLP-1. IntC-GLP-1 and N-terminal domain of DnaB mini-intein (IntN) protein were prepared in a denatured buffer of pH 8.0. IntC-GLP-1 was diluted 1:8 into the phosphate buffer of pH 6.6. IntN was added into the diluted solution of IntC-GLP-1 at the molar ratio of 1:2. Then, rhGLP-1 was released from IntC-GLP-1 via inducible C-terminal peptide-bond cleavage by shifting pH from 8.0 to 6.6 at 25 °C for 24-H incubation. Then, the supernatant was applied to a Ni-Sepharose column, and the pass through fraction was collected. About 5.34 mg of rhGLP-1 with the purity of 97% was obtained from 1 L of culture medium. Mass spectrometry showed the molecular weight of 3,300.45 Da, which was equal to the theoretical value of GLP-1/7-36. The glucose-lowering activity of rhGLP-1 was confirmed by the glucose tolerance test in mice. In conclusion, the reported method was an efficient strategy to produce rhGLP-1 without using enzyme or chemical reagents, which could also be used for other similar peptides.

  1. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.

    PubMed

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Mikkelsen, Jens D; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-09-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD.

  2. Satiation and Stress-Induced Hypophagia: Examining the Role of Hindbrain Neurons Expressing Prolactin-Releasing Peptide or Glucagon-Like Peptide 1

    PubMed Central

    Maniscalco, James W.; Kreisler, Alison D.; Rinaman, Linda

    2013-01-01

    Neural circuits distributed within the brainstem, hypothalamus, and limbic forebrain interact to control food intake and energy balance under normal day-to-day conditions, and in response to stressful conditions under which homeostasis is threatened. Experimental studies using rats and mice have generated a voluminous literature regarding the functional organization of circuits that inhibit food intake in response to satiety signals, and in response to stress. Although the central neural bases of satiation and stress-induced hypophagia often are studied and discussed as if they were distinct, we propose that both behavioral states are generated, at least in part, by recruitment of two separate but intermingled groups of caudal hindbrain neurons. One group comprises a subpopulation of noradrenergic (NA) neurons within the caudal nucleus of the solitary tract (cNST; A2 cell group) that is immunopositive for prolactin-releasing peptide (PrRP). The second group comprises non-adrenergic neurons within the cNST and nearby reticular formation that synthesize glucagon-like peptide 1 (GLP-1). Axonal projections from PrRP and GLP-1 neurons target distributed brainstem and forebrain regions that shape behavioral, autonomic, and endocrine responses to actual or anticipated homeostatic challenge, including the challenge of food intake. Evidence reviewed in this article supports the view that hindbrain PrRP and GLP-1 neurons contribute importantly to satiation and stress-induced hypophagia by modulating the activity of caudal brainstem circuits that control food intake. Hindbrain PrRP and GLP-1 neurons also engage hypothalamic and limbic forebrain networks that drive parallel behavioral and endocrine functions related to food intake and homeostatic challenge, and modulate conditioned and motivational aspects of food intake. PMID:23346044

  3. Glucagon-like peptide-1 protects cardiomyocytes from advanced oxidation protein product-induced apoptosis via the PI3K/Akt/Bad signaling pathway.

    PubMed

    Zhang, Hua; Xiong, Zhouyi; Wang, Jiao; Zhang, Shuangshuang; Lei, Lei; Yang, Li; Zhang, Zhen

    2016-02-01

    Cardiomyocyte apoptosis is a major event in the pathogenesis of diabetic cardiomyopathy. Currently, no single effective treatment for diabetic cardiomyopathy exists. The present study investigated whether advanced oxidative protein products (AOPPs) have a detrimental role in the survival of cardiomyocytes and if glucagon-like peptide-1 (GLP-1) exerts a cardioprotective effect under these circumstances. The present study also aimed to determine the underlying mechanisms. H9c2 cells were exposed to increasing concentrations of AOPPs in the presence or absence of GLP-1, and the viability and apoptotic rate were detected using a cell counting kit-8 assay and flow cytometry, respectively. In addition, a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor, LY294002, was employed to illustrate the mechanism of the antiapoptotic effect of GLP-1. The expression levels of the apoptotic-associated proteins, Akt, B-cell lymphoma (Bcl)-2, Bcl-2-associated death promoter (Bad), Bcl-2-associated X protein (Bax) and caspase-3 were measured by western blotting. It was revealed that GLP-1 significantly attenuated AOPP-induced cell toxicity and apoptosis. AOPPs inactivated the phosphorylation of Akt, reduced the phosphorylation of Bad, decreased the expression of Bcl-2, increased the expression of Bax and the activation of caspase-3 in H9c2 cells. GLP-1 reversed the above changes induced by AOPPs and the protective effects of GLP-1 were abolished by the PI3K inhibitor, LY294002. In conclusion, the present data suggested that GLP-1 protected cardiomyocytes against AOPP-induced apoptosis, predominantly via the PI3K/Akt/Bad pathway. These results provided a conceivable mechanism for the development of diabetic cardiomyopathy and rendered a novel application of GLP-1 exerting favorable cardiac effects for the treatment of diabetic cardiomyopathy.

  4. Substitution of the cysteine 438 residue in the cytoplasmic tail of the glucagon-like peptide-1 receptor alters signal transduction activity.

    PubMed

    Vázquez, Patricia; Roncero, Isabel; Blázquez, Enrique; Alvarez, Elvira

    2005-04-01

    Several G-protein-coupled receptors contain cysteine residues in the C-terminal tail that may modulate receptor function. In this work we analysed the substitution of Cys438 by alanine in the glucagon-like peptide-1 (GLP-1) receptor (GLPR), which led to a threefold decrease in cAMP production, although endocytosis and cellular redistribution of GLP-1 receptor agonist-induced processes were unaffected. Additionally, cysteine residues in the C-terminal tail of several G-protein-coupled receptors were found to act as substrates for palmitoylation, which might modify the access of protein kinases to this region. His-tagged GLP-1 receptors incorporated 3H-palmitate. Nevertheless, substitution of Cys438 prevented the incorporation of palmitate. Accordingly, we also investigated the effect of substitution of the consensus sequence by protein kinase C (PKC) Ser431/432 in both wild-type and Ala438 GLP-1 receptors. Substitution of Ser431/432 by alanine did not modify the ability of wild-type receptors to stimulate adenylate cyclase or endocytosis and recycling processes. By contrast, the substitution of Ser431/432 by alanine in the receptor containing Ala438 increased the ability to stimulate adenylate cyclase. All types of receptors were mainly internalised through coated pits. Thus, cysteine 438 in the cytoplasmic tail of the GLP-1 receptor would regulate its interaction with G-proteins and the stimulation of adenylyl cyclase. Palmitoylation of this residue might control the access of PKC to Ser431/432.

  5. Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

    PubMed

    Gil-Lozano, Manuel; Hunter, Paola M; Behan, Lucy-Ann; Gladanac, Bojana; Casper, Robert F; Brubaker, Patricia L

    2016-01-01

    The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways. PMID:26530153

  6. Glucagon-like peptide-1 protects cardiomyocytes from advanced oxidation protein product-induced apoptosis via the PI3K/Akt/Bad signaling pathway

    PubMed Central

    ZHANG, HUA; XIONG, ZHOUYI; WANG, JIAO; ZHANG, SHUANGSHUANG; LEI, LEI; YANG, LI; ZHANG, ZHEN

    2016-01-01

    Cardiomyocyte apoptosis is a major event in the pathogenesis of diabetic cardiomyopathy. Currently, no single effective treatment for diabetic cardiomyopathy exists. The present study investigated whether advanced oxidative protein products (AOPPs) have a detrimental role in the survival of cardiomyocytes and if glucagon-like peptide-1 (GLP-1) exerts a cardioprotective effect under these circumstances. The present study also aimed to determine the underlying mechanisms. H9c2 cells were exposed to increasing concentrations of AOPPs in the presence or absence of GLP-1, and the viability and apoptotic rate were detected using a cell counting kit-8 assay and flow cytometry, respectively. In addition, a phosphatidylino-sitol-4,5-bisphosphate 3-kinase (PI3K) inhibitor, LY294002, was employed to illustrate the mechanism of the antiapoptotic effect of GLP-1. The expression levels of the apoptotic-associated proteins, Akt, B-cell lymphoma (Bcl)-2, Bcl-2-associated death promoter (Bad), Bcl-2-associated X protein (Bax) and caspase-3 were measured by western blotting. It was revealed that GLP-1 significantly attenuated AOPP-induced cell toxicity and apoptosis. AOPPs inactivated the phosphorylation of Akt, reduced the phosphorylation of Bad, decreased the expression of Bcl-2, increased the expression of Bax and the activation of caspase-3 in H9c2 cells. GLP-1 reversed the above changes induced by AOPPs and the protective effects of GLP-1 were abolished by the PI3K inhibitor, LY294002. In conclusion, the present data suggested that GLP-1 protected cardiomyocytes against AOPP-induced apoptosis, predominantly via the PI3K/Akt/Bad pathway. These results provided a conceivable mechanism for the development of diabetic cardiomyopathy and rendered a novel application of GLP-1 exerting favorable cardiac effects for the treatment of diabetic cardiomyopathy. PMID:26717963

  7. Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

    PubMed

    Gil-Lozano, Manuel; Hunter, Paola M; Behan, Lucy-Ann; Gladanac, Bojana; Casper, Robert F; Brubaker, Patricia L

    2016-01-01

    The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways.

  8. Progesterone Receptor Membrane Component 1 Is a Functional Part of the Glucagon-like Peptide-1 (GLP-1) Receptor Complex in Pancreatic β Cells*

    PubMed Central

    Zhang, Ming; Robitaille, Mélanie; Showalter, Aaron D.; Huang, Xinyi; Liu, Ying; Bhattacharjee, Alpana; Willard, Francis S.; Han, Junfeng; Froese, Sean; Wei, Li; Gaisano, Herbert Y.; Angers, Stéphane; Sloop, Kyle W.; Dai, Feihan F.; Wheeler, Michael B.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates glucose homeostasis. Because of their direct stimulation of insulin secretion from pancreatic β cells, GLP-1 receptor (GLP-1R) agonists are now important therapeutic options for the treatment of type 2 diabetes. To better understand the mechanisms that control the insulinotropic actions of GLP-1, affinity purification and mass spectrometry (AP-MS) were employed to uncover potential proteins that functionally interact with the GLP-1R. AP-MS performed on Chinese hamster ovary cells or MIN6 β cells, both expressing the human GLP-1R, revealed 99 proteins potentially associated with the GLP-1R. Three novel GLP-1R interactors (PGRMC1, Rab5b, and Rab5c) were further validated through co-immunoprecipitation/immunoblotting, fluorescence resonance energy transfer, and immunofluorescence. Functional studies revealed that overexpression of PGRMC1, a novel cell surface receptor that associated with liganded GLP-1R, enhanced GLP-1-induced insulin secretion (GIIS) with the most robust effect. Knockdown of PGRMC1 in β cells decreased GIIS, indicative of positive interaction with GLP-1R. To gain insight mechanistically, we demonstrated that the cell surface PGRMC1 ligand P4-BSA increased GIIS, whereas its antagonist AG-205 decreased GIIS. It was then found that PGRMC1 increased GLP-1-induced cAMP accumulation. PGRMC1 activation and GIIS induced by P4-BSA could be blocked by inhibition of adenylyl cyclase/EPAC signaling or the EGF receptor–PI3K signal transduction pathway. These data reveal a dual mechanism for PGRMC1-increased GIIS mediated through cAMP and EGF receptor signaling. In conclusion, we identified several novel GLP-1R interacting proteins. PGRMC1 expressed on the cell surface of β cells was shown to interact with the activated GLP-1R to enhance the insulinotropic actions of GLP-1. PMID:25044020

  9. Association of Anti-Diabetic Medications Targeting the Glucagon-Like Peptide-1 Pathway and Heart Failure Events in Patients with Diabetes

    PubMed Central

    Velez, Mauricio; Peterson, Edward L.; Wells, Karen; Swadia, Tanmay; Sabbah, Hani N.; Williams, L. Keoki; Lanfear, David E.

    2014-01-01

    Background Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors (GLP-1 agents) may be protective in heart failure (HF). We set out to determine whether GLP-1 agent use is associated with HF risk in diabetics. Methods and Results Retrospective cohort study of members of a large health system. We identified >19,000 adult diabetics from January 1, 2000–July 1, 2012. GLP-1 agent users were matched 1:2 to controls using propensity matching based on age, race, gender, coronary disease, HF, diabetes duration, and number of anti-diabetic medications. The association of GLP-1 agents with time to HF hospitalization was tested with multivariable Cox regression. All-cause hospitalization and mortality were secondary endpoints. We identified 1,426 users of GLP-1 agents and 2,798 controls. Both were similar except for angiotensin-converting enzyme inhibitors/angiotensin receptor blocker (ACEi/ARB) use, number of anti-diabetic medications and age. There were 199 hospitalizations, of which 128 were for HF, and 114 deaths. GLP-1 agents were associated with reduced risk of HF hospitalization (adjusted hazard ratio [aHR] 0.51; 95% confidence interval [CI] 0.34–0.77, p=0.002), all-cause hospitalization (aHR 0.54; 95% CI 0.38–0.74, p=0.001), and death (aHR 0.31; 95% CI 0.18–0.53, p=0.001). Conclusions GLP-1 agents may reduce the risk of HF events in diabetics. PMID:25451709

  10. A silica-based pH-sensitive nanomatrix system improves the oral absorption and efficacy of incretin hormone glucagon-like peptide-1

    PubMed Central

    Qu, Wei; Li, Yong; Hovgaard, Lars; Li, Song; Dai, Wenbin; Wang, Jiancheng; Zhang, Xuan; Zhang, Qiang

    2012-01-01

    Background Glucagon-like peptide-1 (GLP-1) (7–36) is a peptide incretin hormone released from the endocrine L-cells of the intestinal mucosa with unique antidiabetic potential. Due to low absorption efficiency and instability in the gastrointestinal tract, the introduction of orally active GLP-1 is a large challenge. Here we developed a novel silica-based pH-sensitive nanomatrix of GLP-1 (SPN-GLP-1) in order to provide a strategy for oral peptide delivery. Methods SPN-GLP-1 composed of silica nanoparticles and pH-sensitive Eudragit® was prepared and characterized by dynamic light scattering, scanning electron microscope, transmission electron microscope, high-performance liquid chromatography, surface analysis, drug release, and so on. Its permeability across the Caco-2 cell monolayer and intestinal mucosa, proteolytic stability against the intestinal enzymes, pharmacokinetics, hypoglycemic effect in the intraperitoneal glucose tolerance test (IPGTT), and primary toxicity were then evaluated. Results It was indicated that the nanomatrix system obtained had a unique nanoscale structure and pH-sensitivity in drug release. It displayed a five-fold intestinal mucosa permeability and significantly higher proteolytic stability compared to native GLP-1 (P < 0.001). A longer half-life was observed after oral administration of SPN-GLP-1, and its relative bioavailability was 35.67% in comparison to intraperitoneal GLP-1. Oral delivery of SPN-GLP-1 significantly reduced the blood glucose level and its hypoglycemic effect over intraperitoneal GLP-1 reached 77%. There was no evident toxicity of SPN-GLP-1 found from both animal status and histochemical analysis of gastrointestinal tissues. Conclusion The silica-based pH-sensitive nanomatrix designed and prepared here might be considered as a potential oral delivery system not only for GLP-1, but also for other peptide or macromolecular drugs. PMID:23028226

  11. Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats

    SciTech Connect

    Yu, Yunli; Wang, Xinting; Liu, Can; Yao, Dan; Hu, Mengyue; Li, Jia; Hu, Nan; Liu, Li; Liu, Xiaodong

    2013-02-01

    Accumulating evidences have showed that gatifloxacin causes dysglycemia in both diabetic and non-diabetic patients. Our preliminary study demonstrated that gatifloxacin stimulated glucagon-like peptide 1 (GLP-1) secretion from intestinal cells. The aim of the study was to investigate the association between gatifloxacin-stimulated GLP-1 release and dysglycemia in both normal and streptozotocin-induced diabetic rats and explore the possible mechanisms. Oral administration of gatifloxacin (100 mg/kg/day and 200 mg/kg/day) for 3 and 12 days led to marked elevation of GLP-1 levels, accompanied by significant decrease in insulin levels and increase in plasma glucose. Similar results were found in normal rats treated with 3-day gatifloxacin. Gatifloxacin-stimulated GLP-1 release was further confirmed in NCI-H716 cells, which was abolished by diazoxide, a K{sub ATP} channel opener. QT-PCR analysis showed that gatifloxacin also upregulated expression of proglucagon and prohormone convertase 3 mRNA. To clarify the contradiction on elevated GLP-1 without insulinotropic effect, effects of GLP-1 and gatifloxacin on insulin release were investigated using INS-1 cells. We found that short exposure (2 h) to GLP-1 stimulated insulin secretion and biosynthesis, whereas long exposure (24 h and 48 h) to high level of GLP-1 inhibited insulin secretion and biosynthesis. Moreover, we also confirmed gatifloxacin acutely stimulated insulin secretion while chronically inhibited insulin biosynthesis. All the results gave an inference that gatifloxacin stimulated over-secretion of GLP-1, in turn, high levels of GLP-1 and gatifloxacin synergistically impaired insulin release, worsening hyperglycemia. -- Highlights: ► Gatifloxacin induced hyperglycemia both in diabetic rats and normal rats. ► Gatifloxacin enhanced GLP-1 secretion but inhibited insulin secretion in rats. ► Long-term exposure to high GLP-1 inhibited insulin secretion and biosynthesis. ► GLP-1 over-secretion may be

  12. Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance.

    PubMed

    Wiśniewski, Kazimierz; Sueiras-Diaz, Javier; Jiang, Guangcheng; Galyean, Robert; Lu, Mark; Thompson, Dorain; Wang, Yung-Chih; Croston, Glenn; Posch, Alexander; Hargrove, Diane M; Wiśniewska, Halina; Laporte, Régent; Dwyer, John J; Qi, Steve; Srinivasan, Karthik; Hartwig, Jennifer; Ferdyan, Nicky; Mares, Monica; Kraus, John; Alagarsamy, Sudarkodi; Rivière, Pierre J M; Schteingart, Claudio D

    2016-04-14

    Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesized. In vitro receptor potency at the human GLP-2, selectivity vs the human GLP-1 and GCG receptors, and PK profile in rats were determined for the new analogues. A number of compounds more potent at the hGLP-2R than the native hormone, showing excellent receptor selectivity and very low systemic clearance (CL) were discovered. Analogues 69 ([Gly(2),Nle(10),D-Thi(11),Phe(16)]hGLP-2-(1-30)-NH2), 72 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-OH), 73 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH2), 81 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NHEt), and 85 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH-((CH2)2O)4-(CH2)2-CONH2) displayed the desired profiles (EC50 (hGLP-2R) < 100 pM, CL in rat <0.3 mL/min/kg, selective vs hGLP-1R and hGCGR). Compound 73 (FE 203799) was selected as a candidate for clinical development. PMID:26986178

  13. Circulating concentrations of glucagon-like peptide 1, glucose-dependent insulinotropic peptide, peptide YY, and insulin in client-owned lean, overweight, and diabetic cats.

    PubMed

    McMillan, C J; Zapata, R C; Chelikani, P K; Snead, E C R; Cosford, K

    2016-01-01

    Our objectives were to measure plasma concentrations of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) in client-owned newly diagnosed diabetic cats and nondiabetic lean or overweight cats and to determine whether circulating concentrations of these hormones differed between study groups and if they increased postprandially as seen in other species. A total of 31 cats were recruited and placed into 1 of 3 study groups: lean (body condition score 4-5 on a scale of 1-9; n = 10), overweight (body condition score 6-8; n = 11), or diabetic (n = 10). Diabetics were newly diagnosed and had not had prior insulin therapy. Preprandial (fasting) and postprandial (60 min after meal) plasma hormone and glucose concentrations were measured at baseline and 2 and 4 wk. All cats were exclusively fed a commercially available high-protein and low-carbohydrate diet commonly prescribed to feline diabetic patients for 2 wk before the 2-wk assessment and continued through the 4-wk assessment. Results showed that plasma concentrations of GLP-1, GIP, PYY, and insulin increased in general after a meal in all study groups. Plasma PYY concentrations did not differ (P > 0.10) between study groups. Diabetics had greater plasma concentrations of GLP-1 and GIP compared with the other study groups at baseline (P < 0.05), and greater preprandial and postprandial GLP-1 concentrations than lean cats at 2 and 4 wk (P < 0.05). Preprandial plasma GIP concentrations were greater in diabetics than obese and lean (P < 0.05) cats at week 4. Postprandial plasma GIP concentrations in diabetics were greater than lean (P < 0.05) at week 2 and obese and lean cats (P < 0.05) at week 4. Together, our findings suggest that diabetic status is an important determinant of circulating concentrations of GLP-1 and GIP, but not PYY, in cats. The role of GLP-1, GIP, and PYY in the pathophysiology of feline obesity and diabetes remains to be determined.

  14. Plasma Free Amino Acid Responses to Intraduodenal Whey Protein, and Relationships with Insulin, Glucagon-Like Peptide-1 and Energy Intake in Lean Healthy Men

    PubMed Central

    Luscombe-Marsh, Natalie D.; Hutchison, Amy T.; Soenen, Stijn; Steinert, Robert E.; Clifton, Peter M.; Horowitz, Michael; Feinle-Bisset, Christine

    2016-01-01

    This study determined the effects of increasing loads of intraduodenal (ID) dairy protein on plasma amino acid (AA) concentrations, and their relationships with serum insulin, plasma glucagon-like peptide-1 (GLP-1) and energy intake. Sixteen healthy men had concentrations of AAs, GLP-1 and insulin measured in response to 60-min ID infusions of hydrolysed whey protein administered, in double-blinded and randomised order, at 2.1 (P2.1), 6.3 (P6.3) or 12.5 (P12.5) kJ/min (encompassing the range of nutrient emptying from the stomach), or saline control (C). Energy intake was quantified immediately afterwards. Compared with C, the concentrations of 19/20 AAs, the exception being cysteine, were increased, and this was dependent on the protein load. The relationship between AA concentrations in the infusions and the area under the curve from 0 to 60 min (AUC0–60 min) of each AA profile was strong for essential AAs (R2 range, 0.61–0.67), but more variable for non-essential (0.02–0.54) and conditional (0.006–0.64) AAs. The AUC0–60 min for each AA was correlated directly with the AUC0–60 min of insulin (R2 range 0.3–0.6), GLP-1 (0.2–0.6) and energy intake (0.09–0.3) (p < 0.05, for all), with the strongest correlations being for branched-chain AAs, lysine, methionine and tyrosine. These findings indicate that ID whey protein infused at loads encompassing the normal range of gastric emptying increases plasma concentrations of 19/20 AAs in a load-dependent manner, and provide novel information on the close relationships between the essential AAs, leucine, valine, isoleucine, lysine, methionine, and the conditionally-essential AA, tyrosine, with energy intake, insulin and GLP-1. PMID:26742062

  15. Dissociated effects of glucose-dependent insulinotropic polypeptide vs glucagon-like peptide-1 on beta-cell secretion and insulin clearance in mice.

    PubMed

    Pacini, Giovanni; Thomaseth, Karl; Ahrén, Bo

    2010-07-01

    Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) potently augment insulin response to glucose. It is less known what their effects are insulin clearance, which also contributes to peripheral hyperinsulinemia observed after administration of incretins together with glucose. The aims of this study were the quantification of C-peptide secretion and the evaluation of insulin clearance after administration of GIP with glucose. This allows the assessment of GIP's effects on hyperinsulinemia. In addition, GIP's effects were compared with those of GLP-1. Anesthetized female NMRI mice were injected intravenously with glucose alone (1 g/kg, n = 35) or glucose together with GIP (50 microg/kg, n = 12). Samples were taken through the following 50 minutes, and C-peptide and insulin concentrations were used to reconstruct C-peptide secretion rate and insulin clearance. In a previous study, GLP-1 (10 microg/kg) was used in 12 mice; and we used those GLP-1 results to compare GIP effects with those of GLP-1. C-peptide secretion rate peaked at 1 minute after glucose injection, and the immediate part of the insulin-releasing process was markedly augmented by both incretin hormones (1-minute suprabasal increment secretory rate was 20 +/- 2 pmol/min for GIP and 28 +/- 2 pmol/min for GLP-1, vs only 9 +/- 1 pmol/min for glucose alone; P < .001). Until 10 minutes after administration, C-peptide secretion remained higher with incretins (P < .0001), whereas starting from 20 minutes, the 3 patterns were undistinguishable (P > .2). Insulin clearance, previously shown to be abridged by 46% with GLP-1, was reduced only by a nonsignificant (P = .27) 21% with GIP. This study thus shows that the 2 incretins markedly augment glucose-stimulated insulin secretion in mice by a preferential action on the immediate response to glucose of insulin secretion. However, the action of GIP is less effective than that of GLP-1. Insulin clearance with GIP is not significantly

  16. Effects of oligofructose on appetite profile, glucagon-like peptide 1 and peptide YY3-36 concentrations and energy intake.

    PubMed

    Verhoef, Sanne P M; Meyer, Diederick; Westerterp, Klaas R

    2011-12-01

    In rats, oligofructose has been shown to stimulate satiety hormone secretion, reduce energy intake and promote weight loss. The present study aimed to examine the effect of oligofructose supplementation on appetite profiles, satiety hormone concentrations and energy intake in human subjects. A total of thirty-one healthy subjects (ten men and twenty-one women) aged 28 (SEM 3) years with a BMI of 24·8 (SEM 0·3) kg/m(2) were included in a randomised double-blind, cross-over study. The subjects received 10 g oligofructose, 16 g oligofructose or 16 g placebo (maltodextrin) daily for 13 d, with a 2-week washout period between treatments. Appetite profile, active glucagon-like peptide 1 (GLP-1) and peptide YY3-36 (PYY) concentrations and energy intake were assessed on days 0 and 13 of the treatment period. Time × treatment interaction revealed a trend of reduction in energy intake over days 0-13 by oligofructose (P = 0·068). Energy intake was significantly reduced (11 %) over time on day 13 compared with day 0 with 16 g/d oligofructose (2801 (SEM 301) v. 3217 (SEM 320) kJ, P < 0·05). Moreover, energy intake was significantly lower with 16 g/d oligofructose compared with 10 g/d oligofructose on day 13 (2801 (SEM 301) v. 3177 (SEM 276) kJ, P < 0·05). Area under the curve (AUC) for GLP-1 on day 13 was significantly higher with 16 g/d oligofructose compared with 10 g/d oligofructose (45 (SEM 4) v. 41 (SEM 3) pmol/l × h, P < 0·05). In the morning until lunch, AUC(0-230 min) for PYY on day 13 was significantly higher with 16 g/d oligofructose compared with 10 g/d oligofructose and placebo (409 (SEM 35) v. 222 (SEM 19) and 211 (SEM 20) pg/ml × h, P < 0·01). In conclusion, 16 g/d and not 10 g/d oligofructose may be an effective dose to reduce energy intake, possibly supported by higher GLP-1 and PYY concentrations.

  17. Efficacy and Acceptability of Glycemic Control of Glucagon-Like Peptide-1 Receptor Agonists among Type 2 Diabetes: A Systematic Review and Network Meta-Analysis

    PubMed Central

    Li, Zhixia; Zhang, Yuan; Quan, Xiaochi; Yang, Zhirong; Zeng, Xiantao; Ji, Linong

    2016-01-01

    Objective To synthesize current evidence of the impact of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on hypoglycemia, treatment discontinuation and glycemic level in patients with type 2 diabetes. Design Systematic review and network meta-analysis. Data Sources Literature search (Medline, Embase, the Cochrane library), website of clinical trial, bibliographies of published systematic reviews. Eligibility Criteria Randomized controlled trials with available data comparing GLP-1 RAs with placebo or traditional anti-diabetic drugs in patients with type 2 diabetes. Data Synthesis Traditional pairwise meta-analyses within DerSimonian-Laird random effects model and network meta-analysis within a Bayesian framework were performed to calculate odds ratios for the incidence of hypoglycemia, treatment discontinuation, HbA1c<7.0% and HbA1c<6.5%. Ranking probabilities for all treatments were estimated to obtain a treatment hierarchy using the surface under the cumulative ranking curve (SUCRA) and mean ranks. Results 78 trials with 13 treatments were included. Overall, all GLP-1 RAs except for albiglutide increased the risk of hypoglycemia when compared to placebo. Reduction in the incidence of hypoglycemia was found for all GLP-1 RAs versus insulin (except for dulaglutide) and sulphonylureas. For the incidence of treatment discontinuation, increase was found for exenatide, liraglutide, lixisenatide and taspoglutide versus placebo, insulin and sitagliptin. For glycemic level, decrease was found for all GLP-1 RAs versus placebo. Dulaglutide, exenatide long-acting release (exe_lar), liraglutide and taspoglutide had significant lowering effect when compared with sitagliptin (HbA1c<7.0%) and insulin (HbA1c<6.5%). Finally, according to SUCRAs, placebo, thiazolidinediones and albiglutide had the best decrease effect on hypoglycemia; sulphanylureas, sitagliptin and insulin decrease the incidence of treatment discontinuation most; exe_lar and dulaglutide had the highest

  18. Mycoprotein reduces energy intake and postprandial insulin release without altering glucagon-like peptide-1 and peptide tyrosine-tyrosine concentrations in healthy overweight and obese adults: a randomised-controlled trial.

    PubMed

    Bottin, Jeanne H; Swann, Jonathan R; Cropp, Eleanor; Chambers, Edward S; Ford, Heather E; Ghatei, Mohammed A; Frost, Gary S

    2016-07-01

    Dietary mycoprotein decreases energy intake in lean individuals. The effects in overweight individuals are unclear, and the mechanisms remain to be elucidated. This study aimed to investigate the effect of mycoprotein on energy intake, appetite regulation, and the metabolic phenotype in overweight and obese volunteers. In two randomised-controlled trials, fifty-five volunteers (age: 31 (95 % CI 27, 35) years), BMI: 28·0 (95 % CI 27·3, 28·7) kg/m2) consumed a test meal containing low (44 g), medium (88 g) or high (132 g) mycoprotein or isoenergetic chicken meals. Visual analogue scales and blood samples were collected to measure appetite, glucose, insulin, peptide tyrosine-tyrosine (PYY) and glucagon-like peptide-1 (GLP-1). Ad libitum energy intake was assessed after 3 h in part A (n 36). Gastric emptying by the paracetamol method, resting energy expenditure and substrate oxidation were recorded in part B (n 14). Metabonomics was used to compare plasma and urine samples in response to the test meals. Mycoprotein reduced energy intake by 10 % (280 kJ (67 kcal)) compared with chicken at the high content (P=0·009). All mycoprotein meals reduced insulin concentrations compared with chicken (incremental AUClow (IAUClow): -8 %, IAUCmedium: -12 %, IAUChigh: -21 %, P=0·004). There was no significant difference in glucose, PYY, GLP-1, gastric emptying rate and energy expenditure. Following chicken intake, paracetamol-glucuronide was positively associated with fullness. After mycoprotein, creatinine and the deamination product of isoleucine, α-keto-β-methyl-N-valerate, were inversely related to fullness, whereas the ketone body, β-hydroxybutyrate, was positively associated. In conclusion, mycoprotein reduces energy intake and insulin release in overweight volunteers. The mechanism does not involve changes in PYY and GLP-1. The metabonomics analysis may bring new understanding to the appetite regulatory properties of food.

  19. Acute effects of the glucagon-like peptide 2 analogue, teduglutide, on intestinal adaptation in short bowel syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neonatal short bowel syndrome following massive gut resection is associated with malabsorption of nutrients. The intestinotrophic factor glucagon-like peptide 2 (GLP-2) improves gut function in adult patients with short bowel syndrome, but its effect in pediatric patients remains unknown. Our object...

  20. Glucagon-like peptide-1 receptor agonists versus insulin glargine for type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials

    PubMed Central

    Li, Wei-Xin; Gou, Jian-Feng; Tian, Jin-Hui; Yan, Xiang; Yang, Lin

    2010-01-01

    Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of hypoglycemic drugs, including exenatide, liraglutide, albiglutide, lixisenatide, and taspoglutide. Insulin glargine is a standard agent used to supplement basal insulin in type 2 diabetes mellitus (T2DM). Objective: The aim of this study was to review the efficacy and safety profiles of GLP-1 receptor agonists versus insulin glargine in type 2 diabetic patients who have not achieved treatment goals with oral hypoglycemic agents. Methods: The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and the database of ongoing trials were searched from inception through April 2010. Additional data were sought from relevant Web sites, the American Diabetes Association, reference lists of included trials and related (systematic) reviews, and industry. Randomized controlled trials (RCTs) were selected if they were ≥3 months in duration, compared GLP-1 receptor agonists with insulin glargine in patients with T2DM, and included ≥1 of the following outcomes: mortality, complications of T2DM, glycemie control, weight, lipids, blood pressure, adverse effects, and health-related quality of life. Quasirandomized controlled trials were excluded. The quality of the eligible studies was assessed on the basis of the following aspects: randomization procedure, allocation concealment, blinding, incomplete outcome data (intent-to-treat [ITT] analysis), selective outcome reporting, and publication bias. Results: A total of 410 citations were retrieved; 5 multicenter RCTs that met the inclusion criteria were identified. They were all open-label designs with an insulin glargine arm, predefined outcomes reported, and ITT analysis. One trial had an unclear randomization procedure and allocation concealment. Publication bias was not able to be determined. No data wete found with regard to mortality or diabetes-associated complications, and few data were found on quality of life. The results of

  1. Pharmacokinetics and metabolism studies on the glucagon-like peptide-1 (GLP-1)-derived metabolite GLP-1(9-36)amide in male Beagle dogs.

    PubMed

    Eng, Heather; Sharma, Raman; McDonald, Thomas S; Landis, Margaret S; Stevens, Benjamin D; Kalgutkar, Amit S

    2014-09-01

    Glucagon-like peptide-1 (GLP-1)(7-36)amide is a 30-amino acid peptide hormone that is secreted from intestinal enteroendocrine L-cells in response to nutrients. GLP-1(7-36)amide possesses potent insulinotropic actions in the augmentation of glucose-dependent insulin secretion. GLP-1(7-36)amide is rapidly metabolized by dipeptidyl peptidase-IV to yield GLP-1(9-36)amide as the principal metabolite. Contrary to the earlier notion that peptide cleavage products of native GLP-1(7-36)amide [including GLP-1(9-36)amide] are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with GLP-1(9-36)amide in mice, dogs and humans. In the present work, in vitro metabolism and pharmacokinetic properties of GLP-1(9-36)amide have been characterized in dogs, since this preclinical species has been used as an animal model to demonstrate the in vivo vasodilatory and cardioprotective effects of GLP-1(9-36)amide. A liquid chromatography tandem mass spectrometry assay was developed for the quantitation of the intact peptide in hepatocyte incubations as opposed to a previously reported enzyme-linked immunosorbent assay. Although GLP-1(9-36)amide was resistant to proteolytic cleavage in dog plasma and bovine serum albumin (t1/2>240 min), the peptide was rapidly metabolized in dog hepatocytes with a t1/2 of 110 min. Metabolite identification studies in dog hepatocytes revealed a variety of N-terminus cleavage products, most of which, have also been observed in human and mouse hepatocytes. Proteolysis at the C-terminus was not observed in GLP-1(9-36)amide. Following the administration of a single intravenous bolus dose (20 µg/kg) to male Beagle dogs, GLP-1(9-36)amide exhibited a mean plasma clearance of 15 ml/min/kg and a low steady state distribution volume of 0.05 l/kg, which translated into a short elimination half life of 0.05 h. Following subcutaneous administration of GLP-1(9-36)amide at 50 µg/kg, systemic exposure of

  2. Effects of Green Tea Extract on Insulin Resistance and Glucagon-Like Peptide 1 in Patients with Type 2 Diabetes and Lipid Abnormalities: A Randomized, Double-Blinded, and Placebo-Controlled Trial

    PubMed Central

    Liu, Chia-Yu; Huang, Chien-Jung; Huang, Lin-Huang; Chen, I-Ju; Chiu, Jung-Peng; Hsu, Chung-Hua

    2014-01-01

    The aim of this study is to investigate the effect of green tea extract on patients with type 2 diabetes mellitus and lipid abnormalities on glycemic and lipid profiles, and hormone peptides by a double-blinded, randomized and placebo-controlled clinical trial. This trial enrolled 92 subjects with type 2 diabetes mellitus and lipid abnormalities randomized into 2 arms, each arm comprising 46 participants. Of the participants, 39 in therapeutic arm took 500 mg green tea extract, three times a day, while 38 in control arm took cellulose with the same dose and frequency to complete the 16-week study. Anthropometrics measurements, glycemic and lipid profiles, safety parameters, and obesity-related hormone peptides were analyzed at screening and after 16-week course. Within-group comparisons showed that green tea extract caused a significant decrease in triglyceride and homeostasis model assessment of insulin resistance index after 16 weeks. Green tea extract also increased significantly high density lipoprotein cholesterol. The HOMA-IR index decreased from 5.4±3.9 to 3.5±2.0 in therapeutic arm only. Adiponectin, apolipoprotein A1, and apolipoprotein B100 increased significantly in both arms, but only glucagon-like peptide 1 increased in the therapeutic arm. However, only decreasing trend in triglyceride was found in between-group comparison. Our study suggested that green tea extract significantly improved insulin resistance and increased glucagon-like peptide 1 only in within-group comparison. The potential effects of green tea extract on insulin resistance and glucagon-like peptide 1 warrant further investigation. Trial Registration ClinicalTrials.gov NCT01360567 PMID:24614112

  3. The Melanocortin-4 Receptor is Expressed in Enteroendocrine L Cells and Regulates the Release of Peptide YY and Glucagon-Like Peptide 1 In Vivo

    PubMed Central

    Panaro, Brandon L.; Tough, Iain R.; Engelstoft, Maja Storm; Matthews, Robert T.; Digby, Gregory J.; Møller, Cathrine Laustrup; Svendsen, Berit; Gribble, Fiona; Reimann, Frank; Holst, Jens J.; Holst, Birgitte; Schwartz, Thue W.; Cox, Helen M.; Cone, Roger D.

    2014-01-01

    SUMMARY The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves, and regulates a number of aspects of gastrointestinal function. Here we show that the receptor is also diffusely expressed in cells of the gastrointestinal system, from stomach to descending colon. Furthermore, MC4R is the second most highly expressed GPCR in peptide YY (PYY) and glucagon-like peptide one (GLP-1) expressing enteroendocrine L cells. When vectorial ion transport is measured across mouse or human intestinal mucosa, administration of α-MSH induces a MC4R-specific PYY-dependent anti-secretory response consistent with a role for the MC4R in paracrine inhibition of electrolyte secretion. Finally, MC4R-dependent acute PYY and GLP-1 release from L cells can be stimulated in vivo by intraperitoneal administration of melanocortin peptides to mice. This suggests physiological significance for MC4R in L cells, and indicates a previously unrecognized peripheral role for the MC4R, complementing vagal and central receptor functions. PMID:25453189

  4. The Incretins and Pancreatic beta-Cells: Use of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide to Cure Type 2 Diabetes Mellitus.

    PubMed

    Kim, Mi-Hyun; Lee, Moon-Kyu

    2010-02-01

    Type 2 diabetes mellitus (T2DM) is increasing in prevalence worldwide. The complications associated with T2DM result in increased mortality and financial cost for those affected. T2DM has long been known to be associated with insulin resistance in peripheral tissues and a relative degree of insulin deficiency. However, the concept that insulin secretion and insulin sensitivity are not linked through a hyperbolic relationship in T2DM has continuously been demonstrated in many clinical trials. Thus, in order to prevent and treat T2DM, it is necessary to identify the substance(s) that will improve the function and survival of the pancreatic beta-cells in both normal and pathologic conditions, so that production and secretion of insulin can be enhanced. Incretin hormones, such as glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), have been shown to lower the postprandial and fasting glucose and the glycated hemoglobin levels, suppress the elevated glucagon level, and stimulate glucose-dependent insulin synthesis and secretion. In this report, we will review the biological actions and mechanisms associated with the actions of incretin hormones, GLP-1 and GIP, on beta-cell health and compare the differences between GLP-1 and GIP.

  5. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats.

    PubMed

    Hoelmkjaer, Kirsten M; Wewer Albrechtsen, Nicolai J; Holst, Jens J; Cronin, Anna M; Nielsen, Dorte H; Mandrup-Poulsen, Thomas; Bjornvad, Charlotte R

    2016-01-01

    Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight) was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all). Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4%) in the exenatide group versus 3.2% (range -5.3 to 5.7%) in the placebo group (P = 0.10). Body composition and adipokine levels were unaffected by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats. PMID:27136422

  6. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats

    PubMed Central

    Hoelmkjaer, Kirsten M.; Wewer Albrechtsen, Nicolai J.; Holst, Jens J.; Cronin, Anna M.; Nielsen, Dorte H.; Mandrup-Poulsen, Thomas; Bjornvad, Charlotte R.

    2016-01-01

    Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight) was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all). Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4%) in the exenatide group versus 3.2% (range -5.3 to 5.7%) in the placebo group (P = 0.10). Body composition and adipokine levels were unaffected by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats. PMID:27136422

  7. Intrameal Hepatic Portal and Intraperitoneal Infusions of Glucagon-Like Peptide-1 Reduce Spontaneous Meal Size in the Rat via Different Mechanisms

    PubMed Central

    Rüttimann, Elisabeth B.; Arnold, Myrtha; Hillebrand, Jacquelien J.; Geary, Nori; Langhans, Wolfgang

    2009-01-01

    Peripheral administration of glucagon-like peptide (GLP)-1 reduces food intake in animals and humans, but the sites and mechanism of this effect and its physiological significance are not yet clear. To investigate these issues, we prepared rats with chronic catheters and infused GLP-1 (0.2 ml/min; 2.5 or 5.0 min) during the first spontaneous dark-phase meals. Infusions were remotely triggered 2–3 min after meal onset. Hepatic portal vein (HPV) infusion of 1.0 or 3.0 (but not 0.33) nmol/kg GLP-1 reduced the size of the ongoing meal compared with vehicle without affecting the subsequent intermeal interval, the size of subsequent meals, or cumulative food intake. In double-cannulated rats, HPV and vena cava infusions of 1.0 nmol/kg GLP-1 reduced meal size similarly. HPV GLP-1 infusions of 1.0 nmol/kg GLP-1 also reduced meal size similarly in rats with subdiaphragmatic vagal deafferentations and in sham-operated rats. Finally, HPV and ip infusions of 10 nmol/kg GLP-1 reduced meal size similarly in sham-operated rats, but only HPV GLP-1 reduced meal size in subdiaphragmatic vagal deafferentation rats. These data indicate that peripherally infused GLP-1 acutely and specifically reduces the size of ongoing meals in rats and that the satiating effect of ip, but not iv, GLP-1 requires vagal afferent signaling. The findings suggest that iv GLP-1 infusions do not inhibit eating via hepatic portal or hepatic GLP-1 receptors but may act directly on the brain. PMID:18948395

  8. Sardine protein diet increases plasma glucagon-like peptide-1 levels and prevents tissue oxidative stress in rats fed a high-fructose diet.

    PubMed

    Madani, Zohra; Sener, Abdullah; Malaisse, Willy J; Dalila, Ait Yahia

    2015-11-01

    The current study investigated whether sardine protein mitigates the adverse effects of fructose on plasma glucagon‑like peptide-1 (GLP-1) and oxidative stress in rats. Rats were fed casein (C) or sardine protein (S) with or without high‑fructose (HF) for 2 months. Plasma glucose, insulin, GLP‑1, lipid and protein oxidation and antioxidant enzymes were assayed. HF rats developed obesity, hyperglycemia, hyperinsulinemia, insulin resistance and oxidative stress despite reduced energy and food intakes. High plasma creatinine and uric acid levels, in addition to albuminuria were observed in the HF groups. The S‑HF diet reduced plasma glucose, insulin, creatinine, uric acid and homeostasis model assessment‑insulin resistance index levels, however increased GLP‑1 levels compared with the C‑HF diet. Hydroperoxides were reduced in the liver, kidney, heart and muscle of S‑HF fed rats compared with C‑HF fed rats. A reduction in liver, kidney and heart carbonyls was observed in S‑HF fed rats compared with C‑HF fed rats. Reduced levels of nitric oxide (NO) were detected in the liver, kidney and heart of the S‑HF fed rats compared with C‑HF fed rats. The S diet compared with the C diet reduced levels of liver hydroperoxides, heart carbonyls and kidney NO. The S‑HF diet compared with the C‑HF diet increased the levels of liver and kidney superoxide dismutase, liver and muscle catalase, liver, heart and muscle glutathione peroxidase and liver ascorbic acid. The S diet prevented and reversed insulin resistance and oxidative stress, and may have benefits in patients with metabolic syndrome.

  9. The effect of glucose when added to a fat load on the response of glucagon-like peptide-1 (GLP-1) and apolipoprotein B-48 in the postprandial phase.

    PubMed

    Zemánková, K; Mrázková, J; Piťha, J; Kovář, J

    2015-01-01

    Increased and prolonged postprandial lipemia has been identified as a risk factor of cardiovascular disease. However, there is no consensus on how to test postprandial lipemia, especially with respect to the composition of an experimental meal. To address this question of how glucose, when added to a fat load, affects the selected parameters of postprandial lipemia, we carried out a study in 30 healthy male volunteers. Men consumed an experimental meal containing either 75 g of fat + 25 g of glucose (F+G meal) or 75 g of fat (F meal) in a control experiment. Blood was taken before the meal and at selected time points within the following 8 h. Glucose, when added to a fat load, induced an increase of glycemia and insulinemia and, surprisingly, a 20 % reduction in the response of both total and active glucagon-like peptide-1 (GLP-1) concentration. The addition of glucose did not affect the magnitude of postprandial triglyceridemia and TRL-C and TRL-TG concentrations but stimulated a faster response of chylomicrons to the test meal, evaluated by changes in apolipoprotein B-48 concentrations. The addition of glucose induced the physiological response of insulin and the lower response of GLP-1 to the test meal during the early postprandial phase, but had no effect on changes of TRL-cholesterol and TRL-TG within 8 h after the meal. PMID:26680669

  10. Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1.

    PubMed

    den Besten, Gijs; Gerding, Albert; van Dijk, Theo H; Ciapaite, Jolita; Bleeker, Aycha; van Eunen, Karen; Havinga, Rick; Groen, Albert K; Reijngoud, Dirk-Jan; Bakker, Barbara M

    2015-01-01

    The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR) γ repression and AMP-activated protein kinase (AMPK) activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention. PMID:26292284

  11. Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1

    PubMed Central

    den Besten, Gijs; Gerding, Albert; van Dijk, Theo H.; Ciapaite, Jolita; Bleeker, Aycha; van Eunen, Karen; Havinga, Rick; Groen, Albert K.; Reijngoud, Dirk-Jan; Bakker, Barbara M.

    2015-01-01

    The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR) γ repression and AMP-activated protein kinase (AMPK) activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention. PMID:26292284

  12. The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence.

    PubMed

    Suchankova, P; Yan, J; Schwandt, M L; Stangl, B L; Caparelli, E C; Momenan, R; Jerlhag, E; Engel, J A; Hodgkinson, C A; Egli, M; Lopez, M F; Becker, H C; Goldman, D; Heilig, M; Ramchandani, V A; Leggio, L

    2015-06-16

    The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.

  13. Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns.

    PubMed

    Elliott, R M; Morgan, L M; Tredger, J A; Deacon, S; Wright, J; Marks, V

    1993-07-01

    The acute effects of different macronutrients on the secretion of glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) and glucose-dependent insulinotropic polypeptide (GIP) were compared in healthy human subjects. Circulating levels of the two hormones were measured over a 24-h period during which subjects consumed a mixed diet. In the first study, eight subjects consumed three equicaloric (375 kcal) test meals of carbohydrate, fat and protein. Small increases in plasma GLP-1(7-36) amide were found after all meals. Levels reached a maximum 30 min after the carbohydrate and 150 min after the fat load. Ingestion of both carbohydrate and fat induced substantial rises in GIP secretion, but the protein meal had no effect. In a second study, eight subjects consumed 75 g glucose or the equivalent portion of complex carbohydrate as boiled brown rice or barley. Plasma GIP, insulin and glucose levels increased after all three meals, the largest increase being observed following glucose and the smallest following the barley meal. Plasma GLP-1(7-36)amide levels rose only following the glucose meal. In the 24-h study, plasma GLP-1(7-36)amide and GIP concentrations were increased following every meal and remained elevated throughout the day, only falling to fasting levels at night. The increases in circulating GLP-1(7-36)amide and GIP levels following carbohydrate or a mixed meal are consistent with their role as incretins. The more sustained rises observed in the daytime during the 24-h study are consistent with an anabolic role in lipid metabolism.

  14. Modeling analysis of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization under the control of glucagon-like peptide-1 in mouse pancreatic β-cells.

    PubMed

    Takeda, Yukari; Shimayoshi, Takao; Holz, George G; Noma, Akinori

    2016-03-01

    Glucagon-like peptide-1 (GLP-1) is an intestinally derived blood glucose-lowering hormone that potentiates glucose-stimulated insulin secretion from pancreatic β-cells. The secretagogue action of GLP-1 is explained, at least in part, by its ability to stimulate cAMP production so that cAMP may facilitate the release of Ca(2+) from inositol trisphosphate receptor (IP3R)-regulated Ca(2+) stores. However, a quantitative model has yet to be provided that explains the molecular mechanisms and dynamic processes linking GLP-1-stimulated cAMP production to Ca(2+) mobilization. Here, we performed simulation studies to investigate how GLP-1 alters the abilities of Ca(2+) and IP3 to act as coagonists at IP3R Ca(2+) release channels. A new dynamic model was constructed based on the Kaftan model, which demonstrates dual steady-state allosteric regulation of the IP3R by Ca(2+) and IP3. Data obtained from β-cells were then analyzed to understand how GLP-1 facilitates IP3R-mediated Ca(2+) mobilization when UV flash photolysis is used to uncage Ca(2+) and IP3 intracellularly. When the dynamic model for IP3R activation was incorporated into a minimal cell model, the Ca(2+) transients and oscillations induced by GLP-1 were successfully reconstructed. Simulation studies indicated that transient and oscillatory responses to GLP-1 were produced by sequential positive and negative feedback regulation due to fast activation and slow inhibition of the IP3R by Ca(2+). The slow rate of Ca(2+)-dependent inhibition was revealed to provide a remarkable contribution to the time course of the decay of cytosolic Ca(2+) transients. It also served to drive and pace Ca(2+) oscillations that are significant when evaluating how GLP-1 stimulates insulin secretion. PMID:26741144

  15. The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence

    PubMed Central

    Suchankova, P; Yan, J; Schwandt, M L; Stangl, B L; Caparelli, E C; Momenan, R; Jerlhag, E; Engel, J A; Hodgkinson, C A; Egli, M; Lopez, M F; Becker, H C; Goldman, D; Heilig, M; Ramchandani, V A; Leggio, L

    2015-01-01

    The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case–control analysis (N=908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N=3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N=81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N=22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P=0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P=0.033). The 168Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD. PMID:26080318

  16. Deoxynivalenol (Vomitoxin)-Induced Cholecystokinin and Glucagon-Like Peptide-1 Release in the STC-1 Enteroendocrine Cell Model Is Mediated by Calcium-Sensing Receptor and Transient Receptor Potential Ankyrin-1 Channel.

    PubMed

    Zhou, Hui-Ren; Pestka, James J

    2015-06-01

    Food refusal is a hallmark of exposure of experimental animals to the trichothecene mycotoxin deoxynivalenol (DON), a common foodborne contaminant. Although studies in the mouse suggest that DON suppresses food intake by aberrantly inducing the release of satiety hormones from enteroendocrine cells (EECs) found in the gut epithelium, the underlying mechanisms for this effect are not understood. To address this gap, we employed the murine neuroendocrine tumor STC-1 cell line, a widely used EEC model, to test the hypothesis that DON-induced hormone exocytosis is mediated by G protein-coupled receptor (GPCR)-mediated Ca(2+) signaling. The results indicate for the first time that DON elicits Ca(2)-dependent secretion of cholecystokinin (CCK) and glucagon-like peptide-1(7-36) amide (GLP-1), hormones that regulate food intake and energy homeostasis and that are products of 2 critical EEC populations--I cells of the small intestine and L cells of the large intestine, respectively. Furthermore, these effects were mediated by the GPCR Ca(2+)-sensing receptor (CaSR) and involved the following serial events: (1)PLC-mediated activation of the IP3 receptor and mobilization of intracellular Ca(2+) stores, (2) activation of transient receptor potential melastatin-5 ion channel and resultant L-type voltage-sensitive Ca(2+) channel-facilitated extracellular Ca(2+) entry, (3) amplification of extracellular Ca(2+) entry by transient receptor potential ankyrin-1 channel activation, and finally (4) Ca(2+)-driven CCK and GLP-1 excytosis. These in vitro findings provide a foundation for future investigation of mechanisms by which DON and other trichothecenes modulate EEC function in ex vivo and in vivo models. PMID:25787141

  17. Demonstration of the innate electrophilicity of 4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a small-molecule positive allosteric modulator of the glucagon-like peptide-1 receptor.

    PubMed

    Eng, Heather; Sharma, Raman; McDonald, Thomas S; Edmonds, David J; Fortin, Jean-Philippe; Li, Xianping; Stevens, Benjamin D; Griffith, David A; Limberakis, Chris; Nolte, Whitney M; Price, David A; Jackson, Margaret; Kalgutkar, Amit S

    2013-08-01

    4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagon-like peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore the quantitative pharmacology associated with GLP-1R agonism in preclinical species, the in vivo pharmacokinetics of BETP were examined in rats after i.v. and oral dosing. Failure to detect BETP in circulation after oral administration of a 10-mg/kg dose in rats was consistent with the lack of an insulinotropic effect of orally administered BETP in this species. Likewise, systemic concentrations of BETP in the rat upon i.v. administration (1 mg/kg) were minimal (and sporadic). In vitro incubations in bovine serum albumin, plasma, and liver microsomes from rodents and humans indicated a facile degradation of BETP. Failure to detect metabolites in plasma and liver microsomal incubations in the absence of NADP was suggestive of a covalent interaction between BETP and a protein amino acid residue(s) in these matrices. Incubations of BETP with glutathione (GSH) in buffer revealed a rapid nucleophilic displacement of the ethylsulfoxide functionality by GSH to yield adduct M1, which indicated that BETP was intrinsically electrophilic. The structure of M1 was unambiguously identified by comparison of its chromatographic and mass spectral properties with an authentic standard. The GSH conjugate of BETP was also characterized in NADPH- and GSH-supplemented liver microsomes and in plasma samples from the pharmacokinetic studies. Unlike BETP, M1 was inactive as an allosteric modulator of the GLP-1R. PMID:23653442

  18. Role of capsaicin-sensitive peripheral sensory neurons in anorexic responses to intravenous infusions of cholecystokinin, peptide YY-(3-36), and glucagon-like peptide-1 in rats.

    PubMed

    Reidelberger, Roger; Haver, Alvin; Anders, Krista; Apenteng, Bettye

    2014-10-15

    Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

  19. A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures

    PubMed Central

    Reynolds, Christopher A.; Koole, Cassandra; Smith, Kevin J.; Mobarec, Juan C.; Simms, John; Quon, Tezz; Coudrat, Thomas; Furness, Sebastian G. B.; Miller, Laurence J.; Christopoulos, Arthur; Sexton, Patrick M.

    2016-01-01

    The glucagon-like peptide 1 (GLP-1) receptor is a class B G protein-coupled receptor (GPCR) that is a key target for treatments for type II diabetes and obesity. This receptor, like other class B GPCRs, displays biased agonism, though the physiologic significance of this is yet to be elucidated. Previous work has implicated R2.60190, N3.43240, Q7.49394, and H6.52363 as key residues involved in peptide-mediated biased agonism, with R2.60190, N3.43240, and Q7.49394 predicted to form a polar interaction network. In this study, we used novel insight gained from recent crystal structures of the transmembrane domains of the glucagon and corticotropin releasing factor 1 (CRF1) receptors to develop improved models of the GLP-1 receptor that predict additional key molecular interactions with these amino acids. We have introduced E6.53364A, N3.43240Q, Q7.49394N, and N3.43240Q/Q7.49394N mutations to probe the role of predicted H-bonding and charge-charge interactions in driving cAMP, calcium, or extracellular signal-regulated kinase (ERK) signaling. A polar interaction between E6.53364 and R2.60190 was predicted to be important for GLP-1- and exendin-4-, but not oxyntomodulin-mediated cAMP formation and also ERK1/2 phosphorylation. In contrast, Q7.49394, but not R2.60190/E6.53364 was critical for calcium mobilization for all three peptides. Mutation of N3.43240 and Q7.49394 had differential effects on individual peptides, providing evidence for molecular differences in activation transition. Collectively, this work expands our understanding of peptide-mediated signaling from the GLP-1 receptor and the key role that the central polar network plays in these events. PMID:26700562

  20. Effects of glucagon-like peptide-1 receptor stimulation and blockade on food consumption and body weight in rats treated with a cannabinoid CB1 receptor agonist WIN 55,212-2

    PubMed Central

    Radziszewska, Elżbieta; Bojanowska, Ewa

    2013-01-01

    Background Glucagon-like peptide-1 (GLP-1) and endocannabinoids are involved in appetite control. Recently we have demonstrated that cannabinoid (CB)1 receptor antagonist and GLP-1 receptor agonist synergistically suppress food intake in the rat. The aim of the present study was to determine the effects of GLP-1 receptor stimulation or blockade on feeding behavior in rats treated with WIN 55,212-2, a CB1 receptor agonist. Material/Methods Experiments were performed on adult male Wistar rats. In the first experiment the effects of increasing doses (0.5–4.0 mg/kg) of WIN 55,212-2 injected intraperitoneally on 24-hour food consumption were tested. In further experiments a GLP-1 receptor antagonist, exendin (9-39), and WIN 55,212-2 or a GLP-1 receptor agonist, exendin-4, and WIN 55,212-2 were injected intraperitoneally at subthreshold doses (that alone did not change food intake and body weight) to investigate whether these agents may interact to affect food intake in rats. Results WIN 55,212-2 administered at low doses (0.5–2 mg/kg) did not markedly change 24-hour food consumption; however, at the highest dose, daily food intake was inhibited. Combined administration of WIN 55,212-2 and exendin (9-39) did not change the amount of food consumed compared to either the control group or to each agent injected alone. Combined injection of WIN 55,212-2 and exendin-4 at subthreshold doses resulted in a significant decrease in food intake and body weight in rats. Conclusions Stimulation of the peripheral CB1 receptor by its agonist WIN 55,212-2 can induce anorexigenic effects or potentiate, even at a subthreshold dose, the effects of exendin-4, a known anorectic agent. Hence, this dual action of the cannabinoid system should be considered in the medical use of CB1 agonists. PMID:23291632

  1. Potentiation of insulin secretion and improvement of glucose intolerance by combining a novel G protein-coupled receptor 40 agonist DS-1558 with glucagon-like peptide-1 receptor agonists.

    PubMed

    Nakashima, Ryutaro; Yano, Tatsuya; Ogawa, Junko; Tanaka, Naomi; Toda, Narihiro; Yoshida, Masao; Takano, Rieko; Inoue, Masahiro; Honda, Takeshi; Kume, Shoen; Matsumoto, Koji

    2014-08-15

    G protein-coupled receptor 40 (GPR40) is a Gq-coupled receptor for free fatty acids predominantly expressed in pancreatic β-cells. In recent years, GPR40 agonists have been investigated for use as novel therapeutic agents in the treatment of type 2 diabetes. We discovered a novel small molecule GPR40 agonist, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (DS-1558). The GPR40-mediated effects of DS-1558 on glucose-stimulated insulin secretion were evaluated in isolated islets from GPR40 knock-out and wild-type (littermate) mice. The GPR40-mediated effects on glucose tolerance and insulin secretion were also confirmed by an oral glucose tolerance test in these mice. Furthermore, oral administration of DS-1558 (0.03, 0.1 and 0.3mg/kg) significantly and dose-dependently improved hyperglycemia and increased insulin secretion during the oral glucose tolerance test in Zucker fatty rats, the model of insulin resistance and glucose intolerance. Next, we examined the combination effects of DS-1558 with glucagon like peptide-1 (GLP-1). DS-1558 not only increased the glucose-stimulated insulin secretion by GLP-1 but also potentiated the maximum insulinogenic effects of GLP-1 after an intravenous glucose injection in normal Sprague Dawley rats. Furthermore, the glucose lowering effects of exendin-4, a GLP-1 receptor agonist, were markedly potentiated by the DS-1558 (3mg/kg) add-on in diabetic db/db mice during an intraperitoneal glucose tolerance test. In conclusion, our results indicate that add-on GPR40 agonists to GLP-1 related agents might be a potential treatment compared to single administration of these compounds. Therefore the combinations of these agents are a novel therapeutic option for type 2 diabetes.

  2. Effects of glucagon-like peptide-1 on advanced glycation endproduct-induced aortic endothelial dysfunction in streptozotocin-induced diabetic rats: possible roles of Rho kinase- and AMP kinase-mediated nuclear factor κB signaling pathways.

    PubMed

    Tang, Song-Tao; Zhang, Qiu; Tang, Hai-Qin; Wang, Chang-Jiang; Su, Huan; Zhou, Qing; Wei, Wei; Zhu, Hua-Qing; Wang, Yuan

    2016-07-01

    Interaction between advanced glycation endproducts (AGEs) and receptor for AGEs (RAGE) as well as downstream pathways leads to vascular endothelial dysfunction in diabetes. Glucagon-like peptide-1 (GLP-1) has been reported to attenuate endothelial dysfunction in the models of atherosclerosis. However, whether GLP-1 exerts protective effects on aortic endothelium in diabetic animal model and the underlying mechanisms are still not well defined. Experimental diabetes was induced through administration with combination of high-fat diet and intraperitoneal injection of streptozotocin. Rats were randomly divided into four groups, including controls, diabetes, diabetes + sitagliptin (30 mg/kg/day), diabetes + exenatide (3 μg/kg/12 h). Eventually, endothelial damage, markers of inflammation and oxidative stress, were measured. After 12 weeks administration, diabetic rats received sitagliptin and exenatide showed significant elevation of serum NO level and reduction of ET-1 as well as inflammatory cytokines levels. Moreover, sitagliptin and exenatide significantly inhibited aortic oxidative stress level and improved aortic endothelial function in diabetic rats. Importantly, these drugs inhibited the protein expression level in AGE/RAGE-induced RhoA/ROCK/NF-κB/IκBα signaling pathways and activated AMPK in diabetic aorta. Finally, the target proteins of p-eNOS, iNOS, and ET-1, which reflect endothelial function, were also changed by these drugs. Our present study indicates that sitagliptin and exenatide administrations can improve endothelial function in diabetic aorta. Of note, RAGE/RhoA/ROCK and AMPK mediated NF-κB signaling pathways may be the intervention targets of these drugs to protect aortic endothelium. PMID:26758998

  3. JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, suppresses food intake and gastric emptying with the elevation of plasma peptide YY and glucagon-like peptide-1 in a dietary fat-dependent manner.

    PubMed

    Hata, Takahiro; Mera, Yasuko; Ishii, Yukihito; Tadaki, Hironobu; Tomimoto, Daisuke; Kuroki, Yukiharu; Kawai, Takashi; Ohta, Takeshi; Kakutani, Makoto

    2011-03-01

    The microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. In this study, we investigated the effects of diethyl-2-({3-dimethylcarbamoyl-4-[(4'-trifluoromethylbiphenyl-2-carbonyl) amino] phenyl}acetyloxymethyl)-2-phenylmalonate (JTT-130), a novel intestine-specific MTP inhibitor, on food intake, gastric emptying, and gut peptides using Sprague-Dawley rats fed 3.1% fat, 13% fat, or 35% fat diets. JTT-130 treatment suppressed cumulative food intake and gastric emptying in rats fed a 35% fat diet, but not a 3.1% fat diet. In rats fed a 13% fat diet, JTT-130 treatment decreased cumulative food intake but not gastric emptying. In addition, treatment with orlistat, a lipase inhibitor, completely abolished the reduction of food intake and gastric emptying by JTT-130 in rats fed a 35% fat diet. On the other hand, JTT-130 treatment increased the plasma concentrations of gut peptides, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) but not cholecystokinin, in the portal vein in rats fed a 35% fat diet. These elevations in PYY and GLP-1 were also abolished by treatment with orlistat. Furthermore, JTT-130 treatment in rats fed a 35% fat diet increased the contents of triglycerides and free fatty acids in the intestinal lumen, which might contribute to the elevation of PYY and GLP-1 levels. The present findings indicate that JTT-130 causes satiety responses, decreased food intake, and gastric emptying in a dietary fat-dependent manner, with enhanced production of gut peptides such as PYY and GLP-1 from the intestine.

  4. Deoxynivalenol (Vomitoxin)-Induced Cholecystokinin and Glucagon-Like Peptide-1 Release in the STC-1 Enteroendocrine Cell Model Is Mediated by Calcium-Sensing Receptor and Transient Receptor Potential Ankyrin-1 Channel.

    PubMed

    Zhou, Hui-Ren; Pestka, James J

    2015-06-01

    Food refusal is a hallmark of exposure of experimental animals to the trichothecene mycotoxin deoxynivalenol (DON), a common foodborne contaminant. Although studies in the mouse suggest that DON suppresses food intake by aberrantly inducing the release of satiety hormones from enteroendocrine cells (EECs) found in the gut epithelium, the underlying mechanisms for this effect are not understood. To address this gap, we employed the murine neuroendocrine tumor STC-1 cell line, a widely used EEC model, to test the hypothesis that DON-induced hormone exocytosis is mediated by G protein-coupled receptor (GPCR)-mediated Ca(2+) signaling. The results indicate for the first time that DON elicits Ca(2)-dependent secretion of cholecystokinin (CCK) and glucagon-like peptide-1(7-36) amide (GLP-1), hormones that regulate food intake and energy homeostasis and that are products of 2 critical EEC populations--I cells of the small intestine and L cells of the large intestine, respectively. Furthermore, these effects were mediated by the GPCR Ca(2+)-sensing receptor (CaSR) and involved the following serial events: (1)PLC-mediated activation of the IP3 receptor and mobilization of intracellular Ca(2+) stores, (2) activation of transient receptor potential melastatin-5 ion channel and resultant L-type voltage-sensitive Ca(2+) channel-facilitated extracellular Ca(2+) entry, (3) amplification of extracellular Ca(2+) entry by transient receptor potential ankyrin-1 channel activation, and finally (4) Ca(2+)-driven CCK and GLP-1 excytosis. These in vitro findings provide a foundation for future investigation of mechanisms by which DON and other trichothecenes modulate EEC function in ex vivo and in vivo models.

  5. Glucagon-like peptide 1 (GLP-1) can reverse AMP-activated protein kinase (AMPK) and S6 kinase (P70S6K) activities induced by fluctuations in glucose levels in hypothalamic areas involved in feeding behaviour.

    PubMed

    Hurtado-Carneiro, Verónica; Sanz, Carmen; Roncero, Isabel; Vazquez, Patricia; Blazquez, Enrique; Alvarez, Elvira

    2012-04-01

    The anorexigenic peptide, glucagon-like peptide-1 (GLP-1), reduces glucose metabolism in the human hypothalamus and brain stem. The brain activity of metabolic sensors such as AMP-activated protein kinase (AMPK) responds to changes in glucose levels. The mammalian target of rapamycin (mTOR) and its downstream target, p70S6 kinase (p70S6K), integrate nutrient and hormonal signals. The hypothalamic mTOR/p70S6K pathway has been implicated in the control of feeding and the regulation of energy balances. Therefore, we investigated the coordinated effects of glucose and GLP-1 on the expression and activity of AMPK and p70S6K in the areas involved in the control of feeding. The effect of GLP-1 on the expression and activities of AMPK and p70S6K was studied in hypothalamic slice explants exposed to low- and high-glucose concentrations by quantitative real-time RT-PCR and by the quantification of active-phosphorylated protein levels by immunoblot. In vivo, the effects of exendin-4 on hypothalamic AMPK and p70S6K activation were analysed in male obese Zucker and lean controls 1 h after exendin-4 injection to rats fasted for 48 h or after re-feeding for 2-4 h. High-glucose levels decreased the expression of Ampk in the lateral hypothalamus and treatment with GLP-1 reversed this effect. GLP-1 treatment inhibited the activities of AMPK and p70S6K when the activation of these protein kinases was maximum in both the ventromedial and lateral hypothalamic areas. Furthermore, in vivo s.c. administration of exendin-4 modulated AMPK and p70S6K activities in those areas, in both fasted and re-fed obese Zucker and lean control rats.

  6. Comparative Effects of the Endogenous Agonist Glucagon-Like Peptide-1 (GLP-1)-(7-36) Amide and the Small-Molecule Ago-Allosteric Agent “Compound 2” at the GLP-1 Receptor

    PubMed Central

    Coopman, Karen; Huang, Yan; Johnston, Neil; Bradley, Sophie J.; Wilkinson, Graeme F.

    2010-01-01

    Glucagon-like peptide-1 (GLP-1) mediates antidiabetogenic effects through the GLP-1 receptor (GLP-1R), which is targeted for the treatment of type 2 diabetes. Small-molecule GLP-1R agonists have been sought due to difficulties with peptide therapeutics. Recently, 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (compound 2) has been described as a GLP-1R allosteric modulator and agonist. Using human embryonic kidney-293 cells expressing human GLP-1Rs, we extended this work to consider the impact of compound 2 on G protein activation, Ca2+ signaling and receptor internalization and particularly to compare compound 2 and GLP-1 across a range of functional assays in intact cells. GLP-1 and compound 2 activated Gαs in cell membranes and increased cellular cAMP in intact cells, with compound 2 being a partial and almost full agonist, respectively. GLP-1 increased intracellular [Ca2+] by release from intracellular stores, which was mimicked by compound 2, with slower kinetics. In either intact cells or membranes, the orthosteric antagonist exendin-(9-39), inhibited GLP-1 cAMP generation but increased the efficacy of compound 2. GLP-1 internalized enhanced green fluorescent protein-tagged GLP-1Rs, but the speed and magnitude evoked by compound 2 were less. Exendin-(9-39) inhibited internalization by GLP-1 and also surprisingly that by compound 2. Compound 2 displays GLP-1R agonism consistent with action at an allosteric site, although an orthosteric antagonist increased its efficacy on cAMP and blocked compound 2-mediated receptor internalization. Full assessment of the properties of compound 2 was potentially hampered by damaging effects that were particularly manifest in either longer term assays with intact cells or in acute assays with membranes. PMID:20507928

  7. Effects of the glucagon-like polypeptide-1 analogue (Val8)GLP-1 on learning, progenitor cell proliferation and neurogenesis in the C57B/16 mouse brain.

    PubMed

    McGovern, Stephen F J; Hunter, Kerry; Hölscher, Christian

    2012-09-14

    Type 2 diabetes (T2DM) has been identified as a risk factor for Alzheimer's disease. Here, we tested the properties of the glucagon-like polypetide-1 (GLP-1) analogue (Val8)GLP-1, a drug originally developed as a treatment for T2DM at a range of doses (2.5 nmol; 25 nmol; 100 nmol; or 250 nmol/kg bw ip.) in an acute memory study in wild type C57B/l6 mice. We also tested (Val8)GLP-1 and the GLP-1 receptor antagonist exendin (9-39) in a chronic study (3 weeks at 25 nmol/kg bw ip. once-daily). We found that (Val8)GLP-1 crossed the blood brain barrier readily and that peripheral injection increased levels in the brain 30 min post-injection ip. but not 2h post-injection in rats. In the acute study, the low dose of 2.5 nmol/kg ip. enhanced motor activity in the open field task, while total distance travelled, exploratory behaviour and anxiety was not affected at any dose. Learning an object recognition task was not affected either. In the chronic study, no effect was observed in the open field assessment. The antagonist exendin (9-39) impaired object recognition learning and spatial learning in a water maze task, demonstrating the importance of GLP-1 signalling in memory formation. Locomotor activity was also affected in some cases. Blood sugar levels and insulin sensitivity was not affected in chronically treated mice. Neuronal stem cells and neurogenesis was enhanced by (Val8)GLP-1 in the dentate gyrus of wild type mice. The results demonstrate that (Val8)GLP-1 is safe in a range of doses, crosses the BBB and has potentially beneficial effects in the CNS by enhancing neurogenesis. PMID:22867941

  8. Simultaneous quantification of the glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) receptor agonists in rodent plasma by on-line solid phase extraction and LC-MS/MS.

    PubMed

    Wang, Yan; Roth, Jonathan D; Taylor, Steven W

    2014-04-15

    Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) and the cholecystokinin-1 receptor (CCK1-R) have therapeutic potential because of their marked anorexigenic and weight lowering effects. Furthermore, recent studies in rodents have shown that co-administration of these agents may prove more effective than treatment either of the peptide classes alone. To correlate the pharmacodynamic effects to the pharmacokinetics of these peptide drugs in vivo, a sensitive and robust bioanalytical method is essential. Furthermore, the simultaneous determination of both analytes in plasma samples by a single method offers obvious advantages. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is well suited to this goal through its ability to simultaneously monitor multiple analytes through selected reaction monitoring (SRM). However, it is a challenge to find appropriate conditions that allow two peptides with widely disparate physiochemical properties to be simultaneously analyzed while maintaining the necessary sensitivity for their accurate plasma concentrations. Herein, we report an on-line solid phase extraction (SPE) LC-MS/MS method for simultaneous quantification of the CCK1-R agonist AC170222 and the GLP-1R agonist AC3174 in rodent plasma. The assay has a linear range from 0.0975 to 100ng/mL, with lower limits of quantification of 0.0975ng/mL and 0.195ng/mL for AC3174 and AC170222, respectively. The intra- and inter-day precisions were below 15%. The developed LC-MS/MS method was used to simultaneously quantify AC3174 and AC170222, the results showed that the terminal plasma concentrations of AC3174 or AC170222 were comparable between groups of animals that were administered with the peptides alone (247±15pg/mL of AC3174 and 1306±48pg/mL of AC170222), or in combination (222±32pg/mL and 1136±47pg/mL of AC3174 and AC170222, respectively). These data provide information on the drug exposure to aid in assessing the combination effects of AC3174 and AC

  9. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    PubMed

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  10. The effect of a glucagon-like peptide-1 receptor agonist on glucose tolerance in women with previous gestational diabetes mellitus: protocol for an investigator-initiated, randomised, placebo-controlled, double-blinded, parallel intervention trial

    PubMed Central

    Foghsgaard, Signe; Vedtofte, Louise; Mathiesen, Elisabeth R; Svare, Jens A; Gluud, Lise L; Holst, Jens J; Damm, Peter; Knop, Filip K; Vilsbøll, Tina

    2013-01-01

    Introduction Pregnancy is associated with decreased insulin sensitivity, which is usually overcome by a compensatory increase in insulin secretion. Some pregnant women are not able to increase their insulin secretion sufficiently, and consequently develop gestational diabetes mellitus (GDM). The disease normally disappears after delivery. Nevertheless, women with previous GDM have a high risk of developing type 2 diabetes (T2D) later in life. We aim to investigate the early development of T2D in women with previous GDM and to evaluate whether treatment with the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, may modify their risk of developing T2D. Methods and analyses 100 women with previous GDM will be randomised to either liraglutide or placebo treatment for 1 year (blinded) with an open-label extension for another 4 years. Additionally, 15 women without previous GDM will constitute a baseline control group. Women will be tested with an oral glucose tolerance test (primary endpoint: area under the curve for plasma glucose) and an isoglycaemic intravenous glucose infusion at baseline, after 1 year and after 5 years. Additional evaluations include a glucagon test, dual-energy X-ray absorptiometry, imaging of the liver (ultrasound elastography and fibroscanning), an ad libitum meal for food intake evaluation and questionnaires related to appetite, quality of life and alcohol consumption habits. Ethics and dissemination The protocol has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark, and the Danish Data Protection Agency and will be carried out under the surveillance and guidance of the GCP unit at Copenhagen University Hospital Bispebjerg in compliance with the ICH-GCP guidelines and in accordance with the Helsinki Declaration. Positive, negative and inconclusive results will be published at scientific conferences and as one or more scientific manuscripts in peer

  11. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

    PubMed Central

    Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i.e. the ‘London’ (hAPPLon/PS1A246E) and ‘Swedish’ mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  12. In vitro metabolism of the glucagon-like peptide-1 (GLP-1)-derived metabolites GLP-1(9-36)amide and GLP-1(28-36)amide in mouse and human hepatocytes.

    PubMed

    Sharma, Raman; McDonald, Thomas S; Eng, Heather; Limberakis, Chris; Stevens, Benjamin D; Patel, Sheena; Kalgutkar, Amit S

    2013-12-01

    Previous studies have revealed that the glucoincretin hormone glucagon-like peptide-1 (GLP-1)(7-36)amide is metabolized by dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase 24.11 (NEP) to yield GLP-1(9-36)amide and GLP-1(28-36)amide, respectively, as the principal metabolites. Contrary to the previous notion that GLP-1(7-36)amide metabolites are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with both GLP-1(9-36)amide and GLP-1(28-36)amide in animals and humans. In the present work, we examined the metabolic stability of the two GLP-1(7-36)amide metabolites in cryopreserved hepatocytes, which have been used to demonstrate the in vitro insulin-like effects of GLP-1(9-36)amide and GLP-1(28-36)amide on gluconeogenesis. To examine the metabolic stability of the GLP-1(7-36)amide metabolites, a liquid chromatography-tandem mass spectrometry assay was developed for the quantitation of the intact peptides in hepatocyte incubations. GLP-1(9-36)amide and GLP-1(28-36)amide were rapidly metabolized in mouse [GLP-1(9-36)amide: t(1/2) = 52 minutes; GLP-1(28-36)amide: t(1/2) = 13 minutes] and human hepatocytes [GLP-1(9-36)amide: t(1/2) = 180 minutes; GLP-1(28-36)amide: t(1/2) = 24 minutes), yielding a variety of N-terminal cleavage products that were characterized using mass spectrometry. Metabolism at the C terminus was not observed for either peptides. The DPP-IV and NEP inhibitors diprotin A and phosphoramidon, respectively, did not induce resistance in the two peptides toward proteolytic cleavage. Overall, our in vitro findings raise the intriguing possibility that the insulinomimetic effects of GLP-1(9-36)amide and GLP-1(28-36)amide on gluconeogenesis and oxidative stress might be due, at least in part, to the actions of additional downstream metabolites, which are obtained from the enzymatic cleavage of the peptide backbone in the parent compounds.

  13. Examination of mercaptobenzyl sulfonates as catalysts for native chemical ligation: application to the assembly of a glycosylated Glucagon-Like Peptide 1 (GLP-1) analogue.

    PubMed

    Cowper, Ben; Sze, Tsz Mei; Premdjee, Bhavesh; Bongat White, Aileen F; Hacking, Andrew; Macmillan, Derek

    2015-02-21

    3/4-Mercaptobenzyl sulfonates were investigated as aryl thiol catalysts for native chemical ligation (NCL). Whilst catalysing NCL processes at a similar rate to 4-mercaptophenyl acetic acid (MPAA), the increased polarity and solubility of 3-mercaptobenzyl sulfonate in particular may favour its selection as NCL catalyst in many instances. PMID:25605668

  14. 99mTc Labeled Glucagon-Like Peptide-1-Analogue (99mTc-GLP1) Scintigraphy in the Management of Patients with Occult Insulinoma

    PubMed Central

    Sowa-Staszczak, Anna; Trofimiuk-Müldner, Małgorzata; Stefańska, Agnieszka; Tomaszuk, Monika; Buziak-Bereza, Monika; Gilis-Januszewska, Aleksandra; Jabrocka-Hybel, Agata; Głowa, Bogusław; Małecki, Maciej; Bednarczuk, Tomasz; Kamiński, Grzegorz; Kowalska, Aldona; Mikołajczak, Renata; Janota, Barbara; Hubalewska-Dydejczyk, Alicja

    2016-01-01

    Introduction The aim of this study was to assess the utility of [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 scintigraphy in the management of patients with hypoglycemia, particularly in the detection of occult insulinoma. Materials and Methods Forty patients with hypoglycemia and increased/confusing results of serum insulin and C-peptide concentration and negative/inconclusive results of other imaging examinations were enrolled in the study. In all patients GLP-1 receptor imaging was performed to localise potential pancreatic lesions. Results Positive results of GLP-1 scintigraphy were observed in 28 patients. In 18 patients postsurgical histopathological examination confirmed diagnosis of insulinoma. Two patients had contraindications to the surgery, one patient did not want to be operated. One patient, who presented with postprandial hypoglycemia, with positive result of GLP-1 imaging was not qualified for surgery and is in the observational group. Eight patients were lost for follow up, among them 6 patients with positive GLP-1 scintigraphy result. One patient with negative scintigraphy was diagnosed with malignant insulinoma. In two patients with negative scintigraphy Munchausen syndrome was diagnosed (patients were taking insulin). Other seven patients with negative results of 99mTcGLP-1 scintigraphy and postprandial hypoglycemia with C-peptide and insulin levels within the limits of normal ranges are in the observational group. We would like to mention that 99mTc-GLP1-SPECT/CT was also performed in 3 pts with nesidioblastosis (revealing diffuse tracer uptake in two and a focal lesion in one case) and in two patients with malignant insulinoma (with the a focal uptake in the localization of a removed pancreatic headin one case and negative GLP-1 1 scintigraphy in the other patient). Conclusions 99mTc-GLP1-SPECT/CT could be helpful examination in the management of patients with hypoglycemia enabling proper localization of the pancreatic lesion and effective surgical treatment. This imaging technique may eliminate the need to perform invasive procedures in case of occult insulinoma. PMID:27526057

  15. Examination of mercaptobenzyl sulfonates as catalysts for native chemical ligation: application to the assembly of a glycosylated Glucagon-Like Peptide 1 (GLP-1) analogue.

    PubMed

    Cowper, Ben; Sze, Tsz Mei; Premdjee, Bhavesh; Bongat White, Aileen F; Hacking, Andrew; Macmillan, Derek

    2015-02-21

    3/4-Mercaptobenzyl sulfonates were investigated as aryl thiol catalysts for native chemical ligation (NCL). Whilst catalysing NCL processes at a similar rate to 4-mercaptophenyl acetic acid (MPAA), the increased polarity and solubility of 3-mercaptobenzyl sulfonate in particular may favour its selection as NCL catalyst in many instances.

  16. Glucagon-like peptide 1: a potent glycogenic hormone.

    PubMed

    Valverde, I; Morales, M; Clemente, F; López-Delgado, M I; Delgado, E; Perea, A; Villanueva-Peñacarrillo, M L

    1994-08-01

    GLP-1(7-36)amide is an insulinotropic peptide derived from the intestinal post-translational proglucagon process, the release of which is increased mainly after a carbohydrate meal; also, its anti-diabetogenic effect in normal and diabetic states has been reported. In this study, GLP-1(7-36)amide stimulates the formation of glycogen from glucose in isolated rat hepatocytes, such a glycogenic effect being achieved with physiological concentrations of the peptide. The GLP-1(7-36)amide-induced glycogenesis is abolished by glucagon, and it is accompanied by stimulation of the glycogen synthase alpha activity and by a decrease in the basal and glucagon-stimulated cyclic AMP content. These findings could explain, at least in part, the GLP-1(7-36)amide insulin-independent plasma glucose lowering effect.

  17. Efficacy and safety of the glucagon-like peptide-1 receptor agonist liraglutide added to insulin therapy in poorly regulated patients with type 1 diabetes—a protocol for a randomised, double-blind, placebo-controlled study: The Lira-1 study

    PubMed Central

    Dejgaard, Thomas Fremming; Knop, Filip Krag; Tarnow, Lise; Frandsen, Christian Seerup; Hansen, Tanja Stenbæk; Almdal, Thomas; Holst, Jens Juul; Madsbad, Sten; Andersen, Henrik Ullits

    2015-01-01

    Introduction Intensive insulin therapy is recommended for the treatment of type 1 diabetes (T1D). Hypoglycaemia and weight gain are the common side effects of insulin treatment and may reduce compliance. In patients with insulin-treated type 2 diabetes, the addition of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy has proven effective in reducing weight gain and insulin dose. The present publication describes a protocol for a study evaluating the efficacy and safety of adding a GLP-1RA to insulin treatment in overweight patients with T1D in a randomised, double-blinded, controlled design. Methods and analysis In total, 100 patients with type 1 diabetes, poor glycaemic control (glycated haemoglobin (HbA1c) >8%) and overweight (body mass index >25 kg/m2) will be randomised to either liraglutide 1.8 mg once daily or placebo as an add-on to intensive insulin therapy in this investigator initiated, double-blinded, placebo-controlled parallel study. The primary end point is glycaemic control as measured by changes in HbA1c. Secondary end points include changes in the insulin dose, hypoglyacemic events, body weight, lean body mass, fat mass, food preferences and adverse events. Glycaemic excursions, postprandial glucagon levels and gastric emptying rate during a standardised liquid meal test will also be studied. Ethics and dissemination The study is approved by the Danish Medicines Authority, the Regional Scientific-Ethical Committee of the Capital Region of Denmark and the Data Protection Agency. The study will be carried out under the surveillance and guidance of the good clinical practice (GCP) unit at Copenhagen University Hospital Bispebjerg in accordance with the ICH-GCP guidelines and the Helsinki Declaration. Trial registration number NCT01612468. PMID:25838513

  18. Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways

    PubMed Central

    Farkas, Imre; Vastagh, Csaba; Farkas, Erzsébet; Bálint, Flóra; Skrapits, Katalin; Hrabovszky, Erik; Fekete, Csaba; Liposits, Zsolt

    2016-01-01

    Glucagon-like peptide-1 (GLP-1), a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R) have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM–5 μM) elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs) frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9–39) (1 μM). Intracellular application of the G-protein inhibitor GDP-β-S (2 mM) impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO) synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 100 μM) or N5-[Imino(propylamino)methyl]-L-ornithine hydrochloride (NPLA; 1 μM) or intracellular scavenging of NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO; 1 mM) partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using cannabinoid receptor type-1 (CB1) inverse-agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl) pyrazole-3-carboxamide (AM251; 1 μM). Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the transient receptor potential vanilloid 1 (TRPV1)-antagonist 2E-N-(2, 3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1, 1-dimethylethyl)phenyl]-2-Propenamide (AMG9810; 10 μM) or the fatty acid amide hydrolase (FAAH)-inhibitor PF3845 (5 μM) impeded the GLP-1-triggered endocannabinoid

  19. Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways.

    PubMed

    Farkas, Imre; Vastagh, Csaba; Farkas, Erzsébet; Bálint, Flóra; Skrapits, Katalin; Hrabovszky, Erik; Fekete, Csaba; Liposits, Zsolt

    2016-01-01

    Glucagon-like peptide-1 (GLP-1), a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R) have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM-5 μM) elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs) frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9-39) (1 μM). Intracellular application of the G-protein inhibitor GDP-β-S (2 mM) impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO) synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 100 μM) or N(5)-[Imino(propylamino)methyl]-L-ornithine hydrochloride (NPLA; 1 μM) or intracellular scavenging of NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO; 1 mM) partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using cannabinoid receptor type-1 (CB1) inverse-agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl) pyrazole-3-carboxamide (AM251; 1 μM). Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the transient receptor potential vanilloid 1 (TRPV1)-antagonist 2E-N-(2, 3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1, 1-dimethylethyl)phenyl]-2-Propenamide (AMG9810; 10 μM) or the fatty acid amide hydrolase (FAAH)-inhibitor PF3845 (5 μM) impeded the GLP-1-triggered endocannabinoid

  20. Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways.

    PubMed

    Farkas, Imre; Vastagh, Csaba; Farkas, Erzsébet; Bálint, Flóra; Skrapits, Katalin; Hrabovszky, Erik; Fekete, Csaba; Liposits, Zsolt

    2016-01-01

    Glucagon-like peptide-1 (GLP-1), a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R) have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM-5 μM) elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs) frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9-39) (1 μM). Intracellular application of the G-protein inhibitor GDP-β-S (2 mM) impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO) synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 100 μM) or N(5)-[Imino(propylamino)methyl]-L-ornithine hydrochloride (NPLA; 1 μM) or intracellular scavenging of NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO; 1 mM) partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using cannabinoid receptor type-1 (CB1) inverse-agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl) pyrazole-3-carboxamide (AM251; 1 μM). Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the transient receptor potential vanilloid 1 (TRPV1)-antagonist 2E-N-(2, 3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1, 1-dimethylethyl)phenyl]-2-Propenamide (AMG9810; 10 μM) or the fatty acid amide hydrolase (FAAH)-inhibitor PF3845 (5 μM) impeded the GLP-1-triggered endocannabinoid

  1. Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways

    PubMed Central

    Farkas, Imre; Vastagh, Csaba; Farkas, Erzsébet; Bálint, Flóra; Skrapits, Katalin; Hrabovszky, Erik; Fekete, Csaba; Liposits, Zsolt

    2016-01-01

    Glucagon-like peptide-1 (GLP-1), a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R) have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM–5 μM) elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs) frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9–39) (1 μM). Intracellular application of the G-protein inhibitor GDP-β-S (2 mM) impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO) synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 100 μM) or N5-[Imino(propylamino)methyl]-L-ornithine hydrochloride (NPLA; 1 μM) or intracellular scavenging of NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO; 1 mM) partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using cannabinoid receptor type-1 (CB1) inverse-agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl) pyrazole-3-carboxamide (AM251; 1 μM). Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the transient receptor potential vanilloid 1 (TRPV1)-antagonist 2E-N-(2, 3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1, 1-dimethylethyl)phenyl]-2-Propenamide (AMG9810; 10 μM) or the fatty acid amide hydrolase (FAAH)-inhibitor PF3845 (5 μM) impeded the GLP-1-triggered endocannabinoid

  2. Glucagon-like peptides activate hepatic gluconeogenesis.

    PubMed

    Mommsen, T P; Andrews, P C; Plisetskaya, E M

    1987-07-13

    Piscine (anglerfish, catfish, coho salmon) glucagon-like peptides (GLPs), applied at 3.5 nM, stimulate (1.1-1.9-fold) flux through gluconeogenesis above control levels in isolated trout and salmon hepatocytes. Human GLP-1 and GLP-2 also activate gluconeogenesis, but to a lesser degree than their piscine counterparts. Minor increases of substrate oxidation are noticed at times of peak gluconeogenic activation through GLPs. These hormones, which are derived from the same precursor peptide as glucagon are more potent activators of gluconeogenesis than glucagon when applied at equimolar concentrations, and do not appear to employ cAMP or cGMP as the intracellular messenger in hepatic tissue. PMID:3109952

  3. Glucagon-like receptor 1 agonists and DPP-4 inhibitors: potential therapies for the treatment of stroke

    PubMed Central

    Darsalia, Vladimer; Larsson, Martin; Nathanson, David; Klein, Thomas; Nyström, Thomas; Patrone, Cesare

    2015-01-01

    During the past decades, candidate drugs that have shown neuroprotective efficacy in the preclinical setting have failed in clinical stroke trials. As a result, no treatment for stroke based on neuroprotection is available today. The activation of the glucagon-like peptide 1 receptor (GLP-1) for reducing stroke damage is a relatively novel concept that has shown neuroprotective effects in animal models. In addition, clinical studies are currently ongoing. Herein, we review this emerging research field and discuss the next milestones to be achieved to develop a novel antistroke therapy. PMID:25669907

  4. Naturally-occurring TGR5 agonists modulating glucagon-like peptide-1 biosynthesis and secretion.

    PubMed

    Jafri, Laila; Saleem, Samreen; Calderwood, Danielle; Gillespie, Anna; Mirza, Bushra; Green, Brian D

    2016-04-01

    Selective GLP-1 secretagogues represent a novel potential therapy for type 2 diabetes mellitus. This study examined the GLP-1 secretory activity of the ethnomedicinal plant, Fagonia cretica, which is postulated to possess anti-diabetic activity. After extraction and fractionation extracts and purified compounds were tested for GLP-1 and GIP secretory activity in pGIP/neo STC-1 cells. Intracellular levels of incretin hormones and their gene expression were also determined. Crude F. cretica extracts stimulated both GLP-1 and GIP secretion, increased cellular hormone content, and upregulated gene expression of proglucagon, GIP and prohormone convertase. However, ethyl acetate partitioning significantly enriched GLP-1 secretory activity and this fraction underwent bioactivity-guided fractionation. Three isolated compounds were potent and selective GLP-1 secretagogues: quinovic acid (QA) and two QA derivatives, QA-3β-O-β-D-glycopyranoside and QA-3β-O-β-D-glucopyranosyl-(28→1)-β-D-glucopyranosyl ester. All QA compounds activated the TGR5 receptor and increased intracellular incretin levels and gene expression. QA derivatives were more potent GLP-1 secretagogues than QA. This is the first time that QA and its naturally-occurring derivatives have been shown to activate TGR5 and stimulate GLP-1 secretion. These data provide a plausible mechanism for the ethnomedicinal use of F. cretica and may assist in the ongoing development of selective GLP-1 agonists. PMID:26820940

  5. Gut adaptation and the glucagon-like peptides

    PubMed Central

    Drucker, D J

    2002-01-01

    The glucagon-like peptides GLP-1 and GLP-2 are synthesised and then released from enteroendocrine cells in the small and large intestine. GLP-1 promotes efficient nutrient assimilation while GLP-2 regulates energy absorption via effects on nutrient intake, gastric acid secretion and gastric emptying, nutrient absorption, and mucosal permeability. Preliminary human studies indicate that GLP-2 may enhance energy absorption and reduce fluid loss in subjects with short bowel syndrome suggesting that GLP-2 functions as a key regulator of mucosal integrity, permeability, and nutrient absorption. Hence GLP-2 may be therapeutically useful in diseases characterised by injury or dysfunction of the gastrointestinal epithelium. PMID:11839727

  6. Dibutyl Phthalate Exposure Disrupts Evolutionarily Conserved Insulin and Glucagon-Like Signaling in Drosophila Males.

    PubMed

    Williams, Michael J; Wiemerslage, Lyle; Gohel, Priya; Kheder, Sania; Kothegala, Lakshmi V; Schiöth, Helgi B

    2016-06-01

    Phthalate diesters are commonly used as industrial plasticisers, as well as in cosmetics and skin care products, as a result people are constantly exposed to these xenobiotics. Recent epidemiological studies have found a correlation between circulating phthalate levels and type 2 diabetes, whereas animal studies indicate that phthalates are capable of disrupting endocrine signaling. Nonetheless, how phthalates interfere with metabolic function is still unclear. Here, we show that feeding Drosophila males the xenobiotic dibutyl phthalate (DBP) affects conserved insulin- and glucagon-like signaling. We report that raising flies on food containing DBP leads to starvation resistance, increased lipid storage, hyperglycemia, and hyperphagia. We go on to show that the starvation-resistance phenotype can be rescued by overexpression of the glucagon analogue adipokinetic hormone (Akh). Furthermore, although acute DBP exposure in adult flies is able to affect insulin levels, only chronic feeding influences Akh expression. We establish that raising flies on DBP-containing food or feeding adults DBP food affects the expression of homologous genes involved in xenobiotic and lipid metabolism (AHR [Drosophila ss], NR1I2 [Hr96], ABCB1 [MDR50], ABCC3 [MRP], and CYP3A4 [Cyp9f2]). Finally, we determined that the expression of these genes is also influenced by Akh. Our results provide comprehensive evidence that DBP can disrupt metabolism in Drosophila males, by regulating genes involved in glucose, lipid, and xenobiotic metabolism. PMID:27100621

  7. Efficient (18)F-Labeling of Synthetic Exendin-4 Analogues for Imaging Beta Cells.

    PubMed

    Keliher, Edmund J; Reiner, Thomas; Thurber, Greg M; Upadhyay, Rabi; Weissleder, Ralph

    2012-08-01

    A number of exendin derivatives have been developed to target glucagon-like peptide 1 (GLP-1) receptors on beta cells in vivo. Modifications of exendin analogues have been shown to have significant effects on pharmacokinetics and, as such, have been used to develop a variety of therapeutic compounds. Here, we show that an exendin-4, modified at position 12 with a cysteine conjugated to a tetrazine, can be labeled with (18)F-trans-cyclooctene and converted into a PET imaging agent at high yields and with good selectivity. The agent accumulates in beta cells in vivo and has sufficiently high accumulation in mouse models of insulinomas to enable in vivo imaging.

  8. Inhibiting and reversing amyloid-β peptide (1-40) fibril formation with gramicidin S and engineered analogues.

    PubMed

    Luo, Jinghui; Otero, José M; Yu, Chien-Hung; Wärmländer, Sebastian K T S; Gräslund, Astrid; Overhand, Mark; Abrahams, Jan Pieter

    2013-12-16

    In Alzheimer's disease, amyloid-β (Aβ) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidin S significantly inhibited Aβ amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidin S, a cyclic decapeptide that adopts a β-sheet conformation, binds to the Aβ peptide hairpin-stacked fibril through β-sheet interactions. This may explain why gramicidin S reduces fibril formation. Analogues of gramicidin S were also tested. An analogue with a potency that was four-times higher than that of the natural product was identified.

  9. Glucagon-like peptide-1 receptor agonist Liraglutide has anabolic bone effects in ovariectomized rats without diabetes.

    PubMed Central

    Yu, JingJia; Wang, Xiaojing; Liu, Dongmei; Zhao, Lin; Sun, Lihao; Zhao, Hongyan; Tao, Bei; Liu, Jianmin

    2015-01-01

    Recently, a number of studies have demonstrated the potential beneficial role for novel anti-diabetic GLP-1 receptor agonists (GLP-1RAs) in the skeleton metabolism in diabetic rodents and patients. In this study, we evaluated the impacts of the synthetic GLP-1RA Liraglutide on bone mass and quality in osteoporotic rats induced by ovariectomy (OVX) but without diabetes, as well as its effect on the adipogenic and osteoblastogenic differentiation of bone marrow stromal cells (BMSCs). Three months after sham surgery or bilateral OVX, eighteen 5-month old female Wistar rats were randomly divided into three groups to receive the following treatments for 2 months: (1) Sham + normal saline; (2) OVX + normal saline; and (3) OVX + Liraglutide (0.6 mg/day). As revealed by micro-CT analysis, Liraglutide improved trabecular volume, thickness and number, increased BMD, and reduced trabecular spacing in the femurs in OVX rats; similar results were observed in the lumbar vertebrae of OVX rats treated with Liraglutide. Following in vitro treatment of rat and human BMSCs with 10 nM Liraglutide, there was a significant increase in the mRNA expression of osteoblast-specific transcriptional factor Runx2 and the osteoblast markers alkaline phosphatase (ALP) and collagen α1 (Col-1), but a significant decrease in peroxisome proliferator-activated receptor γ (PPARγ). In conclusion, our results indicate that the anti-diabetic drug Liraglutide can exert a bone protective effect even in non-diabetic osteoporotic OVX rats. This protective effect is likely attributable to the impact of Liraglutide on the lineage fate determination of BMSCs. PMID:26177280

  10. Glucagon-like peptide-1 stimulates luteinizing hormone-releasing hormone secretion in a rodent hypothalamic neuronal cell line.

    PubMed Central

    Beak, S A; Heath, M M; Small, C J; Morgan, D G; Ghatei, M A; Taylor, A D; Buckingham, J C; Bloom, S R; Smith, D M

    1998-01-01

    To examine the influence of the putative satiety factor (GLP-1) on the hypothalamo-pituitary-gonadal axis, we used GT1-7 cells as a model of neuronal luteinizing hormone- releasing hormone (LHRH) release. GLP-1 caused a concentration-dependent increase in LHRH release from GT1-7 cells. Specific, saturable GLP-1 binding sites were demonstrated on these cells. The binding of [125I]GLP-1 was time-dependent and consistent with a single binding site (Kd = 0.07+/-0.016 nM; binding capacity = 160+/-11 fmol/mg protein). The specific GLP-1 receptor agonists, exendin-3 and exendin-4, also showed high affinity (Ki = 0.3+/-0.05 and 0.32+/-0.06 nM, respectively) as did the antagonist exendin-(9-39) (Ki = 0.98+/-0.24 nM). At concentrations that increased LHRH release, GLP-1 (0.5-10 nM) also caused an increase in intracellular cAMP in GT1-7 cells (10 nM GLP-1: 7.66+/-0.4 vs. control: 0.23+/-0.02 nmol/mg protein; P < 0.001). Intracerebroventricular injection of GLP-1 at a single concentration (10 microg) produced a prompt increase in the plasma luteinizing hormone concentration in male rats (GLP-1: 1.09+/-0.11 vs. saline: 0.69+/-0.06 ng/ml; P < 0.005). GLP-1 levels in the hypothalami of 48-h-fasted male rats showed a decrease, indicating a possible association of the satiety factor with the low luteinizing hormone levels in animals with a negative energy balance. PMID:9502775

  11. Inositolphosphoglycans are possible mediators of the glucagon-like peptide 1 (7-36)amide action in the liver.

    PubMed

    Trapote, M A; Clemente, F; Galera, C; Morales, M; Alcántara, A I; López-Delgado, M I; Villanueva-Peñacarrillo, M L; Valverde, I

    1996-02-01

    A potent glycogenic effect for GLP-1(7-36)amide has been found in rat hepatocytes and skeletal muscle, and the specific receptors detected for GLP-1(7-36)amide in these tissue membranes do not seem to be associated to adenylate cyclase. On the other hand, inositolphosphoglycan molecules (IPGs) have been implicated as second messengers in the action of insulin. In a human hepatoma cell line (HEP G-2), we have observed the presence of [125I]GLP-1(7-36)amide specific binding, and a stimulatory effect of the peptide upon glycogen synthesis, confirming the findings in isolated rat hepatocytes. Also, GLP-1(7-36)amide modulates the cell content of radiolabelled glycosylphosphatidylinositols (GPIs), in the same manner as insulin, indicating hydrolysis of GPIs and an immediate and short-lived generation of IPGs. Thus, IPGs could be mediators in the GLP-1(7-36)amide glycogenic action in the liver.

  12. Intestinal Permeability and Glucagon-Like Peptide-2 in Children with Autism: A Controlled Pilot Study

    ERIC Educational Resources Information Center

    Robertson, Marli A.; Sigalet, David L.; Holst, Jens J.; Meddings, Jon B.; Wood, Julie; Sharkey, Keith A.

    2008-01-01

    We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response to feeding. Results were compared with sibling controls…

  13. Glucagon-like peptide-2 induces rapid digestive adaptation following intestinal resection in preterm neonates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Short bowel syndrome (SBS) is a frequent complication after intestinal resection in infants suffering from intestinal disease. We tested whether treatment with the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) increases intestinal volume and function in the period immediately following in...

  14. A novel, long-acting glucagon-like peptide receptor-agonist: dulaglutide

    PubMed Central

    Gurung, Tara; Shyangdan, Deepson S; O’Hare, Joseph Paul; Waugh, Norman

    2015-01-01

    Background Dulaglutide is a new, long-acting glucagon-like peptide analogue in the treatment of type 2 diabetes. It is available in two doses, 0.75 and 1.5 mg, given by injection once weekly. This systematic review reports the effectiveness and safety of dulaglutide in type 2 diabetes in dual and triple therapy. Methods MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, and conference abstracts were searched from 2005 to August 2014, and updated in January 2015. Company websites and references of included studies were checked for potentially relevant studies. European Medicines Agency and US Food and Drug Administration websites were searched. Results Four trials were included. All were manufacturer-funded randomized controlled trials from the Assessment of Weekly Administration of Dulaglutide in Diabetes (AWARD) program. AWARD-1 compared dulaglutide 1.5 mg against exenatide 10 µg twice daily and placebo, AWARD-2 compared dulaglutide 0.75 and 1.5 mg against insulin glargine, AWARD-5 compared dulaglutide 0.75 and 1.5 mg against sitagliptin 100 mg and placebo, and AWARD-6 compared dulaglutide 1.5 mg against liraglutide 1.8 mg. The duration of follow-up in the trials ranged from 26 to 104 weeks. The primary outcome of all the included trials was change in HbA1c. At 26 weeks, greater HbA1c reductions were seen with dulaglutide than with twice daily exenatide (dulaglutide 1.5/0.75 mg: −1.5%/−1.3%; exe: 0.99%) and sitagliptin (1.5/0.75 mg −1.22%/−1.01%; sitagliptin: −0.6%). HbA1c change was greater with dulaglutide 1.5 mg (−1.08%) than with glargine (−0.63%), but not with dulaglutide 0.75 mg (−0.76%). Dulaglutide 1.5 mg was found to be noninferior to liraglutide 1.8 mg. More patients treated with dulaglutide achieved HbA1c targets of <7% and ≤6.5%. Reduction in weight was greater with dulaglutide than with sitagliptin and exenatide. Hypoglycemia was infrequent. The main adverse events were nausea, diarrhea, and vomiting. Conclusion

  15. Isolation of alligator gar (Lepisosteus spatula) glucagon, oxyntomodulin, and glucagon-like peptide: amino acid sequences of oxyntomodulin and glucagon-like peptide.

    PubMed

    Pollock, H G; Kimmel, J R; Ebner, K E; Hamilton, J W; Rouse, J B; Lance, V; Rawitch, A B

    1988-01-01

    Oxyntomodulin, glucagon, and a glucagon-like peptide (GLP) have been isolated from the endocrine pancreas of the alligator gar (Lepisosteus spatula), a ganoid fish. The three peptides were isolated by gel filtration and HPLC and were identified by size, composition, and glucagon-like immunoreactivity. The amino acid sequences of the oxyntomodulin and GLP were determined. The oxyntomodulin contains 36 amino acid residues and its sequence is H S Q G T F T N D Y S K Y L D T R R A Q D F V Q W L M S T K R S G G I T. The composition of the glucagon is identical to the N-terminal 29 residues of the gar oxyntomodulin. The single form of GLP found contains 34 amino acid residues in the following sequence: H A D G T Y T S D V S S Y L Q D Q A A K K F V T W L K Q G Q D R R E. These findings suggest that all three peptides are derived from a common precursor. PMID:3282974

  16. Isolation of alligator gar (Lepisosteus spatula) glucagon, oxyntomodulin, and glucagon-like peptide: amino acid sequences of oxyntomodulin and glucagon-like peptide.

    PubMed

    Pollock, H G; Kimmel, J R; Ebner, K E; Hamilton, J W; Rouse, J B; Lance, V; Rawitch, A B

    1988-01-01

    Oxyntomodulin, glucagon, and a glucagon-like peptide (GLP) have been isolated from the endocrine pancreas of the alligator gar (Lepisosteus spatula), a ganoid fish. The three peptides were isolated by gel filtration and HPLC and were identified by size, composition, and glucagon-like immunoreactivity. The amino acid sequences of the oxyntomodulin and GLP were determined. The oxyntomodulin contains 36 amino acid residues and its sequence is H S Q G T F T N D Y S K Y L D T R R A Q D F V Q W L M S T K R S G G I T. The composition of the glucagon is identical to the N-terminal 29 residues of the gar oxyntomodulin. The single form of GLP found contains 34 amino acid residues in the following sequence: H A D G T Y T S D V S S Y L Q D Q A A K K F V T W L K Q G Q D R R E. These findings suggest that all three peptides are derived from a common precursor.

  17. Evidence for the presence of glucagon-like immunoreactivity (GLI) in the pancreas.

    PubMed

    Srikant, C B; Unger, R H

    1976-12-01

    Glucagon-like immunoreactivity (GLI), which can be separated from glucagon by isoelectric focusing, has been detected in partially purified canine pancreatic extracts. Like gastrointestinal GLI, this insular GLI reacts with crossreacting antiserum 78J but not with glucagon "specific" antiserum 30K and has an isoelectric point (pl) of 9.5, whereas canine pancreatic glucagon has a pl of 6.25. When combined with glucagon, the GLI-glucagon mixture gives 48J assay values between GLI and this crossreacting antiglucagon serum and thus conceals it in glucagon-containing extracts.

  18. Efficient (18)F-Labeling of Synthetic Exendin-4 Analogues for Imaging Beta Cells.

    PubMed

    Keliher, Edmund J; Reiner, Thomas; Thurber, Greg M; Upadhyay, Rabi; Weissleder, Ralph

    2012-08-01

    A number of exendin derivatives have been developed to target glucagon-like peptide 1 (GLP-1) receptors on beta cells in vivo. Modifications of exendin analogues have been shown to have significant effects on pharmacokinetics and, as such, have been used to develop a variety of therapeutic compounds. Here, we show that an exendin-4, modified at position 12 with a cysteine conjugated to a tetrazine, can be labeled with (18)F-trans-cyclooctene and converted into a PET imaging agent at high yields and with good selectivity. The agent accumulates in beta cells in vivo and has sufficiently high accumulation in mouse models of insulinomas to enable in vivo imaging. PMID:23997998

  19. Efficient 18F-Labeling of Synthetic Exendin-4 Analogues for Imaging Beta Cells

    PubMed Central

    Keliher, Edmund J; Reiner, Thomas; Thurber, Greg M; Upadhyay, Rabi; Weissleder, Ralph

    2012-01-01

    A number of exendin derivatives have been developed to target glucagon-like peptide 1 (GLP-1) receptors on beta cells in vivo. Modifications of exendin analogues have been shown to have significant effects on pharmacokinetics and, as such, have been used to develop a variety of therapeutic compounds. Here, we show that an exendin-4, modified at position 12 with a cysteine conjugated to a tetrazine, can be labeled with 18F-trans-cyclooctene and converted into a PET imaging agent at high yields and with good selectivity. The agent accumulates in beta cells in vivo and has sufficiently high accumulation in mouse models of insulinomas to enable in vivo imaging. PMID:23997998

  20. Induction of intestinal epithelial proliferation by glucagon-like peptide 2.

    PubMed Central

    Drucker, D J; Erlich, P; Asa, S L; Brubaker, P L

    1996-01-01

    Injury, inflammation, or resection of the small intestine results in severe compromise of intestinal function. Nevertheless, therapeutic strategies for enhancing growth and repair of the intestinal mucosal epithelium are currently not available. We demonstrate that nude mice bearing subcutaneous proglucagon-producing tumors exhibit marked proliferation of the small intestinal epithelium. The factor responsible for inducing intestinal proliferation was identified as glucagon-like peptide 2 (GLP-2), a 33-aa peptide with no previously ascribed biological function. GLP-2 stimulated crypt cell proliferation and consistently induced a marked increase in bowel weight and villus growth of the jejunum and ileum that was evident within 4 days after initiation of GLP-2 administration. These observations define a novel biological role for GLP-2 as an intestinal-derived peptide stimulator of small bowel epithelial proliferation. Images Fig. 1 Fig. 5 PMID:8755576

  1. Pancreatic proglucagon processing: isolation and structures of glucagon and glucagon-like peptide from gene I.

    PubMed

    Nichols, R; Lee, T D; Andrews, P C

    1988-12-01

    The anglerfish endocrine pancreas expresses two different genes for preproglucagon. The regions of the two proglucagons that correspond to glucagon have different sequences, as do the two glucagon-like peptides (GLPs). The products derived from processing the more abundant proglucagon-II have recently been determined. However, it was not known whether proglucagon-I was processed to similar products. The two major biologically active products of preproglucagon-I processing (glucagon-I and GLP-I) have now been purified to homogeneity. Their structures were determined using automated gas phase Edman degradation, tryptic mapping, and fast atom bombardment mass spectrometry. The preproglucagon-I-processing sites were identified. Glucagon-I represents residues 53-81, and GLP-I corresponds to preproglucagon-I-(91-124) (numbering from the initiator Met). PMID:3058456

  2. Characterization of the hypotensive effects of glucagon-like peptide-2 in anesthetized rats.

    PubMed

    Iwai, Takashi; Kaneko, Maki; Sasaki-Hamada, Sachie; Oka, Jun-Ichiro

    2013-08-29

    Glucagon-like peptide-2 (GLP-2) is a proglucagon-derived peptide released from enteroendocrine cells and neurons. We recently reported that GLP-2 induced hypotension. In the present study, we characterized the mechanisms of GLP-2-induced hypotension. GLP-2 was administered peripherally or centrally to male Wistar rats anesthetized with urethane and α-chloralose. The rats were vagotomized or systemically pretreated with atropine, prazosin, or propranolol before the GLP-2 administration. The central and peripheral administration of GLP-2 reduced mean arterial blood pressure (MAP). The maximum change of MAP (maximum ΔMAP) was reduced by vagotomy or prazosin, but not propranolol. The effects of the central but not peripheral administration of GLP-2 were reduced by atropine. These results suggest that GLP-2 modulates vagal afferent inputs and inhibits the sympathetic nervous system in the brain to induce hypotension. PMID:23867714

  3. The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The gut-brain axis plays a key role in the control of energy balance and glucose homeostasis. In response to luminal stimulation of macronutrients and microbiotaderived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine...

  4. Comparative physiology of glucagon-like peptide-2 – Implications and applications for production and health of ruminants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide derived from proteolytic cleavage of proglucagon by prohormone convertase 1/3 in enteroendocrine L-cells. Studies conducted in humans, rodent models, and in vitro indicate that GLP-2 is secreted in response to the presence of molecules in th...

  5. Bile acids induce glucagon-like peptide 2 secretion with limited effects on intestinal adaptation in early weaned pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Early weaning is a stressful event characterized by a transient period of intestinal atrophy that may be mediated by reduced secretion of glucagon-like peptide (GLP) 2. We tested whether enterally fed bile acids or plant sterols could increase nutrient-dependent GLP-2 secretion and improve intestina...

  6. Glucagon-like peptide-2-loaded microspheres as treatment for ulcerative colitis in the murine model.

    PubMed

    Wu, Jie; Qi, Keke; Xu, Ziwei; Wan, Jin

    2015-01-01

    Glucagon-like peptide-2 (GLP-2) is an intestinal hormone that promotes intestinal growth, but the rapid degradation by dipeptidyl peptidase-IV limits its applications. PLGA microsphere is a well-developed drug delivery system, while seldom been studied as a solution for prolonging in vivo effects of GLP-2. In this study, we encapsulated porcine GLP-2 (pGLP-2) into microspheres and investigated its therapeutic effects in dextran sulfate sodium (DSS)-treated mice. pGLP-2 microspheres showed 20.36% in initial burst and constant release for at least 9 d. In the DSS-treated mice, a single injection of GLP-2 microspheres significantly increased the body weight, colonic length, small intestinal weight and mRNA expression of Occludin, decreased the colonic damage score, mRNA expression of IL-6, IL-10, TNF-α and IFN-γ. In conclusion, pGLP-2 microspheres were resistant to degradation and decreased the severity of DSS-induced ulcerative colitis which suggested that GLP-2-loaded microspheres could be a proper candidate for the treatment of ulcerative colitis.

  7. Glucagon-like peptide-2-induced memory improvement and anxiolytic effects in mice.

    PubMed

    Iwai, Takashi; Jin, Kazushi; Ohnuki, Tomoko; Sasaki-Hamada, Sachie; Nakamura, Minami; Saitoh, Akiyoshi; Sugiyama, Azusa; Ikeda, Masaatsu; Tanabe, Mitsuo; Oka, Jun-Ichiro

    2015-02-01

    We investigated the effectiveness of glucagon-like peptide-2 (GLP-2) on memory impairment in lipopolysaccharide (LPS)-treated mice, and anxiety-like behavior in adrenocorticotropic hormone (ACTH)-treated mice. In the Y-maze test, LPS (10 µg/mouse, i.c.v.) significantly decreased spontaneous alternation, which was prevented by pretreatment with GLP-2 (0.01-0.3 µg/mouse, i.c.v.). The GLP-2 treatment just before the Y-maze test also improved LPS-induced memory impairment. Continuous treatment with GLP-2 (3 µg/mouse, i.c.v.) had no effect on the open-field test in saline-treated or ACTH-treated mice. Chronic ACTH treatment did not cause anxiogenic effects in the elevated plus-maze test. GLP-2 showed weak anxiolytic-like effects in the elevated plus-maze test in ACTH-treated, but not saline-treated mice. Moreover, GLP-2 increased 5-HT, but not 5-HIAA and tryptophan hydroxylase 2 levels in the amygdala of ACTH-treated mice. Pharmacological depletion of 5-HT prevented the anxiolytic effects of GLP-2. These results suggest that GLP-2 protected and improved memory function in LPS-treated mice, and also had anxiolytic effects due to changes in the 5-HT system.

  8. Angioplastic necrolytic migratory erythema. Unique association of necrolytic migratory erythema, extensive angioplasia, and high molecular weight glucagon-like polypeptide

    SciTech Connect

    Franchimont, C.; Pierard, G.E.; Luyckx, A.S.; Gerard, J.; Lapiere, C.M.

    1982-12-01

    A diabetic patient developed necrolytic migratory erythema with extensive angioplasia and high molecular weight glucagon-like polypeptide. There was no associated neoplasm such as glucagonoma. Lesions in the skin were studied by standard optical microscopy and by radioautography after incorporation of tritiated thymidine. Alterations in the skin begin as focal necrosis in the epidermis and in epithelial structures of adnexa, followed by marked angioplasia and a superficial and deep perivascular dermatitis.

  9. Glucagon-Like Peptide-2 Improves Both Acute and Late Experimental Radiation Enteritis in the Rat

    SciTech Connect

    Torres, Sandra

    2007-12-01

    Purpose: Acute and/or chronic radiation enteritis can develop after radiotherapy for pelvic cancers. Experimental and clinical observations have provided evidence of a role played by acute mucosal disruption in the appearance of late effects. The therapeutic potential of acute administration of glucagon-like peptide-2 (GLP-2) against acute and chronic intestinal injury was investigated in this study. Methods and Materials: Intestinal segments were surgically exteriorized and exposed to 16.7 or 19 Gy X-rays. The rats were treated once daily with vehicle or a protease-resistant GLP-2 derivative for 14 days before irradiation, with or without 7 days of GLP-2 after treatment. Macroscopic and microscopic observations were made 2 and 15 weeks after radiation exposure. Results: In the control animals, GLP-2 induced an increase in intestinal mucosal mass, along with an increase in villus height and crypt depth. GLP-2 administration before and after irradiation completely prevented the acute radiation-induced mucosal ulcerations observed after exposure to 16.7 Gy. GLP-2 treatment strikingly reduced the late radiation damage observed after 19 Gy irradiation. Microscopic observations revealed an improved organization of the intestinal wall and an efficient wound healing process, especially in the smooth muscle layers. Conclusion: GLP-2 has a clear therapeutic potential against both acute and chronic radiation enteritis. This therapeutic effect is mediated through an increased mucosal mass before tissue injury and the stimulation of still unknown mechanisms of tissue response to radiation damage. Although these preliminary results still need to be confirmed, GLP-2 might be a way to limit patient discomfort during radiotherapy and reduce the risk of consequential late effects.

  10. Metabolic response of teleost hepatocytes to glucagon-like peptide and glucagon.

    PubMed

    Mommsen, T P; Moon, T W

    1990-07-01

    Salmon glucagon-like peptide (GLP), bovine glucagon (B-glucagon) and anglerfish glucagon (AF-glucagon), all activate glucose production in teleost hepatocytes through gluconeogenesis and glycogenolysis, but notable species differences exist in their respective effectiveness. In trout hepatocytes, gluconeogenesis appears to be the main target of hormone action. In eel cells, sampled in November, glycogenolysis was activated threefold, while gluconeogenesis was increased by 12% only. In March, glycogenolytic activation was 1.7-fold, while gluconeogenesis was increased by about 1.7-fold after exposure to B-glucagon. In brown bullhead cells, increases in glycogenolysis from seven- (GLP) to tenfold (B- and AF-glucagon) were noted, while activation of gluconeogenesis was slight. Fragments of two AF-glucagons (19-29) revealed only insignificant metabolic activity. Treatment of eel cells with B-glucagon led to large (up to 20-fold) increases in intracellular cyclic AMP (cAMP) concentrations, while exposure to GLP was accompanied by a modest (less than twofold) increase in cAMP, although metabolic effectiveness (gluconeogenesis and glycogenolysis) was similar for the two treatments. Under identical conditions, brown bullhead cellular cAMP responded poorly. Levels of cAMP peaked within 15 min following hormone application. The results imply that no simple or direct relationship exists between the amount of intracellular cAMP and the metabolic action of the glucagon family of hormones. It can further be concluded that GLPs are important regulators of hepatic metabolism, influencing identical targets as glucagon, while the mechanisms of action seem to differ. PMID:2166124

  11. Glucagon-like peptide-2 induces rapid digestive adaptation following intestinal resection in preterm neonates

    PubMed Central

    Vegge, Andreas; Thymann, Thomas; Lund, Pernille; Stoll, Barbara; Bering, Stine B.; Hartmann, Bolette; Jelsing, Jacob; Qvist, Niels; Burrin, Douglas G.; Jeppesen, Palle B.; Holst, Jens J.

    2013-01-01

    Short bowel syndrome (SBS) is a frequent complication after intestinal resection in infants suffering from intestinal disease. We tested whether treatment with the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) increases intestinal volume and function in the period immediately following intestinal resection in preterm pigs. Preterm pigs were fed enterally for 48 h before undergoing resection of 50% of the small intestine and establishment of a jejunostomy. Following resection, pigs were maintained on total parenteral nutrition (TPN) without (SBS, n = 8) or with GLP-2 treatment (3.5 μg/kg body wt per h, SBS+GLP-2, n = 7) and compared with a group of unresected preterm pigs (control, n = 5). After 5 days of TPN, all piglets were fed enterally for 24 h, and a nutrient balance study was performed. Intestinal resection was associated with markedly reduced endogenous GLP-2 levels. GLP-2 increased the relative absorption of wet weight (46 vs. 22%), energy (79 vs. 64%), and all macronutrients (all parameters P < 0.05). These findings were supported by a 200% increase in sucrase and maltase activities, a 50% increase in small intestinal epithelial volume (P < 0.05), as well as increased DNA and protein contents and increased total protein synthesis rate in SBS+GLP-2 vs. SBS pigs (+100%, P < 0.05). Following intestinal resection in preterm pigs, GLP-2 induced structural and functional adaptation, resulting in a higher relative absorption of fluid and macronutrients. GLP-2 treatment may be a promising therapy to enhance intestinal adaptation and improve digestive function in preterm infants with jejunostomy following intestinal resection. PMID:23764891

  12. Glucagon-like polypeptide agonists in type 2 diabetes mellitus: efficacy and tolerability, a balance

    PubMed Central

    Tella, Sri Harsha

    2015-01-01

    Glucagon-like polypeptide (GLP-1) receptor agonist treatment has multiple effects on glucose metabolism, supports the β cell, and promotes weight loss. There are now five GLP-1 agonists in clinical use with more in development. GLP-1 treatment typically can induce a lowering of hemoglobin A1c (HbA1c) of 0.5–1.5% over time with weight loss of 2–5%. In some individuals, a progressive loss of weight occurs. There is evidence that GLP-1 therapy opposes the loss of β cells which is a feature of type 2 diabetes. The chief downside of GLP-1 treatment is the gastrointestinal motility disturbance which is one of the modes of action of the hormone; significant nausea, vomiting, and diarrhea may lead to discontinuation of treatment. Although daily injection of GLP-1 agents is successful, the development of extended release preparations allows for injection once weekly, and perhaps much longer in the future. The indication for GLP-1 use is diabetes, but now, liraglutide has been approved for primary treatment of obesity. When oral agents fail to control glucose levels in type 2 diabetes, there is a choice between long-acting insulin and GLP-1 agonists as additional treatments. The lowering of HbA1c by either modality is equivalent in most studies. Patients lose weight with GLP-1 treatment and gain weight on insulin. There is a lower incidence of hypoglycemia with GLP-1 therapy but a much higher incidence of gastrointestinal complaints. Insulin dosing is flexible while GLP-1 agents have historically been administered at fixed dosages. Now, the use of combined long-acting insulin and GLP-1 agonists is promising a major therapeutic change. Combined therapy takes advantage of the benefits of both insulin and GLP-1 agents. Furthermore, direct admixture of both in the same syringe will permit flexible dosing, improvement of glucose levels, and reduction of both hypoglycemia and gastrointestinal side effects. PMID:26137215

  13. Glucagon-like peptide-2 and mouse intestinal adaptation to a high-fat diet.

    PubMed

    Baldassano, Sara; Amato, Antonella; Cappello, Francesco; Rappa, Francesca; Mulè, Flavia

    2013-04-01

    Endogenous glucagon-like peptide-2 (GLP2) is a key mediator of refeeding-induced and resection-induced intestinal adaptive growth. This study investigated the potential role of GLP2 in mediating the mucosal responses to a chronic high-fat diet (HFD). In this view, the murine small intestine adaptive response to a HFD was analyzed and a possible involvement of endogenous GLP2 was verified using GLP2 (3-33) as GLP2 receptor (GLP2R) antagonist. In comparison with animals fed a standard diet, mice fed a HFD for 14 weeks exhibited an increase in crypt-villus mean height (duodenum, 27.5±3.0%; jejunum, 36.5±2.9%; P<0.01), in the cell number per villus (duodenum, 28.4±2.2%; jejunum, 32.0±2.9%; P<0.01), and in Ki67-positive cell number per crypt. No change in the percent of caspase-3-positive cell in the villus-crypt was observed. The chronic exposure to a HFD also caused a significant increase in GLP2 plasma levels and in GLP2R intestinal expression. Daily administration of GLP2 (3-33) (30-60  ng) for 4 weeks did not modify the crypt-villus height in control mice. In HFD-fed mice, chronic treatment with GLP2 (3-33) reduced the increase in crypt-villus height and in the cell number per villus through reduction of cell proliferation and increase in apoptosis. This study provides the first experimental evidence for a role of endogenous GLP2 in the intestinal adaptation to HFD in obese mice and for a dysregulation of the GLP2/GLP2R system after a prolonged HFD.

  14. Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation

    PubMed Central

    Chang, Tien-Jyun; Tseng, Hsing-Chi; Liu, Meng-Wei; Chang, Yi-Cheng; Hsieh, Meng-Lun; Chuang, Lee-Ming

    2016-01-01

    Accumulation of methylglyoxal (MG) contributes to glucotoxicity and mediates beta cell apoptosis. The molecular mechanism by which GLP-1 protects MG-induced beta cell apoptosis remains unclear. Metformin is a first-line drug for treating type 2 diabetes associated with AMPK activation. However, whether metformin prevents MG-induced beta cell apoptosis is controversial. Here, we explored the signaling pathway involved in the anti-apoptotic effect of GLP-1, and investigated whether metformin had an anti-apoptotic effect on beta cells. MG treatment induced apoptosis of beta cells, impaired mitochondrial function, and prolonged activation of AMP-dependent protein kinase (AMPK). The MG-induced pro-apoptotic effects were abolished by an AMPK inhibitor. Pretreatment of GLP-1 reversed MG-induced apoptosis, and mitochondrial dysfunction, and suppressed prolonged AMPK activation. Pretreatment of GLP-1 reversed AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR)-induced apoptosis, and suppressed prolonged AMPK activation. However, metformin neither leads to beta cell apoptosis nor ameliorates MG-induced beta cell apoptosis. In parallel, GLP-1 also prevents MG-induced beta cell apoptosis through PKA and PI3K-dependent pathway. In conclusion, these data indicates GLP-1 but not metformin protects MG-induced beta cell apoptosis through improving mitochondrial function, and alleviating the prolonged AMPK activation. Whether adding GLP-1 to metformin provides better beta cell survival and delays disease progression remains to be validated. PMID:26997114

  15. New Insights Concerning the Glucose-dependent Insulin Secretagogue Action of Glucagon-like Peptide-1 in Pancreatic β-Cells

    PubMed Central

    Holz, G.

    2010-01-01

    The GLP-1 receptor is a Class B heptahelical G-protein-coupled receptor that stimulates cAMP production in pancreatic β-cells. GLP-1 utilizes this receptor to activate two distinct classes of cAMP-binding proteins: protein kinase A (PKA) and the Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs). Actions of GLP-1 mediated by PKA and Epac include the recruitment and priming of secretory granules, thereby increasing the number of granules available for Ca2+-dependent exocytosis. Simultaneously, GLP-1 promotes Ca2+ influx and mobilizes an intracellular source of Ca2+. GLP-1 sensitizes intracellular Ca2+ release channels (ryanodine and IP3 receptors) to stimulatory effects of Ca2+, thereby promoting Ca2+-induced Ca2+ release (CICR). In the model presented here, CICR activates mitochondrial dehydrogenases, thereby upregulating glucose-dependent production of ATP. The resultant increase in cytosolic [ATP]/[ADP] concentration ratio leads to closure of ATP-sensitive K+ channels (K-ATP), membrane depolarization, and influx of Ca2+ through voltage-dependent Ca2+ channels (VDCCs). Ca2+ influx stimulates exocytosis of secretory granules by promoting their fusion with the plasma membrane. Under conditions where Ca2+ release channels are sensitized by GLP-1, Ca2+ influx also stimulates CICR, generating an additional round of ATP production and K-ATP channel closure. In the absence of glucose, no “fuel” is available to support ATP production, and GLP-1 fails to stimulate insulin secretion. This new “feed-forward” hypothesis of β-cell stimulus-secretion coupling may provide a mechanistic explanation as to how GLP-1 exerts a beneficial blood glucose-lowering effect in type 2 diabetic subjects. PMID:15655710

  16. [Roles of rs 6923761 gene variant in glucagon-like peptide 1 receptor on weight, cardiovascular risk factor and serum adipokine levels in morbid obese patients].

    PubMed

    de Luis, Daniel Antonio; Pacheco, David; Aller, Rocío; Izaola, Olatz; Bachiller, Rosario

    2014-04-01

    Antecedentes: Los estudios de receptor de GLP-1 se han dirigido a la identificación de polimorfismos en el gen receptor de GLP- 1 que pueden ser un factor que contribuye en la patogénesis de la diabetes mellitus y factores de riesgo cardiovascular. Sin embargo, el papel de las variantes del receptor de GLP-1 variantes en el peso corporal, factores de riesgo cardiovasculares y adipocitoquinas sigue estando poco estudiado en pacientes con obesidad morbida. Objetivo: Nuestro objetivo fue analizar los efectos del polimorfismo del receptor de GLP-1 rs6923761 sobre el peso corporal, factores de riesgo cardiovascular y los niveles de adipocitoquinas séricas en pacientes con obesidad mórbida. Diseño: Se estudió una muestra de 175 obesos mórbidos. La glucosa en ayunas, proteína C reactiva (PCR), insulina, resistencia a la insulina ( HOMA), colesterol total, LDL- colesterol, HDL- colesterol, triglicéridos y la concentración de adipoquinas se midieron. También se determinaron el peso, índice de masa corporal, circunferencia de la cintura, masa grasa a través de bioimpedancia y la presión arterial. Resultados: Un total de 87 obesos (49,7%) tenían el genotipo GG y 88 (50,3%) de los sujetos del estudio tenían los siguientes genotipos; GA (71 obesos, el 40,6%) o AA (17 sujetos del estudio, el 9,7%) ( segundo grupo) . En el grupo con genotipo GG, los niveles de glucosa (4,4 ± 2,3 mg/dl, p < 0,05), triglicéridos (6,8 ± 4,3 mg/dl , p < 0,05), insulina (4,5 ± 2,3 UI/l , p < 0,05) y HOMA (1,5 ± 0,9 unidades, p < 0,05 ) fueron mayores que en el grupo mutante. No se detectaron diferencias en el resto de parámetros analizados Conclusión: Existe una asociación entre los parámetros metabólicos y el alelo mutante (A) del polimorfismo rs6923761 del receptor de GLP- 1 en pacientes con obesidad mórbida. Los niveles de triglicéridos, insulina y resistencia a la insulina son más elevados en los sujetos portadores del alelo A.

  17. Combination of soya protein and polydextrose reduces energy intake and glycaemic response via modulation of gastric emptying rate, ghrelin and glucagon-like peptide-1 in Chinese.

    PubMed

    Soong, Yean Yean; Lim, Wen Xin; Leow, Melvin Khee Shing; Siow, Phei Ching; Teh, Ai Ling; Henry, Christiani Jeyakumar

    2016-06-01

    The short-term effect of soya protein, polydextrose and their combination on energy intake (EI) was investigated in Chinese. In total, twenty-seven healthy, normotensive and lean Chinese men aged 21-40 years were given four different soyabean curd preloads with or without polydextrose. The study was a repeated-measure, randomised, cross-over design. The consumption of high-protein soyabean curd alone or in addition with polydextrose as a preload led to greater reduction in EI at a subsequent meal. A similar observation was also found after intake of low-protein soyabean curd with polydextrose. The gut hormone responses mirrored the reduction in food intake. It appears that incorporation of polydextrose either with low- or high-protein soyabean curd could be a potential strategy to reduce EI and assist with weight management. The popular consumption of soyabean curd in Chinese makes it an ideal vehicle for incorporation of polydextrose. This evidence-based dietary approach can serve as a guideline for developing functional foods for weight reduction and weight maintenance. PMID:27185412

  18. Glucagon-like peptide-1 (7-36) but not (9-36) augments cardiac output during myocardial ischemia via a Frank-Starling mechanism.

    PubMed

    Goodwill, Adam G; Tune, Johnathan D; Noblet, Jillian N; Conteh, Abass M; Sassoon, Daniel; Casalini, Eli D; Mather, Kieren J

    2014-01-01

    This study examined the cardiovascular effects of GLP-1 (7-36) or (9-36) on myocardial oxygen consumption, function and systemic hemodynamics in vivo during normal perfusion and during acute, regional myocardial ischemia. Lean Ossabaw swine received systemic infusions of saline vehicle or GLP-1 (7-36 or 9-36) at 1.5, 3.0, and 10.0 pmol/kg/min in sequence for 30 min at each dose, followed by ligation of the left circumflex artery during continued infusion at 10.0 pmol/kg/min. Systemic GLP-1 (9-36) had no effect on coronary flow, blood pressure, heart rate or indices of cardiac function before or during regional myocardial ischemia. Systemic GLP-1 (7-36) exerted no cardiometabolic or hemodynamic effects prior to ischemia. During ischemia, GLP-1 (7-36) increased cardiac output by approximately 2 L/min relative to vehicle-controls (p = 0.003). This response was not diminished by treatment with the non-depolarizing ganglionic blocker hexamethonium. Left ventricular pressure-volume loops measured during steady-state conditions with graded occlusion of the inferior vena cava to assess load-independent contractility revealed that GLP-1 (7-36) produced marked increases in end-diastolic volume (74 ± 1 to 92 ± 5 ml; p = 0.03) and volume axis intercept (8 ± 2 to 26 ± 8; p = 0.05), without any change in the slope of the end-systolic pressure-volume relationship vs. vehicle during regional ischemia. GLP-1 (9-36) produced no changes in any of these parameters compared to vehicle. These findings indicate that short-term systemic treatment with GLP-1 (7-36) but not GLP-1 (9-36) significantly augments cardiac output during regional myocardial ischemia, via increases in ventricular preload without changes in cardiac inotropy.

  19. Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation.

    PubMed

    Chang, Tien-Jyun; Tseng, Hsing-Chi; Liu, Meng-Wei; Chang, Yi-Cheng; Hsieh, Meng-Lun; Chuang, Lee-Ming

    2016-01-01

    Accumulation of methylglyoxal (MG) contributes to glucotoxicity and mediates beta cell apoptosis. The molecular mechanism by which GLP-1 protects MG-induced beta cell apoptosis remains unclear. Metformin is a first-line drug for treating type 2 diabetes associated with AMPK activation. However, whether metformin prevents MG-induced beta cell apoptosis is controversial. Here, we explored the signaling pathway involved in the anti-apoptotic effect of GLP-1, and investigated whether metformin had an anti-apoptotic effect on beta cells. MG treatment induced apoptosis of beta cells, impaired mitochondrial function, and prolonged activation of AMP-dependent protein kinase (AMPK). The MG-induced pro-apoptotic effects were abolished by an AMPK inhibitor. Pretreatment of GLP-1 reversed MG-induced apoptosis, and mitochondrial dysfunction, and suppressed prolonged AMPK activation. Pretreatment of GLP-1 reversed AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR)-induced apoptosis, and suppressed prolonged AMPK activation. However, metformin neither leads to beta cell apoptosis nor ameliorates MG-induced beta cell apoptosis. In parallel, GLP-1 also prevents MG-induced beta cell apoptosis through PKA and PI3K-dependent pathway. In conclusion, these data indicates GLP-1 but not metformin protects MG-induced beta cell apoptosis through improving mitochondrial function, and alleviating the prolonged AMPK activation. Whether adding GLP-1 to metformin provides better beta cell survival and delays disease progression remains to be validated. PMID:26997114

  20. Do Lactation-Induced Changes in Ghrelin, Glucagon-Like Peptide-1, and Peptide YY Influence Appetite and Body Weight Regulation during the First Postpartum Year?

    PubMed Central

    Larson-Meyer, D. Enette; Schueler, Jessica; Kyle, Erin; Austin, Kathleen J.; Hart, Ann Marie; Alexander, Brenda M.

    2016-01-01

    To determine whether fasting and meal-induced appetite-regulating hormones are altered during lactation and associated with body weight retention after childbearing, we studied 24 exclusively breastfeeding women (BMI = 25.2 ± 3.6 kg/m2) at 4-5 weeks postpartum and 20 never-pregnant controls (BMI = 24.0 ± 3.1 kg/m2). Ghrelin, PYY, GLP-1, and appetite ratings were measured before/and 150 minutes after a standardized breakfast and 60 minutes after an ad libitum lunch. Body weight/composition were measured at 6 and 12 months. Fasting and area under-the-curve responses for appetite-regulating hormones did not differ between lactating and control groups; ghrelinacyl, however, tended to track higher after the standardized breakfast in lactating women and was higher (p < 0.05) after the ad libitum lunch despite a 24% higher energy intake (p < 0.05). By 12 months, lactating women lost 5.3 ± 2.2 kg (n = 18), whereas control women (n = 15) remained weight stable (p = 0.019); fifteen of the lactating women returned to within ±2.0 kg of prepregnancy weight but three retained >6.0 kg. The retainers had greater (p < 0.05) postmeal ghrelin rebound responses following breakfast. Overall these studies do not support the hypothesis that appetite-regulating hormones are altered during lactation and associated with postpartum weight retention. Altered ghrelin responses, however, deserve further exploration. PMID:27313876

  1. Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity.

    PubMed

    Hwang, Injae; Park, Yoon Jeong; Kim, Yeon-Ran; Kim, Yo Na; Ka, Sojeong; Lee, Ho Young; Seong, Je Kyung; Seok, Yeong-Jae; Kim, Jae Bum

    2015-06-01

    Firmicutes and Bacteroidetes, 2 major phyla of gut microbiota, are involved in lipid and bile acid metabolism to maintain systemic energy homeostasis in host. Recently, accumulating evidence has suggested that dietary changes promptly induce the alteration of abundance of both Firmicutes and Bacteroidetes in obesity and its related metabolic diseases. Nevertheless, the metabolic roles of Firmicutes and Bacteroidetes on such disease states remain unclear. The aim of this study was to determine the effects of antibiotic-induced depletion of Firmicutes and Bacteroidetes on dysregulation of energy homeostasis in obesity. Treatment of C57BL/6J mice with the antibiotics (vancomycin [V] and bacitracin [B]), in the drinking water, before diet-induced obesity (DIO) greatly decreased both Firmicutes and Bacteroidetes in the gut as revealed by pyrosequencing of the microbial 16S rRNA gene. Concomitantly, systemic glucose intolerance, hyperinsulinemia, and insulin resistance in DIO were ameliorated via augmentation of GLP-1 secretion (active form; 2.03-fold, total form; 5.09-fold) independently of obesity as compared with untreated DIO controls. Furthermore, there were increases in metabolically beneficial metabolites derived from the gut. Together, our data suggest that Firmicutes and Bacteroidetes potentially mediate insulin resistance through modulation of GLP-1 secretion in obesity.

  2. Glucagon-like peptide 2 therapy reduces negative effects of diarrhea on calf gut.

    PubMed

    Connor, E E; Kahl, S; Elsasser, T H; Baldwin, R L; Fayer, R; Santin-Duran, M; Sample, G L; Evock-Clover, C M

    2013-03-01

    Damage to the intestinal epithelium reduces nutrient absorption and animal growth, and can have negative long-term health effects on livestock. Because the intestinotropic hormone glucagon-like peptide 2 (GLP-2) has been shown to contribute to gut integrity, reduce inflammation, and improve nutrient absorption, the present study was designed to determine whether administration of GLP-2 to calves with coccidiosis in the first month of life affects intestinal growth and mediates negative effects of the proinflammatory response. Holstein bull calves (n=19) were assigned to 4 treatment groups of 4 to 5 calves each: (1) infected with Eimeria bovis, GLP-2 treated; (2) noninfected, GLP-2 treated; (3) infected with E. bovis, buffer treated; and (4) noninfected, buffer treated. Infected calves received 100,000 to 200,000 sporulated E. bovis oocysts suspended in milk replacer on d 0 of the study. On d 18, calves in the GLP-2 groups received a subcutaneous injection of 50 μg of bovine GLP-2/kg of body weight twice daily for 10 d, and calves in the buffer-treated groups received an equivalent volume of sodium bicarbonate buffer only. On d 28, calves were slaughtered 2h after injection of 5-bromo-2'-deoxyuridine (BrdU). Intestinal tissues were measured and villus height, crypt depth, and BrdU immunostaining were evaluated in segments of the small intestine. Nitrotyrosine immunostaining, a measure of nitro-oxidative damage, was evaluated in the ileum and cecum. No GLP-2 treatment by E. bovis infection interaction was observed for any parameter measured, with the exception of nitrotyrosine immunostaining in the cecum. Large intestinal weight was greater in infected than noninfected calves and with GLP-2 treatment relative to buffer treatment. Calves that received GLP-2 also had greater small intestinal weight but no difference in cell proliferation, as assessed by BrdU labeling, relative to buffer-treated calves. No treatment effects were detected for villus height, crypt depth

  3. Glucagon like peptide-2 induces intestinal restitution through VEGF release from subepithelial myofibroblasts.

    PubMed

    Bulut, Kerem; Pennartz, Christian; Felderbauer, Peter; Meier, Juris J; Banasch, Matthias; Bulut, Daniel; Schmitz, Frank; Schmidt, Wolfgang E; Hoffmann, Peter

    2008-01-14

    Glucagon like peptide-2 (GLP-2) exerts intestinotrophic actions, but the underlying mechanisms are still a matter of debate. Recent studies demonstrated the expression of the GLP-2 receptor on fibroblasts located in the subepithelial tissue, where it might induce the release of growth factors such as keratinocyte growth factor (KGF) or vascular endothelial growth factor (VEGF). Therefore, in the present studies we sought to elucidate the downstream mechanisms involved in improved intestinal adaptation by GLP-2. Human colonic fibroblasts (CCD-18Co), human colonic cancer cells (Caco-2 cells) and rat ileum IEC-18 cells were used. GLP-2 receptor mRNA expression was determined using real time RT-PCR. Conditioned media from CCD-18Co cells were obtained following incubation with GLP-2 (50-250 nM) for 24 h. Cell viability was assessed by a 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide (MTT)-assay, and wound healing was determined with an established migration-assay. Transforming Growth Factor beta (TGF-beta), VEGF and KGF mRNA levels were determined by RT-PCR. Protein levels of VEGF and TGF-beta in CCD-18Co cells following GLP-2 stimulation were determined using ELISA. Neutralizing TGF-beta and VEGF-A antibodies were utilized to assess the role of TGF-beta and VEGF-A in the process of wound healing. GLP-2 receptor expression was detected in CCD-18Co cells. Conditioned media from CCD-18Co cells dose-dependently induced proliferation in Caco-2 cells, but not in IEC-18 cells. Conditioned media also enhanced cell migration in IEC-18 cells (P<0.01), while migration was even inhibited in Caco-2 cells (P<0.0012). GLP-2 significantly stimulated mRNA expression of VEGF and TGF-beta, but not of KGF in CCD-18Co. The migratory effects of GLP-2 were completely abolished in the presence of TGF-beta and VEGF-A antibodies. GLP-2 exerts differential effects on the epithelium of the small intestine and the colon. Thus, in small intestinal cells GLP-2 stimulates wound

  4. Glucagon-like peptide-2 intracellularly stimulates eNOS phosphorylation and specifically induces submucosal arteriole vasodilation via a sheer stress-independent, local neural mechanism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glucagon-like peptide-2 (GLP-2) is a nutrient-responsive neuropeptide that exerts diverse actions in the gastrointestinal tract, including enhancing mucosal cell survival and proliferation, mucosal blood flow, luminal nutrient uptake, and suppressing gastric motility and secretion. We have shown th...

  5. Glucagon-like peptide-2 (GLP-2) increases net amino acid utilization by the portal-drained viscera of ruminatinhg calves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glucagon-like peptide-2 (GLP-2) increases small intestinal mass and blood flow in ruminant calves, but its impact on nutrient metabolism across the portal-drained viscera (PDV) and liver is unknown. Eight Holstein calves with catheters in the carotid artery, mesenteric vein, portal vein and hepatic ...

  6. The glucagon-like peptide 2 receptor is expressed in enteric neurons and not in the epithelium of the intestine.

    PubMed

    Pedersen, Jens; Pedersen, Nis B; Brix, Sophie W; Grunddal, Kaare Villum; Rosenkilde, Mette M; Hartmann, Bolette; Ørskov, Cathrine; Poulsen, Steen S; Holst, Jens J

    2015-05-01

    Glucagon-like peptide 2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential in the treatment of intestinal deficiencies. It has recently been approved for the treatment of short bowel syndrome. The effects of GLP-2 are mediated by specific binding of the hormone to the GLP-2 receptor (GLP-2R) which was cloned in 1999. However, consensus about the exact receptor localization in the intestine has never been established. By physical, chemical and enzymatic tissue fragmentation, we were able to divide rat jejunum into different compartments consisting of: (1) epithelium alone, (2) mucosa with lamina propria and epithelium, (3) the external muscle coat including myenteric plexus, (4) a compartment enriched for the myenteric plexus and (5) intestine without epithelium. Expression of Glp2r; chromogranin A; tubulin, beta 3; actin, gamma 2, smooth muscle, enteric and glial fibrillary acidic protein in these isolated tissue fractions was quantified with qRT-PCR. Expression of the Glp2r was confined to compartments containing enteric neurons and receptor expression was absent in the epithelium. Our findings provide evidence for the expression of the GLP-2R in intestinal compartments rich in enteric neurons and, importantly they exclude significant expression in the epithelium of rat jejunal mucosa.

  7. Structure and biological activity of glucagon and glucagon-like peptide from a primitive bony fish, the bowfin (Amia calva).

    PubMed Central

    Conlon, J M; Youson, J H; Mommsen, T P

    1993-01-01

    The bowfin, Amia calva (order Amiiformes) occupies an important position in phylogeny as a surviving representative of a group of primitive ray-finned fishes from which the present-day teleosts may have evolved. Glucagon and glucagon-like peptide (GLP) were isolated from an extract of bowfin pancreas and their primary structures determined. Bowfin glucagon shows only four amino acid substitutions compared with human glucagon, and bowfin glucagon was equipotent and equally effective as human glucagon in stimulation of glycogenolysis in dispersed hepatocytes from a teleost fish, the copper rockfish, Sebastes caurinus. In contrast, bowfin GLP shows 15 amino acid substitutions and three amino acid deletions compared with the corresponding region of human GLP-1-(7-37)-peptide. In particular, the bowfin peptide contains an N-terminal tyrosine residue rather than the N-terminal histidine residue found in all other glucagon-related peptides so far characterized. Bowfin GLP stimulated glycogenolysis in rockfish hepatocytes, but was 3-fold less effective and 23-fold less potent than human GLP-1-(7-37)-peptide. We speculate that selective mutations in the GLP domain of bowfin preproglucagon may be an adaptive response to the previously demonstrated low biological potency of bowfin insulin. PMID:8240302

  8. Isolation and structure of the principal products of preproglucagon processing, including an amidated glucagon-like peptide.

    PubMed

    Andrews, P C; Hawke, D H; Lee, T D; Legesse, K; Noe, B D; Shively, J E

    1986-06-25

    The principal products derived from in vivo processing of anglerfish preproglucagon II were isolated and their structures determined. The structures were confirmed by a combination of automated Edman degradation, amino acid analysis, and fast atom bombardment mass spectrometry. The peptide corresponding to anglerfish preproglucagon II-(22-49) (numbering from the amino terminus of preproglucagon) was isolated intact and defines the site of signal cleavage to be between Gln-21 and Met-22. Glucagon from the anglerfish preproglucagon gene II was found to correspond to preproglucagon II-(52-80) (numbering from the amino terminus). Three forms of a glucagon-like peptide derived from preproglucagon II were also isolated. The structure of the longest form was consistent with the sequence of preproglucagon II-(89-122) deduced from the cDNA, His-Ala-Asp-Gly-Thr-Tyr-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Gln-Asp-Gln-Ala- Ala-Lys-Asp-Phe-Val-Ser-Trp-Leu-Lys-Ala-Gly-Arg-Gly-Arg-Arg-Glu. The carboxyl-terminal portion deduced from the cDNA remains intact in this form. A second form, preproglucagon II-(89-119) appears to result from proteolytic processing of the major form at the two adjacent arginine residues occurring at the carboxyl terminus. This second form has a glycine residue at its carboxyl terminus and is processed to the third form (preproglucagon II-(89-118)) which contains a carboxyl-terminal arginineamide. Radiolabeling studies in primary tissue culture support the observation that glucagon (preproglucagon II-(52-80], preproglucagon II-(89-122), and preproglucagon II-(89-119) are products of proglucagon processing in vivo. PMID:3755132

  9. Glucagon-like peptide-2 modulates neurally evoked mucosal chloride secretion in guinea pig small intestine in vitro

    PubMed Central

    Baldassano, Sara; Liu, Sumei; Qu, Mei-Hu; Mulè, Flavia

    2009-01-01

    Glucagon-like peptide-2 (GLP-2) is an important neuroendocrine peptide in intestinal physiology. It influences digestion, absorption, epithelial growth, motility, and blood flow. We studied involvement of GLP-2 in intestinal mucosal secretory behavior. Submucosal-mucosal preparations from guinea pig ileum were mounted in Ussing chambers for measurement of short-circuit current (Isc) as a surrogate for chloride secretion. GLP-2 action on neuronal release of acetylcholine was determined with ELISA. Enteric neuronal expression of the GLP-2 receptor (GLP-2R) was studied with immunohistochemical methods. Application of GLP-2 (0.1–100 nM) to the serosal or mucosal side of the preparations evoked no change in baseline Isc and did not alter transepithelial ionic conductance. Transmural electrical field stimulation (EFS) evoked characteristic biphasic increases in Isc, with an initially rapid rising phase followed by a sustained phase. Application of GLP-2 reduced the EFS-evoked biphasic responses in a concentration-dependent manner. The GLP-2R antagonist GLP-2-(3-33) significantly reversed suppression of the EFS-evoked responses by GLP-2. Tetrodotoxin, scopolamine, and hexamethonium, but not vasoactive intestinal peptide type 1 receptor (VPAC1) antagonist abolished or reduced to near zero the EFS-evoked responses. GLP-2 suppressed EFS-evoked acetylcholine release as measured by ELISA. Pretreatment with GLP-2-(3-33) offset this action of GLP-2. In the submucosal plexus, GLP-2R immunoreactivity (-IR) was expressed in choline acetyltransferase-IR neurons, somatostatin-IR neurons, neuropeptide Y-IR neurons, and vasoactive intestinal peptide-IR neurons. We conclude that submucosal neurons in the guinea pig ileum express GLP-2R. Activation of GLP-2R decreases neuronally evoked epithelial chloride secretion by suppressing acetylcholine release from secretomotor neurons. PMID:19628655

  10. Effect of Glucagon-Like Peptide 2 on Hepatic, Renal, and Intestinal Disposition of 1-Chloro-2,4-dinitrobenzene

    PubMed Central

    Villanueva, Silvina S. M.; Perdomo, Virginia G.; Ruiz, María L.; Rigalli, Juan P.; Arias, Agostina; Luquita, Marcelo G.; Vore, Mary; Catania, Viviana A.

    2012-01-01

    The ability of the liver, small intestine, and kidney to synthesize and subsequently eliminate dinitrophenyl-S-glutathione (DNP-SG), a substrate for multidrug resistance-associated protein 2 (Mrp2), was assessed in rats treated with glucagon-like peptide 2 (GLP-2, 12 μg/100 g b.wt. s.c. every 12 h for 5 consecutive days). An in vivo perfused jejunum model with simultaneous bile and urine collection was used. A single intravenous dose of 30 μmol/kg b.wt. 1-chloro-2,4-dinitrobenzene (CDNB) was administered, and its conjugate, DNP-SG, and dinitrophenyl cysteinyl glycine (DNP-CG), resulting from the action of γ-glutamyltransferase on DNP-SG, were determined in bile, intestinal perfusate, and urine by high-performance liquid chromatography. Tissue content of DNP-SG was also assessed in liver, intestine, and kidneys. Biliary excretion of DNP-SG+DNP-CG was decreased in GLP-2 rats with respect to controls. In contrast, their intestinal excretion was substantially increased, whereas urinary elimination was not affected. Western blot and real-time polymerase chain reaction studies revealed preserved levels of Mrp2 protein and mRNA in liver and renal cortex and a significant increase in intestine in response to GLP-2 treatment. Tissue content of DNP-SG detected 5 min after CDNB administration was decreased in liver, increased in intestine, and unchanged in kidney in GLP-2 versus control group, consistent with GLP-2-induced down-regulation of expression of glutathione transferase (GST) Mu in liver and up-regulation of GST-Alpha in intestine at both protein and mRNA levels. In conclusion, GLP-2 induced selective changes in hepatic and intestinal disposition of a common GST and Mrp2 substrate administered systemically that could be of pharmacological or toxicological relevance under therapeutic treatment conditions. PMID:22453052

  11. Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone in SH-SY5Y cells.

    PubMed

    Jalewa, Jaishree; Sharma, Mohit Kumar; Hölscher, Christian

    2016-10-01

    Currently, there is no viable treatment available for Parkinson's disease (PD) that stops or reverses disease progression. Interestingly, studies testing the glucagon-like-peptide-1 (GLP-1) mimetic Exendin-4 have shown neuroprotective/neurorestorative properties in pre-clinical tests and in a pilot clinical study of PD. Incretin analogues were originally developed to treat type 2 diabetes and several are currently on the market. In this study, we tested novel incretin analogues on the dopaminergic SH-SY5Y neuroblastoma cells against a toxic mitochondrial complex I inhibitor, Rotenone. Here, we investigate for the first time the effects of six different incretin receptor agonists - Liraglutide, D-Ser2-Oxyntomodulin, a GLP-1/GIP Dual receptor agonist, dAla(2)-GIP-GluPal, Val(8)GLP-1-GluPal and exendin-4. Post-treatment with doses of 1, 10 or 100 nM of incretin analogues for 12 h increased the survival of SH-SY5Y cells treated with 1 μM Rotenone for 12 h. Furthermore, we studied the post-treatment effect of 100 nM incretin analogues against 1 μM Rotenone stress on apoptosis, mitochondrial stress and autophagy markers. We found significant protective effects of the analogues against Rotenone stress on cell survival and on mitochondrial and autophagy-associated markers. The novel GLP-1/GIP Dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. Using the Phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, we further show that the neuroprotective effects are partially PI3K-independent. Our data suggest that the neuroprotective properties exhibited by incretin analogues against Rotenone stress involve enhanced autophagy, increased Akt-mediated cell survival and amelioration of mitochondrial dysfunction. These mechanisms can explain the neuroprotective effects of incretin analogues reported in clinical trials. GLP-1, GIP and dual incretin receptor agonists showed protective effects in SH-SY5Y cells

  12. Role of glial cell-line derived neurotropic factor family receptor alpha2 in the actions of the glucagon-like peptides on the murine intestine.

    PubMed

    McDonagh, Sean C; Lee, Jenny; Izzo, Angelo; Brubaker, Patricia L

    2007-08-01

    The intestinal glucagon-like peptides GLP-1 and GLP-2 inhibit intestinal motility, whereas GLP-2 also stimulates growth of the intestinal mucosa. However, the mechanisms of action of these peptides in the intestine remain poorly characterized. To determine the role of the enteric nervous system in the actions of GLP-1 and GLP-2 on the intestine, the glial cell line-derived neurotropic factor family receptor alpha(2) (GFRalpha2) knockout (KO) mouse was employed. The mice exhibited decreased cholinergic staining, as well as reduced mRNA transcripts for substance P-ergic excitatory motoneurons in the enteric nervous system (ENS) (P < 0.05). Examination of parameters of intestinal growth (including small and large intestinal weight and small intestinal villus height, crypt depth, and crypt cell proliferation) demonstrated no differences between wild-type and KO mice in either basal or GLP-2-stimulated mucosal growth. Nonetheless, KO mice exhibited reduced numbers of synaptophysin-positive enteroendocrine cells (P < 0.05), as well as a markedly impaired basal gastrointestinal (GI) transit rate (P < 0.05). Furthermore, acute administration of GLP-1 and GLP-2 significantly inhibited transit rates in wild-type mice (P < 0.05-0.01) but had no effect in GFRalpha2 KO mice. Despite these changes, expression of mRNA transcripts for the GLP receptors was not reduced in the ENS of KO animals, suggesting that GLP-1 and -2 modulate intestinal transit through enhancement of inhibitory input to cholinergic/substance P-ergic excitatory motoneurons. Together, these findings demonstrate a role for GFRalpha2-expressing enteric neurons in the downstream signaling of the glucagon-like peptides to inhibit GI motility, but not in intestinal growth.

  13. Exendin-4, a glucagon-like peptide-1 receptor agonist, inhibits Aβ25-35-induced apoptosis in PC12 cells by suppressing the expression of endoplasmic reticulum stress-related proteins

    PubMed Central

    Zhang, Jianfeng; Wu, Junfeng; Zeng, Weichen; Zhao, Yongfei; Zu, Hengbing

    2015-01-01

    Neurodegenerative disorders are chronic and progressive disease. Exendin-4 (Ex-4) can function as a neuroprotective agent and has novel therapeutic ability for the treatment of neurodegenerative disorders. In this study, we aimed to explore the neuroprotective effect of Ex-4 on PC12 cell apoptosis induced by Aβ25-35 in molecular level. The apoptosis of PC12 cells was detected by MTT assay, TUNEL staining and flow cytometry. The expression of ERS (endoplasmic reticulum stress, ERS) related proteins such as CHOP, GRP78 and Caspase-12 were determined by Western blot and cell immunocytochemistry. Results showed the apoptotic rate of PC12 cells significantly increased after Aβ25-35 addition, which was remarkably reduced after Ex-4 treatment. The expression of CHOP, GRP78 and Caspase-12 were significantly upregulated, and then remarkably reduced after Ex-4 treatment, while in the presence of Exendin9-39, the effect of Ex-4 was reversed. In conclusion, endoplasmic reticulum stress might be involved in the apoptosis process of PC12 cell induced by Aβ25-35 and Ex-4 might provide a potential strategy for the treatment and prevention of cell apoptosis-associated disorders. PMID:26722468

  14. Frog skin peptides (tigerinin-1R, magainin-AM1, -AM2, CPF-AM1, and PGla-AM1) stimulate secretion of glucagon-like peptide 1 (GLP-1) by GLUTag cells.

    PubMed

    Ojo, O O; Conlon, J M; Flatt, P R; Abdel-Wahab, Y H A

    2013-02-01

    Skin secretions of several frog species contain host-defense peptides with multiple biological activities including in vitro and in vivo insulin-releasing actions. This study investigates the effects of tigerinin-1R from Hoplobatrachus rugulosus (Dicroglossidae) and magainin-AM1, magainin-AM2, caerulein precursor fragment (CPF-AM1) and peptide glycine leucine amide (PGLa-AM1) from Xenopus amieti (Pipidae) on GLP-1 secretion from GLUTag cells. Tigerinin-1R showed the highest potency producing a significant (P<0.05) increase in GLP-1 release at a concentration of 0.1nM for the cyclic peptide and 0.3nM for the reduced form. All peptides from X. amieti significantly (P<0.05) stimulated GLP-1 release at concentrations ⩾300nM with magainin-AM2 exhibiting the greatest potency (minimum concentration producing a significant stimulation=1nM). The maximum stimulatory response (3.2-fold of basal rate, P<0.001) was produced by CPF-AM1 at a concentration of 3μM. No peptide stimulated release of the cytosolic enzyme, lactate dehydrogenase from GLUTag cells at concentrations up to 3μM indicating that the integrity of the plasma membrane had been preserved. The data indicate that frog skin peptides, by stimulating GLP-1 release as well as direct effects on insulin secretion, show therapeutic potential as agents for the treatment of type 2 diabetes.

  15. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway.

    PubMed

    He, Qin; Sha, Sha; Sun, Lei; Zhang, Jing; Dong, Ming

    2016-08-01

    The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy. We set up an obesity mouse model with a high-fat diet (HFD) and induced hepatocyte steatosis with free fatty acids (FFA) in human L-O2 cells. LRG and two inhibitors of autophagy, Chloroquine (CQ) and bafilomycin A1 (Baf), were added into each group, respectively. The lipid profiles and morphological modifications of each group were tested. Immunohistochemistry, immunofluorescence staining and transmission electron microscopy (TEM) were used to measure autophagy in this study. The autophagy protein expression of SQSTM1 (P62), and LC3B, along with the signaling pathway proteins of mTOR, phosphorylated mTOR (p-mTOR), AMPK, phosphorylated AMPK (p-AMPK) and Beclin1, were evaluated by western blot. Our results showed that LRG improved hepatocyte steatosis by inducing autophagy, and the AMPK/mTOR pathway is involved. These findings suggest an important mechanism for the positive effects of LRG on hepatic steatosis, and provide new evidence for clinical use of LRG in NAFLD. PMID:27208776

  16. The primary structure of glucagon-like peptide but not insulin has been conserved between the American eel, Anguilla rostrata and the European eel, Anguilla anguilla.

    PubMed

    Conlon, J M; Andrews, P C; Thim, L; Moon, T W

    1991-04-01

    Insulin was isolated from the pancreas of the American eel, Anguilla rostrata, and its primary structure was established as (Formula: see text). Eel insulin contains unusual substitutions at B-21, B-22, and B-26 in the putative receptor-binding region of the molecule compared with other mammalian and fish insulins. The A-chain of insulin from the European eel contains an asparagine rather than a serine residue at position A-12. Similarly, amino acid composition data indicate the B-chain of insulin from the European eel is appreciably different from that from the American eel. The primary structure of glucagon-like peptide (GLP) from the American eel is identical to that from the European eel, Anguilla anguilla. The primary structure of the peptide was established as (Formula: see text). Fast-atom bombardment mass spectrometry demonstrated that the COOH-terminal arginyl residue is alpha-amidated. The strong evolutionary pressure to conserve the structure of GLP provides further support for the assertion that the peptide plays an important regulatory role in teleost fish.

  17. Sustained glucagon-like peptide-2 infusion is required for intestinal adaptation, and cessation reverses increased cellularity in rats with intestinal failure

    PubMed Central

    Koopmann, Matthew C.; Chen, Xueyan; Holst, Jens J.

    2010-01-01

    Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived hormone that is a proposed treatment for human short bowel syndrome (SBS). The objective was to determine how the timing, duration, and cessation of GLP-2 administration affect intestinal adaptation and enterocyte kinetics in a rat model of human SBS that results in intestinal failure requiring total parenteral nutrition (TPN). Rats underwent 60% jejunoileal resection plus cecectomy and jugular vein cannulation and were maintained exclusively with TPN for 18 days in these treatments: TPN control (no GLP-2); sustained GLP-2 (1–18 days); early GLP-2 (1–7 days, killed at 7 or 18 days); and delayed GLP-2 (12–18 days). Body weight gain was similar across groups, and plasma bioactive GLP-2 was significantly increased with coinfusion of GLP-2 (100 μg·kg−1·day−1) with TPN. GLP-2-treated rats showed significant increases in duodenum and jejunum mucosal dry mass, protein, DNA, and sucrase activity compared with TPN control. The increased jejunum cellularity reflected significantly decreased apoptosis and increased crypt mitosis and crypt fission due to GLP-2. When GLP-2 infusion stopped at 7 days, these effects were reversed at 18 days. Sustained GLP-2 infusion significantly increased duodenum length and decreased 18-day mortality to 0% from 37.5% deaths in TPN control (P = 0.08). Colon proglucagon expression quantified by real-time RT-qPCR was increased in TPN controls and attenuated by GLP-2 infusion; jejunal expression of the GLP-2 receptor did not differ among groups. In summary, early, sustained GLP-2 infusion reduces mortality, induces crypt fission, and is required for intestinal adaptation, whereas cessation of GLP-2 reverses gains in mucosal cellularity in a rat model of intestinal failure. PMID:20864657

  18. A pilot study examining the relationship among Crohn disease activity, glucagon-like peptide-2 signalling and intestinal function in pediatric patients

    PubMed Central

    Sigalet, David L; Kravarusic, Dragan; Butzner, Decker; Hartmann, Bolette; Holst, Jens J; Meddings, Jon

    2013-01-01

    BACKGROUND/OBJECTIVES: The relationship between the enteroendocrine hormone glucagon-like peptide 2 (GLP-2) and intestinal inflammation is unclear. GLP-2 promotes mucosal growth, decreases permeability and reduces inflammation in the intestine; physiological stimulation of GLP-2 release is triggered by nutrient contact. The authors hypothesized that ileal Crohn disease (CD) affects GLP-2 release. METHODS: With ethics board approval, pediatric patients hospitalized with CD were studied; controls were recruited from local schools. Inclusion criteria were endoscopy-confirmed CD (primarily of the small intestine) with a disease activity index >150. Fasting and post-prandial GLP-2 levels and quantitative urinary recovery of orally administered 3-O-methyl-glucose (active transport) and lactulose/mannitol (passive) were quantified during the acute and remission phases. RESULTS: Seven patients (mean [± SD] age 15.3±1.3 years) and 10 controls (10.3±1.6 years) were studied. In patients with active disease, fasting levels of GLP-2 remained stable but postprandial levels were reduced. Patients with active disease exhibited reduced glucose absorption and increased lactulose/mannitol recovery; all normalized with disease remission. The change in the lactulose/mannitol ratio was due to both reduced lactulose and increased mannitol absorption. CONCLUSIONS: These findings suggest that pediatric patients with acute ileal CD have decreased postprandial GLP-2 release, reduced glucose absorption and increased intestinal permeability. Healing of CD resulted in normalization of postprandial GLP-2 release and mucosal functioning (nutrient absorption and permeability), the latter due to an increase in mucosal surface area. These findings have implications for the use of GLP-2 and feeding strategies as a therapy in CD patients; further studies of the effects of inflammation and the GLP-2 axis are recommended. PMID:24106731

  19. COMPARATIVE GUT PHYSIOLOGY SYMPOSIUM: Comparative physiology of glucagon-like peptide-2: Implications and applications for production and health of ruminants.

    PubMed

    Connor, E E; Evock-Clover, C M; Walker, M P; Elsasser, T H; Kahl, S

    2015-02-01

    Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide derived from proteolytic cleavage of proglucagon by prohormone convertase 1/3 in enteroendocrine L cells. Studies conducted in humans, in rodent models, and in vitro indicate that GLP-2 is secreted in response to the presence of molecules in the intestinal lumen, including fatty acids, carbohydrates, amino acids, and bile acids, which are detected by luminal chemosensors. The physiological actions of GLP-2 are mediated by its G protein-coupled receptor expressed primarily in the intestinal tract on enteric neurons, enteroendocrine cells, and myofibroblasts. The biological activity of GLP-2 is further regulated by dipeptidyl peptidase IV, which rapidly cleaves the N-terminus of GLP-2 that is responsible for GLP-2 receptor activation. Within the gut, GLP-2 increases nutrient absorption, crypt cell proliferation, and mesenteric blood flow and decreases gut permeability and motility, epithelial cell apoptosis, and inflammation. Outside the gut, GLP-2 reduces bone resorption, can suppress appetite, and is cytoprotective in the lung. Thus, GLP-2 has been studied intensively as a therapeutic to improve intestinal function of humans during parenteral nutrition and following small bowel resection and, more recently, as a treatment for osteoporosis and obesity-related disorders and to reduce cellular damage associated with inflammation of the gut and lungs. Recent studies demonstrate that many biological actions and properties of GLP-2 in ruminants are similar to those in nonruminants, including the potential to reduce intestinal nitro-oxidative stress in calves caused by parasitic diseases such as coccidiosis. Because of its beneficial impacts on nutrient absorption, gut healing, and normal gut development, GLP-2 therapy offers significant opportunities to improve calf health and production efficiency. However, GLP-2 therapies require an extended time course to achieve desired physiological responses, as well as

  20. PEGylated porcine glucagon-like peptide-2 improved the intestinal digestive function and prevented inflammation of weaning piglets challenged with LPS.

    PubMed

    Qi, K K; Wu, J; Deng, B; Li, Y M; Xu, Z W

    2015-09-01

    This study was conducted to determine the effects on intestinal function, anti-inflammatory role and possible mechanism of polyethylene glycosylated (PEGylated) porcine glucagon-like peptide-2 (pGLP-2), a long-acting form of pGLP-2, in weaning piglets challenged with Escherichia coli lipopolysaccharide (LPS). We divided 18 weaned piglets on day 21 into three groups (control, LPS and LPS+PEG-pGLP-2; n=6). The piglets from the LPS+PEG-pGLP-2 group were injected with PEG-pGLP-2 at 10 nmol/kg BW from 5 to 7 days of the trials daily. On 8th day, the piglets in the LPS and LPS+PEG-pGLP-2 groups were intraperitoneally administered with 100 µg LPS/kg. The control group was administered with the same volume of saline solution. The piglets were then sacrificed on day 28. Afterwards, serum, duodenum, jejunum and ileum samples were collected for analysis of structural and functional endpoints. LPS+PEG-pGLP-2 treatment increased (P<0.05) lactase activities in the duodenum and the jejunum compared with LPS treatment. LPS+PEG-pGLP-2 treatment also significantly increased sucrase activity in the jejunum compared with LPS treatment. Furthermore, LPS treatment increased (P<0.05) the mRNA expression levels of interleukin (IL)-8, tumour necrosis factor-α (TNF-α) and IL-10 in the ileum compared with the control treatment. By contrast, LPS+PEG-pGLP-2 treatment decreased (P<0.05) the mRNA expression levels of IL-8, IL-10 and TNF-α in the ileum compared with the LPS treatment. LPS treatment also increased (P<0.05) the mRNA expression level of GLP-2 receptor (GLP-2R) and the percentage of GLP-2R-positive cells in the ileum; by comparison, these results were (P<0.05) reduced by LPS+PEG-pGLP-2 treatment. Moreover, LPS+PEG-pGLP-2 treatment increased (P<0.05) the content of serum keratinocyte growth factor compared with the control group and the LPS group. The protective effects of PEG-pGLP-2 on intestinal digestive function were associated with the release of GLP-2R mediator (keratinocyte

  1. Glucagon-like peptide-2 activates beta-catenin signaling in the mouse intestinal crypt: role of insulin-like growth factor-I.

    PubMed

    Dubé, Philip E; Rowland, Katherine J; Brubaker, Patricia L

    2008-01-01

    Chronic administration of glucagon-like peptide-2 (GLP-2) induces intestinal growth and crypt cell proliferation through an indirect mechanism requiring IGF-I. However, the intracellular pathways through which IGF-I mediates GLP-2-induced epithelial tropic signaling remain undefined. Because beta-catenin and Akt are important regulators of crypt cell proliferation, we hypothesized that GLP-2 activates these signaling pathways through an IGF-I-dependent mechanism. In this study, fasted mice were administered Gly(2)-GLP-2 or LR(3)-IGF-I (positive control) for 0.5-4 h. Nuclear translocation of beta-catenin in non-Paneth crypt cells was assessed by immunohistochemistry and expression of its downstream proliferative markers, c-myc and Sox9, by quantitative RT-PCR. Akt phosphorylation and activation of its targets, glycogen synthase kinase-3beta and caspase-3, were determined by Western blot. IGF-I receptor (IGF-IR) and IGF-I signaling were blocked by preadministration of NVP-AEW541 and through the use of IGF-I knockout mice, respectively. We found that GLP-2 increased beta-catenin nuclear translocation in non-Paneth crypt cells by 72 +/- 17% (P < 0.05) and increased mucosal c-myc and Sox9 mRNA expression by 90 +/- 20 and 376 +/- 170%, respectively (P < 0.05-0.01), with similar results observed with IGF-I. This effect of GLP-2 was prevented by blocking the IGF-IR as well as ablation of IGF-I signaling. GLP-2 also produced a time- and dose-dependent activation of Akt in the intestinal mucosa (P < 0.01), most notably in the epithelium. This action was reduced by IGF-IR inhibition but not IGF-I knockout. We concluded that acute administration of GLP-2 activates beta-catenin and proliferative signaling in non-Paneth murine intestinal crypt cells as well as Akt signaling in the mucosa. However, IGF-I is required only for the GLP-2-induced alterations in beta-catenin.

  2. Characterization of glucagon-like peptide 2 receptor (GLP2R) gene in chickens: functional analysis, tissue distribution, and developmental expression profile of GLP2R in embryonic intestine.

    PubMed

    Mo, C; Zhong, Y; Wang, Y; Yan, Z; Li, J

    2014-07-01

    This study characterized the glucagon-like peptide 2 receptor (GLP2R) gene of chickens because relatively little is known about the underlying mechanism of GLP2 actions in nonmammalian species. With the use of reverse transcription PCR, we first cloned the chicken GLP2R (cGLP2R) from adult intestine, which was predicted to encode a 529-amino acid receptor precursor. With the use of a pGL3-CRE luciferase reporter system, we demonstrated that cGLP2R expressed in Chinese hamster ovary cells could be potently activated by cGLP2 (half maximal effective concentration, 1.06 nM) but not by its structurally related peptides, including the newly identified glucagon-like peptide, indicating that cGLP2R is a functional receptor specific to cGLP2. Reverse transcription PCR assay revealed that cGLP2R mRNA was widely expressed in adult chicken tissues, including pancreas and various parts of the gastrointestinal tract. With the use of quantitative real-time reverse transcription PCR assays, we further investigated the mRNA expression of cGLP2R and its potential downstream mediators, epidermal growth factor receptor (EGFR) ligands (heparin-binding EGF-like growth factor, epiregulin, and amphiregulin), in the distal duodenum of developing embryos. The mRNA expression levels of GLP2R and EGFR ligands (heparin-binding EGF-like growth factor and amphiregulin) were shown to increase (P < 0.05 or 0.01) during the late embryonic stages (E16 and E20), implying a potential coordinated action of GLP2 and EGFR ligands on embryonic intestine development. Taken together, our findings not only establish a molecular basis to explore the physiological roles of GLP2 in birds, but they also provide comparative insights into the roles of GLP2R and its ligand in vertebrates, such as its roles in embryonic intestine development.

  3. Intestinal regulation of urinary sodium excretion and the pathophysiology of diabetic kidney disease: a focus on glucagon-like peptide 1 and dipeptidyl peptidase 4.

    PubMed

    Vallon, Volker; Docherty, Neil G

    2014-09-01

    The tubular hypothesis of glomerular filtration and nephropathy in diabetes is a pathophysiological concept that assigns a critical role to the tubular system, including proximal tubular hyper-reabsorption and growth, which is relevant for early glomerular hyperfiltration and later chronic kidney disease. Here we focus on how harnessing the bioactivity of hormones released from the gut may ameliorate the early effects of diabetes on the kidney in part by attenuating proximal tubular hyper-reabsorption and growth. The endogenous tone of the glucagon-like peptide 1 (GLP-1)/GLP-1 receptor (GLP-1R) system and its pharmacological activation are nephroprotective in diabetes independent of changes in blood glucose. This is associated with suppression of increases in kidney weight and glomerular hyperfiltration, which may reflect, at least in part, its inhibitory effects on tubular hyper-reabsorption and growth. Inhibition of dipeptidyl peptidase 4 (DPP-4) is also nephroprotective independent of changes in blood glucose and involves GLP-1/GLP-1R-dependent and -independent mechanisms. The GLP-1R agonist exendin-4 induces natriuresis via activation of the GLP-1R. In contrast, DPP4 inhibition increases circulating GLP-1, but drives a GLP-1R-independent natriuretic response, implying a role for other DPP-4 substrates. The extent to which the intrarenal DPP-4/GLP-1 receptor system contributes to all these changes remains to be established, as does the direct impact of the system on renal inflammation. PMID:25085841

  4. Basal insulin combined incretin mimetic therapy with glucagon-like protein 1 receptor agonists as an upcoming option in the treatment of type 2 diabetes: a practical guide to decision making

    PubMed Central

    Fleischmann, Holger

    2014-01-01

    The combination of basal insulin and glucagon-like protein 1 receptor agonists (GLP-1 RAs) is a new intriguing therapeutic option for patients with type 2 diabetes. In our daily practice we abbreviate this therapeutic concept with the term BIT (basal insulin combined incretin mimetic therapy) in a certain analogy to BOT (basal insulin supported oral therapy). In most cases BIT is indeed an extension of BOT, if fasting, prandial or postprandial blood glucose values have not reached the target range. In our paper we discuss special features of combinations of short- or prandial-acting and long- or continuous-acting GLP-1 RAs like exenatide, lixisenatide and liraglutide with basal insulin in relation to different glycemic targets. Overall it seems appropriate to use a short-acting GLP-1 RA if, after the near normalization of fasting blood glucose with BOT, the prandial or postprandial values are elevated. A long-acting GLP-1 RA might well be given, if fasting blood glucose values are the problem. Based on pathophysiological findings, recent clinical studies and our experience with BIT and BOT as well as BOTplus we developed chart-supported algorithms for decision making, including features and conditions of patients. The development of these practical tools was guided by the need for a more individualized antidiabetic therapy and the availability of the new BIT principle. PMID:25419451

  5. The Effects of Glucagon-like Peptide-2 on the Tight Junction and Barrier Function in IPEC-J2 Cells through Phosphatidylinositol 3-kinase–Protein Kinase B–Mammalian Target of Rapamycin Signaling Pathway

    PubMed Central

    Yu, Changsong; Jia, Gang; Deng, Qiuhong; Zhao, Hua; Chen, Xiaoling; Liu, Guangmang; Wang, Kangning

    2016-01-01

    Glucagon-like peptide-2 (GLP-2) is important for intestinal barrier function and regulation of tight junction (TJ) proteins, but the intracellular mechanisms of action remain undefined. The purpose of this research was to determine the protective effect of GLP-2 mediated TJ and transepithelial electrical resistance (TER) in lipopolysaccharide (LPS) stressed IPEC-J2 cells and to test the hypothesis that GLP-2 regulate TJ and TER through the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling pathway in IPEC-J2 cells. Wortmannin and LY294002 are specific inhibitors of PI3K. The results showed that 100 μg/mL LPS stress decreased TER and TJ proteins occludin, claudin-1 and zonula occludens protein 1 (ZO-1) mRNA, proteins expressions (p<0.01) respectively. GLP-2 (100 nmol/L) promote TER and TJ proteins occludin, claudin-1, and zo-1 mRNA, proteins expressions in LPS stressed and normal IPEC-J2 cells (p<0.01) respectively. In normal cells, both wortmannin and LY294002, PI3K inhibitors, prevented the mRNA and protein expressions of Akt and mTOR increase induced by GLP-2 (p<0.01) following with the significant decreasing of occludin, claudin-1, ZO-1 mRNA and proteins expressions and TER (p<0.01). In conclusion, these results indicated that GLP-2 can promote TJ’s expression and TER in LPS stressed and normal IPEC-J2 cells and GLP-2 could regulate TJ and TER through the PI3K/Akt/mTOR pathway. PMID:26954146

  6. Immunoreactivity to peptides belonging to the pancreatic polypeptide family (NPY, aPY, PP, PYY) and to glucagon-like peptide in the endocrine pancreas and anterior intestine of adult lampreys, Petromyzon marinus: an immunohistochemical study.

    PubMed

    Cheung, R; Andrews, P C; Plisetskaya, E M; Youson, J H

    1991-01-01

    Immunoreactivity of antisera directed against human neuropeptide Y (NPY), anglerfish polypeptide YG (aPY), bovine pancreatic polypeptide (bPP), salmon pancreatic polypeptide (sPP), porcine peptide tyrosine tyrosine (PYY), and salmon glucagon-like peptide (GLP) was investigated in the endocrine pancreas and anterior intestine of adult lampreys, Petromyzon marinus, by immunohistochemical analysis. There was no immunoreactivity to anti-sPP and anti-bPP in any tissue and anti-GLP immunostaining was only present in the anterior intestine. The immunoreactivity to antisera raised against NPY, aPY, and PYY was colocalized within the same small number of cells in the caudal and cranial pancreas of juveniles and the caudal pancreas of upstream migrant adults. These antibodies did not immunostain B- or D-cells and thus, NPY, aPY, and PYY were likely localized in a third cell type (3a) in the lamprey pancreas. Immunostaining of a few cells with only anti-aPY suggested the possibility of a fourth cell type (3b). Immunoreactivity was similar in the cranial and caudal pancreas of male upstream migrants; however, in the female cranial pancreas, a few cells demonstrated intense immunoreaction to anti-aPY, while weaker immunostaining with this antiserum was observed in B-cells. In the intestine of juvenile and upstream migrant lampreys, positive immunostaining to GLP, NPY, aPY, and PYY antibodies was colocalized within the same cell. We believe that this cell may contain PYY/glucagon family peptides. Other intestinal cells immunostained with either GLP or somatostatin-34 antiserum. PMID:2026316

  7. Neutrophil attractant/activating peptide-1/interleukin-8 in term and preterm parturition.

    PubMed

    Romero, R; Ceska, M; Avila, C; Mazor, M; Behnke, E; Lindley, I

    1991-10-01

    The neutrophil is the leukocyte most frequently recruited into the amniotic fluid in cases of microbial invasion of the amniotic cavity. Neutrophil attractant/activating peptide-1/interleukin-8 is a newly identified cytokine that is capable of inducing selective neutrophil chemotaxis and activation. The purpose of this study was to examine the relationship between amniotic fluid concentrations of neutrophil attractant/activating peptide-1/interleukin-8, microbial invasion of the amniotic cavity, and parturition (term and preterm). Amniotic fluid neutrophil attractant/activating peptide-1/interleukin-8 was measured with an immunoassay validated for human amniotic fluid (sensitivity 0.3 ng/ml). Fluid was obtained from women in the following groups: midtrimester (n = 38), term not in labor (n = 38), term in active labor (n = 67), and preterm labor with intact membranes (n = 62). Fluid was cultured for aerobic and anaerobic bacterial and Mycoplasma. Sterile amniotic fluid from most women in the midtrimester of pregnancy and women at term not in labor did not contain immunoreactive neutrophil attractant/activating peptide-1/interleukin-8. Microbial invasion of the amniotic cavity was associated with increased concentrations of neutrophil attractant/activating peptide-1/interleukin-8. The amniotic fluid of women with preterm labor and sterile amniotic fluid who had preterm delivery contained higher neutrophil attractant/activating peptide-1/interleukin-8 levels than did the amniotic fluid of women who responded to tocolysis and had delivery at term. Term parturition is associated with increased concentrations of neutrophil attractant/activating peptide-1/interleukin-8 in the amniotic fluid. We conclude that neutrophil attractant/activating peptide-1/interleukin-8 is part of the host response to microbial invasion of the amniotic cavity and that increased amniotic fluid availability of this cytokine occurs in term and preterm parturition. PMID:1951537

  8. Survey of Analogue Spacetimes

    NASA Astrophysics Data System (ADS)

    Visser, Matt

    Analogue spacetimes (and more boldly, analogue models both of and for gravity), have attracted significant and increasing attention over the last decade and a half. Perhaps the most straightforward physical example, which serves as a template for most of the others, is Bill Unruh's model for a dumb hole,(mute black hole, acoustic black hole), wherein sound is dragged along by a moving fluid—and can even be trapped behind an acoustic horizon. This and related analogue models for curved spacetimes are useful in many ways: analogue spacetimes provide general relativists with extremely concrete physical models to help focus their thinking, and conversely the techniques of curved spacetime can sometimes help improve our understanding of condensed matter and/or optical systems by providing an unexpected and countervailing viewpoint. In this chapter, I shall provide a few simple examples of analogue spacetimes as general background for the rest of the contributions.

  9. Nonstationary analogue black holes

    NASA Astrophysics Data System (ADS)

    Eskin, Gregory

    2014-12-01

    We study the existence of analogue nonstationary spherically symmetric black holes. The prime example is the acoustic model see Unruh (1981 Phys. Rev. Lett. 46 1351). We consider also a more general class of metrics that could be useful in other physical models of analogue black and white holes. We give examples of the appearance of black holes and of disappearance of white holes. We also discuss the relation between the apparent and the event horizons for the case of analogue black holes. In the end we study the inverse problem of determination of black or white holes by boundary measurements for the spherically symmetric nonstationary metrics.

  10. Biodegradable analogues of DDT*

    PubMed Central

    Metcalf, Robert L.; Kapoor, Inder P.; Hirwe, Asha S.

    1971-01-01

    Despite the immense utility of DDT for vector control its usefulness is prejudiced by its stability in the environment and by the low rate at which it can be degraded biologically. Metabolic studies in insects, in mice, and in a model ecosystem with several food chains have shown that DDT analogues with substituent groups readily attacked by multifunction oxidases undergo a substantial degree of biological degradation and do not appear to be stored readily in animal tissues or concentrated in food chains. Detailed metabolic pathways have been worked out and it is clear that comparative biochemistry can be used to develop DDT analogues that are adequately persistent yet biodegradable. A number of new DDT analogues have been evaluated for insecticidal activity against flies and mosquitos and for their potential usefulness as safe, persistent, and biodegradable insecticides. PMID:5315354

  11. Natural Analogue Synthesis Report

    SciTech Connect

    A. M. Simmons

    2002-05-01

    The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the ''Yucca Mountain Site Description'' (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature, along with results of quantitative studies conducted specifically for the Yucca Mountain Site Characterization Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement drift degradation, waste form degradation, waste package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated zone (SZ) transport, impact of radionuclide

  12. Aspartame and Its Analogues

    NASA Astrophysics Data System (ADS)

    Pavlova, L. A.; Komarova, T. V.; Davidovich, Yurii A.; Rogozhin, S. V.

    1981-04-01

    The results of studies on the biochemistry of the sweet taste are briefly reviewed. The methods of synthesis of "aspartame" — a sweet dipeptide — are considered, its structural analogues are described, and quantitative estimates are made of the degree of sweetness relative to sucrose. Attention is concentrated mainly on problems of the relation between the structure of the substance and its taste in the series of aspartyl derivatives. The bibliography includes 118 references.

  13. Quantum analogue computing.

    PubMed

    Kendon, Vivien M; Nemoto, Kae; Munro, William J

    2010-08-13

    We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

  14. The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide

    PubMed Central

    Barnett, A H

    2012-01-01

    In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM—exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m2, and patients with a BMI <35 kg/m2 who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m2) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin. PMID:22051096

  15. Using and interpreting analogue designs.

    PubMed

    Cook, Bryan G; Rumrill, Phillip D

    2005-01-01

    Researchers in rehabilitation counseling and disability studies sometimes use analogue research, which involves materials that approximate or describe reality (e.g., written vignettes, videotaped exemplars) rather than investigating phenomena in real-world settings. Analogue research often utilizes experimental designs, and it thereby frequently possesses a high degree of internal validity. Analogue research allows investigators to exercise tight control over the implementation of the independent or treatment variable and over potentially confounding variables, which enables them to isolate the effects of those treatment variables on selected outcome measures. However, the simulated nature of analogue research presents an important threat to external validity. As such, the generalizability of analogue research to real-life settings and situations may be problematic. These and other issues germane to analogue research in vocational rehabilitation are discussed in this article, illustrated with examples from the contemporary literature.

  16. Analogue-to-Digital and Digital-to-Analogue Conversion.

    ERIC Educational Resources Information Center

    Gregory, Martin

    1997-01-01

    Discusses circuits for three-bit and four-bit analogue digital converters and digital analogue converters. These circuits feature slow operating speeds that enable the circuitry to be used to demonstrate the mode of operation using oscilloscopes and signal generators. (DDR)

  17. Mammary Analogue Secretory Carcinoma.

    PubMed

    Stevens, Todd M; Parekh, Vishwas

    2016-09-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor that shares the same histologic appearance and ETV6 gene (12p13) rearrangement as secretory carcinoma of the breast. Prior to its recognition, MASC cases were commonly labeled acinic cell carcinoma and adenocarcinoma, not otherwise specified. Despite distinctive histologic features, MASC may be difficult to distinguish from other salivary gland tumors, in particular zymogen-poor acinic cell carcinoma and low-grade salivary duct carcinoma. Although characteristic morphologic and immunohistochemical features form the basis of a diagnosis of MASC, the presence of an ETV6-NTRK3 gene fusion is confirmatory. Given its recent recognition the true prognostic import of MASC is not yet clearly defined. PMID:27575269

  18. NASA/ESMD Analogue Mission Plans

    NASA Technical Reports Server (NTRS)

    Hoffman, Stephen J.

    2007-01-01

    A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

  19. Murine nonvolatile pheromones: isolation of exocrine-gland secreting Peptide 1.

    PubMed

    Kimoto, Hiroko; Touhara, Kazushige

    2013-01-01

    Our search for a substance recognized by the vomeronasal neurons revealed that the extra-orbital lacrimal gland (ELG) isolated from adult male mice produced the male-specific peptide pheromone exocrine gland-secreting peptide 1 (ESP1). The following protocol reveals how ESP1 may be extracted from the ELG, purified using anion-exchange and reverse-phase high-performance liquid chromatography (HPLC), and analyzed by mass spectrometry. This protocol has been specifically designed for the purification of ESP1, but may be modified to isolate a variety of peptides from the exocrine glands. Peptides purified in this manner may help further define the molecular mechanisms underlying pheromone communication in the vomeronasal system.

  20. Similarity in drugs: reflections on analogue design.

    PubMed

    Wermuth, Camille G

    2006-04-01

    A survey of novel small-molecule therapeutics reveals that the majority of them result from analogue design and that their market value represents two-thirds of all small-molecule sales. In natural science, the term analogue, derived from the Latin and Greek analogia, has always been used to describe structural and functional similarity. Extended to drugs, this definition implies that the analogue of an existing drug molecule shares structural and pharmacological similarities with the original compound. Formally, this definition allows the establishment of three categories of drug analogues: analogues possessing chemical and pharmacological similarities (direct analogues); analogues possessing structural similarities only (structural analogues); and chemically different compounds displaying similar pharmacological properties (functional analogues). PMID:16580977

  1. [Potential of pharmacological modulation of level and activity incretins on diabetes mellitus type 2].

    PubMed

    Spasov, A A; Chepljaeva, N I

    2015-01-01

    This review summarizes data on the main approaches used for the search of biologically active compounds modulating the level and physiological activity of incretins. Currently two groups of drugs are used in clinical practice: they either replenish the deficit of incretins (glucagon-like peptide-1 receptor agonists) or inhibit the degradation processes (dipeptidyl peptidase 4 inhibitors). In addition, new groups of substances are actively searched. These include non-peptide agonists of glucagon-like peptide-1 receptors, agonists/antagonists of glucose-dependent insulinotropic peptide, the hybrid polypeptides based on glucagon-like peptide-1 and glucagon.

  2. Electrospun fibers immobilized with bone forming peptide-1 derived from BMP7 for guided bone regeneration.

    PubMed

    Lee, Young Jun; Lee, Ji-Hye; Cho, Hyeong-Jin; Kim, Hyung Keun; Yoon, Taek Rim; Shin, Heungsoo

    2013-07-01

    The development of ideal barrier membranes with appropriate porosity and bioactivity is essential for the guidance of new bone formation in orthopedic and craniomaxillofacial surgery. In this study, we developed bioactive electrospun fibers based on poly (lactide-co-glycolic acid) (PLGA) by immobilizing bone-forming peptide 1 (BFP1) derived from the immature region of bone morphogenetic protein 7 (BMP7). We exploited polydopamine chemistry for the immobilization of BFP1; polydopamine (PD) was coated on the electrospun PLGA fibers, on which BFP1 was subsequently immobilized under weakly basic conditions. The immobilization of BFP1 was verified by characterizing the surface chemical composition and quantitatively measured by fluorescamine assay. The immobilization of BPF1 on the electrospun fibers supported the compact distribution of collagen I and the spreading of human mesenchymal stem cells (hMSCs). SEM micrographs demonstrated the aggregation of globular mineral accretions, with significant increases in ALP activity and calcium deposition when hMSCs were cultured on fibers immobilized with BFP1 for 14 days. We then implanted the prepared fibers onto mouse calvarial defects and analyzed bone formation after 2 months. Semi-quantification of bone growth from representative X-ray images showed that the bone area was approximately 20% in the defect-only group, while the group implanted with PLGA fibers showed significant improvements of 44.27 ± 7.37% and 57.59 ± 15.24% in the groups implanted with PD-coated PLGA and with BFP1-coated PLGA, respectively. Based on these results, our approach may be a promising tool to develop clinically-applicable bioactive membranes for guided bone regeneration."

  3. Revisiting and re-engineering the classical zinc finger peptide: consensus peptide-1 (CP-1).

    PubMed

    Besold, Angelique N; Widger, Leland R; Namuswe, Frances; Michalek, Jamie L; Michel, Sarah L J; Goldberg, David P

    2016-04-01

    Zinc plays key structural and catalytic roles in biology. Structural zinc sites are often referred to as zinc finger (ZF) sites, and the classical ZF contains a Cys2His2 motif that is involved in coordinating Zn(II). An optimized Cys2His2 ZF, named consensus peptide 1 (CP-1), was identified more than 20 years ago using a limited set of sequenced proteins. We have reexamined the CP-1 sequence, using our current, much larger database of sequenced proteins that have been identified from high-throughput sequencing methods, and found the sequence to be largely unchanged. The CCHH ligand set of CP-1 was then altered to a CAHH motif to impart hydrolytic activity. This ligand set mimics the His2Cys ligand set of peptide deformylase (PDF), a hydrolytically active M(II)-centered (M = Zn or Fe) protein. The resultant peptide [CP-1(CAHH)] was evaluated for its ability to coordinate Zn(II) and Co(II) ions, adopt secondary structure, and promote hydrolysis. CP-1(CAHH) was found to coordinate Co(II) and Zn(II) and a pentacoordinate geometry for Co(II)-CP-1(CAHH) was implicated from UV-vis data. This suggests a His2Cys(H2O)2 environment at the metal center. The Zn(II)-bound CP-1(CAHH) was shown to adopt partial secondary structure by 1-D (1)H NMR spectroscopy. Both Zn(II)-CP-1(CAHH) and Co(II)-CP-1(CAHH) show good hydrolytic activity toward the test substrate 4-nitrophenyl acetate, exhibiting faster rates than most active synthetic Zn(II) complexes.

  4. SV-IV Peptide1–16 reduces coagulant power in normal Factor V and Factor V Leiden

    PubMed Central

    Di Micco, Biagio; Lepretti, Marilena; Rota, Lidia; Quaglia, Ilaria; Ferrazzi, Paola; Di Micco, Gianluca; Di Micco, Pierpaolo

    2007-01-01

    Native Factor V is an anticoagulant, but when activated by thrombin, Factor X or platelet proteases, it becomes a procoagulant. Due to these double properties, Factor V plays a crucial role in the regulation of coagulation/anticoagulation balance. Factor V Leiden (FVL) disorder may lead to thrombophilia. Whether a reduction in the activation of Factor V or Factor V Leiden may correct the disposition to thrombophilia is unknown. Therefore we tested SV-IV Peptide 1–16 (i.e. a peptide derived by seminal protein vescicle number IV, SV-IV) to assess its capacity to inhibit the procoagulant activity of normal clotting factor V or Factor V Leiden (FVL). We found that SV-IV protein has potent anti-inflammatory and immunomodulatory properties and also exerts procoagulant activity. In the present work we show that the SV-IV Peptide 1–16, incubated with plasma containing normal Factor V or FVL plasma for 5 minutes reduces the procoagulant capacity of both substances. This is an anticoagulant effect whereas SV-IV protein is a procoagulant. This activity is effective both in terms of the coagulation tests, where coagulation times are increased, and in terms of biochemical tests conducted with purified molecules, where Factor X activation is reduced. Peptide 1–16 was, in the pure molecule system, first incubated for 5 minutes with purified Factor V then it was added to the mix of phosphatidylserine, Ca2+, Factor X and its chromogenic molecule Chromozym X. We observed a more than 50% reduction in lysis of chromogenic molecule Chromozym X by Factor Xa, compared to the sample without Peptide 1–16. Such reduction in Chromozym X lysis, is explained with the reduced activation of Factor X by partial inactivation of Factor V by Peptide 1–16. Thus our study demonstrates that Peptide 1–16 reduces the coagulation capacity of Factor V and Factor V Leiden in vitro, and, in turn, causes factor X reduced activation. PMID:18154667

  5. The incretin hormone glucagon‐like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage‐dependent potassium channel

    PubMed Central

    Llewellyn‐Smith, Ida J.; Gribble, Fiona; Reimann, Frank; Trapp, Stefan; Fadool, Debra Ann

    2016-01-01

    Key points The gut hormone called glucagon‐like peptide 1 (GLP‐1) is a strong moderator of energy homeostasis and communication between the peripheral organs and the brain.GLP‐1 signalling occurs in the brain; using a newly developed genetic reporter line of mice, we have discovered GLP‐synthesizing cells in the olfactory bulb.GLP‐1 increases the firing frequency of neurons (mitral cells) that encode olfactory information by decreasing activity of voltage‐dependent K channels (Kv1.3).Modifying GLP‐1 levels, either therapeutically or following the ingestion of food, could alter the excitability of neurons in the olfactory bulb in a nutrition or energy state‐dependent manner to influence olfactory detection or metabolic sensing.The results of the present study uncover a new function for an olfactory bulb neuron (deep short axon cells, Cajal cells) that could be capable of modifying mitral cell activity through the release of GLP‐1. This might be of relevance for the action of GLP‐1 mimetics now widely used in the treatment of diabetes. Abstract The olfactory system is intricately linked with the endocrine system where it may serve as a detector of the internal metabolic state or energy homeostasis in addition to its classical function as a sensor of external olfactory information. The recent development of transgenic mGLU‐yellow fluorescent protein mice that express a genetic reporter under the control of the preproglucagon reporter suggested the presence of the gut hormone, glucagon‐like peptide (GLP‐1), in deep short axon cells (Cajal cells) of the olfactory bulb and its neuromodulatory effect on mitral cell (MC) first‐order neurons. A MC target for the peptide was determined using GLP‐1 receptor binding assays, immunocytochemistry for the receptor and injection of fluorescence‐labelled GLP‐1 analogue exendin‐4. Using patch clamp recording of olfactory bulb slices in the whole‐cell configuration, we report that GLP‐1 and its

  6. Phosphonate analogue substrates for enolase.

    PubMed

    Anderson, V E; Cleland, W W

    1990-11-20

    Phosphonate analogues in which the bridge between C-2 and phosphorus is a CH2 group are slow substrates for yeast enolase. The pH variation of the kinetic parameters for the methylene analogue of 2-phosphoglycerate suggests that the substrate binds as a dianion and that Mg2+ can bind subsequently only if a metal ligand and the catalytic base are unprotonated. Primary deuterium isotope effects of 4-8 on V/KMg, but ones of only 1.15-1.32 on V for dehydration, show that proton removal to give the carbanion intermediate largely limits V/KMg and that a slow step follows which largely limits V (presumably carbanion breakdown). Since there is a D2O solvent isotope effect on V for the reverse reaction of 5, but not an appreciable one on the forward reaction, it appears that the slow rates with phosphonate analogues result from the fact that the carbanion intermediate is more stable than that formed from the normal substrates, and its reaction in both directions limits V. Increased stability as a result of replacement of oxygen by carbon at C-2 of the carbanion is the expected chemical behavior. PMID:2271661

  7. Substrate analogues for isoprenoid enzymes

    SciTech Connect

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  8. Policy issues in space analogues

    NASA Astrophysics Data System (ADS)

    Auger, Robin N.; Facktor, Debra D.

    Space mission planning is increasingly focusing on destinations beyond Earth orbit. Advancements in technology will inevitably be required to enable long-duration human spaceflight missions, and breakthroughs in the policy arena will also be needed to achieve success in such missions. By exploring how policy issues have been addressed in analogous extreme environments, policymakers can develop a framework for addressing these issues as they apply to long-term human spaceflight. Policy issues that need to be addressed include: crew selection, training, organization, and activities, medical testing, illness, injury, and death; communication; legal accountability and liability; mission safety and risk management; and environmental contamination. This paper outlines the approach of a study underway by The George Washington University and ANSER to examine how these policy issues have been addressed in several analogues and how the experiences of these analogues can help formulate policies for long-duration human spaceflight missions. Analogues being studied include Antarctic bases, submarine voyages, undersea stations, Biosphere 2, and the U.S. Skylab and Russian Mir space stations.

  9. FUNCTION GENERATOR FOR ANALOGUE COMPUTERS

    DOEpatents

    Skramstad, H.K.; Wright, J.H.; Taback, L.

    1961-12-12

    An improved analogue computer is designed which can be used to determine the final ground position of radioactive fallout particles in an atomic cloud. The computer determines the fallout pattern on the basis of known wind velocity and direction at various altitudes, and intensity of radioactivity in the mushroom cloud as a function of particle size and initial height in the cloud. The output is then displayed on a cathode-ray tube so that the average or total luminance of the tube screen at any point represents the intensity of radioactive fallout at the geographical location represented by that point. (AEC)

  10. The Canadian Analogue Research Network (CARN): Opportunities for Terrestrial Analogue Studies in Canada and Abroad

    NASA Astrophysics Data System (ADS)

    Hipkin, V.; Osinski, G. R.; Berinstain, A.; Léveillé, R.

    2007-03-01

    We will present an overview of the Canadian Analogue Research Network (CARN), including a description of the various analogue sites in CARN, potential new sites, and a discussion regarding how CARN is applicable to the global exploration strategy.

  11. Osteoinductive Effects of Free and Immobilized Bone Forming Peptide-1 on Human Adipose-Derived Stem Cells.

    PubMed

    Li, Wenyue; Zheng, Yunfei; Zhao, Xianghui; Ge, Yanjun; Chen, Tong; Liu, Yunsong; Zhou, Yongsheng

    2016-01-01

    Most synthetic polymeric materials currently used for bone tissue engineering lack specific signals through which cells can identify and interact with the surface, resulting in incompatibility and compromised osteogenic activity. Soluble inductive factors also have issues including a short half-live in vivo. Bone forming peptide-1 is a truncated peptide from the immature form of bone morphogenetic protein-7 (BMP-7) that displays higher osteogenic activity than full-length, mature BMP-7. In this study, we used a mussel-inspired immobilization strategy mediated by polymerization of dopamine to introduce recently discovered stimulators of bone forming peptide-1 (BFP-1) onto the surface of poly-lactic-co-glycolic acid (PLGA) substrate to form a biomaterial that overcomes these challenges. Human adipose-derived stem cells (hASCs), being abundant and easy accessible, were used to test the osteogenic activity of BFP-1 and the novel biomaterial. Under osteoinductive conditions, cells treated with both BFP-1 alone and BFP-1-coated biomaterials displayed elevated expression of the osteogenic markers alkaline phosphatase (ALP), osteocalcin (OC), and RUNX2. Furthermore, hASCs associated with poly-dopamine-assisted BFP-1-immobilized PLGA (pDA-BFP-1-PLGA) scaffolds promoted in vivo bone formation in nude mice. Our novel materials may hold great promise for future bone tissue engineering applications.

  12. Osteoinductive Effects of Free and Immobilized Bone Forming Peptide-1 on Human Adipose-Derived Stem Cells.

    PubMed

    Li, Wenyue; Zheng, Yunfei; Zhao, Xianghui; Ge, Yanjun; Chen, Tong; Liu, Yunsong; Zhou, Yongsheng

    2016-01-01

    Most synthetic polymeric materials currently used for bone tissue engineering lack specific signals through which cells can identify and interact with the surface, resulting in incompatibility and compromised osteogenic activity. Soluble inductive factors also have issues including a short half-live in vivo. Bone forming peptide-1 is a truncated peptide from the immature form of bone morphogenetic protein-7 (BMP-7) that displays higher osteogenic activity than full-length, mature BMP-7. In this study, we used a mussel-inspired immobilization strategy mediated by polymerization of dopamine to introduce recently discovered stimulators of bone forming peptide-1 (BFP-1) onto the surface of poly-lactic-co-glycolic acid (PLGA) substrate to form a biomaterial that overcomes these challenges. Human adipose-derived stem cells (hASCs), being abundant and easy accessible, were used to test the osteogenic activity of BFP-1 and the novel biomaterial. Under osteoinductive conditions, cells treated with both BFP-1 alone and BFP-1-coated biomaterials displayed elevated expression of the osteogenic markers alkaline phosphatase (ALP), osteocalcin (OC), and RUNX2. Furthermore, hASCs associated with poly-dopamine-assisted BFP-1-immobilized PLGA (pDA-BFP-1-PLGA) scaffolds promoted in vivo bone formation in nude mice. Our novel materials may hold great promise for future bone tissue engineering applications. PMID:26930062

  13. Osteoinductive Effects of Free and Immobilized Bone Forming Peptide-1 on Human Adipose-Derived Stem Cells

    PubMed Central

    Zhao, Xianghui; Ge, Yanjun; Chen, Tong; Liu, Yunsong; Zhou, Yongsheng

    2016-01-01

    Most synthetic polymeric materials currently used for bone tissue engineering lack specific signals through which cells can identify and interact with the surface, resulting in incompatibility and compromised osteogenic activity. Soluble inductive factors also have issues including a short half-live in vivo. Bone forming peptide-1 is a truncated peptide from the immature form of bone morphogenetic protein-7 (BMP-7) that displays higher osteogenic activity than full-length, mature BMP-7. In this study, we used a mussel-inspired immobilization strategy mediated by polymerization of dopamine to introduce recently discovered stimulators of bone forming peptide-1 (BFP-1) onto the surface of poly-lactic-co-glycolic acid (PLGA) substrate to form a biomaterial that overcomes these challenges. Human adipose-derived stem cells (hASCs), being abundant and easy accessible, were used to test the osteogenic activity of BFP-1 and the novel biomaterial. Under osteoinductive conditions, cells treated with both BFP-1 alone and BFP-1-coated biomaterials displayed elevated expression of the osteogenic markers alkaline phosphatase (ALP), osteocalcin (OC), and RUNX2. Furthermore, hASCs associated with poly-dopamine-assisted BFP-1-immobilized PLGA (pDA-BFP-1-PLGA) scaffolds promoted in vivo bone formation in nude mice. Our novel materials may hold great promise for future bone tissue engineering applications. PMID:26930062

  14. The Valles natural analogue project

    SciTech Connect

    Stockman, H.; Krumhansl, J.; Ho, C.; McConnell, V.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  15. Balancing benefits and risks in patients receiving incretin-based therapies: focus on cardiovascular and pancreatic side effects.

    PubMed

    Haluzík, Martin; Mráz, Miloš; Svačina, Štěpán

    2014-12-01

    Incretin-based therapies either increase endogenous levels of glucagon-like peptide-1 by prolonging its half-life (DPP-4 inhibitors) or directly stimulate its receptor (glucagon-like peptide-1 analogues; GLP-1 RA). They are currently widely used for the treatment of patients with type 2 diabetes mellitus owing to good antidiabetic efficacy, low risk of hypoglycemia, and relatively few other side effects. They also offer potential additional benefits such as weight neutrality or weight loss, positive effects on blood pressure and lipid levels, and potential cardio- and neuroprotectivity. Some experimental and clinical studies have raised concerns with respect to potential cardiovascular and pancreatic side effects of these therapies such as increased risk of heart failure with DPP-4 inhibitors as well as acute pancreatitis and pancreatic cancer with both classes. The available data are at present not robust enough to enable firm conclusions regarding these potential associations. Nevertheless, some recent data suggest a possibility of slightly increased risk of acute pancreatitis with GLP-1 RAs while they do not indicate increased risk of pancreatic cancer. Ongoing cardiovascular outcome trials will shed more light on the possible cardioprotective effects of incretin-based therapies as well as on the possible interconnection of DPP-4 inhibitors and heart failure.

  16. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-11-08

    Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

  17. Continuous analogues of matrix factorizations

    PubMed Central

    Townsend, Alex; Trefethen, Lloyd N.

    2015-01-01

    Analogues of singular value decomposition (SVD), QR, LU and Cholesky factorizations are presented for problems in which the usual discrete matrix is replaced by a ‘quasimatrix’, continuous in one dimension, or a ‘cmatrix’, continuous in both dimensions. Two challenges arise: the generalization of the notions of triangular structure and row and column pivoting to continuous variables (required in all cases except the SVD, and far from obvious), and the convergence of the infinite series that define the cmatrix factorizations. Our generalizations of triangularity and pivoting are based on a new notion of a ‘triangular quasimatrix’. Concerning convergence of the series, we prove theorems asserting convergence provided the functions involved are sufficiently smooth. PMID:25568618

  18. Fully analogue photonic reservoir computer.

    PubMed

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-03-03

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers.

  19. Fully analogue photonic reservoir computer

    PubMed Central

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-01-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers. PMID:26935166

  20. Forum for Injection Techniques, India: The First Indian Recommendations for Best Practice in Insulin Injection Technique

    PubMed Central

    Kalra, Sanjay; Balhara, Yatan Pal Singh; Baruah, Manash P.; Chadha, Manoj; Chandalia, Hemraj B.; Chowdhury, Subhankar; Kumar, K. M. Prasanna; Modi, Sonal; Pitale, Shailesh; Shukla, Rishi; Sahay, Rakesh; Sundaram, Annamalai; Unnikrishnan, Ambika G.; Wangnoo, Subhash K.

    2012-01-01

    Advances in the treatment of diabetes have led to an increase in the number of injectable therapies, such as human insulin, insulin analogues, and glucagon-like peptide-1 analogues. The efficacy of injection therapy in diabetes depends on correct injection technique, among many other factors. Good injection technique is vital in achieving glycemic control and thus preventing complications of diabetes. From the patients’ and health-care providers’ perspective, it is essential to have guidelines to understand injections and injection techniques. The abridged version of the First Indian Insulin Injection technique guidelines developed by the Forum for Injection Technique (FIT) India presented here acknowledge good insulin injection techniques and provide evidence-based recommendations to assist diabetes care providers in improving their clinical practice. PMID:23226630

  1. [The extra-glycemic effects of liraglutide: focus on cardiometabolic markers].

    PubMed

    Giglio, Rosaria Vincenza; Patti, Angelo Maria; Nikolic, Dragana; Castellino, Giuseppa; Noto, Marcello; Parrino, Alessandro; Montalto, Giuseppe; Rizzo, Manfredi

    2016-04-01

    The purpose of innovative therapeutic approaches for type 2 diabetes mellitus is to customize the antidiabetic treatment to each patient's need, in order to intensify glucose-lowering effects without hypoglycemia, reduce adverse events, and prevent cardiovascular events. Glucagon-like peptide 1 (GLP-1) analogues are effective drugs in the treatment of type 2 diabetes, and they also seem to have beneficial effects on several risk factors for cardiovascular disease, leading to cardiovascular risk reduction independent of hypoglycemic effects. Among these new drugs, liraglutide, a GLP-1 analogue with a homology of 97% to native GLP-1, exerts an effect on body weight, lipid parameters, blood pressure and endothelial function, inflammatory markers, markers of oxidative stress, and subclinical atherosclerosis. The results of numerous studies and meta-analyses on liraglutide suggest that this drug improves quality of life through the reduction in hypoglycemic episodes, glucose effectiveness, and the improvement of cardiovascular risk factors.

  2. Plant Volatile Analogues Strengthen Attractiveness to Insect

    PubMed Central

    Sun, Yufeng; Yu, Hao; Zhou, Jing-Jiang; Pickett, John A.; Wu, Kongming

    2014-01-01

    Green leaf bug Apolygus lucorum (Meyer-Dür) is one of the major pests in agriculture. Management of A. lucorum was largely achieved by using pesticides. However, the increasing population of A. lucorum since growing Bt cotton widely and the increased awareness of ecoenvironment and agricultural product safety makes their population-control very challenging. Therefore this study was conducted to explore a novel ecological approach, synthetic plant volatile analogues, to manage the pest. Here, plant volatile analogues were first designed and synthesized by combining the bioactive components of β-ionone and benzaldehyde. The stabilities of β-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than β-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than β-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety. PMID:24911460

  3. Synthesis and biological evaluation of febrifugine analogues.

    PubMed

    Mai, Huong Doan Thi; Thanh, Giang Vo; Tran, Van Hieu; Vu, Van Nam; Vu, Van Loi; Le, Cong Vinh; Nguyen, Thuy Linh; Phi, Thi Dao; Truong, Bich Ngan; Chau, Van Minh; Pham, Van Cuong

    2014-12-01

    A series of febrifugine analogues were designed and synthesized. Antimalarial activity evaluation of the synthetic compounds indicated that these derivatives had a strong inhibition against both chloroquine-sensitive and -resistant Plasmodium falciparum parasites. Many of them were found to be more active than febrifugine hydrochloride. The tested analogues had also a significant cytotoxicity against four cancer cell lines (KB, MCF7, LU1 and HepG2). Among the synthetic analogues, two compounds 17b and 17h displayed a moderate cytotoxicity while they exhibited a remarkable antimalarial activity. PMID:25632466

  4. Antimicrobial activity of resveratrol analogues.

    PubMed

    Chalal, Malik; Klinguer, Agnès; Echairi, Abdelwahad; Meunier, Philippe; Vervandier-Fasseur, Dominique; Adrian, Marielle

    2014-01-01

    Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew). Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold). The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups) and antimicrobial activity. PMID:24918540

  5. Space analogue studies in Antarctica.

    PubMed

    Lugg, D; Shepanek, M

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  6. Antimicrobial activity of resveratrol analogues.

    PubMed

    Chalal, Malik; Klinguer, Agnès; Echairi, Abdelwahad; Meunier, Philippe; Vervandier-Fasseur, Dominique; Adrian, Marielle

    2014-06-10

    Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew). Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold). The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups) and antimicrobial activity.

  7. Space analogue studies in Antarctica

    NASA Technical Reports Server (NTRS)

    Lugg, D.; Shepanek, M.

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  8. Space analogue studies in Antarctica

    NASA Astrophysics Data System (ADS)

    Lugg, D.; Shepanek, M.

    1999-09-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mltogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  9. Condensed matter analogues of cosmology

    NASA Astrophysics Data System (ADS)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the

  10. Sulfur analogues of psychotomimetic agents. Monothio analogues of mescaline and isomescaline.

    PubMed

    Jacob, P; Shulgin, A T

    1981-11-01

    Two monothio analogues of mescaline and three monothio analogues of 2,3,4-trimethoxyphenethylamine (isomescaline) have been synthesized and characterized. Only the two mescaline analogues (3-and 4-thiomescaline) were found to be psychotomimetics in man, being 6 and 12 times more potent than mescaline, respectively. All five compounds can serve as substrates for bovine plasma monoamine oxidase in vitro, but no positive correlation is apparent between the extent of enzymatic degradation and human psychotomimetic potency.

  11. The structure activity relationship of discodermolide analogues.

    PubMed

    Shaw, Simon J

    2008-03-01

    The marine polyketide discodermolide is a member of a class of natural products that stabilize microtubules. Many analogues have been synthesized suggesting that few changes can be made to the internal carbon backbone. Both ends of the molecule, however, can be modified. The majority of analogues have been generated via modification of the lactone region. This suggests that significant simplifications can be made in this region provided that the lactone moiety is maintained.

  12. Phosphorous-containing analogues of aspartame.

    PubMed

    Nelson, V; Mastalerz, P

    1984-12-01

    Four analogues of aspartame (aspartylphenylalanine methyl ester) were prepared in which one of the carboxylate groups was replaced by a phosphonate group. None of the peptides so obtained was sweet, in contrast with the parent compound which is over 100 times sweeter than sucrose. These results contrast with several published reports of phosphonate analogues of amino acids and peptides which are potent inhibitors of enzymes containing acceptor sites for the parent compound.

  13. Planetary habitability: lessons learned from terrestrial analogues

    NASA Astrophysics Data System (ADS)

    Preston, Louisa J.; Dartnell, Lewis R.

    2014-01-01

    Terrestrial analogue studies underpin almost all planetary missions and their use is essential in the exploration of our Solar system and in assessing the habitability of other worlds. Their value relies on the similarity of the analogue to its target, either in terms of their mineralogical or geochemical context, or current physical or chemical environmental conditions. Such analogue sites offer critical ground-truthing for astrobiological studies on the habitability of different environmental parameter sets, the biological mechanisms for survival in extreme environments and the preservation potential and detectability of biosignatures. The 33 analogue sites discussed in this review have been selected on the basis of their congruence to particular extraterrestrial locations. Terrestrial field sites that have been used most often in the literature, as well as some lesser known ones which require greater study, are incorporated to inform on the astrobiological potential of Venus, Mars, Europa, Enceladus and Titan. For example, the possibility of an aerial habitable zone on Venus has been hypothesized based on studies of life at high-altitudes in the terrestrial atmosphere. We also demonstrate why many different terrestrial analogue sites are required to satisfactorily assess the habitability of the changing environmental conditions throughout Martian history, and recommend particular sites for different epochs or potential niches. Finally, habitable zones within the aqueous environments of the icy moons of Europa and Enceladus and potentially in the hydrocarbon lakes of Titan are discussed and suitable analogue sites proposed. It is clear from this review that a number of terrestrial analogue sites can be applied to multiple planetary bodies, thereby increasing their value for astrobiological exploration. For each analogue site considered here, we summarize the pertinent physiochemical environmental features they offer and critically assess the fidelity with which

  14. Large-scale production of soluble recombinant amyloid-β peptide 1-42 using cold-inducible expression system.

    PubMed

    Kim, Eun-Kyung; Moon, Jeong Chan; Lee, Jeong Mi; Jeong, Min Seop; Oh, Choongseob; Ahn, Sung-Min; Yoo, Yung Joon; Jang, Ho Hee

    2012-11-01

    Amyloid-β peptide 1-42 (Aβ(1-42)), the predominant form in senile plaques, plays important roles in the pathogenesis of Alzheimer's disease. Because Aβ(1-42) has aggregation-prone nature, it has been difficult to produce in a soluble state in bacterial expression systems. In this study, we modified our expression system to increase the soluble fraction of Aβ(1-42) in Escherichia coli (E. coli) cells. The expression level and solubility of recombinant Aβ(1-42) induced at the low temperature (16°C) is highly increased compared to that induced at 37°C. To optimize expression temperature, the coding region of Aβ(1-42) was constructed in a pCold vector, pCold-TF, which has a hexahistidine-tagged trigger factor (TF). Recombinant Aβ(1-42) was expressed primarily as a soluble protein using pCold vector system and purified with a nickel-chelating resin. When the toxic effect of recombinant Aβ(1-42) examined on human neuroblastoma SH-SY5Y cells, the purified Aβ(1-42) induced cell toxicity on SH-SY5Y cells. In conclusion, the system developed in this study will provide a useful method for the production of aggregation prone-peptide such as Aβ(1-42).

  15. Surface Behavior and Lipid Interaction of Alzheimer β-Amyloid Peptide 1–42: A Membrane-Disrupting Peptide

    PubMed Central

    Ambroggio, Ernesto E.; Kim, Dennis H.; Separovic, Frances; Barrow, Colin J.; Barnham, Kevin J.; Bagatolli, Luis A.; Fidelio, Gerardo D.

    2005-01-01

    Amyloid aggregates, found in patients that suffer from Alzheimer's disease, are composed of fibril-forming peptides in a β-sheet conformation. One of the most abundant components in amyloid aggregates is the β-amyloid peptide 1–42 (Aβ 1–42). Membrane alterations may proceed to cell death by either an oxidative stress mechanism, caused by the peptide and synergized by transition metal ions, or through formation of ion channels by peptide interfacial self-aggregation. Here we demonstrate that Langmuir films of Aβ 1–42, either in pure form or mixed with lipids, develop stable monomolecular arrays with a high surface stability. By using micropipette aspiration technique and confocal microscopy we show that Aβ 1–42 induces a strong membrane destabilization in giant unilamellar vesicles composed of palmitoyloleoyl-phosphatidylcholine, sphingomyelin, and cholesterol, lowering the critical tension of vesicle rupture. Additionally, Aβ 1–42 triggers the induction of a sequential leakage of low- and high-molecular-weight markers trapped inside the giant unilamellar vesicles, but preserving the vesicle shape. Consequently, the Aβ 1–42 sequence confers particular molecular properties to the peptide that, in turn, influence supramolecular properties associated to membranes that may result in toxicity, including: 1), an ability of the peptide to strongly associate with the membrane; 2), a reduction of lateral membrane cohesive forces; and 3), a capacity to break the transbilayer gradient and puncture sealed vesicles. PMID:15681641

  16. The glucagon‐like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents

    PubMed Central

    Vallöf, Daniel; Maccioni, Paola; Colombo, Giancarlo; Mandrapa, Minja; Jörnulf, Julia Winsa; Egecioglu, Emil; Engel, Jörgen A.

    2015-01-01

    Abstract The incretin hormone, glucagon‐like peptide 1 (GLP‐1), regulates gastric emptying, glucose‐dependent stimulation of insulin secretion and glucagon release, and GLP‐1 analogs are therefore approved for treatment of type II diabetes. GLP‐1 receptors are expressed in reward‐related areas such as the ventral tegmental area and nucleus accumbens, and GLP‐1 was recently shown to regulate several alcohol‐mediated behaviors as well as amphetamine‐induced, cocaine‐induced and nicotine‐induced reward. The present series of experiments were undertaken to investigate the effect of the GLP‐1 receptor agonist, liraglutide, on several alcohol‐related behaviors in rats that model different aspects of alcohol use disorder in humans. Acute liraglutide treatment suppressed the well‐documented effects of alcohol on the mesolimbic dopamine system, namely alcohol‐induced accumbal dopamine release and conditioned place preference in mice. In addition, acute administration of liraglutide prevented the alcohol deprivation effect and reduced alcohol intake in outbred rats, while repeated treatment of liraglutide decreased alcohol intake in outbred rats as well as reduced operant self‐administration of alcohol in selectively bred Sardinian alcohol‐preferring rats. Collectively, these data suggest that GLP‐1 receptor agonists could be tested for treatment of alcohol dependence in humans. PMID:26303264

  17. Optically Pure, Structural, and Fluorescent Analogues of a Dimeric Y4 Receptor Agonist Derived by an Olefin Metathesis Approach.

    PubMed

    Liu, Mengjie; Mountford, Simon J; Richardson, Rachel R; Groenen, Marleen; Holliday, Nicholas D; Thompson, Philip E

    2016-07-14

    The dimeric peptide 1 (BVD-74D, as a diastereomeric mixture) is a potent and selective neuropeptide Y Y4 receptor agonist. It represents a valuable candidate in developing traceable ligands for pharmacological studies of Y4 receptors and as a lead compound for antiobesity drugs. Its optically pure stereoisomers along with analogues and fluorescently labeled variants were prepared by exploiting alkene metathesis reactions. The (2R,7R)-diaminosuberoyl containing peptide, (R,R)-1, had markedly higher affinity and agonist efficacy than its (S,S)-counterpart. Furthermore, the sulfo-Cy5 labeled (R,R)-14 retained high agonist potency as a novel fluorescent ligand for imaging Y4 receptors.

  18. Optically Pure, Structural, and Fluorescent Analogues of a Dimeric Y4 Receptor Agonist Derived by an Olefin Metathesis Approach.

    PubMed

    Liu, Mengjie; Mountford, Simon J; Richardson, Rachel R; Groenen, Marleen; Holliday, Nicholas D; Thompson, Philip E

    2016-07-14

    The dimeric peptide 1 (BVD-74D, as a diastereomeric mixture) is a potent and selective neuropeptide Y Y4 receptor agonist. It represents a valuable candidate in developing traceable ligands for pharmacological studies of Y4 receptors and as a lead compound for antiobesity drugs. Its optically pure stereoisomers along with analogues and fluorescently labeled variants were prepared by exploiting alkene metathesis reactions. The (2R,7R)-diaminosuberoyl containing peptide, (R,R)-1, had markedly higher affinity and agonist efficacy than its (S,S)-counterpart. Furthermore, the sulfo-Cy5 labeled (R,R)-14 retained high agonist potency as a novel fluorescent ligand for imaging Y4 receptors. PMID:27295337

  19. Presence of cobalamin analogues in animal tissues

    PubMed Central

    Kondo, Haruki; Kolhouse, Fred; Allen, Robert H.

    1980-01-01

    Cobalamin (Cbl, vitamin B-12) has been extracted and isolated from a number of animal tissues by using (i) reverse-affinity chromatography on R protein-Sepharose followed by adsorption to and elution from charcoal-coated agarose and (ii) paper chromatography. Radioisotope dilution assays showed that only 75-97% of the Cbl chromatographed in the position of crystalline Cbl. The remaining 3-25% was present in a number of slower and faster moving fractions. This suggested that Cbl analogues are present in animal tissues because appropriate controls ruled out the possibility that this material was artifactually derived from Cbl during the extraction and purification procedures. With a large-scale isolation from rabbit kidney, the material in five such fractions contained cobalt and had absorption spectra that were similar to but different from the spectrum of Cbl, indicating that they were Cbl analogues. Compared to Cbl, these Cbl analogues had decreased but definite affinities for Cbl-binding proteins with the following order of strength of binding: R protein > transcobalamin II > intrinsic factor. Compared to Cbl, they also had decreased but definite growth-promoting activity for two microorganisms, Euglena gracilis and Lactobacillus leichmannii, which require Cbl for growth. These Cbl analogues differed from each other and from 18 synthetic Cbl analogues, including the most common Cbl analogues synthesized by microorganisms, in at least one of the above features. These studies indicate that animal tissues contain a number of Cbl analogues whose origins, structures, and biologic activities remain to be determined. PMID:6928681

  20. The Canadian Analogue Research Network (CARN): Opportunities for Mars Analogue Studies in the Canadian Arctic

    NASA Astrophysics Data System (ADS)

    Osinski, G. R.; Berinstain, A.; Lebeuf, M.; Léveillé, R.

    2006-10-01

    The Canadian Analogue Research Network has been established by the Canadian Space Agency. This network of analogue sites, many of which are in the Arctic, provides a unique opportunity to further our understanding of the polar regions of Earth and Mars.

  1. Identification of an HIV-1 Mutation in Spacer Peptide 1 That Stabilizes the Immature CA-SP1 Lattice

    PubMed Central

    Keller, Paul W.; Urano, Emiko; Ablan, Sherimay D.

    2015-01-01

    ABSTRACT Upon release of HIV-1 particles from the infected cell, the viral protease cleaves the Gag polyprotein at specific sites, triggering maturation. During this process, which is essential for infectivity, the capsid protein (CA) reassembles into a conical core. Maturation inhibitors (MIs) block HIV-1 maturation by interfering with protease-mediated CA-spacer peptide 1 (CA-SP1) processing, concomitantly stabilizing the immature CA-SP1 lattice; virions from MI-treated cells retain an immature-like CA-SP1 lattice, whereas mutational abolition of cleavage at the CA-SP1 site results in virions in which the CA-SP1 lattice converts to a mature-like form. We previously reported that propagation of HIV-1 in the presence of MI PF-46396 selected for assembly-defective, compound-dependent mutants with amino acid substitutions in the major homology region (MHR) of CA. Propagation of these mutants in the absence of PF-46396 resulted in the acquisition of second-site compensatory mutations. These included a Thr-to-Ile substitution at SP1 residue 8 (T8I), which results in impaired CA-SP1 processing. Thus, the T8I mutation phenocopies PF-46396 treatment in terms of its ability to rescue the replication defect imposed by the MHR mutations and to impede CA-SP1 processing. Here, we use cryo-electron tomography to show that, like MIs, the T8I mutation stabilizes the immature-like CA-SP1 lattice. These results have important implications for the mechanism of action of HIV-1 MIs; they also suggest that T8I may provide a valuable tool for structural definition of the CA-SP1 boundary region, which has thus far been refractory to high-resolution analysis, apparently because of conformational flexibility in this region of Gag. IMPORTANCE HIV-1 maturation involves dissection of the Gag polyprotein by the viral protease and assembly of a conical capsid enclosing the viral ribonucleoprotein. Maturation inhibitors (MIs) prevent the final cleavage step at the site between the capsid protein

  2. Synthesis and anticancer evaluation of spermatinamine analogues.

    PubMed

    Moosa, Basem A; Sagar, Sunil; Li, Song; Esau, Luke; Kaur, Mandeep; Khashab, Niveen M

    2016-03-15

    Spermatinamine was isolated from an Australian marine sponge, Pseudoceratina sp. as an inhibitor of isoprenylcysteine carboxyl methyltransferase (Icmt), an attractive and novel anticancer target. Herein, we report the synthesis of spermatinamine analogues and their cytotoxic evaluation against three human cancer cell lines, that is, cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell lines with the IC50 values in the range of 5-10 μM. The obtained results suggested that longer polyamine linker along with aromatic oxime substitution provided the most potent analogue compounds against cancer cell lines. PMID:26874403

  3. Dolastatin 11 conformations, analogues and pharmacophore.

    PubMed

    Ali, Md Ahad; Bates, Robert B; Crane, Zackary D; Dicus, Christopher W; Gramme, Michelle R; Hamel, Ernest; Marcischak, Jacob; Martinez, David S; McClure, Kelly J; Nakkiew, Pichaya; Pettit, George R; Stessman, Chad C; Sufi, Bilal A; Yarick, Gayle V

    2005-07-01

    Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.

  4. Classical Simulated Annealing Using Quantum Analogues

    NASA Astrophysics Data System (ADS)

    La Cour, Brian R.; Troupe, James E.; Mark, Hans M.

    2016-08-01

    In this paper we consider the use of certain classical analogues to quantum tunneling behavior to improve the performance of simulated annealing on a discrete spin system of the general Ising form. Specifically, we consider the use of multiple simultaneous spin flips at each annealing step as an analogue to quantum spin coherence as well as modifications of the Boltzmann acceptance probability to mimic quantum tunneling. We find that the use of multiple spin flips can indeed be advantageous under certain annealing schedules, but only for long anneal times.

  5. Pyridopyrimidine analogues as novel adenosine kinase inhibitors.

    PubMed

    Zheng, G Z; Lee, C; Pratt, J K; Perner, R J; Jiang, M Q; Gomtsyan, A; Matulenko, M A; Mao, Y; Koenig, J R; Kim, K H; Muchmore, S; Yu, H; Kohlhaas, K; Alexander, K M; McGaraughty, S; Chu, K L; Wismer, C T; Mikusa, J; Jarvis, M F; Marsh, K; Kowaluk, E A; Bhagwat, S S; Stewart, A O

    2001-08-20

    A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2' substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.

  6. Analogues of thiolactomycin as potential antimalarial agents.

    PubMed

    Jones, Simon M; Urch, Jonathan E; Kaiser, Marcel; Brun, Reto; Harwood, John L; Berry, Colin; Gilbert, Ian H

    2005-09-22

    Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum. Alkylation of the C4 hydroxyl group led to the most significant increase in growth inhibition (over a 100-fold increase in activity compared to TLM). To investigate the mode of action, the P. falciparum KASIII enzyme was produced for inhibitor assay. A number of TLM derivatives were identified that showed improved inhibition of this enzyme compared to TLM. Structure-activity relationships for enzyme inhibition were identified for some series of TLM analogues, and these also showed weak correlation with inhibition of parasite growth, but this did not hold for other series. On the basis of the lack of a clear correlation between inhibition of pfKASIII activity and parasite growth, we conclude that pfKASIII is not the primary target of TLM analogues. Some of the analogues also inhibited the growth of the parasitic protozoa Trypanosoma cruzi, T. brucei, and Leishmania donovani.

  7. Dumb holes: analogues for black holes.

    PubMed

    Unruh, W G

    2008-08-28

    The use of sonic analogues to black and white holes, called dumb or deaf holes, to understand the particle production by black holes is reviewed. The results suggest that the black hole particle production is a low-frequency and low-wavenumber process.

  8. Stilbenophane analogues of deoxycombretastatin A-4.

    PubMed

    Mateo, Carmen; Pérez-Melero, Concepción; Peláez, Rafael; Medarde, Manuel

    2005-08-01

    A new family of polyoxygenated stilbenophanes has been synthesized as conformationally restricted analogues of antimitotic combretastatins. By means of the McMurry olefination process, compounds derived from diethyleneglycol and 1,6-hexanediol were obtained, whereas Grubbs' catalyst failed in producing the ring-closing metathesis to this kind of macrocyclic products.

  9. Analogue Representations of Spatial Objects and Tranformations.

    ERIC Educational Resources Information Center

    Cooper, Lynn A.

    Considerable discussion and debate have been devoted to the extent and nature of structural or functional correspondence between internal representations and their external visual counterparts. An analogue representation or process is one in which the relational structure of external events is preserved in the corresponding internal…

  10. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-03-01

    Project overview provides background on carbonic anhydrase transport mechanism for CO2 in the human body and proposed approach for ARPA-E project to create a synthetic enzyme analogue and utilize it in a membrane for CO2 capture from flue gas.

  11. Synthesis and antimicrobial activity of squalamine analogue.

    PubMed

    Kim, H S; Choi, B S; Kwon, K C; Lee, S O; Kwak, H J; Lee, C H

    2000-08-01

    Synthesis and antimicrobial activity of squalamine analogue 2 are reported. The synthesis of 2 was accomplished from bisnoralcohol 3. The spermidine moiety was introduced via reductive amination of an appropriately functionalized 3beta-aminosterol with spermidinyl aldehyde 17 utilizing sodium triacetoxyborohydride as the reducing agent. Compound 2 shows weaker antimicrobial activity than squalamine. PMID:11003150

  12. The dipeptidyl peptidase IV inhibitor NVP-DPP728 reduces plasma glucagon concentration in cats.

    PubMed

    Furrer, Daniela; Kaufmann, Karin; Tschuor, Flurin; Reusch, Claudia E; Lutz, Thomas A

    2010-03-01

    Glucagon-like peptide-1 (GLP-1) analogues and inhibitors of its degrading enzyme, dipeptidyl peptidase IV (DPPIV), are interesting therapy options in human diabetics because they increase insulin secretion and reduce postprandial glucagon secretion. Given the similar pathophysiology of human type 2 and feline diabetes mellitus, this study investigated whether the DPPIV inhibitor NVP-DPP728 reduces plasma glucagon levels in cats. Intravenous glucose tolerance tests (ivGTT; 0.5 g/kg glucose after 12 h fasting) and a meal response test (test meal of 50% of average daily food intake, offered after 24 h fasting) were performed in healthy experimental cats. NVP-DPP728 (0.5-2.5 mg/kg i.v. or s.c.) significantly reduced glucagon output in all tests and increased insulin output in the ivGTT. Follow-up studies will investigate the potential usefulness as therapy in diabetic cats.

  13. [LIRAGUTIDE AT A DOSE OF 3.0 MG (SAXENDA): NEW INDICATION FOR THE TREATMENT OF OBESITY].

    PubMed

    Scheen, A J

    2016-05-01

    Liraglutide is an analogue of Glucagon-Like Peptide-1 (GLP-1) already indicated under the trade name of Victoza for the treatment of type 2 diabetes, at usual doses of 1.2 or 1.8 mg as once daily subcutaneous injection. It is henceforth indicated at a dose of 3.0 mg, also as once daily subcutaneous injection, for the treatment of obesity or overweight with comorbidities under the trade name of Saxenda, in combination with diet and exercise. Besides a specific action on the endocrine pancreas, mainly responsible for the antihyperglycaemic effect, liraglutide helps controlling appetite at the hypothamalic level. A specific programme of controlled trials (especially SCALE studies) demonstrated both efficacy and safety of the 3.0 mg dose of liraglutide in obese or overweight patients with various comorbidities.

  14. Mono-ADP-ribosyltransferase as a potential pharmacological drug target in the GLP-1 based therapy of obesity and diabetes mellitus type 2.

    PubMed

    Bavec, Aljosa

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) based therapy is well established for treating diabetes mellitus type 2. Moreover, GLP-1 receptor agonists influence weight loss, and have potential for treating obesity. GLP-1 receptor agonists should be administered in low doses, together with drugs that potentiate insulin release, to avoid some minor side effects. We have focused on incretin hormones, especially GLP-1 and its analogues. Here we discuss the effect of the third intracellular loop-derived peptide of GLP-1 receptor on intracellular mono-ADP-ribosyltransferase and its role in regulating the receptor. We suggest that this intracellular mono-ADP-ribosyltransferase could constitute a possible novel pharmacological target in the treatment of diabetes mellitus type 2 and obesity.

  15. The Influence of Incretin Mimetics on Cardiovascular Risk Factors in Diabetes

    PubMed Central

    Kinalska, Ida; Bednarska-Chabowska, Dorota; Adamiec-Mroczek, Joanna; Hak, Łukasz

    2012-01-01

    The authors discuss the strategy of use of incretin hormones in type 2 diabetes treatment in the context of cardiovascular complications. The results of the phase III study on human GLP-1 (Glucagon-like peptide-1) analogue-liraglutide have been presented under common acronym LEAD (Liraglutide-Effect and Action In Diabetes). The liraglutide therapy improved glycemic control with low hypoglycemia risk and decreased glycated hemoglobin by an average 1,13%. Decreases in systolic pressure and significant body weight loss were observed. Not only did the index describing beta cells function HOMA-B improve but also did the ratio of insulin to proinsulin. Summing up, incretin hormones beneficially influence blood glucose level, moreover, their use decreases blood pressure and body weight which might indicate their positive influence on cardiovascular system in diabetic patients. PMID:22462016

  16. [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1.

    PubMed

    Cai, Yunxin; Lu, Dandan; Chen, Zhen; Ding, Yi; Chung, Nga N; Li, Tingyou; Schiller, Peter W

    2016-08-01

    Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2',6'-dialkylated Tyr analogues, including 2',4',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2'-isopropyl-6'-methyltyrosine (Imt) and 2',6'-diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt(1)-, Emt(1) and Det(1)-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt(1)- and Emt(1)-analogues showed improved antioxidant activity compared to the Dmt(1)-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment.

  17. [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1.

    PubMed

    Cai, Yunxin; Lu, Dandan; Chen, Zhen; Ding, Yi; Chung, Nga N; Li, Tingyou; Schiller, Peter W

    2016-08-01

    Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2',6'-dialkylated Tyr analogues, including 2',4',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2'-isopropyl-6'-methyltyrosine (Imt) and 2',6'-diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt(1)-, Emt(1) and Det(1)-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt(1)- and Emt(1)-analogues showed improved antioxidant activity compared to the Dmt(1)-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment. PMID:27301366

  18. Synthesis and biological evaluation of hydrazidomycin analogues.

    PubMed

    Meyer, Florian; Ueberschaar, Nico; Dahse, Hans-Martin; Hertweck, Christian

    2013-11-15

    Hydrazidomycin A is an unusual secondary metabolite of Streptomyces atratus that features a rare enehydrazide core. To learn more about structure-activity relationships of the reported cytotoxic and antiproliferative agent several synthetic routes were explored to synthesize a variety of hydrazidomycin derivatives. Specifically, the size of the side chains, the nature of the double bond and the polar head group were altered. Overall, fourteen analogues were tested for their cytotoxic and antiproliferative effects. Re-examination of synthetic hydrazidomycin A suggests that the antiproliferative activity is attributed to a yet unknown compound that results from degradation or rearrangement. Several of the less complex analogues, however, show antiproliferative activities against individual cancer cell lines and turned out to be more potent than hydrazidomycin A.

  19. Synthesis of constrained analogues of tryptophan

    PubMed Central

    Negrato, Marco; Abbiati, Giorgio; Dell’Acqua, Monica

    2015-01-01

    Summary A Lewis acid-catalysed diastereoselective [4 + 2] cycloaddition of vinylindoles and methyl 2-acetamidoacrylate, leading to methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate derivatives, is described. Treatment of the obtained cycloadducts under hydrolytic conditions results in the preparation of a small library of compounds bearing the free amino acid function at C-3 and pertaining to the class of constrained tryptophan analogues. PMID:26664620

  20. Platinum analogues in preclinical and clinical development.

    PubMed

    Hamilton, T C; O'Dwyer, P J; Ozols, R F

    1993-11-01

    The impact of cisplatin on chemotherapy for solid tumors has led to the synthesis of many molecules with platinum as their central building block. These so-called platinum analogues have been developed with the obvious goals of improving the antitumor activity of cisplatin and hopefully, at the same time, altering the dose-limiting side effects of the prototype drug. At least 10 such molecules are in clinical development, whereas several others are at various stages of preclinical testing. PMID:8305533

  1. The Brookhaven electron analogue, 1953--1957

    SciTech Connect

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  2. Blood Loss Estimation Using Gauze Visual Analogue

    PubMed Central

    Ali Algadiem, Emran; Aleisa, Abdulmohsen Ali; Alsubaie, Huda Ibrahim; Buhlaiqah, Noora Radhi; Algadeeb, Jihad Bagir; Alsneini, Hussain Ali

    2016-01-01

    Background Estimating intraoperative blood loss can be a difficult task, especially when blood is mostly absorbed by gauze. In this study, we have provided an improved method for estimating blood absorbed by gauze. Objectives To develop a guide to estimate blood absorbed by surgical gauze. Materials and Methods A clinical experiment was conducted using aspirated blood and common surgical gauze to create a realistic amount of absorbed blood in the gauze. Different percentages of staining were photographed to create an analogue for the amount of blood absorbed by the gauze. Results A visual analogue scale was created to aid the estimation of blood absorbed by the gauze. The absorptive capacity of different gauze sizes was determined when the gauze was dripping with blood. The amount of reduction in absorption was also determined when the gauze was wetted with normal saline before use. Conclusions The use of a visual analogue may increase the accuracy of blood loss estimation and decrease the consequences related to over or underestimation of blood loss. PMID:27626017

  3. Blood Loss Estimation Using Gauze Visual Analogue

    PubMed Central

    Ali Algadiem, Emran; Aleisa, Abdulmohsen Ali; Alsubaie, Huda Ibrahim; Buhlaiqah, Noora Radhi; Algadeeb, Jihad Bagir; Alsneini, Hussain Ali

    2016-01-01

    Background Estimating intraoperative blood loss can be a difficult task, especially when blood is mostly absorbed by gauze. In this study, we have provided an improved method for estimating blood absorbed by gauze. Objectives To develop a guide to estimate blood absorbed by surgical gauze. Materials and Methods A clinical experiment was conducted using aspirated blood and common surgical gauze to create a realistic amount of absorbed blood in the gauze. Different percentages of staining were photographed to create an analogue for the amount of blood absorbed by the gauze. Results A visual analogue scale was created to aid the estimation of blood absorbed by the gauze. The absorptive capacity of different gauze sizes was determined when the gauze was dripping with blood. The amount of reduction in absorption was also determined when the gauze was wetted with normal saline before use. Conclusions The use of a visual analogue may increase the accuracy of blood loss estimation and decrease the consequences related to over or underestimation of blood loss.

  4. Digitoxin Analogues with Improved Anticytomegalovirus Activity

    PubMed Central

    2014-01-01

    Cardiac glycosides are potent inhibitors of cancer cell growth and possess antiviral activities at nanomolar concentrations. In this study we evaluated the anticytomegalovirus (CMV) activity of digitoxin and several of its analogues. We show that sugar type and sugar length attached to the steroid core structure affects its anticytomegalovirus activity. Structure–activity relationship (SAR) studies identified the l-sugar containing cardiac glycosides as having improved anti-CMV activity and may lead to better understanding of how these compounds inhibit CMV replication. PMID:24900847

  5. Materials analogue of zero-stiffness structures

    NASA Astrophysics Data System (ADS)

    Kumar, Arun; Subramaniam, Anandh

    2011-04-01

    Anglepoise lamps and certain tensegrities are examples of zero-stiffness structures. These structures are in a state of neutral equilibrium with respect to changes in configuration of the system. Using Eshelby's example of an edge dislocation in a thin plate that can bend, we report the discovery of a non-trivial new class of material structures as an analogue to zero-stiffness structures. For extended positions of the edge dislocation in these structures, the dislocation experiences a zero image force. Salient features of these material structures along with the key differences from conventional zero-stiffness structures are pointed out.

  6. Spectroscopic study of solar twins and analogues

    NASA Astrophysics Data System (ADS)

    Datson, Juliet; Flynn, Chris; Portinari, Laura

    2015-02-01

    Context. Many large stellar surveys have been and are still being carried out, providing huge amounts of data, for which stellar physical parameters will be derived. Solar twins and analogues provide a means to test the calibration of these stellar catalogues because the Sun is the best-studied star and provides precise fundamental parameters. Solar twins should be centred on the solar values. Aims: This spectroscopic study of solar analogues selected from the Geneva-Copenhagen Survey (GCS) at a resolution of 48 000 provides effective temperatures and metallicities for these stars. We test whether our spectroscopic parameters, as well as the previous photometric calibrations, are properly centred on the Sun. In addition, we search for more solar twins in our sample. Methods: The methods used in this work are based on literature methods for solar twin searches and on methods we developed in previous work to distinguish the metallicity-temperature degeneracies in the differential comparison of spectra of solar analogues versus a reference solar reflection spectrum. Results: We derive spectroscopic parameters for 148 solar analogues (about 70 are new entries to the literature) and verify with a-posteriori differential tests that our values are well-centred on the solar values. We use our dataset to assess the two alternative calibrations of the GCS parameters; our methods favour the latest revision. We show that the choice of spectral line list or the choice of asteroid or time of observation does not affect the results. We also identify seven solar twins in our sample, three of which are published here for the first time. Conclusions: Our methods provide an independent means to differentially test the calibration of stellar catalogues around the values of a well-known benchmark star, which makes our work interesting for calibration tests of upcoming Galactic surveys. Based on observations made with ESO Telescopes at the La Silla Observatory under programme ID 077.D

  7. Analogue models of pull-apart basins

    NASA Astrophysics Data System (ADS)

    McClay, Ken; Dooley, Tim

    1995-08-01

    Sandbox analogue models of pull-apart basins that developed in sedimentary strata above releasing steps in underlying basement faults are characterized by rhombic basins that are flat-bottomed box grabens with a subhorizontal synkinematic basin infill. Steep to nearly vertical, sigmoidal oblique-slip and segmented oblique-extensional faults are the dominant bounding structures of the pull-apart basins. Cross-basin, short-cut faults link the offset principal displacement zones that are characterized by flower structure development. The structural architectures of the physical models compare directly in form and dimensions to natural examples of strike-slip pull-apart basins.

  8. U.S. Nuclear Regulatory Commission natural analogue research program

    SciTech Connect

    Kovach, L.A.; Ott, W.R.

    1995-09-01

    This article describes the natural analogue research program of the U.S. Nuclear Regulatory Commission (US NRC). It contains information on the regulatory context and organizational structure of the high-level radioactive waste research program plan. It also includes information on the conditions and processes constraining selection of natural analogues, describes initiatives of the US NRC, and describes the role of analogues in the licensing process.

  9. CO2 Removal using a Synthetic Analogue of Carbonic Anhydrase

    SciTech Connect

    Cordatos, Harry

    2010-09-14

    Project attempts to develop a synthetic analogue for carbonic anhydrase and incorporate it in a membrane for separation of CO2 from coal power plant flue gas. Conference poster presents result of first 9 months of project progress including concept, basic system architecture and membrane properties target, results of molecular modeling for analogue - CO2 interaction, and next steps of testing analogue resistance to flue gas contaminants.

  10. Self-Powered Analogue Smart Skin.

    PubMed

    Shi, Mayue; Zhang, Jinxin; Chen, Haotian; Han, Mengdi; Shankaregowda, Smitha A; Su, Zongming; Meng, Bo; Cheng, Xiaoliang; Zhang, Haixia

    2016-04-26

    The progress of smart skin technology presents unprecedented opportunities for artificial intelligence. Resolution enhancement and energy conservation are critical to improve the perception and standby time of robots. Here, we present a self-powered analogue smart skin for detecting contact location and velocity of the object, based on a single-electrode contact electrification effect and planar electrostatic induction. Using an analogue localizing method, the resolution of this two-dimensional smart skin can be achieved at 1.9 mm with only four terminals, which notably decreases the terminal number of smart skins. The sensitivity of this smart skin is remarkable, which can even perceive the perturbation of a honey bee. Meanwhile, benefiting from the triboelectric mechanism, extra power supply is unnecessary for this smart skin. Therefore, it solves the problems of batteries and connecting wires for smart skins. With microstructured poly(dimethylsiloxane) films and silver nanowire electrodes, it can be covered on the skin with transparency, flexibility, and high sensitivity. PMID:27010713

  11. Long-term predictions using natural analogues

    SciTech Connect

    Ewing, R.C.

    1995-09-01

    One of the unique and scientifically most challenging aspects of nuclear waste isolation is the extrapolation of short-term laboratory data (hours to years) to the long time periods (10{sup 3}-10{sup 5} years) required by regulatory agencies for performance assessment. The direct validation of these extrapolations is not possible, but methods must be developed to demonstrate compliance with government regulations and to satisfy the lay public that there is a demonstrable and reasonable basis for accepting the long-term extrapolations. Natural systems (e.g., {open_quotes}natural analogues{close_quotes}) provide perhaps the only means of partial {open_quotes}validation,{close_quotes} as well as data that may be used directly in the models that are used in the extrapolation. Natural systems provide data on very large spatial (nm to km) and temporal (10{sup 3}-10{sup 8} years) scales and in highly complex terranes in which unknown synergisms may affect radionuclide migration. This paper reviews the application (and most importantly, the limitations) of data from natural analogue systems to the {open_quotes}validation{close_quotes} of performance assessments.

  12. Magnetohydrodynamical Analogue of a Black Hole

    NASA Astrophysics Data System (ADS)

    Zamorano, Nelson; Asenjo, Felipe

    2014-03-01

    We study the conditions that a plasma fluid and its container should meet to generate a magneto-acoustic horizon. This effect becomes an alternative to the analogue black hole found in a transonic fluid flow setting. In this context we use the magnetohydrodynamic formalism (MHD) to analyze the evolution of an irrotational plasma fluid interacting with an external constant magnetic field. Under certain plausible approximations, the dynamic of the field perturbations is described by a scalar field potential that follows a second order differential equation. As we prove here, this equation corresponds to the wave equation associated to a scalar field in a curved space-time. This horizon emerges when the local speed of the medium grows larger than the sound velocity. The magnetic field generates an effective pressure which contributes to the magneto-acoustic speed. We compare these results with the known physics of analogue black holes. We will also refer to our ongoing experiment that, in its first stage, attempts to reproduce the wave horizons found in an open channel with an obstacle: PRL 106, 021302 (2011).

  13. Space Analogue Environments: Are the Populations Comparable?

    NASA Astrophysics Data System (ADS)

    Sandal, G. M.

    Background: Much of our present understanding about psychology in space is based on studies of groups operating in so-called analogue environments where personnel are exposed to many of the same stressors as those experienced by astronauts in space. One possible problem with extrapolating results is that personnel operating in various hazardous and confined environments might differ in characteristics influencing coping, interaction, and performance. The object of this study was to compare the psychological similarity of these populations in order to get a better understanding of whether this extrapolation is justifiable. The samples investigated include polar crossings (N= 22), personnel on Antarctic research stations (N= 183), several military occupations (N= 187), and participants in space simulation studies (N=20). Methods: Personnel in each of these environments were assessed using the Personality Characteristic Inventory (PCI) and Utrecht Coping List (UCL). The PCI is a multidimensional trait assessment battery that measures various aspects of achievement orientation and social competence. The UCL is a questionnaire designed to assess habitual coping strategies when encountering stressful or demanding situations. Results: Only minor differences in use of habitual coping strategies were evident across the different samples. In relation to personality scores, the military subjects and participants in space simulation studies indicated higher competitiveness and negative instrumentality compared to both the personnel on Antarctic research stations and participants in polar expedition. Among the personnel on Antarctic research stations, significant gender differences were found with women scoring lower on competitiveness, negative instrumentality and impatience/irritability. Compared to the other samples, the participants in polar expeditions were found to be more homogeneous in personality and no significant gender differences were evident on the traits that

  14. Tight junction gene expression in gastrointestinal tract of dairy calves with coccidiosis and treated with glucagon-like peptide-2

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Selective permeability of the intestinal epithelium and efficient nutrient absorption are important functions for proper growth and development of calves. Damage to the intestinal mucosa can give rise to harmful long-term health effects and reduce productivity of the mature animal. Tight junction pr...

  15. Energy-Dependent Modulation of Glucagon-Like Signaling in Drosophila via the AMP-Activated Protein Kinase

    PubMed Central

    Braco, Jason T.; Gillespie, Emily L.; Alberto, Gregory E.; Brenman, Jay E.; Johnson, Erik C.

    2012-01-01

    Adipokinetic hormone (AKH) is the equivalent of mammalian glucagon, as it is the primary insect hormone that causes energy mobilization. In Drosophila, current knowledge of the mechanisms regulating AKH signaling is limited. Here, we report that AMP-activated protein kinase (AMPK) is critical for normal AKH secretion during periods of metabolic challenges. Reduction of AMPK in AKH cells causes a suite of behavioral and physiological phenotypes resembling AKH cell ablations. Specifically, reduced AMPK function increases life span during starvation and delays starvation-induced hyperactivity. Neither AKH cell survival nor gene expression is significantly impacted by reduced AMPK function. AKH immunolabeling was significantly higher in animals with reduced AMPK function; this result is paralleled by genetic inhibition of synaptic release, suggesting that AMPK promotes AKH secretion. We observed reduced secretion in AKH cells bearing AMPK mutations employing a specific secretion reporter, confirming that AMPK functions in AKH secretion. Live-cell imaging of wild-type AKH neuroendocrine cells shows heightened excitability under reduced sugar levels, and this response was delayed and reduced in AMPK-deficient backgrounds. Furthermore, AMPK activation in AKH cells increases intracellular calcium levels in constant high sugar levels, suggesting that the underlying mechanism of AMPK action is modification of ionic currents. These results demonstrate that AMPK signaling is a critical feature that regulates AKH secretion, and, ultimately, metabolic homeostasis. The significance of these findings is that AMPK is important in the regulation of glucagon signaling, suggesting that the organization of metabolic networks is highly conserved and that AMPK plays a prominent role in these networks. PMID:22798489

  16. Glucagon-like peptide 2 and its beneficial effects on gut function and health in production animals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous endocrine cell subtypes exist within the intestinal mucosa and produce peptides contributing to the regulation of critical physiological processes including appetite, energy metabolism, gut function, and gut health. The mechanisms of action and the extent of the physiological effects of the...

  17. Energy-dependent modulation of glucagon-like signaling in Drosophila via the AMP-activated protein kinase.

    PubMed

    Braco, Jason T; Gillespie, Emily L; Alberto, Gregory E; Brenman, Jay E; Johnson, Erik C

    2012-10-01

    Adipokinetic hormone (AKH) is the equivalent of mammalian glucagon, as it is the primary insect hormone that causes energy mobilization. In Drosophila, current knowledge of the mechanisms regulating AKH signaling is limited. Here, we report that AMP-activated protein kinase (AMPK) is critical for normal AKH secretion during periods of metabolic challenges. Reduction of AMPK in AKH cells causes a suite of behavioral and physiological phenotypes resembling AKH cell ablations. Specifically, reduced AMPK function increases life span during starvation and delays starvation-induced hyperactivity. Neither AKH cell survival nor gene expression is significantly impacted by reduced AMPK function. AKH immunolabeling was significantly higher in animals with reduced AMPK function; this result is paralleled by genetic inhibition of synaptic release, suggesting that AMPK promotes AKH secretion. We observed reduced secretion in AKH cells bearing AMPK mutations employing a specific secretion reporter, confirming that AMPK functions in AKH secretion. Live-cell imaging of wild-type AKH neuroendocrine cells shows heightened excitability under reduced sugar levels, and this response was delayed and reduced in AMPK-deficient backgrounds. Furthermore, AMPK activation in AKH cells increases intracellular calcium levels in constant high sugar levels, suggesting that the underlying mechanism of AMPK action is modification of ionic currents. These results demonstrate that AMPK signaling is a critical feature that regulates AKH secretion, and, ultimately, metabolic homeostasis. The significance of these findings is that AMPK is important in the regulation of glucagon signaling, suggesting that the organization of metabolic networks is highly conserved and that AMPK plays a prominent role in these networks. PMID:22798489

  18. Immunoreactive prohormone atrial natriuretic peptides 1-30 and 31-67 - Existence of a single circulating amino-terminal peptide

    NASA Technical Reports Server (NTRS)

    Chen, Yu-Ming; Whitson, Peggy A.; Cintron, Nitza M.

    1990-01-01

    Sep-Pak C18 extraction of human plasma and radioimmunoassay using antibodies which recognize atrial natriuretic peptide (99-128) and the prohormone sequences 1-30 and 31-67 resulted in mean values from 20 normal subjects of 26.2 (+/- 9.2), 362 (+/- 173) and 368 (+/- 160) pg/ml, respectively. A high correlation coefficient between values obtained using antibodies recognizing prohormone sequences 1-30 and 31-67 was observed (R = 0.84). Extracted plasma immunoreactivity of 1-30 and 31-67 both eluted at 46 percent acetonitrile. In contrast, chromatographic elution of synthetic peptides 1-30 and 31-67 was observed at 48 and 39 percent acetonitrile, respectively. Data suggest that the radioimmunoassay of plasma using antibodies recognizing prohormone sequences 1-30 and 31-67 may represent the measurement of a unique larger amino-terminal peptide fragment containing antigenic sites recognized by both antisera.

  19. Solution Processed PEDOT Analogues in Electrochemical Supercapacitors.

    PubMed

    Österholm, Anna M; Ponder, James F; Kerszulis, Justin A; Reynolds, John R

    2016-06-01

    We have designed fully soluble ProDOTx-EDOTy copolymers that are electrochemically equivalent to electropolymerized PEDOT without using any surfactants or dispersants. We show that these copolymers can be incorporated as active layers in solution processed thin film supercapacitors to demonstrate capacitance, stability, and voltage similar to the values of those that use electrodeposited PEDOT as the active material with the added advantage of the possibility for large scale, high-throughput processing. These Type I supercapacitors provide exceptional cell voltages (up to 1.6 V), highly symmetrical charge/discharge behavior, promising long-term stability exceeding 50 000 charge/discharge cycles, as well as energy (4-18 Wh/kg) and power densities (0.8-3.3 kW/kg) that are comparable to those of electrochemically synthesized analogues. PMID:27195798

  20. Jupiter analogues and planets of active stars

    NASA Astrophysics Data System (ADS)

    Kürster, M.; Zechmeister, M.; Endl, M.; Lo Curto, G.; Hartman, H.; Nilsson, H.; Henning, T.; Hatzes, A. P.; Cochran, W. D.

    2013-04-01

    Combined results are now available from a 15 year long search for Jupiter analogues around solar-type stars using the ESO CAT + CES, ESO 3.6 m + CES, and ESO 3.6 m + HARPS instruments. They comprise planet (co-)discoveries (ι Hor and HR 506) and confirmations (three planets in HR 3259) as well as non-confirmations of planets (HR 4523 and ɛ Eri) announced elsewhere. A long-term trend in ɛ Ind found by our survey is probably attributable to a Jovian planet with a period >30 yr, but we cannot fully exclude stellar activity effects as the cause. A 3.8 year periodic variation in HR 8323 can be attributed to stellar activity.

  1. Current european regulatory perspectives on insulin analogues.

    PubMed

    Enzmann, Harald G; Weise, Martina

    2011-01-01

    Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions. PMID:21736748

  2. Natural analogues of nuclear waste glass corrosion.

    SciTech Connect

    Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

    1999-01-06

    This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.

  3. Terrestrial Analogues for Lunar Impact Melt Flows

    NASA Technical Reports Server (NTRS)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; Osinski, G. R.; Lim, D.; Heldmann, J. L.

    2016-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pahoehoe and ?a ?a lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pahoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pahoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  4. Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

    PubMed

    Segal, Meirav; Fischer, Bilha

    2012-02-28

    Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

  5. Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues.

    PubMed

    Roselli, Mariagrazia; Carocci, Alessia; Budriesi, Roberta; Micucci, Matteo; Toma, Maddalena; Di Cesare Mannelli, Lorenzo; Lovece, Angelo; Catalano, Alessia; Cavalluzzi, Maria Maddalena; Bruno, Claudio; De Palma, Annalisa; Contino, Marialessandra; Perrone, Maria Grazia; Colabufo, Nicola Antonio; Chiarini, Alberto; Franchini, Carlo; Ghelardini, Carla; Habtemariam, Solomon; Lentini, Giovanni

    2016-10-01

    Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation. PMID:27267000

  6. Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues.

    PubMed

    Roselli, Mariagrazia; Carocci, Alessia; Budriesi, Roberta; Micucci, Matteo; Toma, Maddalena; Di Cesare Mannelli, Lorenzo; Lovece, Angelo; Catalano, Alessia; Cavalluzzi, Maria Maddalena; Bruno, Claudio; De Palma, Annalisa; Contino, Marialessandra; Perrone, Maria Grazia; Colabufo, Nicola Antonio; Chiarini, Alberto; Franchini, Carlo; Ghelardini, Carla; Habtemariam, Solomon; Lentini, Giovanni

    2016-10-01

    Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.

  7. Insulin, insulin analogues and diabetic retinopathy.

    PubMed

    Chantelau, Ernst; Kimmerle, Renate; Meyer-Schwickerath, Rolf

    2008-02-01

    Insulin is absolutely vital for living beings. It is not only involved in metabolism, but also in the regulation of growth factors, e.g. IGF-1. In this review we address the role insulin has in the natural evolution of diabetic retinopathy. On the one hand, chronic deficiency of insulin and IGF-1 at the retina is thought to cause capillary degeneration, with subsequent ischaemia. On the other hand, acute abundance of (exogenously administered) insulin and IGF-1 enhances ischaemia-induced VEGF expression. A critical ratio of tissue VEGF-susceptibility: VEGF-availability triggers vascular proliferation (i.e. of micro-aneurysms and/or abnormal vessels). The patent-protected insulin analogues Lispro, Glulisine, Aspart, Glargine and Detemir are artificial insulin derivatives with altered biological responses compared to natural insulin (e.g. divergent insulin and /or IGF-1 receptor-binding characteristics, signalling patterns, and mitogenicity). Their safety profiles concerning diabetic retinopathy remain to be established by randomised controlled trials. Anecdotal reports and circumstantial evidence suggest that Lispro and Glargine might worsen diabetic retinopathy.

  8. Actions of Thyroid Hormone Analogues on Chemokines.

    PubMed

    Davis, Paul J; Glinsky, Gennadi V; Lin, Hung-Yun; Mousa, Shaker A

    2016-01-01

    The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID:27493972

  9. Inhibition of monoamine oxidase by benzoxathiolone analogues.

    PubMed

    Mostert, Samantha; Petzer, Anél; Petzer, Jacobus P

    2016-02-15

    Inhibitors of the monoamine oxidase (MAO) enzymes are considered useful therapeutic agents, and are used in the clinic for the treatment of depressive illness and Parkinson's disease. In addition, MAO inhibitors are also under investigation for the treatment of certain cardiovascular pathologies and as possible aids to smoking cessation. In an attempt to discover novel classes of compounds that inhibit the MAOs, the current study examines the human MAO inhibitory properties of a small series of 2H-1,3-benzoxathiol-2-one analogues. The results show that the benzoxathiolones are potent MAO-B inhibitors with IC50 values ranging from 0.003 to 0.051 μM. Although the benzoxathiolones are selective for the MAO-B isoform, two compounds display good MAO-A inhibition with IC50 values of 0.189 and 0.424 μM. Dialysis studies show that a selected compound inhibits the MAOs reversibly. It may thus be concluded that the benzoxathiolone class is suitable for the design and development of MAO-B inhibitors, and that in some instances good MAO-A inhibition may also be achieved.

  10. Fluorescent polyene ceramide analogues as membrane probes.

    PubMed

    Nieves, Ingrid; Artetxe, Ibai; Abad, José Luis; Alonso, Alicia; Busto, Jon V; Fajarí, Lluís; Montes, L Ruth; Sot, Jesús; Delgado, Antonio; Goñi, Félix M

    2015-03-01

    Three ceramide analogues have been synthesized, with sphingosine-like chains containing five conjugated double bonds. Pentaene I has an N-palmitoyl acyl chain, while the other two pentaenes contain also a doxyl radical, respectively, at C5 (Penta5dox) and at C16 (Penta16dox) positions of the N-acyl chain. Pentaene I maximum excitation and emission wavelengths in a phospholipid bilayer are 353 and 478 nm, respectively. Pentaene I does not segregate from the other lipids in the way natural ceramide does, but rather mixes with them in a selective way according to the lipid phases involved. Fluorescence confocal microscopy studies show that when lipid domains in different physical states coexist, Pentaene I emission is higher in gel than in fluid domains, and in liquid-ordered than in liquid-disordered areas. Electron paramagnetic resonance of the pentaene doxyl probes confirms that these molecules are sensitive to the physical state of the bilayer. Calorimetric and fluorescence quenching experiments suggest that the lipids under study orient themselves in lipid bilayers with their polar moieties located at the lipid-water interface. The doxyl radical in the N-acyl chain quenches the fluorescence of the pentaene group when in close proximity. Because of this property, Penta16dox can detect gel-fluid transitions in phospholipids. The availability of probes for lipids in the gel phase is important in view of novel evidence for the existence of gel microdomains in cell membranes.

  11. Inhibition of firefly luciferase by alkane analogues.

    PubMed

    Takehara, Kô; Kamaya, Hiroshi; Ueda, Issaku

    2005-01-18

    We reported that anesthetics increased the partial molal volume of firefly luciferase (FFL), while long-chain fatty acids (LCFA) decreased it. The present study measured the actions of dodecanol (neutral), dodecanoic acid (negatively charged), and dodecylamine (positively charged) hydrophobic molecules on FFL. The interaction modes are measured by (1) ATP-induced bioluminescence of FFL and (2) fluorescence of 2-(p-toluidino)naphthalene-6-sulfonate (TNS). TNS fluoresces brightly in hydrophobic media. It competes with the substrate luciferin on the FFL binding. From the Scatchard plot of TNS titration, the maximum binding number of TNS was 0.83, and its binding constant was 8.27 x 10(5) M(-1). Job's plot also showed that the binding number is 0.89. From the TNS titration of FFL, the binding constant was estimated to be 8.8 x 10(5) M(-1). Dodecanoic acid quenched the TNS fluorescence entirely. Dodecanol quenched about 25% of the fluorescence, whereas dodecylamine increased it. By comparing the fluorescence of TNS and bioluminescence of FFL, the binding modes and the inhibition mechanisms of these dodecane analogues are classified in three different modes: competitive (dodecanoic acid), noncompetitive (dodecylamine), and mixed (dodecanol).

  12. Radiolabeled Somatostatin Analogue Therapy Of Gastroenteropancreatic Cancer.

    PubMed

    Bodei, Lisa; Kwekkeboom, Dik J; Kidd, Mark; Modlin, Irvin M; Krenning, Eric P

    2016-05-01

    Peptide receptor radionuclide therapy (PRRT) has been utilized for more than two decades and has been accepted as an effective therapeutic modality in the treatment of inoperable or metastatic gastroenteropancreatic neuroendocrine neoplasms (NENs) or neuroendocrine tumors (NETs). The two most commonly used radiopeptides for PRRT, (90)Y-octreotide and (177)Lu-octreotate, produce disease-control rates of 68%-94%, with progression-free survival rates that compare favorably with chemotherapy, somatostatin analogues, and newer targeted therapies. In addition, biochemical and symptomatic responses are commonly observed. In general, PRRT is well tolerated with only low to moderate toxicity in most individuals. In line with the need to place PRRT in the therapeutic sequence of gastroenteropancreatic NENs, a recently sponsored phase III randomized trial in small intestine NENs treated with (177)Lu-octreotate vs high-dose octreotide long-acting release demonstrated that (177)Lu-octreotate significantly improved progression-free survival. Other strategies that are presently being developed include combinations with targeted therapies or chemotherapy, intra-arterial PRRT, and salvage treatments. Sophisticated molecular tools need to be incorporated into the management strategy to more effectively define therapeutic efficacy and for an early identification of adverse events. The strategy of randomized controlled trials is a key issue to standardize the treatment and establish the position of PRRT in the therapeutic algorithm of NENs. PMID:27067503

  13. Actions of Thyroid Hormone Analogues on Chemokines

    PubMed Central

    Glinsky, Gennadi V.

    2016-01-01

    The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3′-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID:27493972

  14. Mammary analogue secretory carcinoma mimicking salivary adenoma.

    PubMed

    Williams, Lindsay; Chiosea, Simion I

    2013-12-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor characterized by ETV6 translocation. It appears that prior studies have identified MASC by reviewing salivary gland carcinomas, such as acinic cell carcinoma and adenocarcinoma, not otherwise specified. To address the possibility of MASC mimicking benign salivary neoplasms we reviewed 12 salivary gland (cyst)adenomas diagnosed prior to the discovery of MASC. One encapsulated (cyst)adenoma of the parotid gland demonstrated features of MASC. The diagnosis was confirmed by fluorescence in situ hybridization with an ETV6 break-apart probe. An unusual complex pattern of ETV6 rearrangement with duplication of the telomeric/distal ETV6 probe was identified. This case illustrates that MASC may mimic salivary (cyst)adenomas. To more accurately assess true clinical and morphologic spectrum of MASC, future studies may have to include review of salivary (cyst)adenomas. The differential diagnosis of MASC may have to be expanded to include cases resembling salivary (cyst)adenomas.

  15. From BPA to its analogues: Is it a safe journey?

    PubMed

    Usman, Afia; Ahmad, Masood

    2016-09-01

    Bisphenol-A (BPA) is one of the most abundant synthetic chemicals in the world due to its uses in plastics. Its widespread exposure vis-a-vis low dose effects led to a reduction in its safety dose and imposition of ban on its use in infant feeding bottles. This restriction paved the way for the gradual market entry of its analogues. However, their structural similarity to BPA has put them under surveillance for endocrine disrupting potential. The application of these analogues is increasing and so are the studies reporting their toxicity. This review highlights the reasons which led to the ban of BPA and also reports the exposure and toxicological data available on its analogues. Hence, this compilation is expected to answer in a better way whether the replacement of BPA by these analogues is safer or more harmful?

  16. Cell-Cycle Analyses Using Thymidine Analogues in Fission Yeast

    PubMed Central

    Anda, Silje; Boye, Erik; Grallert, Beata

    2014-01-01

    Thymidine analogues are powerful tools when studying DNA synthesis including DNA replication, repair and recombination. However, these analogues have been reported to have severe effects on cell-cycle progression and growth, the very processes being investigated in most of these studies. Here, we have analyzed the effects of 5-ethynyl-2′-deoxyuridine (EdU) and 5-Chloro-2′-deoxyuridine (CldU) using fission yeast cells and optimized the labelling procedure. We find that both analogues affect the cell cycle, but that the effects can be mitigated by using the appropriate analogue, short pulses of labelling and low concentrations. In addition, we report sequential labelling of two consecutive S phases using EdU and 5-bromo-2′-deoxyuridine (BrdU). Furthermore, we show that detection of replicative DNA synthesis is much more sensitive than DNA-measurements by flow cytometry. PMID:24551125

  17. From BPA to its analogues: Is it a safe journey?

    PubMed

    Usman, Afia; Ahmad, Masood

    2016-09-01

    Bisphenol-A (BPA) is one of the most abundant synthetic chemicals in the world due to its uses in plastics. Its widespread exposure vis-a-vis low dose effects led to a reduction in its safety dose and imposition of ban on its use in infant feeding bottles. This restriction paved the way for the gradual market entry of its analogues. However, their structural similarity to BPA has put them under surveillance for endocrine disrupting potential. The application of these analogues is increasing and so are the studies reporting their toxicity. This review highlights the reasons which led to the ban of BPA and also reports the exposure and toxicological data available on its analogues. Hence, this compilation is expected to answer in a better way whether the replacement of BPA by these analogues is safer or more harmful? PMID:27262103

  18. Effects of Prostaglandin Analogues on Aqueous Humor Outflow Pathways

    PubMed Central

    Winkler, Nelson S.

    2014-01-01

    Abstract Elevated intraocular pressure (IOP) is the most prevalent risk factor for glaucoma. All treatments, whether surgical or pharmaceutical, are aimed at lowering IOP. Prostaglandin analogues are a first line therapy for glaucoma due to their ability to reduce IOP, once-daily dosing, efficacy, and minimal side-effect profile. Whereas prostaglandin analogues have been known to alter aqueous humor outflow through the unconventional (uveoscleral) pathway, more recent evidence suggests their action also occurs through the conventional (trabecular) pathway. Understanding how prostaglandin analogues successfully lower IOP is important, as this information may lead to the discovery of new molecular targets for future therapeutic intervention. This review explores the current understanding of prostaglandin analogue biology as it pertains to IOP reduction and improved aqueous humor outflow facility. PMID:24359106

  19. Analogues for Wild2: Carbonaceous Chondrites Shot into Aerogel

    NASA Astrophysics Data System (ADS)

    Hicks, L. J.; Bridges, J. C.; MacArthur, J. L.; Wickham-Eade, J. E.; Price, M. C.; Burchell, M. J.; Butterworth, A. L.; Baker, S. H.

    2016-08-01

    Comet Wild2 particles show similarities to carbonaceous chondrites. We compare Wild2 grains to analogue shots of CV3 and CR2 powders in aerogel tracks, using the same techniques, to make accurate comparisons.

  20. Mars Methane Analogue Mission (M3): Analytical Techniques and Operations

    NASA Astrophysics Data System (ADS)

    Cloutis, E.; Vrionis, H.; Qadi, A.; Bell, J. F.; Berard, G.; Boivin, A.; Ellery, A.; Jamroz, W.; Kruzelecky, R.; Mann, P.; Samson, C.; Stromberg, J.; Strong, K.; Tremblay, A.; Whyte, L.; Wing, B.

    2011-03-01

    The Mars Methane Analogue Mission (M3) project is designed to simulate a rover-based search for, and analysis of, methane sources on Mars at a serpentinite open pit mine in Quebec, using a variety of instruments.

  1. Sulphur Spring: Busy Intersection and Possible Martian Analogue

    NASA Technical Reports Server (NTRS)

    Nankivell, A.; Andre, N.; Thomas-Keprta, K.; Allen, C.; McKay, D.

    2000-01-01

    Life in extreme environments exhibiting conditions similar to early Earth and Mars, such as Sulphur Spring, may harbor microbiota serving as both relics from the past as well as present day Martian analogues.

  2. Photochemical synthesis of nucleoside analogues from cyclobutanones: bicyclic and isonucleosides.

    PubMed

    Jaffer, Mileina; Ebead, Abdelaziz; Lee-Ruff, Edward

    2010-05-26

    The preparation of two nucleoside analogues are reported. Both syntheses involve a key photochemical ring-expansion of cyclobutanones to an oxacarbene and its subsequent scavenging by 6-chloropurine. The synthesis of a bicyclic (locked) purine starts from a oxabicycloheptanone with a hydroxymethyl pendant. The preparation of an isonucleoside uses a cyclobutanone with an alpha-substituted 6-chloropurine. Irradiation of the latter produces an isonucleoside and acyclic nucleoside analogues.

  3. Analogue and digital linear modulation techniques for mobile satellite

    NASA Technical Reports Server (NTRS)

    Whitmarsh, W. J.; Bateman, A.; Mcgeehan, J. P.

    1990-01-01

    The choice of modulation format for a mobile satellite service is complex. The subjective performance is summarized of candidate schemes and voice coder technologies. It is shown that good performance can be achieved with both analogue and digital voice systems, although the analogue system gives superior performance in fading. The results highlight the need for flexibility in the choice of signaling format. Linear transceiver technology capable of using many forms of narrowband modulation is described.

  4. Carbacaprazamycins: Chemically Stable Analogues of the Caprazamycin Nucleoside Antibiotics.

    PubMed

    Ichikawa, Satoshi; Yamaguchi, Mayumi; Hsuan, Lee Shang; Kato, Yuta; Matsuda, Akira

    2015-04-10

    Carbacaprazamycins, which are chemically stable analogues of caprazamycins, were designed and synthesized. These analogues were active against drug-resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, and their activities were comparable to those of the parent caprazamycins. The effect of treatment with carbacaprazamycin on morphological changes in S. aureus indicated that the mode of action was completely different from those of existing peptidoglycan inhibitors. PMID:27622529

  5. Molecular cloning and expression analysis of liver-expressed antimicrobial peptide 1 (LEAP-1) and LEAP-2 genes in the blunt snout bream (Megalobrama amblycephala).

    PubMed

    Liang, Tao; Ji, Wei; Zhang, Gui-Rong; Wei, Kai-Jian; Feng, Ke; Wang, Wei-Min; Zou, Gui-Wei

    2013-08-01

    Liver-expressed antimicrobial peptide 1 (LEAP-1) and LEAP-2 are widespread in fish and extremely important components of the host innate immune system. In this study, full-length cDNAs of LEAP-1 and LEAP-2 were cloned and sequenced from blunt snout bream, Megalobrama amblycephala. The open reading frames (ORF) of LEAP-1 and LEAP-2 genes encode putative peptides of 94 and 92 amino acids, which possess eight and four conserved cysteine residues, respectively. The homologous identities of deduced amino acid sequences show that the LEAP-1 and LEAP-2 of blunt snout bream share considerable similarity with those of grass carp. The mRNA expressions of LEAP-1 and LEAP-2 were detectable at different early developmental stages of blunt snout bream and varied with embryonic and larval growth. LEAP-1 and LEAP-2 were expressed in a wide range of adult tissues, with the highest expression levels in the liver and midgut, respectively. Bacterial challenge experiments showed that the levels of LEAP-1 and LEAP-2 mRNA expression were up-regulated in the liver, spleen, gill and brain of juvenile blunt snout bream. These results indicate that the LEAP-1 and LEAP-2 may play important roles in early development of embryos and fry, and may contribute to the defense against the pathogenic bacterial invasion. This study will further our understanding of the function of LEAP-1 and LEAP-2 and the molecular mechanism of innate immunity in teleosts.

  6. Mutation-based structural modification and dynamics study of amyloid beta peptide (1-42): An in-silico-based analysis to cognize the mechanism of aggregation.

    PubMed

    Panda, Pritam Kumar; Patil, Abhaysinha Satish; Patel, Priyam; Panchal, Hetalkumar

    2016-03-01

    Alzheimer's disease is the prevalent cause of premature senility, a progressive mental disorder due to degeneration in brain and deposition of amyloid β peptide (1-42, a misfolded protein) in the form of aggregation that prevails for a prolonged time and obstructs every aspect of life. One of the primary hallmarks of the neuropathological disease is the accretion of amyloid β peptide in the brain that leads to Alzheimer's disease, but the mechanism is still a mystery. Several investigations have shown that mutations at specific positions have a significant impact in stability of the peptide as predicted from aggregation profiles. Here in our study, we have analyzed the mutations by substituting residues at position A22G, E22G, E22K, E22Q, D23N, L34V and molecular dynamics have been performed to check the deviation in stability and conformation of the peptide. The results validated that the mutations at specific positions lead to instability and the proline substitution at E22P and L34P stalled the aggregation of the peptide. PMID:26981406

  7. Mutation-based structural modification and dynamics study of amyloid beta peptide (1–42): An in-silico-based analysis to cognize the mechanism of aggregation

    PubMed Central

    Panda, Pritam Kumar; Patil, Abhaysinha Satish; Patel, Priyam; Panchal, Hetalkumar

    2016-01-01

    Alzheimer's disease is the prevalent cause of premature senility, a progressive mental disorder due to degeneration in brain and deposition of amyloid β peptide (1–42, a misfolded protein) in the form of aggregation that prevails for a prolonged time and obstructs every aspect of life. One of the primary hallmarks of the neuropathological disease is the accretion of amyloid β peptide in the brain that leads to Alzheimer's disease, but the mechanism is still a mystery. Several investigations have shown that mutations at specific positions have a significant impact in stability of the peptide as predicted from aggregation profiles. Here in our study, we have analyzed the mutations by substituting residues at position A22G, E22G, E22K, E22Q, D23N, L34V and molecular dynamics have been performed to check the deviation in stability and conformation of the peptide. The results validated that the mutations at specific positions lead to instability and the proline substitution at E22P and L34P stalled the aggregation of the peptide. PMID:26981406

  8. Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

    PubMed Central

    Satishkumar, Sakilam; Vuram, Prasanna K.; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J.; Montemayor, Michelle M. Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K.

    2016-01-01

    Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest on the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL), and chronic lymphocytic leukemia (CLL) cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribo analogue of cladribine possessed activity, but was least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, only cladribine and its ribose analogue were most active. PMID:26556315

  9. Bisphenol A and Its Analogues Activate Human Pregnane X Receptor

    PubMed Central

    Sui, Yipeng; Ai, Ni; Park, Se-Hyung; Rios-Pilier, Jennifer; Perkins, Jordan T.; Welsh, William J.

    2012-01-01

    Background: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA and its analogues are present in environmental and human samples. Many endocrine-disrupting chemicals, including BPA, have been shown to activate the pregnane X receptor (PXR), a nuclear receptor that functions as a master regulator of xenobiotic metabolism. However, the detailed mechanism by which these chemicals activate PXR remains unknown. Objective: We investigated the mechanism by which BPA interacts with and activates PXR and examined selected BPA analogues to determine whether they bind to and activate PXR. Methods: Cell-based reporter assays, in silico ligand–PXR docking studies, and site-directed mutagenesis were combined to study the interaction between BPA and PXR. We also investigated the influence of BPA and its analogues on the regulation of PXR target genes in human LS180 cells. Results: We found that BPA and several of its analogues are potent agonists for human PXR (hPXR) but do not affect mouse PXR activity. We identified key residues within hPXR’s ligand-binding pocket that constitute points of interaction with BPA. We also deduced the structural requirements of BPA analogues that activate hPXR. BPA and its analogues can also induce PXR target gene expression in human LS180 cells. Conclusions: The present study advances our understanding of the mechanism by which BPA interacts with and activates human PXR. Activation of PXR by BPA may explain some of the adverse effects of BPA in humans. PMID:22214767

  10. Habitability & Astrobiology Research in Mars Terrestrial Analogues

    NASA Astrophysics Data System (ADS)

    Foing, Bernard

    2014-05-01

    We performed a series of field research campaigns (ILEWG EuroMoonMars) in the extreme Utah desert relevant to Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL), or Moon geochemistry (SMART-1, LRO). We shall give an update on the sample analysis in the context of habitability and astrobiology. Methods & Results: In the frame of ILEWG EuroMoonMars campaigns (2009 to 2013) we deployed at Mars Desert Research station, near Hanksville Utah, a suite of instruments and techniques [A, 1, 2, 9-11] including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. Among the important findings are the diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed [3,4,9]. A dominant factor seems to be soil porosity and lower clay-sized particle content [6-8]. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples [10, 11]. We compare the 2009 campaign results [1-9] to new measurements from 2010-2013 campaigns [10-12] relevant to: comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life. Keywords: field analogue research, astrobiology, habitability, life detection, Earth-Moon-Mars, organics References [A] Foing, Stoker & Ehrenfreund (Editors, 2011) "Astrobiology field Research in Moon/Mars Analogue Environments", Special Issue of International

  11. Chemotactic peptide analogues. Synthesis and chemotactic activity of N-formyl-Met-Leu-Phe analogues containing (S)-phenylalaninol derivatives.

    PubMed

    Zecchini, G P; Paradisi, M P; Torrini, I; Spisani, S

    1995-09-01

    The synthesis and the biological activity towards human neutrophils of some N-formyl-Met-Leu-Phe-OMe analogues containing (S)-phenylalaninol (Pheol) or its derivatives in place of the native phenylalanine are reported. While the analogue containing Pheol (4) was found to be devoid of significant biological activity, its esters 3 and 5, although inactive as chemoattractants, are able to strongly stimulate superoxide production and are active with a lower efficacy in the lysozyme release. PMID:7487425

  12. Incorporation of tryptophan analogues into the lantibiotic nisin.

    PubMed

    Zhou, Liang; Shao, Jinfeng; Li, Qian; van Heel, Auke J; de Vries, Marcel P; Broos, Jaap; Kuipers, Oscar P

    2016-05-01

    Lantibiotics are posttranslationally modified peptides with efficient inhibitory activity against various Gram-positive bacteria. In addition to the original modifications, incorporation of non-canonical amino acids can render new properties and functions to lantibiotics. Nisin is the most studied lantibiotic and contains no tryptophan residues. In this study, a system was constructed to incorporate tryptophan analogues into nisin, which included the modification machinery (NisBTC) and the overexpression of tryptophanyl-tRNA synthetase (TrpRS). Tryptophan and three different tryptophan analogues (5-fluoroTrp (5FW), 5-hydroxyTrp (5HW) and 5-methylTrp (5MeW)) were successfully incorporated at four different positions of nisin (I1W, I4W, M17W and V32W). The incorporation efficiency of tryptophan analogues into mutants I1W, M17W and V32W was over 97 %, while the mutant I4W showed relatively low incorporation efficiency (69-93 %). The variants with 5FW showed relatively higher production yield, while 5MeW-containing variants showed the lowest yield. The dehydration efficiency of serines or threonines was affected by the tryptophan mutants of I4W and V32W. The affinity of the peptides for the cation-ion exchange and reverse phase chromatography columns was significantly reduced when 5HW was incorporated. The antimicrobial activity of IIW and its 5FW analogue both decreased two times compared to that of nisin, while that of its 5HW analogue decreased four times. The 5FW analogue of I4W also showed two times decreased activity than nisin. However, the mutant M17W and its 5HW analogue both showed 32 times reduced activity relative to that of nisin.

  13. Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives.

    PubMed

    Monte, A P; Waldman, S R; Marona-Lewicka, D; Wainscott, D B; Nelson, D L; Sanders-Bush, E; Nichols, D E

    1997-09-12

    hallucinogens, that such compounds must be full agonists at the 5-HT2A receptor subtype. In contrast to the 2,5-dimethoxy-substituted phenethylamines, where rigidification of the methoxy groups had no deleterious effect on activity, the loss of activity in the 3,4,5-trioxygenated mescaline analogues may suggest that the 3 and 5 methoxy groups must remain conformationally mobile to enable receptor activation.

  14. Terrestrial research in Mars analogue environments

    NASA Astrophysics Data System (ADS)

    Osipov, G.

    Fatty acids (FA) content was measured by GC-MS SIM technique in Sulfide ores of present day (Mid-Atlantic Ridge and others) and ancient (Ural Paleocene, Russia) black smokers; Early Proterozoic kerites of Volyn; Siberian, Canadian and Antarctic permafrosts and also in rocks of East-European platform Achaean crystalline basement. Analysis was shown presence those and only those fatty acids which are specific to microorganisms. FA with 12 up 19 of carbon atoms are thought to be a bacterial biomass sign. 3-Hydroxy fatty acids also found in samples and are strong specific markers of gram-negative bacteria. Cultivation yield living bacteria in some cases. The East-European platform Achaean crystalline basement rocks opened by Vorotilov Deep Well (VDW) drilled through Puchezh-Katunski impact structure were studied within depths 2575 - 2805 m. 34 microbial lipid markers were detected by GC-MS and 22 species were identified. Bacteria of g. Bacillus reached 6,8 % in subsurface communities. However, members of gg. Clostridium (37,1 - 33,2 %) and Rhodococcus (27,6 - 33,7 %) were absolute dominants within studied depth interval. Some lipid patterns of kerite samples could be assessed to definite genera or, in special cases, to species of contemporary microorganisms. For instance, 2-hydroxylauric acid is specific to Pseudomonas putida group or Acinetobacter spp., and hydroxymyristic together with hydroxypalmitic are specific to P.cepacea and cyanobacteria. 3-hydroxystearic acid was known as component of Acetobacter diazothrophycus and Gloebacter violaceous cyanobacterium. 10-hydroxystearic acid associated with Nocardia spp., which oxidizes oleic acid in organic substrates. 10-methylhexadecanoic (10Me16) acid together with 10Me14, 10Me15 and 10Me17 analogues are markers of actinomycetes. Significant part of Black Smokers organic matter is probably biogenic. Fatty acid features strongly assigns it to bacterial, microeucariotic and planta cells. Par example 3-hydroxy acids are

  15. Spectral analysis of lunar analogue samples

    NASA Astrophysics Data System (ADS)

    Offringa, Marloes; Foing, Bernard

    2016-04-01

    Analyses of samples derived from terrestrial analogue sites are used to study lunar processes in their geological context (Foing, Stoker, Ehrenfreund, 2011). For this study samples from the volcanic region of the Eifel, Germany collected during field campaigns (Foing et al., 2010), are analyzed with a variety of spectrometers. The aim is to obtain a database of analyzed samples that could be used as a reference for future in situ measurements. Equipment used in the laboratory consists of a Fourier Transform Infrared (FTIR) spectrometer, an X-Ray Fluorescence (XRF) spectrometer, a Raman laser spectrometer, as well as UV-VIS and NIR reflectance spectrometers. The Raman, UV-VIS and NIR are also used in combination with the EXoGeoLab mock-up lander during field campaigns (Foing, Stoker, Ehrenfreund, 2011). Calibration of the UV-VIS and NIR reflectance spectrometers is the main focus of this research in order to obtain the clearest spectra. The calibration of the UV-VIS and NIR reflectance spectrometers requires the use of a good light source as well as suitable optical fibers to create a signal that covers the widest range in wavelengths available. To eliminate noise towards the edges of this range, multiple measurements are averaged and data is processed by dividing the signal by reference spectra. Calibration of the devices by creating a new dark and reference spectra has to take place after every sample measurement. In this way we take into account changes that occur in the signal due to the eating of the devices during the measurements. Moreover, the integration time is adjusted to obtain a clear signal without leading to oversaturation in the reflectance spectrum. The typical integration times for the UV-VIS reflectance spectrometer vary between 1 - 18 s, depending on the amount of daylight during experiments. For the NIR reflectance spectrometer the integration time resulting in the best signals is approximately 150 ms in combination with a broad spectrum light

  16. Iron isotopes in an Archean ocean analogue

    NASA Astrophysics Data System (ADS)

    Busigny, Vincent; Planavsky, Noah J.; Jézéquel, Didier; Crowe, Sean; Louvat, Pascale; Moureau, Julien; Viollier, Eric; Lyons, Timothy W.

    2014-05-01

    Iron isotopes have been extensively used to trace the history of microbial metabolisms and the redox evolution of the oceans. Archean sedimentary rocks display greater variability in iron isotope ratios and more markedly negative values than those deposited in the Proterozoic and Phanerozoic. This increased variability has been linked to changes in either water column iron cycling or the extent of benthic microbial iron reduction through time. We tested these contrasting scenarios through a detailed study of anoxic and ferruginous Lac Pavin (France), which can serve as a modern analogue of the Archean ocean. A depth-profile in the water column of Lac Pavin shows a remarkable increase in dissolved Fe concentration (0.1-1200 μM) and δ56Fe values (-2.14‰ to +0.31‰) across the oxic-anoxic boundary to the lake bottom. The largest Fe isotope variability is found at the redox boundary and is related to partial oxidation of dissolved ferrous iron, leaving the residual Fe enriched in light isotopes. The analysis of four sediment cores collected along a lateral profile (one in the oxic layer, one at the redox boundary, one in the anoxic zone, and one at the bottom of the lake) indicates that bulk sediments, porewaters, and reactive Fe mostly have δ56Fe values near 0.0 ± 0.2‰, similar to detrital iron. In contrast, pyrite δ56Fe values in sub-chemocline cores (60, 65, and 92 m) are highly variable and show significant deviations from the detrital iron isotope composition (δ56Fepyrite between -1.51‰ and +0.09‰; average -0.93‰). Importantly, the pyrite δ56Fe values mirror the δ56Fe of dissolved iron at the redox boundary—where near quantitative sulfate and sulfide drawdown occurs—suggesting limited iron isotope fractionation during iron sulfide formation. This finding has important implications for the Archean environment. Specifically, this work suggests that in a ferruginous system, most of the Fe isotope variability observed in sedimentary pyrites can

  17. EXENATIDE IMPROVES HYPERTENSION IN A RAT MODEL OF THE METABOLIC SYNDROME

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Exenatide is a peptide incretin mimetic that has glucoregulatory actions associated with weight reduction. Previous reports demonstrated acute increases in blood pressure after systemic or intracerebroventricular administration of exenatide or glucagon-like peptide-1 (GLP-1) in rats. However, there ...

  18. Brain GLP-1 and insulin sensitivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Type 2 diabetes is often treated with a class of drugs referred to as glucagon-like peptide-1 (GLP-1) analogs. GLP-1 is a peptide secreted by the gut that acts through only one known receptor, the GLP-1 receptor. The primary function of GLP-1 is thought to be lowering of postprandial glucose levels....

  19. Theoretical study on absorption and emission spectra of adenine analogues.

    PubMed

    Liu, Hongxia; Song, Qixia; Yang, Yan; Li, Yan; Wang, Haijun

    2014-04-01

    Fluorescent nucleoside analogues have attracted much attention in studying the structure and dynamics of nucleic acids in recent years. In the present work, we use theoretical calculations to investigate the structural and optical properties of four adenine analogues (termed as A1, A2, A3, and A4), and also consider the effects of aqueous solution and base pairing. The results show that the fluorescent adenine analogues can pair with thymine to form stable H-bonded WC base pairs. The excited geometries of both adenine analogues and WC base pairs are similar to the ground geometries. The absorption and emission maxima of adenine analogues are greatly red shifted compared with nature adenine, the oscillator strengths of A1 and A2 are stronger than A3 and A4 in both absorption and emission spectra. The calculated low-energy peaks in the absorption spectra are in good agreement with the experimental data. In general, the aqueous solution and base pairing can slightly red-shift both the absorption and emission maxima, and can increase the oscillator strengths of absorption spectra, but significantly decrease the oscillator strengths of A3 in emission spectra.

  20. Central effects of angiotensin II, its fragment and analogues.

    PubMed

    Georgiev, V P; Klousha, V E; Petkov, V D; Markovska, V L; Svirskis, S V; Mountsinietse, R K; Anouans, Z E

    1984-01-01

    The effects of the octapeptide angiotensin II (AT II), its fragment Ile8 AT3-8 and the analogues Sar1 Ala8 AT II, Ala8 AT II and Ile8 AT II were studied with respect to: the level of biogenic amines (DA, 5-HT and their metabolites HVA and 5-HIAA) in the forebrain; the behaviour of the animals--haloperidol catalepsy, apomorphine stereotypy, unconditioned jumping reaction (UJR), convulsive threshold. Good correlation was found between the biochemical and behavioural effects. The fragment of AT II where phenylalanine is substituted at the C-terminal by Ile reduces the haloperidol-increased content of HVA, potentiates apomorphine stereotypy and reduces catalepsy, whereas the AT II analogues (where the C-terminal phenylalanine is substituted by Ala, and the N-terminal--by Sar) potentiate the effect of haloperidol increasing the HVA content, reduce apomorphine stereotypy and potentiate catalepsy; saralasine independently applied induces brief catalepsy; AT II, its fragment and analogues inhibit UJR, in combination with amphetamine and PTZ this effect becomes deeper; the duration of hexobarbital sleep is increased. The peptides investigated increase the convulsive threshold. The results show that the hexapeptide fragment has preserved the effects of AT II, whereas in the analogues (with changed C- and N-terminals) they are changed. The results obtained may be explained with the modulating influence of AT II-receptors on the DA-ergic receptors in the brain structures with which AT II and its fragment and analogues enter in contact.

  1. Review of Insulin and its Analogues in Diabetes Mellitus

    PubMed Central

    Mane, Krishnappa; Chaluvaraju, KC; Niranjan, MS; Zaranappa, TR; Manjuthej, TR

    2012-01-01

    Diabetes is a metabolic disorder where in human body does not produce or properly uses insulin, a hormone that is required to convert sugar, starches and other food into energy. Diabetes finally leads to more complications and to prevent these complications insulin and its analogues are used. After more than half a century of treating diabetics with animal insulin’s, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogues were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid, intermediate and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analogue, lispro, confirmed the hopes by showing that improved glycaemic control can be achieved without an increase in hypoglycaemic events. Two new insulin analogues, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States and several other analogues are being intensively tested. PMID:24826038

  2. Analogue modelling of syntectonic leucosomes in migmatitic schists

    NASA Astrophysics Data System (ADS)

    Druguet, Elena; Carreras, Jordi

    2006-10-01

    Migmatites from the Cap de Creus tectonometamorphic belt display a wide variety of structures, from those formed when the leucosomes were melt-bearing, to those developed during solid-state deformation. The observed field structures have been modelled by means of analogue experiments. The materials used in the models are layered plasticine as a schist analogue, and chocolate as analogue of the crystallizing leucosome. A model for the development of syntectonic migmatites is proposed in which initial melt-bearing patches, preferentially formed within fertile pelitic layers, progressively evolve towards lens-shaped veins. Furthermore, heterogeneous deformation of anisotropic metasediments facilitates formation of extensional sites for further melt accumulation and transport. Melt crystallization implies a rapid increase in effective viscosity of leucosomes producing a reversal in competence contrast with respect to the enclosing schists. During the whole process, deformation localizes around crystallizing veins, giving rise to different and contrasting structures for melt-bearing and for solid-state stages.

  3. Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine

    PubMed Central

    Kwon, Yongseok; Song, Jayoung; Bae, Hoon; Kim, Woo-Jung; Lee, Joo-Youn; Han, Geun-Hee; Lee, Sang Kook; Kim, Sanghee

    2015-01-01

    A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1. PMID:25654428

  4. Migrastatin analogues target fascin to block tumour metastasis

    SciTech Connect

    Chen, L.; Jakoncic, J.; Yang, S.; Zhang, J.; Huang, X.Y.

    2010-04-15

    Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

  5. New rubrolide analogues as inhibitors of photosynthesis light reactions.

    PubMed

    Varejão, Jodieh O S; Barbosa, Luiz C A; Ramos, Gabriela Álvarez; Varejão, Eduardo V V; King-Díaz, Beatriz; Lotina-Hennsen, Blas

    2015-04-01

    Natural products called rubrolides have been investigated as a model for the development of new herbicides that act on the photosynthesis apparatus. This study comprises a comprehensive analysis of the photosynthesis inhibitory ability of 27 new structurally diverse rubrolide analogues. In general, the results revealed that the compounds exhibited efficient inhibition of the photosynthetic process, but in some cases low water solubility may be a limiting factor. To elucidate their mode of action, the effects of the compounds on PSII and PSI, as well as their partial reaction on chloroplasts and the chlorophyll a fluorescence transients were measured. Our results showed that some of the most active rubrolide analogues act as a Hill reaction inhibitors at the QB level by interacting with the D1 protein at the reducing side of PSII. All of the active analogues follow Tice's rule of 5, which indicates that these compounds present physicochemical properties suitable for herbicides.

  6. Synthesis and cytotoxic activities of semisynthetic zearalenone analogues.

    PubMed

    Tadpetch, Kwanruthai; Kaewmee, Benyapa; Chantakaew, Kittisak; Kantee, Kawalee; Rukachaisirikul, Vatcharin; Phongpaichit, Souwalak

    2016-08-01

    Zearalenone is a β-resorcylic acid macrolide with various biological activities. Herein we report the synthesis and cytotoxic activities of 34 zearalenone analogues against human oral epidermoid carcinoma (KB) and human breast adenocarcinoma (MCF-7) cells as well as noncancerous Vero cells. Some zearalenone analogues showed moderately enhanced cytotoxic activities against the two cancer cell lines. We have discovered the potential lead compounds with diminished or no cytotoxicity to Vero cells. Preliminary structure-activity relationship studies revealed that the double bond at the 1' and 2' positions of zearalenone core was crucial for cytotoxic activities on both cell lines. In addition, for zearalenol analogues, the unprotected hydroxyl group at C-2 and an alkoxy substituent at C-4 played key roles on cytotoxic effects of both cell lines.

  7. Conception, synthesis, and biological evaluation of original discodermolide analogues.

    PubMed

    de Lemos, Elsa; Agouridas, Evangelos; Sorin, Geoffroy; Guerreiro, Antonio; Commerçon, Alain; Pancrazi, Ange; Betzer, Jean-François; Lannou, Marie-Isabelle; Ardisson, Janick

    2011-08-29

    Due to its intriguing biological activity profile and potential chemotherapeutic application discodermolide (DDM) proved to be an attractive target. Therefore, notable efforts have been carried out directed toward its total synthesis and toward the production and evaluation of synthetic analogues. Recently, we achieved the total synthesis of DDM. At the present, guided by the knowledge gained during our DDM total synthesis and by the requirement of keeping the bioactive "U" shape conformation, we report the convergent preparation of five original analogues. Three types of changes were realized through modification of the terminal (Z)-diene moiety, of the methyl group at the C14-position, and the lactone region. All analogues were active in the nanomolar range and two of them turned out to be equipotent to DDM.

  8. Synthesis and Biological Evaluation of New (-)-Englerin Analogues.

    PubMed

    López-Suárez, Laura; Riesgo, Lorena; Bravo, Fernando; Ransom, Tanya T; Beutler, John A; Echavarren, Antonio M

    2016-05-01

    We report the synthesis and biological evaluation of a series of (-)-englerin A analogues obtained along our previously reported synthetic route based on a stereoselective gold(I) cycloaddition process. This synthetic route is a convenient platform to access analogues with broad structural diversity and has led us to the discovery of unprecedented and easier-to-synthesize derivatives with an unsaturation in the cyclopentyl ring between C4 and C5. We also introduce novel analogues in which the original isopropyl motif has been substituted with cyclohexyl, phenyl, and cyclopropyl moieties. The high selectivity and growth-inhibitory activity shown by these new derivatives in renal cancer cell lines opens new ways toward the final goal of finding effective drugs for the treatment of renal cell carcinoma (RCC).

  9. Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors.

    PubMed

    Florence, Gordon J; Fraser, Andrew L; Gould, Eoin R; King, Elizabeth F B; Menzies, Stefanie K; Morris, Joanne C; Tulloch, Lindsay B; Smith, Terry K

    2014-11-01

    Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis-tetrahydropyran 1,4-triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure-activity relationship studies. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti-HAT agents.

  10. The Object-analogue approach for probabilistic forecasting

    NASA Astrophysics Data System (ADS)

    Frediani, M. E.; Hopson, T. M.; Anagnostou, E. N.; Hacker, J.

    2015-12-01

    The object-analogue is a new method to estimate forecast uncertainty and to derive probabilistic predictions of gridded forecast fields over larger regions rather than point locations. The method has been developed for improving the forecast of 10-meter wind speed over the northeast US, and it can be extended to other forecast variables, vertical levels, and other regions. The object-analogue approach combines the analog post-processing technique (Hopson 2005; Hamill 2006; Delle Monache 2011) with the Method for Object-based Diagnostic Evaluation (MODE) for forecast verification (Davis et al 2006a, b). Originally, MODE is used to verify mainly precipitation forecasts using features of a forecast region represented by an object. The analog technique is used to reduce the NWP systematic and random errors of a gridded forecast field. In this study we use MODE-derived objects to characterize the wind fields forecasts into attributes such as object area, centroid location, and intensity percentiles, and apply the analogue concept to these objects. The object-analogue method uses a database of objects derived from reforecasts and their respective reanalysis. Given a real-time forecast field, it searches the database and selects the top-ranked objects with the most similar set of attributes using the MODE fuzzy logic algorithm for object matching. The attribute probabilities obtained with the set of selected object-analogues are used to derive a multi-layer probabilistic prediction. The attribute probabilities are combined into three uncertainty layers that address the main concerns of most applications: location, area, and magnitude. The multi-layer uncertainty can be weighted and combined or used independently in such that it provides a more accurate prediction, adjusted according to the application interest. In this study we present preliminary results of the object-analogue method. Using a database with one hundred storms we perform a leave-one-out cross-validation to

  11. Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

    PubMed Central

    Janáky, T; Juhász, A; Bajusz, S; Csernus, V; Srkalovic, G; Bokser, L; Milovanovic, S; Redding, T W; Rékási, Z; Nagy, A

    1992-01-01

    In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or N epsilon-(2,3-diaminopropionyl)-D-lysine and N delta-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,D-Lys6,D-Ala10] LH-RH [where Nal(2) is 3-(2-naphthyl)alanine], [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,N epsilon-(2,3-diaminopropionyl)-D-Lys6,D-Ala10]LH-RH, and their D-Pal(3)3 homologs [Pal(3) is 3-(3-pyridyl)alanine] as well as [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,Tyr5,N epsilon-(2,3-diamino-propionyl)-D-Lys6,D-Ala10]LH-RH were linked to cytotoxic compounds. The hybrid molecules inhibited ovulation in rats at doses of 10 micrograms and suppressed LH release in vitro. The receptor binding of cytotoxic analogues was decreased compared to the precursor peptides, although analogues with 2-(hydroxymethyl)anthraquinone hemiglutarate had high affinities. All of the cytotoxic analogues tested inhibited [3H]thymidine incorporation into DNA in cultures of human breast and prostate cancer cell lines

  12. Five new discodermolide analogues from the marine sponge Discodermia species.

    PubMed

    Gunasekera, Sarath P; Paul, Gopal K; Longley, Ross E; Isbrucker, Richard A; Pomponi, Shirley A

    2002-11-01

    Discodermolide (1) and five new discodermolide analogues trivially named 2-epi-discodermolide (2), 2-des-methyldiscodermolide (3), 5-hydroxymethyldiscodermolate (4), 19-des-aminocarbonyldiscodermolide (5), and 9(13)-cyclodiscodermolide (6) have been isolated from marine sponges belonging to the genus Discodermia collected from the Caribbean Sea. The isolation, structure elucidation, and biological activities of 2-6 are described. The natural analogues, which were isolated in trace amounts, exhibited significant variation of cytotoxicity against the cultured murine P-388 leukemia and A-549 human adenocarcinoma cells and suggested the importance of the C(7) through C(17) moiety for potency against cultured tumor cell lines.

  13. Synthesis and Cytotoxicity of Semisynthetic Withalongolide A Analogues

    PubMed Central

    2013-01-01

    The natural product withaferin A exhibits potent antitumor activity and other diverse pharmacological activities. The recently discovered withalongolide A, a C-19 hydroxylated congener of withaferin A, was recently reported to possess cytotoxic activity against head and neck squamous cell carcinomas. Semisynthetic acetylated analogues of withalongolide A were shown to be considerably more cytotoxic than the parent compound. To further explore the structure–activity relationships, 20 new semisynthetic analogues of withalongolide A were synthesized and evaluated for cytotoxic activity against four different cancer cell lines. A number of derivatives were found to be more potent than the parent compound and withaferin A. PMID:24273633

  14. Tumor imaging and therapy using radiolabeled somatostatin analogues.

    PubMed

    de Jong, Marion; Breeman, Wout A P; Kwekkeboom, Dik J; Valkema, Roelf; Krenning, Eric P

    2009-07-21

    Molecular imaging plays an essential role in balancing the clinical benefits and risks of radionuclide-based cancer therapy. To effectively treat individual patients, careful assessment of biodistribution, dosimetry, and toxicity is essential. In this Account, we describe advances that combine features of molecular imaging and radionuclide therapy to provide new avenues toward individualized cancer treatment. Selective receptor-targeting radiopeptides have emerged as an important class of radiopharmaceuticals for molecular imaging and therapy of tumors that overexpress peptide receptors on the cell membrane. After such peptides labeled with gamma-emitting radionuclides bind to their receptors, they allow clinicians to visualize receptor-expressing tumors non-invasively. Peptides labeled with beta-particle emitters could also eradicate receptor-expressing tumors. The somatostatin receptors, which are overexpressed in a majority of neuroendocrine tumors, represent the first and best example of targets for radiopeptide-based imaging and radionuclide therapy. The somatostatin analogue (111)In-octreotide permits the localization and staging of neuroendocrine tumors that express the appropriate somatostatin receptors. Newer modified somatostatin analogues, including Tyr(3)-octreotide and Tyr(3)-octreotate, are successfully being used for tumor imaging and radionuclide therapy. Because there are few effective therapies for patients with inoperable or metastasized neuroendocrine tumors, this therapy is a promising novel treatment option for these patients. Peptide receptor imaging and radionuclide therapy can be combined in a single probe, called a "theranostic". To select patients who are likely to benefit from this type of intervention, we first use a peptide analogue labeled with a diagnostic radionuclide to obtain a scan. Selected patients will be treated using the same or a similar peptide analogue labeled with a therapeutic radionuclide. The development of such

  15. On slow light as a black hole analogue

    NASA Astrophysics Data System (ADS)

    Unruh, W. G.; Schützhold, R.

    2003-07-01

    Although slow light (electromagnetically induced transparency) would seem an ideal medium in which to institute a “dumb hole” (black hole analogue), it suffers from a number of problems. We show that the high phase velocity in the slow light regime ensures that the system cannot be used as an analogue displaying Hawking radiation. Even though an appropriately designed slow-light setup may simulate classical features of black holes—such as horizon, mode mixing, “Bogoliubov” coefficients, etc.—it does not reproduce the related quantum effects.

  16. Naturally occurring crystalline phases: analogues for radioactive waste forms

    SciTech Connect

    Haaker, R.F.; Ewing, R.C.

    1981-01-01

    Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

  17. Facile Synthesis of Natural Alkoxynaphthalene Analogues from Plant Alkoxybenzenes.

    PubMed

    Tsyganov, Dmitry V; Krayushkin, Mikhail M; Konyushkin, Leonid D; Strelenko, Yuri A; Semenova, Marina N; Semenov, Victor V

    2016-04-22

    Analogues of the bioactive natural alkoxynaphthalene pycnanthulignene D were synthesized by an efficient method. The starting plant allylalkoxybenzenes (1) are easily available from the plant essential oils of sassafras, dill, and parsley. The target 1-arylalkoxynaphthalenes (5) exhibited antiproliferative activity in a phenotypic sea urchin embryo assay. PMID:26910798

  18. Facile Synthesis of Natural Alkoxynaphthalene Analogues from Plant Alkoxybenzenes.

    PubMed

    Tsyganov, Dmitry V; Krayushkin, Mikhail M; Konyushkin, Leonid D; Strelenko, Yuri A; Semenova, Marina N; Semenov, Victor V

    2016-04-22

    Analogues of the bioactive natural alkoxynaphthalene pycnanthulignene D were synthesized by an efficient method. The starting plant allylalkoxybenzenes (1) are easily available from the plant essential oils of sassafras, dill, and parsley. The target 1-arylalkoxynaphthalenes (5) exhibited antiproliferative activity in a phenotypic sea urchin embryo assay.

  19. Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues.

    PubMed

    Hager, Anastasia; Wu, Mingxuan; Wang, Huanchen; Brown, Nathaniel W; Shears, Stephen B; Veiga, Nicolás; Fiedler, Dorothea

    2016-08-22

    The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP-InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions. PMID:27460418

  20. Trehalose Analogues: Latest Insights in Properties and Biocatalytic Production

    PubMed Central

    Walmagh, Maarten; Zhao, Renfei; Desmet, Tom

    2015-01-01

    Trehalose (α-d-glucopyranosyl α-d-glucopyranoside) is a non-reducing sugar with unique stabilizing properties due to its symmetrical, low energy structure consisting of two 1,1-anomerically bound glucose moieties. Many applications of this beneficial sugar have been reported in the novel food (nutricals), medical, pharmaceutical and cosmetic industries. Trehalose analogues, like lactotrehalose (α-d-glucopyranosyl α-d-galactopyranoside) or galactotrehalose (α-d-galactopyranosyl α-d-galactopyranoside), offer similar benefits as trehalose, but show additional features such as prebiotic or low-calorie sweetener due to their resistance against hydrolysis during digestion. Unfortunately, large-scale chemical production processes for trehalose analogues are not readily available at the moment due to the lack of efficient synthesis methods. Most of the procedures reported in literature suffer from low yields, elevated costs and are far from environmentally friendly. “Greener” alternatives found in the biocatalysis field, including galactosidases, trehalose phosphorylases and TreT-type trehalose synthases are suggested as primary candidates for trehalose analogue production instead. Significant progress has been made in the last decade to turn these into highly efficient biocatalysts and to broaden the variety of useful donor and acceptor sugars. In this review, we aim to provide an overview of the latest insights and future perspectives in trehalose analogue chemistry, applications and production pathways with emphasis on biocatalysis. PMID:26084050

  1. Synthesis of chlorins, bacteriochlorins and their tetraaza analogues

    NASA Astrophysics Data System (ADS)

    Dudkin, S. V.; Makarova, E. A.; Lukyanets, E. A.

    2016-07-01

    The currently known methods for the synthesis of hydrogenated derivatives of synthetic porphyrins — chlorins, bacteriochlorins, isobacteriochlorins and their tetraaza analogues — are considered. Reactions involving quasi-isolated double bonds including reduction, oxidative addition and cycloaddition are presented. Examples of direct synthesis of these macroheterocycles are given. The bibliography includes 168 references.

  2. A Macroscopic Analogue of the Nuclear Pairing Potential

    ERIC Educational Resources Information Center

    Dunlap, Richard A.

    2013-01-01

    A macroscopic system involving permanent magnets is used as an analogue to nucleons in a nucleus to illustrate the significance of the pairing interaction. This illustrates that the view of the total nuclear energy based only on the nucleon occupancy of the energy levels can yield erroneous results and it is only when the pairing interaction is…

  3. q-bosons and the q-analogue quantized field

    NASA Technical Reports Server (NTRS)

    Nelson, Charles A.

    1995-01-01

    The q-analogue coherent states are used to identify physical signatures for the presence of a 1-analogue quantized radiation field in the q-CS classical limits where the absolute value of z is large. In this quantum-optics-like limit, the fractional uncertainties of most physical quantities (momentum, position, amplitude, phase) which characterize the quantum field are O(1). They only vanish as O(1/absolute value of z) when q = 1. However, for the number operator, N, and the N-Hamiltonian for a free q-boson gas, H(sub N) = h(omega)(N + 1/2), the fractional uncertainties do still approach zero. A signature for q-boson counting statistics is that (Delta N)(exp 2)/ (N) approaches 0 as the absolute value of z approaches infinity. Except for its O(1) fractional uncertainty, the q-generalization of the Hermitian phase operator of Pegg and Barnett, phi(sub q), still exhibits normal classical behavior. The standard number-phase uncertainty-relation, Delta(N) Delta phi(sub q) = 1/2, and the approximate commutation relation, (N, phi(sub q)) = i, still hold for the single-mode q-analogue quantized field. So, N and phi(sub q) are almost canonically conjugate operators in the q-CS classical limit. The q-analogue CS's minimize this uncertainty relation for moderate (absolute value of z)(exp 2).

  4. Synthesis of 4” manipulated Lewis X trisaccharide analogues

    PubMed Central

    Moore, Christopher J

    2012-01-01

    Summary Three analogues of the Lex trisaccharide antigen (β-D-Galp(1→4)[α-L-Fucp(1→3)]-D-GlcNAcp) in which the galactosyl residue is modified at O-4 as a methyloxy, deoxychloro or deoxyfluoro, were synthesized. We first report the preparation of the modified 4-OMe, 4-Cl and 4-F trichloroacetimidate galactosyl donors and then report their use in the glycosylation of an N-acetylglucosamine glycosyl acceptor. Thus, we observed that the reactivity of these donors towards the BF3·OEt2-promoted glycosylation at O-4 of the N-acetylglucosamine glycosyl acceptors followed the ranking 4-F > 4-OAc ≈ 4-OMe > 4-Cl. The resulting disaccharides were deprotected at O-3 of the glucosamine residue and fucosylated, giving access to the desired protected Lex analogues. One-step global deprotection (Na/NH3) of the protected 4”-methoxy analogue, and two-step deprotections (removal of a p-methoxybenzyl with DDQ, then Zemplén deacylation) of the 4”-deoxychloro and 4”-deoxyfluoro protected Lex analogues gave the desired compounds in good yields. PMID:23019441

  5. An Analysis of an Autoclitic Analogue in Pigeons

    ERIC Educational Resources Information Center

    Kuroda, Toshikazu; Lattal, Kennon A.; García-Penagos, Andrés

    2014-01-01

    Using a conditional discrimination procedure, pigeons were exposed to a nonverbal analogue of qualifying autoclitics such as "definitely" and "maybe." It has been suggested that these autoclitics are similar to tacts except that they are under the control of private discriminative stimuli. Instead of the conventional assumption…

  6. A Laboratory Analogue for the Study of Peer Sexual Harassment

    ERIC Educational Resources Information Center

    Mitchell, Damon; Hirschman, Richard; Angelone, D. J.; Lilly, Roy S.

    2004-01-01

    The purpose of this study was to develop a laboratory analogue for the study of peer sexual harassment, and to examine person and situational factors associated with male on female peer sexual harassment. One hundred twenty-two male participants were given the opportunity to tell jokes to a female confederate from a joke list that included…

  7. New phosphorus analogues of nitrogen classics--no carbon copies.

    PubMed

    Gudat, Dietrich

    2014-05-01

    Getting heavy: The recently prepared phosphorus analogues of two old acquaintances, urea and dinitrogen tetroxide, bear some structural resemblance to their archetypes but are no carbon copies. Their syntheses and chemical properties reveal rather certain peculiarities, which back the doctrine that the electronic properties of the heavier elements in a group differ from those of the lightest congener. PMID:24718995

  8. Non-robust numerical simulations of analogue extension experiments

    NASA Astrophysics Data System (ADS)

    Naliboff, John; Buiter, Susanne

    2016-04-01

    Numerical and analogue models of lithospheric deformation provide significant insight into the tectonic processes that lead to specific structural and geophysical observations. As these two types of models contain distinct assumptions and tradeoffs, investigations drawing conclusions from both can reveal robust links between first-order processes and observations. Recent studies have focused on detailed comparisons between numerical and analogue experiments in both compressional and extensional tectonics, sometimes involving multiple lithospheric deformation codes and analogue setups. While such comparisons often show good agreement on first-order deformation styles, results frequently diverge on second-order structures, such as shear zone dip angles or spacing, and in certain cases even on first-order structures. Here, we present finite-element experiments that are designed to directly reproduce analogue "sandbox" extension experiments at the cm-scale. We use material properties and boundary conditions that are directly taken from analogue experiments and use a Drucker-Prager failure model to simulate shear zone formation in sand. We find that our numerical experiments are highly sensitive to numerous numerical parameters. For example, changes to the numerical resolution, velocity convergence parameters and elemental viscosity averaging commonly produce significant changes in first- and second-order structures accommodating deformation. The sensitivity of the numerical simulations to small parameter changes likely reflects a number of factors, including, but not limited to, high angles of internal friction assigned to sand, complex, unknown interactions between the brittle sand (used as an upper crust equivalent) and viscous silicone (lower crust), highly non-linear strain weakening processes and poor constraints on the cohesion of sand. Our numerical-analogue comparison is hampered by (a) an incomplete knowledge of the fine details of sand failure and sand

  9. Natural analogue studies: present status and performance assessment implications

    NASA Astrophysics Data System (ADS)

    Smellie, John A. T.; Karlsson, Fred; Alexander, W. Russell

    1997-04-01

    Studies of natural geological and archaeological systems as analogues to long-term processes, which are predicted to occur within a radioactive waste repository environment, have become increasingly popular over the last 10 years or so, to the extent that such studies form an integral part of many national programmes for radioactive waste disposal. There is now a common consensus that the natural analogue approach is a very useful scientific methodology to: (a) identify and understand processes and mechanisms analogous to those which could occur in the vicinity of a repository over realistic timescales, (b) derive input data which have been successfully used to test some of the laboratory-based models which form the basis of long-term repository performance assessment, and (c) to produce data which can be input directly to performance assessment models. Increasingly, analogues are playing an important role in public awareness, enabling the layman to understand better the concept of radioactive disposal and demonstrating the reliability of the disposal system over long periods of geological time. The complexity of geological systems means that it is very often difficult and sometimes impossible to quantify precisely the physico-chemical boundary conditions necessary to model a particular geochemical process or mechanism. Consequently, the availability of quantitative analogue data is limited when repository performance assessments are considered. However, this in no way detracts from their value in building confidence by demonstrating that important processes do exist and by showing qualitatively that they behave in a way predicted by models based on laboratory-derived data. The transfer of natural analogue data from the complexity of field studies to simplistic models which, by necessity, are used in performance assessments, is an area of activity which is presently being addressed. Field analogue studies are now being planned to interface with laboratory

  10. Transition States and transition state analogue interactions with enzymes.

    PubMed

    Schramm, Vern L

    2015-04-21

    Enzymatic transition states have lifetimes of a few femtoseconds (fs). Computational analysis of enzyme motions leading to transition state formation suggests that local catalytic site motions on the fs time scale provide the mechanism to locate transition states. An experimental test of protein fs motion and its relation to transition state formation can be provided by isotopically heavy proteins. Heavy enzymes have predictable mass-altered bond vibration states without altered electrostatic properties, according to the Born-Oppenheimer approximation. On-enzyme chemistry is slowed in most heavy proteins, consistent with altered protein bond frequencies slowing the search for the transition state. In other heavy enzymes, structural changes involved in reactant binding and release are also influenced. Slow protein motions associated with substrate binding and catalytic site preorganization are essential to allow the subsequent fs motions to locate the transition state and to facilitate the efficient release of products. In the catalytically competent geometry, local groups move in stochastic atomic motion on the fs time scale, within transition state-accessible conformations created by slower protein motions. The fs time scale for the transition state motions does not permit thermodynamic equilibrium between the transition state and stable enzyme states. Isotopically heavy enzymes provide a diagnostic tool for fast coupled protein motions to transition state formation and mass-dependent conformational changes. The binding of transition state analogue inhibitors is the opposite in catalytic time scale to formation of the transition state but is related by similar geometries of the enzyme-transition state and enzyme-inhibitor interactions. While enzymatic transition states have lifetimes as short as 10(-15) s, transition state analogues can bind tightly to enzymes with release rates greater than 10(3) s. Tight-binding transition state analogues stabilize the rare but

  11. Biological evaluation of a novel sorafenib analogue, t-CUPM.

    PubMed

    Wecksler, Aaron T; Hwang, Sung Hee; Liu, Jun-Yan; Wettersten, Hiromi I; Morisseau, Christophe; Wu, Jian; Weiss, Robert H; Hammock, Bruce D

    2015-01-01

    Sorafenib (Nexavar®) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib.

  12. Cysteine analogues potentiate glucose-induced insulin release in vitro

    SciTech Connect

    Ammon, H.P.; Hehl, K.H.; Enz, G.; Setiadi-Ranti, A.; Verspohl, E.J.

    1986-12-01

    In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhance insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.

  13. Metric optimisation for analogue forecasting by simulated annealing

    NASA Astrophysics Data System (ADS)

    Bliefernicht, J.; Bárdossy, A.

    2009-04-01

    It is well known that weather patterns tend to recur from time to time. This property of the atmosphere is used by analogue forecasting techniques. They have a long history in weather forecasting and there are many applications predicting hydrological variables at the local scale for different lead times. The basic idea of the technique is to identify past weather situations which are similar (analogue) to the predicted one and to take the local conditions of the analogues as forecast. But the forecast performance of the analogue method depends on user-defined criteria like the choice of the distance function and the size of the predictor domain. In this study we propose a new methodology of optimising both criteria by minimising the forecast error with simulated annealing. The performance of the methodology is demonstrated for the probability forecast of daily areal precipitation. It is compared with a traditional analogue forecasting algorithm, which is used operational as an element of a hydrological forecasting system. The study is performed for several meso-scale catchments located in the Rhine basin in Germany. The methodology is validated by a jack-knife method in a perfect prognosis framework for a period of 48 years (1958-2005). The predictor variables are derived from the NCEP/NCAR reanalysis data set. The Brier skill score and the economic value are determined to evaluate the forecast skill and value of the technique. In this presentation we will present the concept of the optimisation algorithm and the outcome of the comparison. It will be also demonstrated how a decision maker should apply a probability forecast to maximise the economic benefit from it.

  14. Analogue Sites for Mars Missions - A report from two workshops

    NASA Astrophysics Data System (ADS)

    Hipkin, V.; Voytek, M. A.; Glamoclija, M.

    2014-12-01

    Fieldwork, at terrestrial sites that are analogous in some way to Mars, has a key role in defining questions addressed by Mars missions. For MSL, the question is whether its landing site was habitable, and for Mars 2020, the question is how do we search for and what are signs of life in ancient habitable environments. Implementing these investigations by means of a rover mission on a distant planetary surface has challenges due to a limited set of tools and period of operations. Using this context of planetary missions is important in shaping how analog research can be used to advance planetary science. Following a successful 2010 AGU fall meeting session entitled "Analogue Sites for Mars Missions", two community workshops were held at The Woodlands, TX March 2011 and the Carnegie Institute of Washington in July 2013. These activities represent an ongoing dialogue with the analogue and mission communities. The AGU session solicited presentations of current analogue research relevant to MSL, at which time the landing site selection process was still considering four final sites. The 2011 Woodlands workshop solicited details on representative science questions and analogue sites by means of an abstract template. The output from The Woodlands workshop was an initial metric to assess the utility of analogue sites against specific science questions, as well as recommendations for future activities. The 2013 Carnegie workshop, followed up on some of the recommendations from 2011. Both on-line interactive dialogue and in person discussions targeted broad topics, including 'the advantages and problems of using a great terrestrial analog for field testing', and 'knowing what we currently do about Mars, what would be the best place on the planet to collect the first suite of samples to be returned to Earth? What would be appropriate analog sites on Earth?'. The results and recommendations from both workshops are summarized to publicize and stimulate this ongoing discussion.

  15. A GLP-1 receptor agonist conjugated to an albumin-binding domain for extended half-life.

    PubMed

    Lindgren, Joel; Refai, Essam; Zaitsev, Sergei V; Abrahmsén, Lars; Berggren, Per-Olof; Karlström, Amelie Eriksson

    2014-05-01

    Glucagon-like peptide 1 (GLP-1) and related peptide agonists have been extensively investigated for glycaemic control in Type 2 diabetes, and may also have therapeutic applications for other diseases. Due to the short half-life (t1/2  < 2 min) of the endogenous peptide, caused by proteolytic degradation and renal clearance, different strategies for half-life extension and sustained release have been explored. In the present study, conjugates between a GLP-1 analogue and a 5 kDa albumin-binding domain (ABD) derived from streptococcal protein G have been chemically synthesized and evaluated. ABD binds with high affinity to human serum albumin, which is highly abundant in plasma and functions as a drug carrier in the circulation. Three different GLP-1-ABD conjugates, with the two peptides connected by linkers of two, four, and six PEG units, respectively, were synthesized and tested in mouse pancreatic islets at high (11 mM) and low (3 mM) glucose concentration. Insulin release upon stimulation was shown to be glucose-dependent, showing no significant difference between the three different GLP-1-ABD conjugates and unconjugated GLP-1 analogue. The biological activity, in combination with the high affinity binding to albumin, make the GLP-1-ABD conjugates promising GLP-1 receptor agonists expected to show extended in vivo half-life.

  16. Neuroprotective role of (Val8)GLP-1-Glu-PAL in an in vitro model of Parkinson's disease

    PubMed Central

    Li, Lin; Liu, Ke; Zhao, Juan; Holscher, Christian; Li, Guang-lai; Liu, Yue-ze

    2016-01-01

    The growth factor glucagon-like peptide-1 (GLP-1) is neuroprotective in several animal models of neurodegeneration. Here, we analyzed the neuroprotective effects of a novel protease-resistant GLP-1 analogue, (Val8)GLP-1-Glu-PAL, which has advantages over older analogues, such as improvement of hippocampal neurogenesis, glucose homeostasis, and insulin secretion. We established an in vitro model of Parkinson's disease using the mitochondrial stressor rotenone in primary cultured mouse neurons pretreated with (Val8)GLP-1-Glu-PAL. (Val8)GLP-1-Glu-PAL alone did not affect neuronal viability, but prevented the rotenone-induced reduction in cell viability in a dose-dependent manner. In addition, (Val8)GLP-1-Glu-PAL pretreatment prevented rotenone-induced proapoptotic changes manifesting as downregulation of procaspase-3 and Bcl-2 and upregulation of cleaved caspase-3. These results demonstrate that the novel agent (Val8)GLP-1-Glu-PAL shows promise as a drug treatment for Parkinson's disease. PMID:27073388

  17. An analogue conceptual rainfall-runoff model for educational purposes

    NASA Astrophysics Data System (ADS)

    Herrnegger, Mathew; Riedl, Michael; Schulz, Karsten

    2016-04-01

    Conceptual rainfall-runoff models, in which runoff processes are modelled with a series of connected linear and non-linear reservoirs, remain widely applied tools in science and practice. Additionally, the concept is appreciated in teaching due to its somewhat simplicity in explaining and exploring hydrological processes of catchments. However, when a series of reservoirs are used, the model system becomes highly parametrized and complex and the traceability of the model results becomes more difficult to explain to an audience not accustomed to numerical modelling. Since normally the simulations are performed with a not visible digital code, the results are also not easily comprehensible. This contribution therefore presents a liquid analogue model, in which a conceptual rainfall-runoff model is reproduced by a physical model. This consists of different acrylic glass containers representing different storage components within a catchment, e.g. soil water or groundwater storage. The containers are equipped and connected with pipes, in which water movement represents different flow processes, e.g. surface runoff, percolation or base flow. Water from a storage container is pumped to the upper part of the model and represents effective rainfall input. The water then flows by gravity through the different pipes and storages. Valves are used for controlling the flows within the analogue model, comparable to the parameterization procedure in numerical models. Additionally, an inexpensive microcontroller-based board and sensors are used to measure storage water levels, with online visualization of the states as time series data, building a bridge between the analogue and digital world. The ability to physically witness the different flows and water levels in the storages makes the analogue model attractive to the audience. Hands-on experiments can be performed with students, in which different scenarios or catchment types can be simulated, not only with the analogue but

  18. Bradykinin antagonists with dehydrophenylalanine analogues at position 5.

    PubMed

    Greiner, G; Dornberger, U; Paegelow, I; Schölkens, B A; Liebmann, C; Reissmann, S

    1998-04-01

    Continuing the studies on structural requirements of bradykinin antagonists, it has been found that analogues with dehydrophenylalanine (deltaPhe) or its ring-substituted analogues (deltaPhe(X)) at position 5 act as antagonists on guinea pig pulmonary artery, and on guinea pig ileum. Because both organs are considered to be bradykinin B2 receptor tissues, the analogues with deltaPhe or deltaPhe(X) at position 5, but without any replacement at position 7, seem to represent a new structural type of B2 receptor antagonist. All the analogues investigated act as partial antagonists; they inhibit the bradykinin-induced contraction at low concentrations and act as agonists at higher concentrations. Ring substitutions by methyl groups or iodine reduce both the agonistic and antagonistic activity. Only substitution by fluorine gives a high potency. Incorporation of deltaPhe into different representative antagonists with key modifications at position 7 does not enhance the antagonist activity of the basic structures, with one exception. Only the combination of deltaPhe at position 5 with DPhe at position 7 increases the antagonistic potency on guinea pig ileum by about one order of magnitude. Radioligand binding studies indicate the importance of position 5 for the discrimination of B2 receptor subtypes. The binding affinity to the low-affinity binding site (KL) was not significantly changed by replacement of Phe by deltaPhe. In contrast, ring-methylation of deltaPhe results in clearly reduced binding to KL. The affinity to the high-affinity binding site (KH) was almost unchanged by the replacement of Phe in position 5 by deltaPhe, whereas the analogue with 2-methyl-dehydrophenylalanine completely failed to detect the KH-site. The peptides were synthesized on the Wang-resin according to the Fmoc/Bu(t) strategy using Mtr protection for the side chain of Arg. The dehydrophenylalanine analogues were prepared by a strategy involving PyBop couplings of the dipeptide unit Fmoc

  19. Hydroxamate-based iron chelators: combinatorial syntheses of desferrioxamine B analogues and evaluation of binding affinities.

    PubMed

    Poreddy, Amruta R; Schall, Otto F; Osiek, Todd A; Wheatley, James R; Beusen, Denise D; Marshall, Garland R; Slomczynska, Urszula

    2004-01-01

    This article describes the solid-phase combinatorial methods developed for the synthesis of polyhydroxamate-based siderophores. This strategy was applied to generate several libraries of structural DFO (1a) analogues that include DFO variants, non-amide analogues, C-terminal modified analogues, reverse-amide analogues, and hybrid analogues. To assess the relative iron-binding affinities of these compounds, a high-throughput spectrophotometric screening method based on competition with 8-hydroxyquinoline-5-sulfonic acid was developed. Some of the promising candidates containing various terminal functional groups were identified and prepared on large scale to enable future studies in animal models for iron-overload diseases.

  20. Design and synthesis of analogues of natural products.

    PubMed

    Maier, Martin E

    2015-05-21

    In this article strategies for the design and synthesis of natural product analogues are summarized and illustrated with some selected examples. Proven strategies include diverted total synthesis (DTS), function-oriented synthesis (FOS), biology-oriented synthesis (BIOS), complexity to diversity (CtD), hybrid molecules, and biosynthesis inspired synthesis. The latter includes mutasynthesis, the synthesis of natural products encoded by silent genes, and propionate scanning. Most of the examples from our group fall in the quite general concept of DTS. Thus, in case an efficient strategy to a natural product is at hand, modifications are possible at almost any stage of a synthesis. However, even for compounds of moderate complexity, organic synthesis remains a bottle neck. Unless some method for predicting the biological activity of a designed molecule becomes available, the design and synthesis of natural product analogues will remain what it is now, namely it will largely rely on trial and error. PMID:25829247

  1. All-dielectric metasurface analogue of electromagnetically induced transparency

    NASA Astrophysics Data System (ADS)

    Yang, Yuanmu; Kravchenko, Ivan I.; Briggs, Dayrl P.; Valentine, Jason

    2014-12-01

    Metasurface analogues of electromagnetically induced transparency (EIT) have been a focus of the nanophotonics field in recent years, due to their ability to produce high-quality factor (Q-factor) resonances. Such resonances are expected to be useful for applications such as low-loss slow-light devices and highly sensitive optical sensors. However, ohmic losses limit the achievable Q-factors in conventional plasmonic EIT metasurfaces to values <~10, significantly hampering device performance. Here we experimentally demonstrate a classical analogue of EIT using all-dielectric silicon-based metasurfaces. Due to extremely low absorption loss and coherent interaction of neighbouring meta-atoms, a Q-factor of 483 is observed, leading to a refractive index sensor with a figure-of-merit of 103. Furthermore, we show that the dielectric metasurfaces can be engineered to confine the optical field in either the silicon resonator or the environment, allowing one to tailor light-matter interaction at the nanoscale.

  2. Analogue Transformations in Physics and their Application to Acoustics

    PubMed Central

    García-Meca, C.; Carloni, S.; Barceló, C.; Jannes, G.; Sánchez-Dehesa, J.; Martínez, A.

    2013-01-01

    Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in diffe