Physiology and emerging biochemistry of the glucagon-like peptide-1 receptor.

PubMed

Willard, Francis S; Sloop, Kyle W

2012-01-01

The glucagon-like peptide-1 (GLP-1) receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM). Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational approaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article reviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular strategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor activators.

Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor

PubMed Central

Willard, Francis S.; Sloop, Kyle W.

2012-01-01

The glucagon-like peptide-1 (GLP-1) receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM). Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational approaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article reviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular strategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor activators. PMID:22666230

Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor.

PubMed

Underwood, Christina Rye; Garibay, Patrick; Knudsen, Lotte Bjerre; Hastrup, Sven; Peters, Günther H; Rudolph, Rainer; Reedtz-Runge, Steffen

2010-01-01

GLP-1 (glucagon-like peptide-1) is an incretin released from intestinal L-cells in response to food intake. Activation of the GLP-1 receptor potentiates the synthesis and release of insulin from pancreatic beta-cells in a glucose-dependent manner. The GLP-1 receptor belongs to class B of the G-protein-coupled receptors, a subfamily characterized by a large N-terminal extracellular ligand binding domain. Exendin-4 and GLP-1 are 50% identical, and exendin-4 is a full agonist with similar affinity and potency for the GLP-1 receptor. We recently solved the crystal structure of the GLP-1 receptor extracellular domain in complex with the competitive antagonist exendin-4(9-39). Interestingly, the isolated extracellular domain binds exendin-4 with much higher affinity than the endogenous agonist GLP-1. Here, we have solved the crystal structure of the extracellular domain in complex with GLP-1 to 2.1 Aresolution. The structure shows that important hydrophobic ligand-receptor interactions are conserved in agonist- and antagonist-bound forms of the extracellular domain, but certain residues in the ligand-binding site adopt a GLP-1-specific conformation. GLP-1 is a kinked but continuous alpha-helix from Thr(13) to Val(33) when bound to the extracellular domain. We supplemented the crystal structure with site-directed mutagenesis to link the structural information of the isolated extracellular domain with the binding properties of the full-length receptor. The data support the existence of differences in the binding modes of GLP-1 and exendin-4 on the full-length GLP-1 receptor.

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. Copyright © 2016 Elsevier Ltd. All rights reserved.

Negative Energy Balance Blocks Neural and Behavioral Responses to Acute Stress by "Silencing" Central Glucagon-Like Peptide 1 Signaling in Rats.

PubMed

Maniscalco, James W; Zheng, Huiyuan; Gordon, Patrick J; Rinaman, Linda

2015-07-29

Previous reports indicate that caloric restriction attenuates anxiety and other behavioral responses to acute stress, and blunts the ability of stress to increase anterior pituitary release of adrenocorticotropic hormone. Since hindbrain glucagon-like peptide-1 (GLP-1) neurons and noradrenergic prolactin-releasing peptide (PrRP) neurons participate in behavioral and endocrine stress responses, and are sensitive to the metabolic state, we examined whether overnight food deprivation blunts stress-induced recruitment of these neurons and their downstream hypothalamic and limbic forebrain targets. A single overnight fast reduced anxiety-like behavior assessed in the elevated-plus maze and acoustic startle test, including marked attenuation of light-enhanced startle. Acute stress [i.e., 30 min restraint (RES) or 5 min elevated platform exposure] robustly activated c-Fos in GLP-1 and PrRP neurons in fed rats, but not in fasted rats. Fasting also significantly blunted the ability of acute stress to activate c-Fos expression within the anterior ventrolateral bed nucleus of the stria terminalis (vlBST). Acute RES stress suppressed dark-onset food intake in rats that were fed ad libitum, whereas central infusion of a GLP-1 receptor antagonist blocked RES-induced hypophagia, and reduced the ability of RES to activate PrRP and anterior vlBST neurons in ad libitum-fed rats. Thus, an overnight fast "silences" GLP-1 and PrRP neurons, and reduces both anxiety-like and hypophagic responses to acute stress. The partial mimicking of these fasting-induced effects in ad libitum-fed rats after GLP-1 receptor antagonism suggests a potential mechanism by which short-term negative energy balance attenuates neuroendocrine and behavioral responses to acute stress. The results from this study reveal a potential central mechanism for the "metabolic tuning" of stress responsiveness. A single overnight fast, which markedly reduces anxiety-like behavior in rats, reduces or blocks the ability of

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Short-term and long-term effects of guar on postprandial plasma glucose, insulin and glucagon-like peptide 1 concentration in healthy rats.

PubMed

Prieto, P G; Cancelas, J; Villanueva-Peñacarrillo, M L; Malaisse, W J; Valverde, I

2006-06-01

Ingestion of guar gum decreases postprandial glycemia and insulinemia and improves sensitivity to insulin in diabetic patients and several animal models of diabetes. The aim of the present study was to compare the short-term and long-term effects of guar on plasma insulin and glucagon-like peptide 1 concentration in healthy rats. In the short-term experiments, the concomitant intragastric administration of glucose and guar reduced the early increment in plasma glucose, insulin and glucagon-like peptide 1 concentration otherwise induced by glucose alone. Comparable findings were made after twelve days of meal training exposing the rats to either a control or guar-enriched diet for fifteen minutes. Mean plasma glucose concentrations were lower while mean insulin concentrations were higher in the guar group than in the controls according to intragastric glucose tolerance tests conducted in overnight fasted rats maintained for 19 to 36 days on either the control or guar-enriched diet. The intestinal content of glucagon-like peptide 1 at the end of the experiments was also lower in the guar group. Changes in body weight over 62 days of observation were comparable in the control and guar rats. Thus, long-term intake of guar improves glucose tolerance and insulin response to glucose absorption, without improving insulin sensitivity, in healthy rats.

Crystal Structure of Glucagon-like Peptide-1 in Complex with the Extracellular Domain of the Glucagon-like Peptide-1 Receptor*

PubMed Central

Underwood, Christina Rye; Garibay, Patrick; Knudsen, Lotte Bjerre; Hastrup, Sven; Peters, Günther H.; Rudolph, Rainer; Reedtz-Runge, Steffen

2010-01-01

GLP-1 (glucagon-like peptide-1) is an incretin released from intestinal L-cells in response to food intake. Activation of the GLP-1 receptor potentiates the synthesis and release of insulin from pancreatic β-cells in a glucose-dependent manner. The GLP-1 receptor belongs to class B of the G-protein-coupled receptors, a subfamily characterized by a large N-terminal extracellular ligand binding domain. Exendin-4 and GLP-1 are 50% identical, and exendin-4 is a full agonist with similar affinity and potency for the GLP-1 receptor. We recently solved the crystal structure of the GLP-1 receptor extracellular domain in complex with the competitive antagonist exendin-4(9–39). Interestingly, the isolated extracellular domain binds exendin-4 with much higher affinity than the endogenous agonist GLP-1. Here, we have solved the crystal structure of the extracellular domain in complex with GLP-1 to 2.1 Åresolution. The structure shows that important hydrophobic ligand-receptor interactions are conserved in agonist- and antagonist-bound forms of the extracellular domain, but certain residues in the ligand-binding site adopt a GLP-1-specific conformation. GLP-1 is a kinked but continuous α-helix from Thr13 to Val33 when bound to the extracellular domain. We supplemented the crystal structure with site-directed mutagenesis to link the structural information of the isolated extracellular domain with the binding properties of the full-length receptor. The data support the existence of differences in the binding modes of GLP-1 and exendin-4 on the full-length GLP-1 receptor. PMID:19861722

Effects of gastric inhibitory polypeptide, glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists on Bone Cell Metabolism.

PubMed

Hansen, Morten S S; Tencerova, Michaela; Frølich, Jacob; Kassem, Moustapha; Frost, Morten

2018-01-01

The relationship between gut and skeleton is increasingly recognized as part of the integrated physiology of the whole organism. The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestine in response to nutrient intake and exhibit several physiological functions including regulation of islet hormone secretion and glucose levels. A number of GLP-1 receptor agonists (GLP-1RAs) are currently used in treatment of type 2 diabetes and obesity. However, GIP and GLP-1 cognate receptors are widely expressed suggesting that incretin hormones mediate effects beyond control of glucose homeostasis, and reports on associations between incretin hormones and bone metabolism have emerged. The aim of this MiniReview was to provide an overview of current knowledge regarding the in vivo and in vitro effects of GIP and GLP-1 on bone metabolism. We identified a total of 30 pre-clinical and clinical investigations of the effects of GIP, GLP-1 and GLP-1RAs on bone turnover markers, bone mineral density (BMD), bone microarchitecture and fracture risk. Studies conducted in cell cultures and rodents demonstrated that GIP and GLP-1 play a role in regulating skeletal homeostasis, with pre-clinical data suggesting that GIP inhibits bone resorption whereas GLP-1 may promote bone formation and enhance bone material properties. These effects are not corroborated by clinical studies. While there is evidence of effects of GIP and GLP-1 on bone metabolism in pre-clinical investigations, clinical trials are needed to clarify whether similar effects are present and clinically relevant in humans. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

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. © FASEB.

Negative Energy Balance Blocks Neural and Behavioral Responses to Acute Stress by “Silencing” Central Glucagon-Like Peptide 1 Signaling in Rats

PubMed Central

Maniscalco, James W.; Zheng, Huiyuan; Gordon, Patrick J.

2015-01-01

Previous reports indicate that caloric restriction attenuates anxiety and other behavioral responses to acute stress, and blunts the ability of stress to increase anterior pituitary release of adrenocorticotropic hormone. Since hindbrain glucagon-like peptide-1 (GLP-1) neurons and noradrenergic prolactin-releasing peptide (PrRP) neurons participate in behavioral and endocrine stress responses, and are sensitive to the metabolic state, we examined whether overnight food deprivation blunts stress-induced recruitment of these neurons and their downstream hypothalamic and limbic forebrain targets. A single overnight fast reduced anxiety-like behavior assessed in the elevated-plus maze and acoustic startle test, including marked attenuation of light-enhanced startle. Acute stress [i.e., 30 min restraint (RES) or 5 min elevated platform exposure] robustly activated c-Fos in GLP-1 and PrRP neurons in fed rats, but not in fasted rats. Fasting also significantly blunted the ability of acute stress to activate c-Fos expression within the anterior ventrolateral bed nucleus of the stria terminalis (vlBST). Acute RES stress suppressed dark-onset food intake in rats that were fed ad libitum, whereas central infusion of a GLP-1 receptor antagonist blocked RES-induced hypophagia, and reduced the ability of RES to activate PrRP and anterior vlBST neurons in ad libitum-fed rats. Thus, an overnight fast “silences” GLP-1 and PrRP neurons, and reduces both anxiety-like and hypophagic responses to acute stress. The partial mimicking of these fasting-induced effects in ad libitum-fed rats after GLP-1 receptor antagonism suggests a potential mechanism by which short-term negative energy balance attenuates neuroendocrine and behavioral responses to acute stress. SIGNIFICANCE STATEMENT The results from this study reveal a potential central mechanism for the “metabolic tuning” of stress responsiveness. A single overnight fast, which markedly reduces anxiety-like behavior in rats

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

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

USDA-ARS?s Scientific Manuscript database

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...

Cell-based delivery of glucagon-like peptide-1 using encapsulated mesenchymal stem cells.

PubMed

Wallrapp, Christine; Thoenes, Eric; Thürmer, Frank; Jork, Anette; Kassem, Moustapha; Geigle, Peter

2013-01-01

Glucagon-like peptide-1 (GLP-1) CellBeads are cell-based implants for the sustained local delivery of bioactive factors. They consist of GLP-1 secreting mesenchymal stem cells encapsulated in a spherically shaped immuno-isolating alginate matrix. A highly standardized and reproducible encapsulation method is described for the manufacturing of homogeneous CellBeads. Viability and sustained secretion was shown for the recombinant GLP-1 and the cell endogenous bioactive factors like vascular endothelial growth factor, neurotrophin 3 (NT-3) and glial cell line-derived neurotrophic factor. Manufacturing and quality control is performed in compliance with good manufacturing practice and fulfils all regulatory requirements for human clinical use. GLP-1 CellBeads combine the neuro- and cardioprotective properties of both GLP-1 and mesenchymal stem cells. First promising results were obtained from preclinical studies and an ongoing safety trial in humans but further studies have to prove the overall potential of CellBead technology in cell-based regenerative medicine.

Unique roles of glucagon and glucagon-like peptides: Parallels in understanding the functions of adipokinetic hormones in stress responses in insects.

PubMed

Bednářová, Andrea; Kodrík, Dalibor; Krishnan, Natraj

2013-01-01

Glucagon is conventionally regarded as a hormone, counter regulatory in function to insulin and plays a critical anti-hypoglycemic role by maintaining glucose homeostasis in both animals and humans. Glucagon performs this function by increasing hepatic glucose output to the blood by stimulating glycogenolysis and gluconeogenesis in response to starvation. Additionally it plays a homeostatic role by decreasing glycogenesis and glycolysis in tandem to try and maintain optimal glucose levels. To perform this action, it also increases energy expenditure which is contrary to what one would expect and has actions which are unique and not entirely in agreement with its role in protection from hypoglycemia. Interestingly, glucagon-like peptides (GLP-1 and GLP-2) from the major fragment of proglucagon (in non-mammalian vertebrates, as well as in mammals) may also modulate response to stress in addition to their other physiological actions. These unique modes of action occur in response to psychological, metabolic and other stress situations and mirror the role of adipokinetic hormones (AKHs) in insects which perform a similar function. The findings on the anti-stress roles of glucagon and glucagon-like peptides in mammalian and non-mammalian vertebrates may throw light on the multiple stress responsive mechanisms which operate in a concerted manner under regulation by AKH in insects thus functioning as a stress responsive hormone while also maintaining organismal homeostasis. Copyright © 2012 Elsevier Inc. All rights reserved.

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

USDA-ARS?s Scientific Manuscript database

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...

Identification and localization of glucagon-related peptides in rat brain.

PubMed

Tager, H; Hohenboken, M; Markese, J; Dinerstein, R J

1980-10-01

Immunochemical and immunocytochemical techniques have been used to identify and characterize glucagon-related peptides of the rat central nervous system. These peptides show immunoreactivity with antiglucagon sera directed towards the central portion of the hormone, but not with antisera specific for the free COOH terminus of glucagon. Highest concentrations were found in hypothalamus (6.1 +/- 1.6 ng/g wet weight) although lower amounts (approximately 2 ng/g) were found in cortex, thalamus, cerebellum, and brain stem. Gel filtration of brain extracts revealed at least two immunoreactive forms, which have molecular weights of about 12,000 and 8000. Both peptides had radioimmunoassay dilution curves parallel to the curve for glucagon and both had identical counterparts in extracts of rat intestine. Digestion of the brain and intestinal peptides with trypsin plus carboxypeptidase B released the immunoreactive COOH-terminal tryptic fragment of pancreatic glucagon from these larger forms. Immunocytochemical studies using antiglucagon serum and peroxidase-antiperoxidase staining identified glucagon-like material in neuronal cell bodie and processes in the magnocellular portion of the paraventricular nucleus, as well as in scattered cells in the supraoptic nucleus and in fibers in the median eminence. These results suggest that glucagon-containing peptides that have undergone the intestinal type of posttranslational modification are present in neuronal cells of the rat hypothalamus.

Glucagon like peptide-1 and its receptor agonists: Their roles in management of Type 2 diabetes mellitus.

PubMed

Gupta, Ankit; Jelinek, Herbert F; Al-Aubaidy, Hayder

This study summarizes major work which investigated the roles of glucagon like peptide-1 (GLP-1) and its receptor (GLP-1R); the use of GLP-1-R agonists and dipeptidyl peptidase 4 inhibitor in the management of type 2 diabetes mellitus. It focuses on the recent therapeutic development which has occurred in this field, and also discusses the potential treatments which can be discovered and implemented in the near future to design an effective therapy for type 2 diabetes mellitus. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Simultaneous quantification of intracellular and secreted active and inactive glucagon-like peptide-1 from cultured cells.

PubMed

Amao, Michiko; Kitahara, Yoshiro; Tokunaga, Ayaka; Shimbo, Kazutaka; Eto, Yuzuru; Yamada, Naoyuki

2015-03-01

Glucagon-like peptide-1 (GLP-1) is an incretin peptide that regulates islet hormone secretion. During recent years, incretin-based therapies have been widely used for patients with type 2 diabetes. GLP-1 peptides undergo N- and C-terminal processing for gain or loss of functions. We developed a method to quantify picomolar quantities of intact GLP-1 peptides using liquid chromatography-tandem mass spectrometry (LC-MS/MS). By employing this label-free selected reaction monitoring (SRM) method, we were able to analyze secreted GLP-1(1-37), GLP-1(7-37), and GLP-1(7-36 amid from human enteroendocrine NCI-H716 cells after stimulation with nateglinide, glucose, and sucralose. The absolute total concentrations of secreted GLP-1 peptides at baseline and after stimulation with nateglinide, glucose, and sucralose were 167.3, 498.9, 238.3, and 143.1 pM, respectively. Meanwhile, the ratios of GLP-1(1-37), GLP-1(7-37), and GLP-1(7-36 amide) to total GLP-1 peptides were similar (6 ± 3, 26 ± 3, and 78 ± 5%, respectively). The SRM assay can analyze the concentrations of individual GLP-1 peptides and, therefore, is a tool to investigate the physiological roles of GLP-1 peptides. Furthermore, the molecular species secreted from NCI-H716 cells were unknown. Therefore, we performed a secretopeptidome analysis of supernatants collected from cultured NCI-H716 cells. Together with GLP-1 peptides, we detected neuroendocrine convertase 1, which regulates peptide hormones released from intestinal endocrine L-cells. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparison Review of Short-Acting and Long-Acting Glucagon-like Peptide-1 Receptor Agonists.

PubMed

Uccellatore, Annachiara; Genovese, Stefano; Dicembrini, Ilaria; Mannucci, Edoardo; Ceriello, Antonio

2015-09-01

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) are useful tools for treating type 2 diabetes mellitus. In their recent position statement, the American Diabetes Association and European Association for the Study of Diabetes recommend GLP1-RAs as add-on to metformin when therapeutic goals are not achieved with monotherapy, particularly for patients who wish to avoid weight gain or hypoglycemia. GLP1-RAs differ substantially in their duration of action, frequency of administration and clinical profile. Members of this class approved for clinical use include exenatide twice-daily, exenatide once-weekly, liraglutide and lixisenatide once-daily. Recently, two new once-weekly GLP1-RAs have been approved: dulaglutide and albiglutide. This article summarizes properties of short- and long-acting GLP-1 analogs, and provides useful information to help choose the most appropriate compound for individual patients.

[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.

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

USDA-ARS?s Scientific Manuscript database

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...

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

USDA-ARS?s Scientific Manuscript database

Damage to the intestinal epithelium caused by diarrhea reduces nutrient absorption and growth rate, and may have long-term effects on the young animal. Glucagon-like peptide 2 (GLP-2) is an intestinotropic hormone that improves gut integrity and nutrient absorption, and has antioxidant effects in th...

Rapid Tachyphylaxis of the Glucagon-Like Peptide 1–Induced Deceleration of Gastric Emptying in Humans

PubMed Central

Nauck, Michael A.; Kemmeries, Guido; Holst, Jens J.; Meier, Juris J.

2011-01-01

OBJECTIVE Glucagon-like peptide (GLP)-1 lowers postprandial glycemia primarily through inhibition of gastric emptying. We addressed whether the GLP-1–induced deceleration of gastric emptying is subject to rapid tachyphylaxis and if so, how this would alter postprandial glucose control. RESEARCH DESIGN AND METHODS Nine healthy volunteers (25 ± 4 years old, BMI: 24.6 ± 4.7 kg/m2) were examined with intravenous infusion of GLP-1 (0.8 pmol · kg−1 . min−1) or placebo over 8.5 h. Two liquid mixed meals were administered at a 4-h interval. Gastric emptying was determined, and blood samples were drawn frequently. RESULTS GLP-1 decelerated gastric emptying significantly more after the first meal compared with the second meal (P = 0.01). This was associated with reductions in pancreatic polypeptide levels (marker of vagal activation) after the first but not the second meal (P < 0.05). With GLP-1, glucose concentrations declined after the first meal but increased after the second meal (P < 0.05). The GLP-1–induced reductions in postprandial insulin and C-peptide levels were stronger during the first meal course (P < 0.05). Likewise, glucagon levels were lowered by GLP-1 after the first meal but increased after the second test meal (P < 0.05). CONCLUSIONS The GLP-1–induced delay in gastric emptying is subject to rapid tachyphylaxis at the level of vagal nervous activation. As a consequence, postprandial glucose control by GLP-1 is attenuated after its chronic administration. PMID:21430088

Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity

PubMed Central

Anandhakrishnan, Ananthi; Korbonits, Márta

2016-01-01

Though the pathophysiology of clinical obesity is undoubtedly multifaceted, several lines of clinical evidence implicate an important functional role for glucagon-like peptide 1 (GLP-1) signalling. Clinical studies assessing GLP-1 responses in normal weight and obese subjects suggest that weight gain may induce functional deficits in GLP-1 signalling that facilitates maintenance of the obesity phenotype. In addition, genetic studies implicate a possible role for altered GLP-1 signalling as a risk factor towards the development of obesity. As reductions in functional GLP-1 signalling seem to play a role in clinical obesity, the pharmacological replenishment seems a promising target for the medical management of obesity in clinical practice. GLP-1 analogue liraglutide at a high dose (3 mg/d) has shown promising results in achieving and maintaining greater weight loss in obese individuals compared to placebo control, and currently licensed anti-obesity medications. Generally well tolerated, provided that longer-term data in clinical practice supports the currently available evidence of superior short- and long-term weight loss efficacy, GLP-1 analogues provide promise towards achieving the successful, sustainable medical management of obesity that remains as yet, an unmet clinical need. PMID:28031776

[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. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

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

PubMed

Chatterjee, Sanjay; Ghosal, Samit; Chatterjee, Saurav

2016-10-15

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.

Pharmacology of the glucagon-like peptide-1 analog exenatide extended-release in healthy cats.

PubMed

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

2015-04-01

Exenatide extended-release (ER) is a microencapsulated formulation of the glucagon-like peptide 1-receptor agonist exenatide. It has a protracted pharmacokinetic profile that allows a once-weekly injection with comparable efficacy to insulin with an improved safety profile in type II diabetic people. Here, we studied the pharmacology of exenatide ER in 6 healthy cats. A single subcutaneous injection of exenatide ER (0.13 mg/kg) was administered on day 0. Exenatide concentrations were measured for 12 wk. A hyperglycemic clamp (target = 225 mg/dL) was performed on days -7 (clamp I) and 21 (clamp II) with measurements of insulin and glucagon concentrations. Glucose tolerance was defined as the amount of glucose required to maintain hyperglycemia during the clamp. Continuous glucose monitoring was performed on weeks 0, 2, and 6 after injection. Plasma concentrations of exenatide peaked at 1 h and 4 wk after injection. Comparing clamp I with clamp II, fasting blood glucose decreased (mean ± standard deviation = -11 ± 8 mg/dL, P = 0.02), glucose tolerance improved (median [range] +33% [4%-138%], P = 0.04), insulin concentrations increased (+36.5% [-9.9% to 274.1%], P = 0.02), and glucagon concentrations decreased (-4.7% [0%-12.1%], P = 0.005). Compared with preinjection values on continuous glucose monitoring, glucose concentrations decreased and the frequency of readings <50 mg/dL increased at 2 and 6 wk after injection of exenatide ER. This did not correspond to clinical hypoglycemia. No other side effects were observed throughout the study. Exenatide ER was safe and effective in improving glucose tolerance 3 wk after a single injection. Further evaluation is needed to determine its safety, efficacy, and duration of action in diabetic cats. Copyright © 2015 Elsevier Inc. All rights reserved.

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

USDA-ARS?s Scientific Manuscript database

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...

Short communication: expression of peptide YY, proglucagon, neuropeptide Y receptor Y2, and glucagon-like peptide-1 receptor in bovine peripheral tissues.

PubMed

Pezeshki, A; Muench, G P; Chelikani, P K

2012-09-01

The role of distal gut signals in control of feed intake and metabolism in cattle has received scant attention. Peptide YY (PYY) and glucagon-like peptide-1, which are secreted from enteroendocrine cells of the distal gut in monogastrics have several functions, including regulation of energy balance. However, little is known of the tissue expression of these peptides and their receptors in cattle. The aim of the current study was to characterize the tissue distribution of PYY, neuropeptide Y receptor Y2 (Y2), proglucagon (GCG), and glucagon-like peptide-1 receptor (GLP1R) in various peripheral tissues of cattle. Four male 7-wk-old dairy calves were euthanized and 16 peripheral tissues were collected. Conventional PCR and quantitative real-time PCR were performed to confirm tissue expression and quantify the transcript abundance in various tissues. The results of conventional PCR revealed that mRNA for both PYY and Y2 was detectable in the rumen, abomasum, duodenum, jejunum, ileum, and colon but not in other tissues. Quantitative real-time PCR data demonstrated that PYY mRNA was 2- to 3-fold greater in the pancreas, kidney, and heart relative to the liver. By conventional PCR, GCG mRNA was detected in the abomasum, duodenum, jejunum, ileum, and colon and GLP1R mRNA was expressed in all gut segments, pancreas, spleen, and kidney. Quantitative real-time PCR data demonstrated that, relative to transcript abundance in the liver, GCG mRNA was 4- to 40-fold higher from abomasum to colon, and GLP1R mRNA was 50- to 300-fold higher from the rumen to colon, 14-fold greater in the pancreas, 18-fold higher in the spleen, and 166-fold greater in the kidney. The tissue distribution of PYY, GCG, and their receptors observed in the current study is, in general, consistent with expression patterns in monogastrics. The predominant expression of PYY, Y2, and GCG in the gut, and the presence of GLP1R in multiple peripheral tissues suggest a role for PYY in controlling gut functions and

Glucagon-related peptides and the regulation of food intake in chickens.

PubMed

Honda, Kazuhisa

2016-09-01

The regulatory mechanisms underlying food intake in chickens have been a focus of research in recent decades to improve production efficiency when raising chickens. Lines of evidence have revealed that a number of brain-gut peptides function as a neurotransmitter or peripheral satiety hormone in the regulation of food intake both in mammals and chickens. Glucagon, a 29 amino acid peptide hormone, has long been known to play important roles in maintaining glucose homeostasis in mammals and birds. However, the glucagon gene encodes various peptides that are produced by tissue-specific proglucagon processing: glucagon is produced in the pancreas, whereas oxyntomodulin (OXM), glucagon-like peptide (GLP)-1 and GLP-2 are produced in the intestine and brain. Better understanding of the roles of these peptides in the regulation of energy homeostasis has led to various physiological roles being proposed in mammals. For example, GLP-1 functions as an anorexigenic neurotransmitter in the brain and as a postprandial satiety hormone in the peripheral circulation. There is evidence that OXM and GLP-2 also induce anorexia in mammals. Therefore, it is possible that the brain-gut peptides OXM, GLP-1 and GLP-2 play physiological roles in the regulation of food intake in chickens. More recently, a novel GLP and its specific receptor were identified in the chicken brain. This review summarizes current knowledge about the role of glucagon-related peptides in the regulation of food intake in chickens. © 2016 The Authors. Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.

Individually timing high-protein preloads has no effect on daily energy intake, peptide YY and glucagon-like peptide-1.

PubMed

Willbond, S M; Doucet, É

2011-01-01

Gut hormones have been shown to influence energy intake (EI). To our knowledge, no study has investigated the effects of dietary patterns aimed at optimizing fullness on EI, appetite and gut hormones. To determine whether individually timing high-protein preloads would impact EI, appetite, and peptide YY and glucagon-like peptide-1 (GLP-1) levels. Ten men (body mass index = 25.5 ± 2.6 kg/m(2)) participated in a randomized crossover trial. The three conditions consisted of the self-selection of snacks (condition 1), or the consumption of a preload (300 kcal: 40% protein, 40% carbohydrates and 20% fat) at either 15 min (condition 2) or ∼ 50 min (individually set) (condition 3) before lunch and dinner. During each condition, a standardized breakfast was served, whereas lunch and dinner were self-selected from a five-item menu, and eaten ad libitum. Mealtime and daily EI were measured. Appetite, peptide YY and GLP-1 were sampled over 9 h. No differences in daily EI were noted across conditions (1 = 3078 ± 720 kcal; 2 = 2929 ± 264 kcal; 3 = 2998 ± 437 kcal; not significant). For the most part, daily profiles as well as premeal levels of peptide YY and GLP-1 were not different between conditions. Desire to eat, hunger and prospective food consumption were found to be lowest during condition 1 (P < 0.05). According to these results, it would seem that individually timing high-protein preloads does not reduce daily EI in healthy human subjects.

Truncated Glucagon-like Peptide-1 and Exendin-4 α-Conotoxin pl14a Peptide Chimeras Maintain Potency and α-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro*

PubMed Central

Swedberg, Joakim E.; Schroeder, Christina I.; Mitchell, Justin M.; Fairlie, David P.; Edmonds, David J.; Griffith, David A.; Ruggeri, Roger B.; Derksen, David R.; Loria, Paula M.; Price, David A.; Liras, Spiros; Craik, David J.

2016-01-01

Glucagon-like peptide-1 (GLP-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with an extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N-terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP-1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide α-conotoxin pl14a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fractional helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C-terminal helical segment (residues 22–27) directing the binding of Phe22 into a hydrophobic pocket on the GLP-1R. PMID:27226591

Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors.

PubMed

Sirohi, Sunil; Schurdak, Jennifer D; Seeley, Randy J; Benoit, Stephen C; Davis, Jon F

2016-07-01

Recent data implicate glucagon-like peptide-1 (GLP-1), a potent anorexigenic peptide released in response to nutrient intake, as a regulator for the reinforcing properties of food, alcohol and psychostimulants. While, both central and peripheral mechanisms mediate effects of GLP-1R signaling on food intake, the extent to which central or peripheral GLP-1R signaling regulates reinforcing properties of drugs of abuse is unknown. Here, we examined amphetamine reinforcement, alcohol intake and hedonic feeding following peripheral administration of EX-4 (a GLP-1 analog) in FLOX and GLP-1R KD(Nestin) (GLP-1R selectively ablated from the central nervous system) mice (n=13/group). First, the effect of EX-4 pretreatment on the expression of amphetamine-induced conditioned place preference (Amp-CPP) was examined in the FLOX and GLP-1R KD(Nestin) mice. Next, alcohol intake (10% v/v) was evaluated in FLOX and GLP-1R KD(Nestin) mice following saline or EX-4 injections. Finally, we assessed the effects of EX-4 pretreatment on hedonic feeding behavior. Results indicate that Amp-CPP was completely blocked in the FLOX mice, but not in the GLP-1R KD(Nestin) mice following EX-4 pretreatment. Ex-4 pretreatment selectively blocked alcohol consumption in the FLOX mice, but was ineffective in altering alcohol intake in the GLP-1R KD(Nestin) mice. Notably, hedonic feeding was partially blocked in the GLP-1R KD(Nestin) mice, whereas it was abolished in the FLOX mice. The present study provides critical insights regarding the nature by which GLP-1 signaling controls reinforced behaviors and underscores the importance of both peripheral and central GLP-1R signaling for the regulation of addictive disorders. Copyright © 2016. Published by Elsevier Inc.

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.

Adjunctive Role of Glucagon-Like Peptide-1 Receptor Agonists in the Management of Type 1 Diabetes Mellitus.

PubMed

Harris, Kira B; Boland, Cassie L

2016-09-01

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used in combination with insulin to manage type 2 diabetes mellitus, and four agents are currently approved for this indication: exenatide, liraglutide, dulaglutide, and albiglutide. The distinctive properties of GLP-1 RAs-potential hemoglobin A1c (A1C) reduction, weight loss, potential to reduce insulin doses, and lower hypoglycemia risk-have made these agents potential treatment options for patients with type 1 diabetes mellitus (T1DM) as well. These positive effects are due to glucose-dependent insulin secretion, reduced glucagon secretion, increased satiety, and delayed gastric emptying. Patients with T1DM are unable to suppress glucagon during meals, which contributes to postprandial hyperglycemia and may be improved with GLP-1 therapy. In this review, we evaluated the available literature on the clinical efficacy and safety of GLP-1 RAs in patients with T1DM. We conducted a search of the PubMed (1966-May 2016) and Ovid (1946-May 2016) databases. Abstracts presented at the scientific and clinical sessions of the American Diabetes Association and the American Association of Clinical Endocrinologists were also searched. The references of the published articles were also reviewed to identify additional studies appropriate for inclusion. All identified articles published in English were evaluated. Studies were included if they evaluated the clinical use or safety of GLP-1 RAs in patients with T1DM. Twelve studies were included, with four evaluating exenatide, one evaluating exenatide extended release, and seven evaluating liraglutide. Both exenatide and liraglutide showed significant reductions in hemoglobin A1C, plasma glucose concentration, body weight, and insulin doses when administered to patients with T1DM already receiving insulin therapy, without increasing the occurrence of hypoglycemia. Adverse effects were mostly gastrointestinal in nature but were mild and transient. Patients who may

Ingestion of diet soda before a glucose load augments glucagon-like peptide-1 secretion.

PubMed

Brown, Rebecca J; Walter, Mary; Rother, Kristina I

2009-12-01

The goal of this study was to determine the effect of artificial sweeteners on glucose, insulin, and glucagon-like peptide (GLP)-1 in humans. For this study, 22 healthy volunteers (mean age 18.5 +/- 4.2 years) underwent two 75-g oral glucose tolerance tests with frequent measurements of glucose, insulin, and GLP-1 for 180 min. Subjects drank 240 ml of diet soda or carbonated water, in randomized order, 10 min prior to the glucose load. Glucose excursions were similar after ingestion of carbonated water and diet soda. Serum insulin levels tended to be higher after diet soda, without statistical significance. GLP-1 peak and area under the curve (AUC) were significantly higher with diet soda (AUC 24.0 +/- 15.2 pmol/l per 180 min) versus carbonated water (AUC 16.2 +/- 9.0 pmol/l per 180 min; P = 0.003). Artificial sweeteners synergize with glucose to enhance GLP-1 release in humans. This increase in GLP-1 secretion may be mediated via stimulation of sweet-taste receptors on L-cells by artificial sweetener.

Estradiol modulates the anorexic response to central glucagon-like peptide 1.

PubMed

Maske, Calyn B; Jackson, Christine M; Terrill, Sarah J; Eckel, Lisa A; Williams, Diana L

2017-07-01

Estrogens suppress feeding in part by enhancing the response to satiation signals. Glucagon-like peptide 1 (GLP-1) acts on receptor populations both peripherally and centrally to affect food intake. We hypothesized that modulation of the central GLP-1 system is one of the mechanisms underlying the effects of estrogens on feeding. We assessed the anorexic effect of 0, 1, and 10μg doses of GLP-1 administered into the lateral ventricle of bilaterally ovariectomized (OVX) female rats on a cyclic regimen of either 2μg β-estradiol-3-benzoate (EB) or oil vehicle 30min prior to dark onset on the day following hormone treatment. Central GLP-1 treatment significantly suppressed food intake in EB-treated rats at both doses compared to vehicle, whereas only the 10μg GLP-1 dose was effective in oil-treated rats. To follow up, we examined whether physiologic-dose cyclic estradiol treatment influences GLP-1-induced c-Fos in feeding-relevant brain areas of OVX females. GLP-1 significantly increased c-Fos expression in the area postrema (AP) and nucleus of the solitary tract (NTS), and the presence of estrogens may be required for this effect in the paraventricular nucleus of the hypothalamus (PVN). Together, these data suggest that modulation of the central GLP-1 system may be one of the mechanisms by which estrogens suppress food intake, and highlight the PVN as a region of interest for future investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterization of glucagon-like peptide-1 receptor-binding determinants.

PubMed

Xiao, Q; Jeng, W; Wheeler, M B

2000-12-01

Glucagon-like peptide 1 (GLP-1) is a potent insulinotropic hormone currently under study as a therapeutic agent for type 2 diabetes. Since an understanding of the molecular mechanisms leading to high-affinity receptor (R) binding and activation may facilitate the development of more potent GLP-1R agonists, we have localized specific regions of GLP-1R required for binding. The purified N-terminal fragment (hereafter referred to as NT) of the GLP-1R produced in either insect (Sf9) or mammalian (COS-7) cells was shown to bind GLP-1. The physical interaction of NT with GLP-1 was first demonstrated by cross-linking ((125)I-GLP-1/NT complex band at approximately 28 kDa) and secondly by attachment to Ni(2+)-NTA beads. The GLP-1R NT protein attached to beads bound GLP-1, but with lower affinity (inhibitory concentration (IC(50)): 4.5 x 10(-7) M) than wild-type (WT) GLP-1R (IC(50): 5.2 x 10(-9)M). The low affinity of GLP-1R NT suggested that other receptor domains may contribute to GLP-1 binding. This was supported by studies using chimeric glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptors. GIP(1-151)/GLP-1R, but not GIP(1-222)/GLP-1R, exhibited specific GLP-1 binding and GLP-1-induced cAMP production, suggesting that the region encompassing transmembrane (TM) domain 1 through to TM3 was required for binding. Since it was hypothesized that certain charged or polar amino acids in this region might be involved in binding, these residues (TM2-TM3) were analyzed by substitution mutagenesis. Five mutants (K197A, D198A, K202A, D215A, R227A) displayed remarkably reduced binding affinity. These studies indicate that the NT domain of the GLP-1R is able to bind GLP-1, but charged residues concentrated at the distal TM2/extracellular loop-1 (EC1) interface (K197, D198, K202) and in EC1 (D215 and R227) probably contribute to the binding determinants of the GLP-1R.

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

Disruption of Glucagon-Like Peptide 1 Signaling in Sim1 Neurons Reduces Physiological and Behavioral Reactivity to Acute and Chronic Stress.

PubMed

Ghosal, Sriparna; Packard, Amy E B; Mahbod, Parinaz; McKlveen, Jessica M; Seeley, Randy J; Myers, Brent; Ulrich-Lai, Yvonne; Smith, Eric P; D'Alessio, David A; Herman, James P

2017-01-04

Organismal stress initiates a tightly orchestrated set of responses involving complex physiological and neurocognitive systems. Here, we present evidence for glucagon-like peptide 1 (GLP-1)-mediated paraventricular hypothalamic circuit coordinating the global stress response. The GLP-1 receptor (Glp1r) in mice was knocked down in neurons expressing single-minded 1, a transcription factor abundantly expressed in the paraventricular nucleus (PVN) of the hypothalamus. Mice with single-minded 1-mediated Glp1r knockdown had reduced hypothalamic-pituitary-adrenal axis responses to both acute and chronic stress and were protected against weight loss associated with chronic stress. In addition, regional Glp1r knockdown attenuated stress-induced cardiovascular responses accompanied by decreased sympathetic drive to the heart. Finally, Glp1r knockdown reduced anxiety-like behavior, implicating PVN GLP-1 signaling in behavioral stress reactivity. Collectively, these findings support a circuit whereby brainstem GLP-1 activates PVN signaling to mount an appropriate whole-organism response to stress. These results raise the possibility that dysfunction of this system may contribute to stress-related pathologies, and thereby provide a novel target for intervention. Dysfunctional stress responses are linked to a number of somatic and psychiatric diseases, emphasizing the importance of precise neuronal control of effector pathways. Pharmacological evidence suggests a role for glucagon-like peptide-1 (GLP-1) in modulating stress responses. Using a targeted knockdown of the GLP-1 receptor in the single-minded 1 neurons, we show dependence of paraventricular nucleus GLP-1 signaling in the coordination of neuroendocrine, autonomic, and behavioral responses to acute and chronic stress. To our knowledge, this is the first direct demonstration of an obligate brainstem-to-hypothalamus circuit orchestrating general stress excitation across multiple effector systems. These findings provide

Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1

PubMed Central

Jang, Hyeung-Jin; Kokrashvili, Zaza; Theodorakis, Michael J.; Carlson, Olga D.; Kim, Byung-Joon; Zhou, Jie; Kim, Hyeon Ho; Xu, Xiangru; Chan, Sic L.; Juhaszova, Magdalena; Bernier, Michel; Mosinger, Bedrich; Margolskee, Robert F.; Egan, Josephine M.

2007-01-01

Glucagon-like peptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion is unknown. We show that human duodenal L cells express sweet taste receptors, the taste G protein gustducin, and several other taste transduction elements. Mouse intestinal L cells also express α-gustducin. Ingestion of glucose by α-gustducin null mice revealed deficiencies in secretion of GLP-1 and the regulation of plasma insulin and glucose. Isolated small bowel and intestinal villi from α-gustducin null mice showed markedly defective GLP-1 secretion in response to glucose. The human L cell line NCI-H716 expresses α-gustducin, taste receptors, and several other taste signaling elements. GLP-1 release from NCI-H716 cells was promoted by sugars and the noncaloric sweetener sucralose, and blocked by the sweet receptor antagonist lactisole or siRNA for α-gustducin. We conclude that L cells of the gut “taste” glucose through the same mechanisms used by taste cells of the tongue. Modulating GLP-1 secretion in gut “taste cells” may provide an important treatment for obesity, diabetes and abnormal gut motility. PMID:17724330

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…

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

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

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

PubMed

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

2015-07-01

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 (Leptin(ob/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.

Grape-seed procyanidins prevent the cafeteria-diet-induced decrease of glucagon-like peptide-1 production.

PubMed

González-Abuín, Noemi; Martínez-Micaelo, Neus; Blay, Mayte; Ardévol, Anna; Pinent, Montserrat

2014-02-05

Grape-seed procyanidin extract (GSPE) has been reported to improve insulin resistance in cafeteria rats. Because glucagon-like peptide-1 (GLP-1) is involved in glucose homeostasis, the preventive effects of GSPE on GLP-1 production, secretion, and elimination were evaluated in a model of diet-induced insulin resistance. Rats were fed a cafeteria diet for 12 weeks, and 25 mg of GSPE/kg of body weight was administered concomitantly. Vehicle-treated cafeteria-fed rats and chow-fed rats were used as controls. The cafeteria diet decreased active GLP-1 plasma levels, which is attributed to a decreased intestinal GLP-1 production, linked to reduced colonic enteroendocrine cell populations. Such effects were prevented by GSPE. In the same context, GSPE avoided the decrease on intestinal dipeptidyl-peptidase 4 (DPP4) activity and modulated the gene expression of GLP-1 and its receptor in the hypothalamus. In conclusion, the preventive treatment with GSPE abrogates the effects of the cafeteria diet on intestinal GLP-1 production and DPP4 activity.

Design of glucagon-like Peptide-1 receptor agonist for diabetes mellitus from traditional chinese medicine.

PubMed

Tang, Hsin-Chieh; Chen, Calvin Yu-Chian

2014-01-01

Glucagon-like peptide-1 (GLP-1) is a promising target for diabetes mellitus (DM) therapy and reduces the occurrence of diabetes due to obesity. However, GLP-1 will be hydrolyzed soon by the enzyme dipeptidyl peptidase-4 (DPP-4). We tried to design small molecular drugs for GLP-1 receptor agonist from the world's largest traditional Chinese medicine (TCM) Database@Taiwan. According to docking results of virtual screening, we selected 2 TCM compounds, wenyujinoside and 28-deglucosylchikusetsusaponin IV, for further molecular dynamics (MD) simulation. GLP-1 was assigned as the control compound. Based on the results of root mean square deviation (RMSD), solvent accessible surface (SAS), mean square deviation (MSD), Gyrate, total energy, root mean square fluctuation (RMSF), matrices of smallest distance of residues, database of secondary structure assignment (DSSP), cluster analysis, and distance of H-bond, we concluded that all the 3 compounds could bind and activate GLP-1 receptor by computational simulation. Wenyujinoside and 28-deglucosylchikusetsusaponin IV were the TCM compounds that could be GLP-1 receptor agonists.

Design of Glucagon-Like Peptide-1 Receptor Agonist for Diabetes Mellitus from Traditional Chinese Medicine

PubMed Central

Tang, Hsin-Chieh; Chen, Calvin Yu-Chian

2014-01-01

Glucagon-like peptide-1 (GLP-1) is a promising target for diabetes mellitus (DM) therapy and reduces the occurrence of diabetes due to obesity. However, GLP-1 will be hydrolyzed soon by the enzyme dipeptidyl peptidase-4 (DPP-4). We tried to design small molecular drugs for GLP-1 receptor agonist from the world's largest traditional Chinese medicine (TCM) Database@Taiwan. According to docking results of virtual screening, we selected 2 TCM compounds, wenyujinoside and 28-deglucosylchikusetsusaponin IV, for further molecular dynamics (MD) simulation. GLP-1 was assigned as the control compound. Based on the results of root mean square deviation (RMSD), solvent accessible surface (SAS), mean square deviation (MSD), Gyrate, total energy, root mean square fluctuation (RMSF), matrices of smallest distance of residues, database of secondary structure assignment (DSSP), cluster analysis, and distance of H-bond, we concluded that all the 3 compounds could bind and activate GLP-1 receptor by computational simulation. Wenyujinoside and 28-deglucosylchikusetsusaponin IV were the TCM compounds that could be GLP-1 receptor agonists. PMID:24891870

Liposomal formulations of glucagon-like peptide-1: improved bioavailability and anti-diabetic effect.

PubMed

Hanato, Junko; Kuriyama, Kazuki; Mizumoto, Takahiro; Debari, Kazuhiro; Hatanaka, Junya; Onoue, Satomi; Yamada, Shizuo

2009-12-01

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is recognized to be potent drug candidate for treatment of diabetes, however its clinical application has been highly limited, because of rapid enzymatic degradation by dipeptidyl-peptidase IV. To protect GLP-1 from enzymatic degradation and improve pharmacological effects, liposomal formulations of GLP-1 were prepared using three types of lyophilized empty liposomes such as anionic, neutral and cationic liposomes. Electron microscopic and dynamic light scattering experiments indicated the uniform size distribution of GLP-1-loaded liposomes with mean diameter of 130-210 nm, and inclusion of GLP-1 did not affect the dispersibility and morphology of each liposome. Of all liposomal formulations tested, anionic liposomal formulation exhibited the highest encapsulation efficiency of GLP-1 (ca. 80%). In intraperitoneal glucose tolerance testing in rats, marked improvement of hypoglycemic effects were observed in anionic liposomal formulation of GLP-1 (100 nmol/kg) with 1.7-fold higher increase of insulin secretion, as compared to GLP-1 solution. In pharmacokinetic studies, intravenous administration of anionic liposomal formulation of GLP-1 (100 nmol/kg) resulted in 3.6-fold higher elevation of serum GLP-1 level as compared to GLP-1 injection. Upon these findings, anionic liposomal formulation of GLP-1 would provide the improved pharmacokinetics and insulinotropic action, possibly leading to efficacious anti-diabetic medication.

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

PubMed Central

Jackson, Christine M.; Greene, Hayden E.; Lilly, Nicole; Maske, Calyn B.; Vallejo, Samantha

2016-01-01

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

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. Copyright © 2016 the American Physiological Society.

Ingestion of Diet Soda Before a Glucose Load Augments Glucagon-Like Peptide-1 Secretion

PubMed Central

Brown, Rebecca J.; Walter, Mary; Rother, Kristina I.

2009-01-01

OBJECTIVE The goal of this study was to determine the effect of artificial sweeteners on glucose, insulin, and glucagon-like peptide (GLP)-1 in humans. RESEARCH DESIGN AND METHODS For this study, 22 healthy volunteers (mean age 18.5 ± 4.2 years) underwent two 75-g oral glucose tolerance tests with frequent measurements of glucose, insulin, and GLP-1 for 180 min. Subjects drank 240 ml of diet soda or carbonated water, in randomized order, 10 min prior to the glucose load. RESULTS Glucose excursions were similar after ingestion of carbonated water and diet soda. Serum insulin levels tended to be higher after diet soda, without statistical significance. GLP-1 peak and area under the curve (AUC) were significantly higher with diet soda (AUC 24.0 ± 15.2 pmol/l per 180 min) versus carbonated water (AUC 16.2 ± 9.0 pmol/l per 180 min; P = 0.003). CONCLUSIONS Artificial sweeteners synergize with glucose to enhance GLP-1 release in humans. This increase in GLP-1 secretion may be mediated via stimulation of sweet-taste receptors on L-cells by artificial sweetener. PMID:19808921

Does Glucagon-like Peptide-1 Ameliorate Oxidative Stress in Diabetes? Evidence Based on Experimental and Clinical Studies

PubMed Central

Petersen, Karen Ekkelund; Rakipovski, Günaj; Raun, Kirsten; Lykkesfeldt, Jens

2016-01-01

Glucagon-like peptide-1 (GLP-1) has shown to influence the oxidative stress status in a number of in vitro, in vivo and clinical studies. Well-known effects of GLP-1 including better glycemic control, decreased food intake, increased insulin release and increased insulin sensitivity may indirectly contribute to this phenomenon, but glucose-independent effects on ROS level, production and antioxidant capacity have been suggested to also play a role. The potential ‘antioxidant’ activity of GLP-1 along with other proposed glucose-independent modes of action related to ameliorating redox imbalance remains a controversial topic but could hold a therapeutic potential against micro- and macrovascular diabetic complications. This review discusses the presently available knowledge from experimental and clinical studies on the effects of GLP-1 on oxidative stress in diabetes and diabetes-related complications. PMID:26381142

Involvement of Glucagon-Like Peptide-1 in the Regulation of Selective Excretion of Sodium or Chloride Ions by the Kidneys.

PubMed

Marina, A S; Kutina, A V; Shakhmatoba, E I; Natochin, Yu V

2017-02-01

An increase of total glucagon-like peptide-1 (GLP-1) concentration in the plasma in rats was revealed 5 min after oral, but not intraperitoneal administration of NaCl or Trizma HCl solutions. The increase in GLP-1 level was similar to that after oral glucose administration. After intraperitoneal administration of 2.5% NaCl, GLP-1 mimetic exenatide accelerated natriuresis and urinary chloride excretion. Under conditions of normonatriemia and hyperchloremia induced by injection of 6.7% Trizma HCl, exenatide stimulated chloride excretion and reabsorption of sodium ions in the kidneys. These findings suggest that GLP-1 participates in selective regulation of the balance of sodium and chloride ions.

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. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Biological activity studies of the novel glucagon-like peptide-1 derivative HJ07.

PubMed

Han, Jing; Sun, Li-Dan; Qian, Hai; Huang, Wen-Long

2014-08-01

To identify the glucose lowering ability and chronic treatment effects of a novel coumarin-glucagon-like peptide-1 (GLP-1) conjugate HJ07. A receptor activation experiment was performed in HEK 293 cells and the glucose lowering ability was evaluated with hypoglycemic duration and glucose stabilizing tests. Chronic treatment was performed by daily injection of exendin-4, saline, and HJ07. Body weight and HbA1c were measured every week, and an intraperitoneal glucose tolerance test was performed before treatment and after treatment. HJ07 showed well-preserved receptor activation efficacy. The hypoglycemic duration test showed that HJ07 possessed a long-acting, glucose-lowering effect and the glucose stabilizing test showed that the antihyperglycemic activity of HJ07 was still evident at a predetermined time (12 h) prior to the glucose challenge (0 h). The long time glucose-lowering effect of HJ07 was better than native GLP-1 and exendin-4. Furthermore, once daily injection of HJ07 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. The biological activity results of HJ07 suggest that HJ07 is a potential long-acting agent for the treatment of type 2 diabetes. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Intracellular signals mediating the food intake suppressive effects of hindbrain glucagon-like-peptide-1 receptor activation

PubMed Central

Hayes, Matthew R.; Leichner, Theresa M.; Zhao, Shiru; Lee, Grace S.; Chowansky, Amy; Zimmer, Derek; De Jonghe, Bart C.; Kanoski, Scott E.; Grill, Harvey J.; Bence, Kendra K.

2011-01-01

Summary Glucagon-like-peptide-1 receptor (GLP-1R) activation within the nucleus tractus solitarius (NTS) suppresses food intake and body weight (BW), but the intracellular signals mediating these effects are unknown. Here, hindbrain (4th icv) GLP-1R activation by Exendin-4 increased PKA and MAPK activity and decreased phosphorylation of AMPK in NTS. PKA and MAPK signaling contribute to food intake and BW suppression by Exendin-4, as inhibitors RpcAMP and U0126 (4th icv), respectively, attenuated Exendin-4's effects. Hindbrain GLP-1R activation inhibited feeding by reducing meal number, not meal size. This effect was attenuated with stimulation of AMPK activity by AICAR (4th icv). The PKA, MAPK and AMPK signaling responses by Ex-4 were present in immortalized GLP-1R-expressing neurons (GT1-7). In conclusion, hindbrain GLP-1R activation suppresses food intake and BW through coordinated PKA-mediated suppression of AMPK and activation of MAPK. Pharmacotherapies targeting these signaling pathways, which mediate intake-suppressive effects of CNS GLP-1R activation, may prove efficacious in treating obesity. PMID:21356521

Vascular Biology of Glucagon Receptor Superfamily Peptides: Mechanistic and Clinical Relevance.

PubMed

Pujadas, Gemma; Drucker, Daniel J

2016-12-01

Regulatory peptides produced in islet and gut endocrine cells, including glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, and glucose-dependent insulinotropic polypeptide, exert actions with considerable metabolic importance and translational relevance. Although the clinical development of GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors has fostered research into how these hormones act on the normal and diseased heart, less is known about the actions of these peptides on blood vessels. Here we review the effects of these peptide hormones on normal blood vessels and highlight their vascular actions in the setting of experimental and clinical vascular injury. The cellular localization and signal transduction properties of the receptors for glucagon, GLP-1, GLP-2, and glucose-dependent insulinotropic polypeptide are discussed, with emphasis on endothelial cells and vascular smooth muscle cells. The actions of these peptides on the control of blood flow, blood pressure, angiogenesis, atherosclerosis, and vascular inflammation are reviewed with a focus on elucidating direct and indirect mechanisms of action. How these peptides traverse the blood-brain barrier is highlighted, with relevance to the use of GLP-1 receptor agonists to treat obesity and neurodegenerative disorders. Wherever possible, we compare actions identified in cell lines and primary cell culture with data from preclinical studies and, when available, results of human investigation, including studies in subjects with diabetes, obesity, and cardiovascular disease. Throughout the review, we discuss pitfalls, limitations, and challenges of the existing literature and highlight areas of controversy and uncertainty. The increasing use of peptide-based therapies for the treatment of diabetes and obesity underscores the importance of understanding the vascular biology of peptide hormone action.

Difference in glucagon-like peptide-1 concentrations between C-peptide negative type 1 diabetes mellitus patients and healthy controls.

PubMed

Zibar, Karin; Ćuća, Jadranka Knežević; Blaslov, Kristina; Bulum, Tomislav; Smirčić-Duvnjak, Lea

2015-03-01

The role of glucagon-like peptide-1 (GLP-1) has become a new scientific interest in the field of pathophysiology of type 1 diabetes mellitus (T1DM), but the results of the published studies were contradictory. The aim of our study was therefore to measure fasting and postprandial GLP-1 concentrations in T1DM patients and in healthy controls and to examine the difference in those concentrations between the two groups of subjects. The cross-sectional study included 30 C-peptide negative T1DM patients, median age 37 years (20-59), with disease duration 22 years (3-45), and 10 healthy controls, median age 30 years (27-47). Fasting and postprandial total and active GLP-1 concentrations were measured by ELISA (ALPCO, USA). The data were statistically analysed by SPSS, and significance level was accepted at P < 0.05. Both fasting total and active GLP-1 concentrations were significantly lower in T1DM patients (total 0.4 pmol/L, 0-6.4 and active 0.2 pmol/L, 0-1.9) compared with healthy controls (total 3.23 pmol/L, 0.2-5.5 and active 0.8 pmol/L, 0.2-3.6), P = 0.008 for total GLP-1 and P = 0.001 for active GLP-1. After adjustment for age, sex and body mass index, binary logistic regression showed that both fasting total and active GLP-1 remained significantly independently lower in T1DM patients (total GLP-1: OR 2.43, 95% CI 1.203-4.909 and active GLP-1: OR 8.73, 95% CI 1.472-51.787). T1DM patients had independently lower total and active GLP-1 fasting concentrations in comparison with healthy people, which supports the potential therapeutic role of incretin therapy, along with insulin therapy, in T1DM patients. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Role of Glucagon-Like Peptide-1 and Gastric Inhibitory Peptide in Anorexia Induction Following Oral Exposure to the Trichothecene Mycotoxin Deoxynivalenol (Vomitoxin).

PubMed

Jia, Hui; Wu, Wen-Da; Lu, Xi; Zhang, Jie; He, Cheng-Hua; Zhang, Hai-Bin

2017-09-01

Deoxynivalenol (DON), which is a Type B trichothecene mycotoxin produced by Fusarium, frequently contaminates cereal staples, such as wheat, barley and corn. DON threatens animal and human health by suppressing food intake and impairing growth. While anorexia induction in mice exposed to DON has been linked to the elevation of the satiety hormones cholecystokinin and peptide YY3-36 in plasma, the effects of DON on the release of other satiety hormones, such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), have not been established. The purpose of this study was to determine the roles of GLP-1 and GIP in DON-induced anorexia. In a nocturnal mouse food consumption model, the elevation of plasma GLP-1 and GIP concentrations markedly corresponded to anorexia induction by DON. Pretreatment with the GLP-1 receptor antagonist Exendin9-39 induced a dose-dependent attenuation of both GLP-1- and DON-induced anorexia. In contrast, the GIP receptor antagonist Pro3GIP induced a dose-dependent attenuation of both GIP- and DON-induced anorexia. Taken together, these results suggest that GLP-1 and GIP play instrumental roles in anorexia induction following oral exposure to DON, and the effect of GLP-1 is more potent and long-acting than that of GIP. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Glucagon-like peptide 1 interacts with ghrelin and leptin to regulate glucose metabolism and food intake through vagal afferent neuron signaling.

PubMed

Ronveaux, Charlotte C; Tomé, Daniel; Raybould, Helen E

2015-04-01

Emerging evidence has suggested a possible physiologic role for peripheral glucagon-like peptide 1 (GLP-1) in regulating glucose metabolism and food intake. The likely site of action of GLP-1 is on vagal afferent neurons (VANs). The vagal afferent pathway is the major neural pathway by which information about ingested nutrients reaches the central nervous system and influences feeding behavior. Peripheral GLP-1 acts on VANs to inhibit food intake. The mechanism of the GLP-1 receptor (GLP-1R) is unlike other gut-derived receptors; GLP-1Rs change their cellular localization according to feeding status rather than their protein concentrations. It is possible that several gut peptides are involved in mediating GLP-1R translocation. The mechanism of peripheral GLP-1R translocation still needs to be elucidated. We review data supporting the role of peripheral GLP-1 acting on VANs in influencing glucose homeostasis and feeding behavior. We highlight evidence demonstrating that GLP-1 interacts with ghrelin and leptin to induce satiation. Our aim was to understand the mechanism of peripheral GLP-1 in the development of noninvasive antiobesity treatments. © 2015 American Society for Nutrition.

Enhanced AMPA Receptor Trafficking Mediates the Anorexigenic Effect of Endogenous Glucagon-like Peptide-1 in the Paraventricular Hypothalamus.

PubMed

Liu, Ji; Conde, Kristie; Zhang, Peng; Lilascharoen, Varoth; Xu, Zihui; Lim, Byung Kook; Seeley, Randy J; Zhu, J Julius; Scott, Michael M; Pang, Zhiping P

2017-11-15

Glucagon-like Peptide 1 (GLP-1)-expressing neurons in the hindbrain send robust projections to the paraventricular nucleus of the hypothalamus (PVN), which is involved in the regulation of food intake. Here, we describe that stimulation of GLP-1 afferent fibers within the PVN is sufficient to suppress food intake independent of glutamate release. We also show that GLP-1 receptor (GLP-1R) activation augments excitatory synaptic strength in PVN corticotropin-releasing hormone (CRH) neurons, with GLP-1R activation promoting a protein kinase A (PKA)-dependent signaling cascade leading to phosphorylation of serine S845 on GluA1 AMPA receptors and their trafficking to the plasma membrane. Finally, we show that postnatal depletion of GLP-1R in the PVN increases food intake and causes obesity. This study provides a comprehensive multi-level (circuit, synaptic, and molecular) explanation of how food intake behavior and body weight are regulated by endogenous central GLP-1. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

Enhanced AMPA receptor trafficking mediates the anorexigenic effect of endogenous glucagon like peptide-1 in the paraventricular hypothalamus

PubMed Central

Liu, Ji; Conde, Kristie; Zhang, Peng; Lilascharoen, Varoth; Xu, Zihui; Lim, Byung Kook; Seeley, Randy J.; Zhu, Julius J.; Scott, Michael M.; Pang, Zhiping P.

2017-01-01

SUMMARY Glucagon Like Peptide 1 (GLP-1)-expressing neurons in the hindbrain send robust projections to the paraventricular nucleus of the hypothalamus (PVN), which is involved in the regulation of food intake. Here, we describe that stimulation of GLP-1 afferent fibers within the PVN is sufficient to suppress food intake independent of glutamate release. We also show that GLP-1 receptor (GLP-1R) activation augments excitatory synaptic strength in PVN corticotropin-releasing hormone (CRH) neurons, with GLP-1R activation promoting a protein kinase A (PKA) dependent signaling cascade leading to phosphorylation of serine S845 on GluA1 AMPA receptors and their trafficking to the plasma membrane. Finally, we show that postnatal depletion of GLP-1R in the PVN increases food intake and causes obesity. This study provides a comprehensive multi-level (circuit, synaptic, and molecular) explanation of how food intake behavior and body weight are regulated by endogenous central GLP-1. PMID:29056294

Exendin-4, a glucagon-like peptide-1 analogue accelerates healing of chronic gastric ulcer in diabetic rats

PubMed Central

Chen, Yen-Cheng; Ho, Ching-Chun; Yi, Chih-Hsun; Liu, Xiu-Zhu; Cheng, Tzu-Ting

2017-01-01

Background Diabetes mellitus is an independent risk factor for impaired healing of peptic ulcers, and there are currently no supplementary therapeutics other than the standard antipeptic medicine to improve the ulcer healing in diabetes. This study examined the potential pleiotropic effect of a glucagon-like peptide (Glp)-1 analogue exendin (Ex)-4 on the regeneration of gastric ulcer in streptozotocin-induced diabetic rats. Methods and results Chronic ulcer was created in rat stomach by submucosal injection of acetic acid and peri-ulcer tissues were analyzed 7 days after operation. Ulcer wound healing was impaired in diabetic rats with suppressed tissue expression of eNOS and enhanced levels of pro-inflammatory reactions. Treatment with intraperitoneal injection of Ex4 (0.5 μg/kg/d) significantly reduced the area of gastric ulcer without changing blood glucose level. Ex-4 restored the expression of pro-angiogenic factors, and attenuated the generation of regional inflammation and superoxide anions. The improvement of ulcer healing was associated with increased expression of MMP-2 and formation of granulation tissue in the peri-ulcer area. Conclusion Administration of Ex4 may induce pro-angiogenic, anti-inflammatory and anti-oxidative reactions in the peri-ulcer tissue of diabetic rats that eventually enhances tissue granulation and closure of ulcerative wounds. Our results support the potential clinical application of Glp-1 analogues as supplementary hypoglycemic agents in the antipeptic ulcer medication in diabetes. PMID:29095895

Glucagon-like peptide 2 therapy reduces the negative impacts the proinflammatory response in the gut of calves with coccidiosis

USDA-ARS?s Scientific Manuscript database

Damage to the intestinal epithelium reduces nutrient absorption and animal growth, and can have negative long-term health effects on livestock. The intestinotropic hormone glucagon-like peptide 2 (GLP-2) contributes to gut integrity, reduces inflammation, and improves nutrient absorption. The presen...

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.

Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R)

PubMed Central

Koole, Cassandra; Reynolds, Christopher A.; Mobarec, Juan C.; Hick, Caroline; Sexton, Patrick M.; Sakmar, Thomas P.

2017-01-01

The glucagon-like peptide-1 receptor (GLP-1R) is a key therapeutic target in the management of type II diabetes mellitus, with actions including regulation of insulin biosynthesis and secretion, promotion of satiety, and preservation of β-cell mass. Like most class B G protein-coupled receptors (GPCRs), there is limited knowledge linking biological activity of the GLP-1R with the molecular structure of an intact, full-length, and functional receptor·ligand complex. In this study, we have utilized genetic code expansion to site-specifically incorporate the photoactive amino acid p-azido-l-phenylalanine (azF) into N-terminal residues of a full-length functional human GLP-1R in mammalian cells. UV-mediated photolysis of azF was then carried out to induce targeted photocross-linking to determine the proximity of the azido group in the mutant receptor with the peptide exendin-4. Cross-linking data were compared directly with the crystal structure of the isolated N-terminal extracellular domain of the GLP-1R in complex with exendin(9–39), revealing both similarities as well as distinct differences in the mode of interaction. Generation of a molecular model to accommodate the photocross-linking constraints highlights the potential influence of environmental conditions on the conformation of the receptor·peptide complex, including folding dynamics of the peptide and formation of dimeric and higher order oligomeric receptor multimers. These data demonstrate that crystal structures of isolated receptor regions may not give a complete reflection of peptide/receptor interactions and should be combined with additional experimental constraints to reveal peptide/receptor interactions occurring in the dynamic, native, and full-length receptor state. PMID:28283573

Effect of Butyrate and Inulin Supplementation on Glycemic Status, Lipid Profile and Glucagon-Like Peptide 1 Level in Patients with Type 2 Diabetes: A Randomized Double-Blind, Placebo-Controlled Trial.

PubMed

Roshanravan, Neda; Mahdavi, Reza; Alizadeh, Effat; Jafarabadi, Mohammad Asghari; Hedayati, Mehdi; Ghavami, Abed; Alipour, Shahriar; Alamdari, Naimeh Mesri; Barati, Meisam; Ostadrahimi, Alireza

2017-11-01

Studies on humans with diabetes mellitus showed that the crosstalk between the intestinal microbiota and the host has a key role in controlling the disease. The aim of this study was to evaluate the effects of sodium butyrate and high performance inulin supplementation simultaneously or singly on glycemic status, lipid profile, and glucagon-like peptide 1 level in adults with type 2 diabetes mellitus. Sixty patients were recruited for the study. The participants were randomly allocated, using randomized block procedure, to one of the four treatment groups (A, B, C, or D). Group A received sodium butyrate capsules, group B received inulin supplement powder, group C was exposed to the concomitant use of inulin and sodium butyrate, and group D consumed placebo for 45 consecutive days. Markers of glycemia, lipid profile, and glucagon-like peptide 1 were measured pre- and post-intervention. Dietary supplementation in groups A, B, and C significantly reduced diastolic blood pressure in comparison with the placebo group (p<0.05). Also, intra-group statistical analysis showed that only treatment with sodium butyrate + inulin (group C) significantly reduced fasting blood sugar (p=0.049) and waist to hip ratio (p=0.020). Waist circumference in groups B and C reduced significantly after the intervention (p=0.007 and p=0.011; respectively). The post hoc Tukey tests showed significant increase in glucagon-like peptide 1 concentration in groups A and C in comparison with group D (p<0.05). The results suggest that inulin supplementation may be useful to diabetic patients and these effects could be increased with butyrate supplement. © Georg Thieme Verlag KG Stuttgart · New York.

Role of central nervous system glucagon-like Peptide-1 receptors in enteric glucose sensing.

PubMed

Knauf, Claude; Cani, Patrice D; Kim, Dong-Hoon; Iglesias, Miguel A; Chabo, Chantal; Waget, Aurélie; Colom, André; Rastrelli, Sophie; Delzenne, Nathalie M; Drucker, Daniel J; Seeley, Randy J; Burcelin, Remy

2008-10-01

Ingested glucose is detected by specialized sensors in the enteric/hepatoportal vein, which send neural signals to the brain, which in turn regulates key peripheral tissues. Hence, impairment in the control of enteric-neural glucose sensing could contribute to disordered glucose homeostasis. The aim of this study was to determine the cells in the brain targeted by the activation of the enteric glucose-sensing system. We selectively activated the axis in mice using a low-rate intragastric glucose infusion in wild-type and glucagon-like peptide-1 (GLP-1) receptor knockout mice, neuropeptide Y-and proopiomelanocortin-green fluorescent protein-expressing mice, and high-fat diet diabetic mice. We quantified the whole-body glucose utilization rate and the pattern of c-Fos positive in the brain. Enteric glucose increased muscle glycogen synthesis by 30% and regulates c-Fos expression in the brainstem and the hypothalamus. Moreover, the synthesis of muscle glycogen was diminished after central infusion of the GLP-1 receptor (GLP-1Rc) antagonist Exendin 9-39 and abolished in GLP-1Rc knockout mice. Gut-glucose-sensitive c-Fos-positive cells of the arcuate nucleus colocalized with neuropeptide Y-positive neurons but not with proopiomelanocortin-positive neurons. Furthermore, high-fat feeding prevented the enteric activation of c-Fos expression. We conclude that the gut-glucose sensor modulates peripheral glucose metabolism through a nutrient-sensitive mechanism, which requires brain GLP-1Rc signaling and is impaired during diabetes.

Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive fashion

PubMed Central

Zhao, Shiru; Kanoski, Scott E.; Yan, Jianqun; Grill, Harvey J.; Hayes, Matthew R.

2011-01-01

Background The physiological control of feeding behavior involves modulation of the intake inhibitory effects of gastrointestinal satiation signaling via endogenous hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) activation. Design and Results Using a variety of dose-combinations of hindbrain delivered (4th icv) leptin and the GLP-1R agonist exendin-4, experiments demonstrate that hindbrain LepR and GLP-1R signaling interact to control food intake and body weight in an additive fashion. In addition, the maximum intake suppressive response that could be achieved by 4th icv leptin alone in non-obese rats (~33%) was shown to be further suppressed when exendin-4 was co-administered. Importantly, it was determined that the interaction between hindbrain LepR signaling and GLP-1R signaling is relevant to endogenous food intake control, as hindbrain GLP-1R blockade by the selective antagonist exendin-(9–39) attenuated the intake inhibitory effects of hindbrain leptin delivery. Conclusions Collectively, the findings reported here show that hindbrain LepR and GLP-1R activation interact in at least an additive fashion to control food intake and body weight. As evidence is accumulating that combination pharmacotherapies offer greater sustained food intake and body weight suppression in obese individuals when compared to mono-drug therapies or lifestyle modifications alone, these findings highlight the need for further examination of combined CNS GLP-1R and LepR signaling as a potential drug target for obesity treatment. PMID:22249232

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

Glucagon-like peptide-1 and cholecystokinin production and signaling in the pancreatic islet as an adaptive response to obesity.

PubMed

Linnemann, Amelia K; Davis, Dawn Belt

2016-04-01

Precise control of blood glucose is dependent on adequate β-cell mass and function. Thus, reductions in β-cell mass and function lead to insufficient insulin production to meet demand, and result in diabetes. Recent evidence suggests that paracrine signaling in the islet might be important in obesity, and disruption of this signaling could play a role in the pathogenesis of diabetes. For example, we recently discovered a novel islet incretin axis where glucagon-like peptide-1 regulates β-cell production of another classic gut hormone, cholecystokinin. This axis is stimulated by obesity, and plays a role in enhancing β-cell survival. In the present review, we place our observations in the wider context of the literature on incretin regulation in the islet, and discuss the potential for therapeutic targeting of these pathways.

A Glucagon-Like Peptide-1 Receptor Agonist Lowers Weight by Modulating the Structure of Gut Microbiota.

PubMed

Zhao, Li; Chen, Yi; Xia, Fangzhen; Abudukerimu, Buatikamu; Zhang, Wen; Guo, Yuyu; Wang, Ningjian; Lu, Yingli

2018-01-01

In addition to improving glucose metabolism, liraglutide, a glucagon-like peptide-1 receptor agonist, has weight-loss effects. The underlying mechanisms are not completely understood. This study was performed to explore whether liraglutide could lower weight by modulating the composition of the gut microbiota in simple obese and diabetic obese rats. In our study, Wistar and Goto-Kakizaki (GK) rats were randomly treated with liraglutide or normal saline for 12 weeks. The biochemical parameters and metabolic hormones were measured. Hepatic glucose production and lipid metabolism were also assessed with isotope tracers. Changes in gut microbiota were analyzed by 16S rRNA gene sequencing. Both glucose and lipid metabolism were significantly improved by liraglutide. Liraglutide lowered body weight independent of glycemia status. The abundance and diversity of gut microbiota were considerably decreased by liraglutide. Liraglutide also decreased obesity-related microbial phenotypes and increased lean-related phenotypes. In conclusion, liraglutide can prevent weight gain by modulating the gut microbiota composition in both simple obese and diabetic obese subjects.

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice.

PubMed

Yamamoto, Takaya; Nakade, Yukiomi; Yamauchi, Taeko; Kobayashi, Yuji; Ishii, Norimitsu; Ohashi, Tomohiko; Ito, Kiyoaki; Sato, Ken; Fukuzawa, Yoshitaka; Yoneda, Masashi

2016-02-28

To investigate whether a glucagon-like peptide-1 (GLP-1) analogue inhibits nonalcoholic steatohepatitis (NASH), which is being increasingly recognized in Asia, in non-obese mice. A methionine-choline-deficient diet (MCD) along with exendin-4 (20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice (non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride (TG) and free fatty acid (FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry. Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fatty acid transport protein 4 (FATP4), a hepatic FFA influx-related gene; macrophage recruitment; and the level of malondialdehyde (MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c (SREBP-1c) mRNA (lipogenesis-related gene) and acyl-coenzyme A oxidase 1 (ACOX1) mRNA (β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein mRNA (a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 mRNA level. These results suggest that GLP-1 inhibits hepatic steatosis and

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice

PubMed Central

Yamamoto, Takaya; Nakade, Yukiomi; Yamauchi, Taeko; Kobayashi, Yuji; Ishii, Norimitsu; Ohashi, Tomohiko; Ito, Kiyoaki; Sato, Ken; Fukuzawa, Yoshitaka; Yoneda, Masashi

2016-01-01

AIM: To investigate whether a glucagon-like peptide-1 (GLP-1) analogue inhibits nonalcoholic steatohepatitis (NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet (MCD) along with exendin-4 (20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice (non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride (TG) and free fatty acid (FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry. RESULTS: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fatty acid transport protein 4 (FATP4), a hepatic FFA influx-related gene; macrophage recruitment; and the level of malondialdehyde (MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c (SREBP-1c) mRNA (lipogenesis-related gene) and acyl-coenzyme A oxidase 1 (ACOX1) mRNA (β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein mRNA (a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 mRNA level. CONCLUSION: These results suggest that GLP-1

Short-acting glucagon-like peptide-1 receptor agonists as add-on to insulin therapy in type 1 diabetes: A review.

PubMed

Albèr, Anders; Brønden, Andreas; Knop, Filip K

2017-07-01

A large proportion of patients with type 1 diabetes do not reach their glycaemic target of glycated hemoglobin (HbA1c) <7.0% (53 mmol/mol) and, furthermore, an increasing number of patients with type 1 diabetes are overweight and obese. Treatment of type 1 diabetes is based on insulin therapy, which is associated with well-described and unfortunate adverse effects such as hypoglycaemia and increased body weight. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are the focus of increasing interest as a possible adjunctive treatment to insulin in type 1 diabetes because of their glucagonostatic and extrapancreatic effects. So far, the focus has mainly been on the long-acting GLP-1RAs, but the risk-benefit ratio emerging from studies evaluating the effect of long-acting GLP-1RAs as adjunctive therapy to insulin therapy in patients with type 1 diabetes has been disappointing. This might be attributable to a lack of glucagonostatic effect of these long-acting GLP-1RAs in type 1 diabetes, alongside development of tachyphylaxis to GLP-1-induced retardation of gastric emptying. In contrast, the short-acting GLP-1RAs seem to have a preserved and sustained effect on glucagon secretion and gastric emptying in patients with type 1 diabetes, which could translate into effective lowering of postprandial glucose excursions; however, these observations regarding short-acting GLP-1RAs are all derived from small open-label trials and should thus be interpreted with caution. In the present paper we review the potential role of GLP-1RAs, in particular short-acting GLP-1RAs, as add-on to insulin in the treatment of type 1 diabetes. © 2017 John Wiley & Sons Ltd.

Ghrelin suppresses cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) in the intestine, and attenuates the anorectic effects of CCK, PYY and GLP-1 in goldfish (Carassius auratus).

PubMed

Blanco, Ayelén Melisa; Bertucci, Juan Ignacio; Valenciano, Ana Isabel; Delgado, María Jesús; Unniappan, Suraj

2017-07-01

Ghrelin is an important gut-derived hormone with an appetite stimulatory role, while most of the intestinal hormones, including cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), are appetite-inhibitors. Whether these important peptides with opposing roles on food intake interact to regulate energy balance in fish is currently unknown. The aim of this study was to characterize the putative crosstalk between ghrelin and CCK, PYY and GLP-1 in goldfish (Carassius auratus). We first determined the localization of CCK, PYY and GLP-1 in relation to ghrelin and its main receptor GHS-R1a (growth hormone secretagogue 1a) in the goldfish intestine by immunohistochemistry. Colocalization of ghrelin/GHS-R1a and CCK/PYY/GLP-1 was found primarily in the luminal border of the intestinal mucosa. In an intestinal explant culture, a significant decrease in prepro-cck, prepro-pyy and proglucagon transcript levels was observed after 60min of incubation with ghrelin, which was abolished by preincubation with the GHS-R1a ghrelin receptor antagonist [D-Lys3]-GHRP-6 (except for proglucagon). The protein expression of PYY and GLP-1 was also downregulated by ghrelin. Finally, intraperitoneal co-administration of CCK, PYY or GLP-1 with ghrelin results in no modification of food intake in goldfish. Overall, results of the present study show for the first time in fish that ghrelin exerts repressive effects on enteric anorexigens. It is likely that these interactions mediate the stimulatory effects of ghrelin on feeding and metabolism in fish. Copyright © 2017 Elsevier Inc. All rights reserved.

TREATMENT OF DIABETES MELLITUS IN A GOLDEN LION TAMARIN (LEONTOPITHECUS ROSALIA) WITH THE GLUCAGON-LIKE PEPTIDE-1 MIMETIC EXENATIDE.

PubMed

Johnson, James G; Langan, Jennifer N; Gilor, Chen

2016-09-01

An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihyperglycemic medications glipizide and metformin that resulted in decreased blood glucose concentrations; however, marked glycosuria persisted. Insufficient improvement on oral antihyperglycemic therapy and poor feasibility of daily subcutaneous insulin therapy led to an investigation into an alternative therapy with extended-release exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, at a dosage of 0.13 mg/kg subcutaneously once per month. Following treatment with exenatide, the persistent glycosuria resolved, the animal maintained normal blood glucose concentrations, and had lower serum fructosamine concentrations compared to pretreatment levels. Based on these findings, extended-release exenatide could be considered as a therapeutic option in nonhuman primates with diabetes mellitus that do not respond to oral antihyperglycemics and in which daily subcutaneous insulin is not feasible.

Refinement of glucagon-like peptide 1 docking to its intact receptor using mid-region photolabile probes and molecular modeling.

PubMed

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

2011-05-06

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 Leu(141) above transmembrane segment one as its site of labeling for the position 16 probe, whereas the position 20 probe labeled receptor residue Trp(297) 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.

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

Wootten, Denise; 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

2016-03-01

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 R2.60(190), N3.43(240), Q7.49(394), and H6.52(363) as key residues involved in peptide-mediated biased agonism, with R2.60(190), N3.43(240), and Q7.49(394) 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 E6.53(364)A, N3.43(240)Q, Q7.49(394)N, and N3.43(240)Q/Q7.49(394)N 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 E6.53(364) and R2.60(190) was predicted to be important for GLP-1- and exendin-4-, but not oxyntomodulin-mediated cAMP formation and also ERK1/2 phosphorylation. In contrast, Q7.49(394), but not R2.60(190)/E6.53(364) was critical for calcium mobilization for all three peptides. Mutation of N3.43(240) and Q7.49(394) 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. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

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

PubMed Central

2014-01-01

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 microbiota-derived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine L cells in the gut and coreleased from preproglucagonergic neurons in the brain stem. Glucagon-like peptides are proposed as key mediators for bariatric surgery-improved glycemic control and energy balance. Little is known about the GLP-2 receptor (Glp2r)-mediated physiological roles in the control of food intake and glucose homeostasis, yet Glp1r has been studied extensively. This review will highlight the physiological relevance of the central nervous system (CNS) Glp2r in the control of energy balance and glucose homeostasis and focuses on cellular mechanisms underlying the CNS Glp2r-mediated neural circuitry and intracellular PI3K signaling pathway. New evidence (obtained from Glp2r tissue-specific KO mice) indicates that the Glp2r in POMC neurons is essential for suppressing feeding behavior, gastrointestinal motility, and hepatic glucose production. Mice with Glp2r deletion selectively in POMC neurons exhibit hyperphagic behavior, accelerated gastric emptying, glucose intolerance, and hepatic insulin resistance. GLP-2 differentially modulates postsynaptic membrane excitability of hypothalamic POMC neurons in Glp2r- and PI3K-dependent manners. GLP-2 activates the PI3K-Akt-FoxO1 signaling pathway in POMC neurons by Glp2r-p85α interaction. Intracerebroventricular GLP-2 augments glucose tolerance, suppresses glucose production, and enhances insulin sensitivity, which require PI3K (p110α) activation in POMC neurons. Thus, the CNS Glp2r plays a physiological role in the control of food intake and glucose homeostasis. This review will also discuss key questions for future studies. PMID:24990862

Short-term glucagon stimulation test of C-peptide effect on glucose utilization in patients with type 1 diabetes mellitus.

PubMed

Mojto, Viliam; Rausova, Zuzana; Chrenova, Jana; Dedik, Ladislav

2015-12-01

This work aimed to evaluate the use of a four-point glucagon stimulation test of C-peptide effect on glucose utilization in type 1 diabetic patients using a new mathematical model. A group of 32 type 1 diabetic patients and a group of 10 healthy control subjects underwent a four-point glucagon stimulation test with blood sampling at 0, 6, 15 and 30 min after 1 mg glucagon bolus intravenous administration. Pharmacokinetic and pharmacokinetic/pharmacodynamic models of C-peptide effect on glucose utilization versus area under curve (AUC) were used. A two-sample t test and ANOVA with Bonferroni correction were used to test the significance of differences between parameters. A significant difference between control and patient groups regarding the coefficient of whole-body glucose utilization and AUC C-peptide/AUC glucose ratio (p ≪ 0.001 and p = 0.002, respectively) was observed. The high correlation (r = 0.97) between modeled coefficient of whole-body glucose utilization and numerically calculated AUC C-peptide/AUC glucose ratio related to entire cohort indicated the stability of used method. The short-term four-point glucagon stimulation test allows the numerically calculated AUC C-peptide/AUC glucose ratio and/or the coefficient of whole-body glucose utilization calculated from model to be used to diagnostically identify type 1 diabetic patients.

One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer.

PubMed

Luginbuhl, Kelli M; Schaal, Jeffrey L; Umstead, Bret; Mastria, Eric M; Li, Xinghai; Banskota, Samagya; Arnold, Susan; Feinglos, Mark; D'Alessio, David; Chilkoti, Ashutosh

2017-01-01

Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes because of pleiotropic effects, including the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-live owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics leads to 10 days of glycemic control in three different mouse models of diabetes, as well as to the reduction of glycosylated hemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.

Glucagon-like peptide-1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway.

PubMed

Wu, Lujin; Wang, Ke; Wang, Wei; Wen, Zheng; Wang, Peihua; Liu, Lei; Wang, Dao Wen

2018-04-16

Lipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon-like peptide-1 (GLP-1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP-1 analog exendin-4 and the dipeptidyl peptidase-4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high-fat diets were significantly reversed by exendin-4 and saxagliptin treatments for 8 weeks. We found that exendin-4 inhibited abnormal activation of the (PPARα)-CD36 pathway by stimulating protein kinase A (PKA) but suppressing the Rho-associated protein kinase (ROCK) pathway in DM hearts, palmitic acid (PA)-treated rat h9c2 cardiomyocytes (CMs), and isolated adult mouse CMs. Cardioprotection in DM mediated by exendin-4 was abolished by combination therapy with the PPARα agonist wy-14643 but mimicked by PPARα gene deficiency. Therefore, the PPARα pathway accounted for the effects of exendin-4. This conclusion was confirmed in cardiac-restricted overexpression of PPARα mediated by adeno-associated virus serotype-9 containing a cardiac troponin T promoter. Our results provide the first direct evidence that GLP-1 protects cardiac function by inhibiting the ROCK/PPARα pathway, thereby ameliorating lipotoxicity in diabetic cardiomyopathy. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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

Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain

PubMed Central

Cork, Simon C.; Richards, James E.; Holt, Marie K.; Gribble, Fiona M.; Reimann, Frank; Trapp, Stefan

2015-01-01

Objective Although Glucagon-like peptide 1 is a key regulator of energy metabolism and food intake, the precise location of GLP-1 receptors and the physiological relevance of certain populations is debatable. This study investigated the novel GLP-1R-Cre mouse as a functional tool to address this question. Methods Mice expressing Cre-recombinase under the Glp1r promoter were crossed with either a ROSA26 eYFP or tdRFP reporter strain to identify GLP-1R expressing cells. Patch-clamp recordings were performed on tdRFP-positive neurons in acute coronal brain slices from adult mice and selective targeting of GLP-1R cells in vivo was achieved using viral gene delivery. Results Large numbers of eYFP or tdRFP immunoreactive cells were found in the circumventricular organs, amygdala, hypothalamic nuclei and the ventrolateral medulla. Smaller numbers were observed in the nucleus of the solitary tract and the thalamic paraventricular nucleus. However, tdRFP positive neurons were also found in areas without preproglucagon-neuronal projections like hippocampus and cortex. GLP-1R cells were not immunoreactive for GFAP or parvalbumin although some were catecholaminergic. GLP-1R expression was confirmed in whole-cell recordings from BNST, hippocampus and PVN, where 100 nM GLP-1 elicited a reversible inward current or depolarisation. Additionally, a unilateral stereotaxic injection of a cre-dependent AAV into the PVN demonstrated that tdRFP-positive cells express cre-recombinase facilitating virally-mediated eYFP expression. Conclusions This study is a comprehensive description and phenotypic analysis of GLP-1R expression in the mouse CNS. We demonstrate the power of combining the GLP-1R-CRE mouse with a virus to generate a selective molecular handle enabling future in vivo investigation as to their physiological importance. PMID:26500843

Immunohistochemical study on the ontogenetic development of the regional distribution of peptide YY, pancreatic polypeptide, and glucagon-like peptide 1 endocrine cells in bovine gastrointestinal tract.

PubMed

Pyarokhil, Asadullah Hamid; Ishihara, Miyuki; Sasaki, Motoki; Kitamura, Nobuo

2012-04-10

The regional distribution and relative frequency of peptide YY (PYY)-, pancreatic polypeptide (PP)-, and glucagon-like peptide 1 (GLP-1)-immunoreactive (IR) cells were determined immunohistochemically in the gastrointestinal tract at seven ontogenetic stages in pre- and postnatal cattle. Different frequencies of PYY-, PP-, and GLP-1-IR cells were found in the intestines at all stages; they were not found in the esophagus and stomach. The frequencies varied depending on the intestinal segment and the developmental stage. The frequencies of PYY- and PP-IR cells were lower in the small intestine and increased from ileum to rectum, whereas GLP-1-IR cells were more numerous in duodenum and jejunum, decreased in ileum and cecum, and increased again in colon and rectum. The frequencies also varied according to pre- and postnatal stages. All three cell types were most numerous in fetus, and decreased in calf and adult groups, indicating that the frequencies of these three types of endocrine cells decrease with postnatal development. The results suggest that these changes vary depending on feeding habits and adaptation of growth, secretion, and motility of intestine at different ontogenetic stages of cattle. Copyright © 2011 Elsevier B.V. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ohara-Imaizumi, Mica; Aoyagi, Kyota; Akimoto, Yoshihiro

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 typesmore » of granules may be a common mechanism in glucose-evoked hormone release from endocrine cells.« less

Bacterial metabolite S-equol modulates glucagon-like peptide-1 secretion from enteroendocrine L cell line GLUTag cells via actin polymerization.

PubMed

Harada, Kazuki; Sada, Shoko; Sakaguchi, Hidekazu; Takizawa, Mai; Ishida, Rika; Tsuboi, Takashi

2018-07-02

S-equol is one of gut bacterial metabolites produced from soybean isoflavone daizein. While S-equol is known to promote glucose-induced insulin secretion from pancreatic β cells, whether S-equol affects glucagon-like peptide-1 (GLP-1) secretion from enteroendoceine L cells remains unclear. Here we assessed the effect of S-equol on GLP-1 secretion from mouse enteroendocrine L cell line GLUTag cells. GLUTag cells expressed GPR30 and estrogen receptors, which are putative S-equol receptors. Application of S-equol induced an increase in intracellular Ca 2+ levels via GPR30. However, S-equol did not enhance GLP-1 exocytosis, and long-term treatment of S-equol suppressed GLP-1 secretion. Moreover, immunocytochemistry revealed that S-equol increased the density of cortical actin filaments via G 12/13 signaling under GPR30. These data suggest that S-equol prevents GLP-1 secretion as a result of competing regulation between Ca 2+ mobilization and actin reorganization. Copyright © 2018 Elsevier Inc. All rights reserved.

Oleic acid stimulates glucagon-like peptide-1 release from enteroendocrine cells by modulating cell respiration and glycolysis.

PubMed

Clara, Rosmarie; Langhans, Wolfgang; Mansouri, Abdelhak

2016-03-01

Glucagon-like peptide-1 (GLP-1) is a potent satiating and incretin hormone released by enteroendocrine L-cells in response to eating. Dietary fat, in particular monounsaturated fatty acids, such as oleic acid (OA), potently stimulates GLP-1 secretion from L-cells. It is, however, unclear whether the intracellular metabolic handling of OA is involved in this effect. First we determined the optimal medium for the bioenergetics measurements. Then we examined the effect of OA on the metabolism of the immortalized enteroendocrine GLUTag cell model and assessed GLP-1 release in parallel. We measured oxygen consumption rate and extracellular acidification rate in response to OA and to different metabolic inhibitors with the Seahorse extracellular flux analyzer. OA increased cellular respiration and potently stimulated GLP-1 release. The fatty acid oxidation inhibitor etomoxir did neither reduce OA-induced respiration nor affect the OA-induced GLP-1 release. In contrast, inhibition of the respiratory chain or of downstream steps of aerobic glycolysis reduced the OA-induced GLP-1 release, and an inhibition of the first step of glycolysis by addition of 2-deoxy-d-glucose even abolished it. These findings indicate that an indirect stimulation of glycolysis is crucial for the OA-induced release of GLP-1. Copyright © 2015 Elsevier Inc. All rights reserved.

Bitter tastant quinine modulates glucagon-like peptide-1 exocytosis from clonal GLUTag enteroendocrine L cells via actin reorganization.

PubMed

Harada, Kazuki; Sakaguchi, Hidekazu; Sada, Shoko; Ishida, Rika; Hayasaka, Yuki; Tsuboi, Takashi

2018-06-07

Enteroendocrine L cells in the gastrointestinal tract secrete glucagon-like peptide-1 (GLP-1), which plays an important role in glucose homeostasis. Here we investigated the effect of bitter tastant quinine on GLP-1 secretion using clonal GLUTag mouse enteroendocrine L cells. We found that GLUTag cells expressed putative quinine receptors at mRNA levels. Although application of quinine resulted in an increase of intracellular Ca 2+ levels, which was mediated by Ca 2+ release from the endoplasmic reticulum and Ca 2+ influx through voltage-sensitive Ca 2+ channels, quinine had little effect on GLP-1 secretion. Total internal reflection fluorescence microscopy and immunocytochemistry revealed that GLP-1-containing vesicles remained unfused with the plasma membrane and facilitated actin polymerization beneath the plasma membrane after application of quinine, respectively. Interestingly, application of forskolin together with quinine induced GLP-1 exocytosis from the cells. These results suggest that quinine does not induce GLP-1 secretion because it facilitates Ca 2+ increase and actin reorganization but not cAMP increase, and both Ca 2+ and cAMP are essential for GLP-1 secretion. Copyright © 2018 Elsevier Inc. All rights reserved.

Expression, purification, and C-terminal site-specific PEGylation of cysteine-mutated glucagon-like peptide-1.

PubMed

Gao, Mingming; Tian, Hong; Ma, Chen; Gao, Xiangdong; Guo, Wei; Yao, Wenbing

2010-09-01

Glucagon-like peptide-1 (GLP-1) is attracting increasing interest on account of its prominent benefits in type 2 diabetes. However, its clinical application is limited because of short biological half-life. This study was designed to produce a C-terminal site-specific PEGylated analog of cysteine-mutated GLP-1 (cGLP-1) to prolong its action. The gene of cGLP-1 was inserted into pET32a to construct a thioredoxinA fusion protein. After expression in BL21 (DE3) strain, the fusion protein was purified with Ni-affinity chromatography and then was PEGylated with methoxy-polyethylene glycol-maleimide (mPEG(10K)-MAL). The PEGylated fusion protein was purified with anion exchange chromatography and then was cleaved by enterokinase. The digested product was further purified with reverse-phase chromatography. Finally, 8.7 mg mPEG(10K)-cGLP-1 with a purity of up to 98% was obtained from the original 500 ml culture. The circular dichroism spectra indicated that mPEG(10K)-cGLP-1 maintained the secondary structure of native GLP-1. As compared with that of native GLP-1, the plasma glucose lowering activity of mPEG(10K)-cGLP-1 was significantly extended. These results suggest that our method will be useful in obtaining a large quantity of mPEG(10K)-cGLP-1 for further study and mPEG(10K)-cGLP-1 might find a role in the therapy of type 2 diabetes through C-terminal site-specific PEGylation.

Basal and glucagon-stimulated plasma C-peptide concentrations in healthy dogs, dogs with diabetes mellitus, and dogs with hyperadrenocorticism.

PubMed

Montgomery, T M; Nelson, R W; Feldman, E C; Robertson, K; Polonsky, K S

1996-01-01

, there was a trend for higher plasma C-peptide concentrations in untreated diabetic dogs compared with insulin-treated diabetic dogs during the glucagon stimulation test. Baseline C-peptide concentrations also were significantly higher (P < .05) in diabetic dogs treated with insulin for less than 6 months, compared with diabetic dogs treated for longer than 1 year. Finally, 7 of 42 diabetic dogs had baseline plasma C-peptide concentrations greater than 2 SD (ie, > 0.29 pmol/mL) above the normal mean plasma C-peptide concentration; values that were significantly higher, compared with the results in healthy dogs (P < .001) and with the other 35 diabetic dogs (P < .001). In summary, measurement of plasma C-peptide concentration during glucagon stimulation testing allowed differentiation among healthy dogs, dogs with impaired beta-cell function (ie, diabetes mellitus), and dogs with increased beta-cell responsiveness to glucagon (ie, insulin resistance). Plasma C-peptide concentrations during glucagon stimulation testing were variable in diabetic dogs and may represent dogs with type-1 and type-2 diabetes or, more likely, differences in severity of beta-cell loss in dogs with type-1 diabetes.

Exogenous glucagon-like peptide-1 reduces body weight and cholecystokinin-8 enhances this reduction in diet-induced obese male rats.

PubMed

Mhalhal, Thaer R; Washington, Martha C; Newman, Kayla; Heath, John C; Sayegh, Ayman I

2017-10-01

The sites of action regulating meal size (MS) and intermeal interval (IMI) length by glucagon like peptide-1 (7-36) (GLP-1 (7-36)) and cholecystokinin-8 (CCK-8) reside in the areas supplied by the two major branches of the abdominal aorta, celiac and cranial mesenteric arteries. We hypothesized that infusing GLP-1 near those sites reduces body weight (BW) and adding CCK-8 to this infusion enhances the reduction. Here, we measured BW in diet-induced obese (DIO) male rats maintained and tested on normal rat chow and infused with saline, GLP-1 (0.5nmol/kg) and GLP-1+CCK-8 (0.5nmol/kg each) in the aorta once daily for 21days. We found that GLP-1 and GLP-1+CCK-8 decrease BW relative to saline vehicle and GLP-1+CCK-8 reduced it more than GLP-1 alone. Reduction of BW by GLP-1 alone was accompanied by decreased 24-h food intake, first MS, duration of first meal and number of meals, and an increase in latency to first meal. Reduction of BW by the combination of the peptides was accompanied by decrease 24-h food intake, first MS, duration of first meal and number of meals, and increase in the IMI length, satiety ratio and latency to first meal. In conclusion, GLP-1 reduces BW and CCK-8 enhances this reduction if the peptides are given near their sites of action. Copyright © 2017 Elsevier Inc. All rights reserved.

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

PubMed

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

2016-06-10

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). 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. 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. Plasma fasting active GLP-1 is an independent predictive marker for the efficacy of dipeptidyl peptidase 4 inhibitor sitagliptin.

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

The glucagon-like peptides: a new genre in therapeutic targets for intervention in Alzheimer's disease.

PubMed

Perry, TracyAnn; Greig, Nigel H

2002-12-01

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an insulinotropic hormone, secreted from the enteroendocrine L cells of the intestinal tract in response to nutrient ingestion. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose in patients with type 2 diabetes mellitus. GLP-1 receptors, which are coupled to the cyclic AMP second messenger pathway, are expressed throughout the brains of rodents and humans. The chemoarchitecture of receptor distribution in the brain correlates well with a central role for GLP-1 in the regulation of food intake and response to aversive stress. We have recently reported that GLP-1 and several longer acting analogs that bind at the GLP-1 receptor, possess neurotrophic properties, and offer protection against glutamate-induced apoptosis and oxidative injury in cultured neuronal cells. Furthermore, GLP-1 can modify processing of the amyloid beta- protein precursor in cell culture and dose-dependently reduces amyloid beta-peptide levels in the brain in vivo. As such, this review discusses the known role of GLP-1 within the central nervous system, and considers the potential of GLP-1 and analogs as novel therapeutic targets for intervention in Alzheimer's disease (AD) and potentially other central and peripheral neurodegenerative conditions.

High fat diet impairs the function of glucagon-like peptide-1 producing L-cells.

PubMed

Richards, Paul; Pais, Ramona; Habib, Abdella M; Brighton, Cheryl A; Yeo, Giles S H; Reimann, Frank; Gribble, Fiona M

2016-03-01

Glucagon-like peptide-1 (GLP-1) acts as a satiety signal and enhances insulin release. This study examined how GLP-1 production from intestinal L-cells is modified by dietary changes. Transgenic mouse models were utilized in which L-cells could be purified by cell specific expression of a yellow fluorescent protein, Venus. Mice were fed on chow or 60% high fat diet (HFD) for 2 or 16 weeks. L-cells were purified by flow cytometry and analysed by microarray and quantitative RT-PCR. Enteroendocrine cell populations were examined by FACS analysis, and GLP-1 secretion was assessed in primary intestinal cultures. Two weeks HFD reduced the numbers of GLP-1 positive cells in the colon, and of GIP positive cells in the small intestine. Purified small intestinal L-cells showed major shifts in their gene expression profiles. In mice on HFD for 16 weeks, significant reductions were observed in the expression of L-cell specific genes, including those encoding gut hormones (Gip, Cck, Sct, Nts), prohormone processing enzymes (Pcsk1, Cpe), granins (Chgb, Scg2), nutrient sensing machinery (Slc5a1, Slc15a1, Abcc8, Gpr120) and enteroendocrine-specific transcription factors (Etv1, Isl1, Mlxipl, Nkx2.2 and Rfx6). A corresponding reduction in the GLP-1 secretory responsiveness to nutrient stimuli was observed in primary small intestinal cultures. Mice fed on HFD exhibited reduced expression in L-cells of many L-cell specific genes, suggesting an impairment of enteroendocrine cell function. Our results suggest that a western style diet may detrimentally affect the secretion of gut hormones and normal post-prandial signaling, which could impact on insulin secretion and satiety. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Long-term management of type 2 diabetes with glucagon-like peptide-1 receptor agonists.

PubMed

Courtney, Hamish; Nayar, Rahul; Rajeswaran, Chinnadorai; Jandhyala, Ravi

2017-01-01

Continuously reducing excess blood glucose is a primary goal for the management of type 2 diabetes (T2D). Most patients with T2D require glucose-lowering medications to achieve and maintain adequate glycemic control; however, treatment failure may occur, limiting treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an emerging therapeutic class that can be prescribed for patients instead of basal insulin after the failure of oral therapies. Recent studies have focused on the durability and tolerability of long-term GLP-1RA therapy. This review summarizes the key efficacy and safety findings from prospective phase 3 clinical studies of at least 76 weeks' duration for the GLP-1RAs currently approved in the United States and the European Union (albiglutide, dulaglutide, exenatide twice daily [BID], exenatide once weekly [QW], liraglutide, and lixisenatide). Currently, most of the long-term data are from uncontrolled extension studies, and continuous patient benefit has been observed for up to 3 years with multiple GLP-1RAs. Four-year comparative data demonstrated a longer time to treatment failure for exenatide BID than for sulfonylurea, and 3-year comparative extension data demonstrated greater glycated hemoglobin (HbA1c) reductions and weight loss with exenatide QW than with insulin glargine. Currently, the longest extension study for a GLP-1RA is the DURATION-1 study of exenatide QW, with >7 years of clinical data available. Data from DURATION-1 demonstrated that continuous HbA1c reductions and weight loss were observed for the patients continuing on the treatment, with no unexpected adverse events. Taken together, these data support GLP-1RAs as a long-term noninsulin treatment option after the failure of oral therapies.

Effect of the Glucagon-like Peptide-1 Analogue Exenatide Extended Release in Cats with Newly Diagnosed Diabetes Mellitus.

PubMed

Riederer, A; Zini, E; Salesov, E; Fracassi, F; Padrutt, I; Macha, K; Stöckle, T M; Lutz, T A; Reusch, C E

2016-01-01

Exenatide extended release (ER) is a glucagon-like peptide-1 analogue that increases insulin secretion, inhibits glucagon secretion and induces satiation in humans with type 2 diabetes mellitus. The use of exenatide ER is safe and stimulates insulin secretion in healthy cats. The objective of this study is to assess the safety of exenatide ER and its effect on body weight, remission and metabolic control in newly diagnosed diabetic cats receiving insulin and a low-carbohydrate diet. Thirty client-owned cats. Prospective placebo-controlled clinical trial. Cats were treated with exenatide ER or 0.9% saline, administered SC, once weekly. Both groups received insulin glargine and a low-carbohydrate diet. Exenatide ER was administered for 16 weeks, or in cats that achieved remission it was given for 4 weeks after discontinuing insulin treatment. Nonparametric tests were used for statistical analysis. Cats in the exenatide ER and placebo groups had transient adverse signs including decreased appetite (60% vs. 20%, respectively, P = .06) and vomiting (53% vs. 40%, respectively, P = .715). Body weight increased significantly in the placebo group (P = .002), but not in cats receiving exenatide ER. Cats on exenatide ER achieved remission or good metabolic control in 40% or 89%, respectively, whereas in control cats percentages were 20% or 58% (P = .427 and P = .178, respectively). Exenatide ER is safe in diabetic cats and does not result in weight gain. Our pilot study suggests that, should there be an additional clinically relevant beneficial effect of exenatide ER in insulin-treated cats on rate of remission and good metabolic control, it would likely approximate 20% and 30%, respectively. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Purification of family B G protein-coupled receptors using nanodiscs: Application to human glucagon-like peptide-1 receptor.

PubMed

Cai, Yingying; Liu, Yuting; Culhane, Kelly J; DeVree, Brian T; Yang, Yang; Sunahara, Roger K; Yan, Elsa C Y

2017-01-01

Family B G protein-coupled receptors (GPCRs) play vital roles in hormone-regulated homeostasis. They are drug targets for metabolic diseases, including type 2 diabetes and osteoporosis. Despite their importance, the signaling mechanisms for family B GPCRs at the molecular level remain largely unexplored due to the challenges in purification of functional receptors in sufficient amount for biophysical characterization. Here, we purified the family B GPCR human glucagon-like peptide-1 (GLP-1) receptor (GLP1R), whose agonists, e.g. exendin-4, are used for the treatment of type 2 diabetes mellitus. The receptor was expressed in HEK293S GnTl- cells using our recently developed protocol. The protocol incorporates the receptor into the native-like lipid environment of reconstituted high density lipoprotein (rHDL) particles, also known as nanodiscs, immediately after the membrane solubilization step followed by chromatographic purification, minimizing detergent contact with the target receptor to reduce denaturation and prolonging stabilization of receptor in lipid bilayers without extra steps of reconstitution. This method yielded purified GLP1R in nanodiscs that could bind to GLP-1 and exendin-4 and activate Gs protein. This nanodisc purification method can potentially be a general strategy to routinely obtain purified family B GPCRs in the 10s of microgram amounts useful for spectroscopic analysis of receptor functions and activation mechanisms.

Purification of family B G protein-coupled receptors using nanodiscs: Application to human glucagon-like peptide-1 receptor

PubMed Central

Cai, Yingying; Liu, Yuting; Culhane, Kelly J.; DeVree, Brian T.; Yang, Yang; Sunahara, Roger K.; Yan, Elsa C. Y.

2017-01-01

Family B G protein-coupled receptors (GPCRs) play vital roles in hormone-regulated homeostasis. They are drug targets for metabolic diseases, including type 2 diabetes and osteoporosis. Despite their importance, the signaling mechanisms for family B GPCRs at the molecular level remain largely unexplored due to the challenges in purification of functional receptors in sufficient amount for biophysical characterization. Here, we purified the family B GPCR human glucagon-like peptide-1 (GLP-1) receptor (GLP1R), whose agonists, e.g. exendin-4, are used for the treatment of type 2 diabetes mellitus. The receptor was expressed in HEK293S GnTl- cells using our recently developed protocol. The protocol incorporates the receptor into the native-like lipid environment of reconstituted high density lipoprotein (rHDL) particles, also known as nanodiscs, immediately after the membrane solubilization step followed by chromatographic purification, minimizing detergent contact with the target receptor to reduce denaturation and prolonging stabilization of receptor in lipid bilayers without extra steps of reconstitution. This method yielded purified GLP1R in nanodiscs that could bind to GLP-1 and exendin-4 and activate Gs protein. This nanodisc purification method can potentially be a general strategy to routinely obtain purified family B GPCRs in the 10s of microgram amounts useful for spectroscopic analysis of receptor functions and activation mechanisms. PMID:28609478

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in the Treatment of Obese Women with Polycystic Ovary Syndrome.

PubMed

Tzotzas, Themistoklis; Karras, Spyridon N; Katsiki, Niki

2017-01-01

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females and is often associated with a number of cardiometabolic disorders such as central obesity, dyslipidaemia, hypertension, insulin resistance, hyperinsulinaemia, glucose intolerance and type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 (GLP-1), a gut hormone secreted after a meal, enhances glucosestimulated insulin secretion and additionally suppresses appetite and gastric motility. Most studies found impaired GLP-1 kinetics in obese individuals, whereas small studies in PCOS reported reduced, normal or even elevated GLP-1 levels. Apart from their efficacy in patients with T2DM, some GLP-1 receptor agonists (GLP-1 RAs) have been successfully tested in terms of both efficiency and safety in obese individuals without diabetes and liraglutide 3 mg once daily has been approved as an antiobesity drug in the USA and the European Union. Recently, some small trials of short duration using GLP-1 RAs as monotherapy or combined with metformin in obese PCOS women showed positive results regarding weight reduction and a decrease in testosterone levels but without significant effects on insulin levels, insulin sensitivity and menstrual patterns. Longer term studies with more patients and higher doses of liraglutide (as this drug is already approved for obese individuals) are required to determine the precise indications of GLP-1 RAs in PCOS and to evaluate safety issues. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Mucosal glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide cell numbers in the super-obese human foregut after gastric bypass.

PubMed

Nergård, Bent J; Lindqvist, Andreas; Gislason, Hjörtur G; Groop, Leif; Ekelund, Mikael; Wierup, Nils; Hedenbro, Jan L

2015-01-01

Super-obesity, a body mass index>50 kg/m(2), is difficult to treat. Many studies have focused on the anatomic changes of the intestines; the physiologic background is not clearly identified. It is established that Roux-en-Y gastric bypass (RYGB) augments secretion of glucagon-like peptide-1 (GLP-1), peptide tyrosine tyrosine (PYY), and insulin, but other aspects of gut hormone cell function in the alimentary limb are unknown. To study the effects of laparoscopic RYGB on enteroendocrine cells. University-affiliated, high-volume bariatric surgery center. Eighteen nondiabetic patients were drawn from the present study (NCT 01514799), randomizing between biliopancreatic (BP) limbs of either 60 cm (BP60) or 200 cm (BP200). Demographic characteristics did not differ at baseline or 12 months. Pouch and jejunal biopsies were obtained intraoperatively and using endoscopy at 12 months. Mucosal height and density of hormone-producing cell populations were assessed and mRNA expression measured with real-time polymerase chain reaction. In perianastomotic jejunum, a 4.9-fold increase in GLP-1 cell density was evident 12 months after RYGB, most pronounced in the BP200-group. The densities of glucose-dependent insulinotropic polypeptide (GIP) cells and PYY immunoreactive cells were doubled after 12 months. GIP mRNA was unaffected, but GLP-1 and PYY mRNA were lower 12 months after RYGB. RYGB had no impact on villi length or density of ghrelin-, cholecystokinin-, neurotensin-, secretin-, or serotonin-producing cells after 12 months. Pouch mucosal height and cell densities of ghrelin-, histamine-, serotonin-, and somatostatin-producing cells remained unaffected by RYGB in both groups. RYGB selectively increased the density of incretin-producing cell populations in the jejunum. This may provide anatomic explanation for the observed increased plasma levels of incretins. Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell.

PubMed

Mulherin, Andrew J; Oh, Amy H; Kim, Helena; Grieco, Anthony; Lauffer, Lina M; Brubaker, Patricia L

2011-12-01

Glucagon-like peptide-1(7-36NH2) (GLP-1) is secreted by the intestinal L cell in response to both nutrient and neural stimulation, resulting in enhanced glucose-dependent insulin secretion. GLP-1 is therefore an attractive therapeutic for the treatment of type 2 diabetes. The antidiabetic drug, metformin, is known to increase circulating GLP-1 levels, although its mechanism of action is unknown. Direct effects of metformin (5-2000 μm) or another AMP kinase activator, aminoimidazole carboxamide ribonucleotide (100-1000 μm) on GLP-1 secretion were assessed in murine human NCI-H716, and rat FRIC L cells. Neither agent stimulated GLP-1 secretion in any model, despite increasing AMP kinase phosphorylation (P < 0.05-0.01). Treatment of rats with metformin (300 mg/kg, per os) or aminoimidazole carboxamide ribonucleotide (250 mg/kg, sc) increased plasma total GLP-1 over 2 h, reaching 37 ± 9 and 29 ± 9 pg/ml (P < 0.001), respectively, compared with basal (7 ± 1 pg/ml). Plasma activity of the GLP-1-degrading enzyme, dipeptidylpeptidase-IV, was not affected by metformin treatment. Pretreatment with the nonspecific muscarinic antagonist, atropine (1 mg/kg, iv), decreased metformin-induced GLP-1 secretion by 55 ± 11% (P < 0.05). Pretreatment with the muscarinic (M) 3 receptor antagonist, 1-1-dimethyl-4-diphenylacetoxypiperidinium iodide (500 μg/kg, iv), also decreased the GLP-1 area under curve, by 48 ± 8% (P < 0.05), whereas the antagonists pirenzepine (M1) and gallamine (M2) had no effect. Furthermore, chronic bilateral subdiaphragmatic vagotomy decreased basal secretion compared with sham-operated animals (7 ± 1 vs. 13 ± 1 pg/ml, P < 0.001) but did not alter the GLP-1 response to metformin. In contrast, pretreatment with the gastrin-releasing peptide antagonist, RC-3095 (100 μg/kg, sc), reduced the GLP-1 response to metformin, by 55 ± 6% (P < 0.01) at 30 min. These studies elucidate the mechanism underlying metformin-induced GLP-1 secretion and highlight the

Acarbose improves hypoglycaemia following gastric bypass surgery without increasing glucagon-like peptide 1 levels.

PubMed

Valderas, Juan Patricio; Ahuad, Jessica; Rubio, Lorena; Escalona, Manuel; Pollak, Felipe; Maiz, Alberto

2012-04-01

Postprandial hypoglycaemia is a severe complication of Roux-en-Y gastric bypass (RYGBP). Acarbose, an α-glucosidase inhibitor (AGI), is employed in its treatment. Several studies have shown that AGIs increase the postprandial levels of glucagon-like peptide 1 (GLP-1). However, an excessive level of GLP-1 is one of the factors involved in the physiopathology of this condition. We analysed the effect of acarbose oral administration in eight RYBGP patients with clinically significant hypoglycaemia or dumping syndrome. Glucose, insulin and GLP-1 plasma levels in fasting and after ingestion of a standard meal (Ensure Plus®; 13 g protein, 50 g carbohydrate, 11 g fat) were measured. The test was repeated the following week with the oral administration of 100 mg of acarbose 15 min prior to the meal. Five patients developed asymptomatic hypoglycaemia during the test (glucose level <50 mg/dl) with inappropriately high insulin levels and exaggerated GLP-1 response. Acarbose ingestion avoided hypoglycaemia in all of the patients and increased the lowest plasma glucose level (46.4 ± 4.8 vs. 59.0 ± 2.6 mg/dl, p < 0.01). Acarbose ingestion decreased the area under the curve for serum insulin and GLP-1 levels at 15 min after the meal. Acarbose avoided postprandial hypoglycaemia following RYGBP by decreasing the hyperinsulinemic response. This was associated with a decrease in early GLP-1 secretion, in contrast to that observed in non-surgical subjects. This finding could be explained by the reduction of glucose load in the jejunum produced by the α-glucosidase inhibition, which is the main stimulus for GLP-1 secretion.

Compensation for obesity-induced insulin resistance in dogs: assessment of the effects of leptin, adiponectin, and glucagon-like peptide-1 using path analysis.

PubMed

Verkest, K R; Fleeman, L M; Morton, J M; Ishioka, K; Rand, J S

2011-07-01

The hormonal mediators of obesity-induced insulin resistance and compensatory hyperinsulinemia in dogs have not been identified. Plasma samples were obtained after a 24-h fast from 104 client-owned lean, overweight, and obese dogs. Plasma glucose and insulin concentrations were used to calculate insulin sensitivity and β-cell function with the use of the homeostasis model assessment (HOMA(insulin sensitivity) and HOMA(β-cell function), respectively). Path analysis with multivariable linear regression was used to identify whether fasting plasma leptin, adiponectin, or glucagon-like peptide-1 concentrations were associated with adiposity, insulin sensitivity, and basal insulin secretion. None of the dogs were hyperglycemic. In the final path model, adiposity was positively associated with leptin (P < 0.01) and glucagon-like peptide-1 (P = 0.04) concentrations. No significant total effect of adiposity on adiponectin in dogs (P = 0.24) was observed. If there is a direct effect of leptin on adiponectin, then our results indicate that this is a positive relationship, which at least partly counters a negative direct relationship between adiposity and adiponectin. Fasting plasma leptin concentration was directly negatively associated with fasting insulin sensitivity (P = 0.01) and positively associated with β-cell function (P < 0.01), but no direct association was observed between adiponectin concentration and either insulin sensitivity or β-cell function (P = 0.42 and 0.11, respectively). We conclude that dogs compensate effectively for obesity-induced insulin resistance. Fasting plasma leptin concentrations appear to be associated with obesity-associated changes in insulin sensitivity and compensatory hyperinsulinemia in naturally occurring obese dogs. Adiponectin does not appear to be involved in the pathophysiology of obesity-associated changes in insulin sensitivity. Copyright © 2011 Elsevier Inc. All rights reserved.

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

LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose.

PubMed

Powell, David R; Smith, Melinda; Greer, Jennifer; Harris, Angela; Zhao, Sharon; DaCosta, Christopher; Mseeh, Faika; Shadoan, Melanie K; Sands, Arthur; Zambrowicz, Brian; Ding, Zhi-Ming

2013-05-01

LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], a dual sodium/glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor, is thought to decrease both renal glucose reabsorption by inhibiting SGLT2 and intestinal glucose absorption by inhibiting SGLT1. In clinical trials in patients with type 2 diabetes mellitus (T2DM), LX4211 treatment improved glycemic control while increasing circulating levels of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2-/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1-/- mice had increased levels of plasma GLP-1, plasma PYY, and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area under the curve (AUC) values, whereas SGLT2-/- mice showed no response. LX4211-treated mice and SGLT1-/- mice also had increased GLP-1 AUC values, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC values, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice and were decreased in SGLT1-/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels 5 minutes after oral glucose. These data suggest that LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM.

Sustained glucagon-like peptide 1 expression from encapsulated transduced cells to treat obese diabetic rats

PubMed Central

Moralejo, Daniel; Yanay, Ofer; Kernan, Kelly; Bailey, Adam; Lernmark, Ake; Osborne, William

2011-01-01

Obesity and type 2 diabetes (T2D) are two prevalent chronic diseases that have become a major public health concern in industrialized countries. T2D is characterized by hyperglycemia and islet beta cell dysfunction. Glucagon-like peptide 1 (GLP-1) promotes β cell proliferation and neogenesis and has a potent insulinotropic effect. Leptin receptor deficient male rats are obese and diabetic and provide a model of T2D. We hypothesized that their treatment by sustained expression of GLP-1 using encapsulated cells may prevent or delay diabetes onset. Vascular smooth muscle cells (VSMC) retrovirally transduced to secrete GLP-1 were seeded into TheraCyteTM encapsulation devices, implanted subcutaneously and rats monitored for diabetes. Rats that received cell implants showed mean plasma GLP-1 level of 119.3±10.2 pM that was significantly elevated over control values of 32.4±2.9 pM (P<0.001). GLP-1 treated rats had mean insulin levels of 45.9±2.3 ng/ml that were significantly increased over control levels of 7.3±1.5 ng/ml (P<0.001). In rats treated before diabetes onset elevations in blood glucose were delayed and rats treated after onset became normoglycemic and showed improved glucose tolerance tests. Untreated diabetic rats possess abnormal islet structures characterized by enlarged islets with β-cell infiltration and multifocal vacuolization. GLP-1 treatment induced normalization of islet structures including a mantle of β-cells and increased islet mass. These data suggest encapsulated transduced cells may offer a potential long term treatment of patients. PMID:21216666

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. © 2016 John Wiley & Sons Ltd.

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

Integrative function of adrenaline receptors for glucagon-like peptide-1 exocytosis in enteroendocrine L cell line GLUTag.

PubMed

Harada, Kazuki; Kitaguchi, Tetsuya; Tsuboi, Takashi

2015-05-15

Adrenaline reacts with three types of adrenergic receptors, α1, α2 and β-adrenergic receptors (ARs), inducing many physiological events including exocytosis. Although adrenaline has been shown to induce glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells, the precise molecular mechanism by which adrenaline regulates GLP-1 secretion remains unknown. Here we show by live cell imaging that all types of adrenergic receptors are stimulated by adrenaline in enteroendocrine L cell line GLUTag cells and are involved in GLP-1 exocytosis. We performed RT-PCR analysis and found that α1B-, α2A-, α2B-, and β1-ARs were expressed in GLUTag cells. Application of adrenaline induced a significant increase of intracellular Ca(2+) and cAMP concentration ([Ca(2+)]i and [cAMP]i, respectively), and GLP-1 exocytosis in GLUTag cells. Blockade of α1-AR inhibited adrenaline-induced [Ca(2+)]i increase and exocytosis but not [cAMP]i increase, while blockade of β1-AR inhibited adrenaline-induced [cAMP]i increase and exocytosis but not [Ca(2+)]i increase. Furthermore, overexpression of α2A-AR suppressed the adrenaline-induced [cAMP]i increase and exocytosis. These results suggest that the fine-turning of GLP-1 secretion from enteroendocrine L cells is established by the balance between α1-, α2-, and β-ARs activation. Copyright © 2015 Elsevier Inc. All rights reserved.

Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus: A Position Statement of the Korean Diabetes Association.

PubMed

Kim, Hyun Jin; Park, Seok O; Ko, Seung Hyun; Rhee, Sang Youl; Hur, Kyu Yeon; Kim, Nan Hee; Moon, Min Kyong; Lee, Byung Wan; Kim, Jin Hwa; Choi, Kyung Mook

2017-12-01

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin in the position statement of the Korean Diabetes Association 2017 for pharmacological therapy. Many randomized clinical trials and systematic reviews report that GLP-1RAs have considerable glucose-lowering effect and lead to weight reduction and low risk of hypoglycemia when used as a monotherapy or combination therapy. The cardiovascular safety of GLP-1RAs has been assessed in several randomized clinical trials and systematic reviews. The results of cardiovascular outcome trials of long-acting GLP-1RAs (liraglutide, semaglutide) demonstrated cardiovascular benefits in subjects with type 2 diabetes mellitus and a high risk of cardiovascular disease. The GLP-1RA may be a choice of therapy when weight control and avoidance of hypoglycemia are important, and patients with high risk of cardiovascular disease might also favor choosing GLP-1RA. Copyright © 2017 Korean Diabetes Association.

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

Reducing gut effects from Cryptosporidium parvum infection in dairy calves through prophylactic glucagon-like peptide 2 therapy or feeding of an artificial sweetener

USDA-ARS?s Scientific Manuscript database

Glucagon-like peptide 2 (GLP-2) therapy was shown previously to reduce inflammation-related gut damage from coccidiosis in dairy calves, and feeding of artificial sweetener stimulates GLP-2 secretion from intestinal L cells. The purpose of this study was to determine whether GLP-2 treatment or artif...

Acute but not chronic activation of brain glucagon-like peptide-1 receptors enhances glucose-stimulated insulin secretion in mice.

PubMed

Tudurí, E; Beiroa, D; Porteiro, B; López, M; Diéguez, C; Nogueiras, R

2015-08-01

To investigate the role of brain glucagon-like peptide-1 (GLP-1) in pancreatic β-cell function. To determine the role of brain GLP-1 receptor (GLP-1R) on β-cell function, we administered intracerebroventricular (i.c.v.) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), in both an acute and a chronic setting. We observed that acute i.c.v. GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired glucose excursion after a glucose load. Sustained activation of central nervous system GLP-1R, however, did not produce any effect on either GSIS or glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with i.c.v. GLP-1 resulted in no differences compared with controls. In addition, in mice fed a high-fat diet we observed that acute i.c.v. GLP-1 infusion improved glucose tolerance without changes in GSIS, while chronic GLP-1R activation had no effect on glucose homeostasis. Our results indicate that, under non-clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents. © 2015 John Wiley & Sons Ltd.

Hyperphagia and Increased Fat Accumulation in Two Models of Chronic CNS Glucagon-Like Peptide-1 Loss of Function

PubMed Central

Jones, Kenneth R.; Herman, James P.; D'Alessio, David A.; Woods, Stephen C.; Seeley, Randy J.

2011-01-01

Central administration of glucagon-like peptide-1 (GLP-1) causes a dose-dependent reduction in food intake, but the role of endogenous CNS GLP-1 in the regulation of energy balance remains unclear. Here, we tested the hypothesis that CNS GLP-1 activity is required for normal energy balance by using two independent methods to achieve chronic CNS GLP-1 loss of function in rats. Specifically, lentiviral-mediated expression of RNA interference was used to knock down nucleus of the solitary tract (NTS) preproglucagon (PPG), and chronic intracerebroventricular (ICV) infusion of the GLP-1 receptor (GLP-1r) antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r. NTS PPG knockdown caused hyperphagia and exacerbated high-fat diet (HFD)-induced fat accumulation and glucose intolerance. Moreover, in control virus-treated rats fed the HFD, NTS PPG expression levels correlated positively with fat mass. Chronic ICV Ex9 also caused hyperphagia; however, increased fat accumulation and glucose intolerance occurred regardless of diet. Collectively, these data provide the strongest evidence to date that CNS GLP-1 plays a physiologic role in the long-term regulation of energy balance. Moreover, they suggest that this role is distinct from that of circulating GLP-1 as a short-term satiation signal. Therefore, it may be possible to tailor GLP-1-based therapies for the prevention and/or treatment of obesity. PMID:21389245

Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function.

PubMed

Barrera, Jason G; Jones, Kenneth R; Herman, James P; D'Alessio, David A; Woods, Stephen C; Seeley, Randy J

2011-03-09

Central administration of glucagon-like peptide-1 (GLP-1) causes a dose-dependent reduction in food intake, but the role of endogenous CNS GLP-1 in the regulation of energy balance remains unclear. Here, we tested the hypothesis that CNS GLP-1 activity is required for normal energy balance by using two independent methods to achieve chronic CNS GLP-1 loss of function in rats. Specifically, lentiviral-mediated expression of RNA interference was used to knock down nucleus of the solitary tract (NTS) preproglucagon (PPG), and chronic intracerebroventricular (ICV) infusion of the GLP-1 receptor (GLP-1r) antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r. NTS PPG knockdown caused hyperphagia and exacerbated high-fat diet (HFD)-induced fat accumulation and glucose intolerance. Moreover, in control virus-treated rats fed the HFD, NTS PPG expression levels correlated positively with fat mass. Chronic ICV Ex9 also caused hyperphagia; however, increased fat accumulation and glucose intolerance occurred regardless of diet. Collectively, these data provide the strongest evidence to date that CNS GLP-1 plays a physiologic role in the long-term regulation of energy balance. Moreover, they suggest that this role is distinct from that of circulating GLP-1 as a short-term satiation signal. Therefore, it may be possible to tailor GLP-1-based therapies for the prevention and/or treatment of obesity.

Sustained glucagon-like peptide 1 expression from encapsulated transduced cells to treat obese diabetic rats.

PubMed

Moralejo, Daniel; Yanay, Ofer; Kernan, Kelly; Bailey, Adam; Lernmark, Ake; Osborne, William

2011-04-01

Obesity and type 2 diabetes (T2D) are two prevalent chronic diseases that have become a major public health concern in industrialized countries. T2D is characterized by hyperglycemia and islet beta cell dysfunction. Glucagon-like peptide 1 (GLP-1) promotes β cell proliferation and neogenesis and has a potent insulinotropic effect. Leptin receptor deficient male rats are obese and diabetic and provide a model of T2D. We hypothesized that their treatment by sustained expression of GLP-1 using encapsulated cells may prevent or delay diabetes onset. Vascular smooth muscle cells (VSMC) retrovirally transduced to secrete GLP-1 were seeded into TheraCyte(TM) encapsulation devices, implanted subcutaneously and rats were monitored for diabetes. Rats that received cell implants showed mean plasma GLP-1 level of 119.3 ± 10.2pM that was significantly elevated over control values of 32.4 ± 2.9pM (P<0.001). GLP-1 treated rats had mean insulin levels of 45.9 ± 2.3ng/ml that were significantly increased over control levels of 7.3±1.5ng/ml (P<0.001). In rats treated before diabetes onset elevations in blood glucose were delayed and rats treated after onset became normoglycemic and showed improved glucose tolerance tests. Untreated diabetic rats possess abnormal islet structures characterized by enlarged islets with α-cell infiltration and multifocal vacuolization. GLP-1 treatment induced normalization of islet structures including a mantle of α-cells and increased islet mass. These data suggest that encapsulated transduced cells may offer a potential long term treatment of patients. Copyright © 2010 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Update in Cardiovascular Safety of Glucagon Like Peptide-1 Receptor Agonists In Patients With Type 2 Diabetes. A Mixed Treatment Comparison Meta-Analysis of Randomised Controlled Trials.

PubMed

Al Yami, Majed S; Alfayez, Osamah M; Alsheikh, Razan

2018-03-29

The aim of this mixed treatment comparison (MTC) meta-analysis was to determine glucagon like peptide-1 (GLP-1) receptor agonists' effects on cardiovascular (CV) outcomes in patients with type 2 diabetes (T2DM). A comprehensive, systematic review was conducted using EMBASE and Medline databases. All included trials were large CV outcome trials of GLP-1 agonists versus placebo in T2DM. The primary outcomes of this MTC meta-analysis were death from CV causes, non-fatal MI, and non-fatal stroke. Hospitalisation for heart failure (HF) was evaluated as a secondary endpoint. A total of four trials, including 33,457 patients, met eligibility criteria and were retained for the meta-analysis. Our pairwise meta-analysis results showed a 13% reduction in death from cardiovascular causes in patients who received GLP-1 agonists versus placebo (RR 0.87, 95% CI: 0.78-0.96). However, no statistically significant reduction was observed with GLP-1 agonists in terms of reducing non-fatal MI (RR 0.95, 95% CI: 0.86-1.04), non-fatal stroke events (RR 0.89, 95% CI: 0.76-1.03), and rates of HF hospitalisation (RR 0.94, 95% CI: 0.84-1.04). The network meta-analysis (NMA) showed no significant differences among all the interventions. Glucagon like peptide-1 therapy was associated with a significant reduction in cardiovascular (CV) death. However, GLP-1 agonists seem to have a safety profile comparable to placebo in terms of reducing non-fatal myocardial infarction (MI), non-fatal stroke events, and rates of HF hospitalisation. Copyright © 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Glucagon-Like Peptide 1 Recruits Muscle Microvasculature and Improves Insulin’s Metabolic Action in the Presence of Insulin Resistance

PubMed Central

Chai, Weidong; Zhang, Xingxing; Barrett, Eugene J.

2014-01-01

Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid infusion) or chronically (high-fat diet [HFD]) before and after a euglycemic-hyperinsulinemic clamp (3 mU/kg/min) with or without superimposed systemic GLP-1 infusion. Insulin significantly recruited muscle microvasculature and addition of GLP-1 further expanded muscle MBV and increased insulin-mediated glucose disposal. GLP-1 infusion potently recruited muscle microvasculature in the presence of either acute or chronic insulin resistance by increasing muscle MBV. This was associated with an increased muscle delivery of insulin and muscle interstitial oxygen saturation. Muscle insulin sensitivity was completely restored in the presence of systemic lipid infusion and significantly improved in rats fed an HFD. We conclude that GLP-1 infusion potently expands muscle microvascular surface area and improves insulin’s metabolic action in the insulin-resistant states. This may contribute to improved glycemic control seen in diabetic patients receiving incretin-based therapy. PMID:24658303

[Glucagon-like peptide 2, a neurotransmitter with a newly discovered role in the regulation of food ingestion].

PubMed

Tang-Christensen, M; Larsen, P J; Thulesen, J; Nielsen, J R; Vrang, N

2001-01-15

We report here that glucagon-like peptide 2(GLP-2) and its receptor constitute a distinct projection system connecting the nucleus of the solitary tract with the dorsomedial hypothalamic nucleus (DMH). The DMH contains a dense plexus of GLP-2 immunoreactive fibres and is the only hypothalamic nucleus expressing GLP-2 receptor mRNA. Consistent with this, central application of GLP-2 activates the expression of neurones solely in the DMH. Furthermore, central administration of GLP-2 causes a dose-related, a pharmacologically and behaviourally specific inhibition of food intake in rats. Surprisingly, the alleged GLP-1 receptor antagonist, Exending (9-39), proved a functional antagonist of centrally applied GLP-2. These data implicate GLP-2 as an important neurotransmitter in the regulation of food intake and likely bodyweight. Our data therefore point to the DMH as a crossroad for endocrine and visceral information affecting feeding behaviour.

Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses.

PubMed

Bouhlal, Sofia; Ellefsen, Kayla N; Sheskier, Mikela B; Singley, Erick; Pirard, Sandrine; Gorelick, David A; Huestis, Marilyn A; Leggio, Lorenzo

2017-11-01

Food intake and use of drugs of abuse like cocaine share common central and peripheral physiological pathways. Appetitive hormones play a major role in regulating food intake; however, little is known about the effects of acute cocaine administration on the blood concentrations of these hormones in cocaine users. We evaluated serum concentrations of six appetitive hormones: ghrelin (total and acyl-ghrelin), amylin, glucagon-like peptide-1 (GLP-1), insulin, leptin and peptide YY (PYY), as well as acute cardiorespiratory and subjective responses of 8 experienced cocaine users who received 25mg intravenous (IV) cocaine. Serum concentrations of GLP-1 (p=0.014) and PYY (p=0.036) were significantly decreased one hour following IV cocaine administration; there was a trend towards a decrease for insulin (p=0.055) and amylin (p=0.063) concentrations, while no significant IV cocaine effect was observed for ghrelin (total or acyl-ghrelin) or leptin concentrations (p's≫>0.5). We also observed associations between hormone concentrations acutely affected by IV cocaine (GLP-1, PYY, insulin, amylin) and some cocaine-related cardiorespiratory and subjective responses (e.g., increased heart and respiratory rates; feeling high and anxious). These findings show a significant effect of acute IV cocaine administration on some appetitive hormones and suggest potential associations between these hormones and cocaine-related cardiorespiratory and subjective responses. Additional research is needed to further investigate the potential mechanisms underlining these associations. Published by Elsevier B.V.

First cytoplasmic loop of glucagon-like peptide-1 receptor can function at the third cytoplasmic loop position of rhodopsin.

PubMed

Yamashita, Takahiro; Tose, Koji; Shichida, Yoshinori

2008-01-01

G protein-coupled receptors (GPCRs) are classified into several families based on their amino acid sequences. In family 1, GPCRs such as rhodopsin and adrenergic receptor, the structure-function relationship has been extensively investigated to demonstrate that exposure of the third cytoplasmic loop is essential for selective G protein activation. In contrast, much less is known about other families. Here we prepared chimeric mutants between Gt-coupled rhodopsin and Gi/Go- and Gs-coupled glucagon-like peptide-1 (GLP-1) receptor of family 2 and tried to identify the loop region that functions at the third cytoplasmic loop position of rhodopsin. We succeeded in expressing a mutant having the first cytoplasmic loop of GLP-1 receptor and found that this mutant activated Gi and Go efficiently but did not activate Gt. Moreover, the rhodopsin mutant having the first loop of Gs-coupled secretin receptor of family 2 decreased the Gi and Go activation efficiencies. Therefore, the first loop of GLP-1 receptor would share a similar role to the third loop of rhodopsin in G protein activation. This result strongly suggested that different families of GPCRs have maintained molecular architectures of their ancestral types to generate a common mechanism, namely exposure of the cytoplasmic loop, to activate peripheral G protein.

Glucagon-related peptides in the mouse retina and the effects of deprivation of form vision.

PubMed

Mathis, Ute; Schaeffel, Frank

2007-02-01

In chickens, retinal glucagon amacrine cells play an important role in emmetropization, since they express the transcription factor ZENK (also known as NGFI-A, zif268, tis8, cef5, Krox24) in correlation with the sign of imposed image defocus. Pharmacological studies have shown that glucagon can act as a stop signal for axial eye growth, making it a promising target for pharmacological intervention of myopia. Unfortunately, in mammalian retina, glucagon itself has not yet been detected by immunohistochemical staining. To learn more about its possible role in emmetropization in mammals, we studied the expression of different members of the glucagon hormone family in mouse retina, and whether their abundance is regulated by visual experience. Black wildtype C57BL/6 mice, raised under a 12/12 h light/dark cycle, were studied at postnatal ages between P29 and P40. Frosted hemispherical thin plastic shells (diffusers) were placed in front of the right eyes to impose visual conditions that are known to induce myopia. The left eyes remained uncovered and served as controls. Transversal retinal cryostat sections were single- or double-labeled by indirect immunofluorescence for early growth response protein 1 (Egr-1, the mammalian ortholog of ZENK), glucagon, glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), peptide histidine isoleucine (PHI), growth hormone-releasing hormone (GHRH), pituitary adenylate cyclase-activating polypeptide (PACAP), secretin, and vasoactive intestinal polypeptide (VIP). In total, retinas of 45 mice were studied, 28 treated with diffusers, and 17 serving as controls. Glucagon itself was not detected in mouse retina. VIP, PHI, PACAP and GIP were localized. VIP was co-localized with PHI and Egr-1, which itself was strongly regulated by retinal illumination. Diffusers, applied for various durations (1, 2, 6, and 24 h) had no effect on the expression of VIP, PHI, PACAP, and GIP, at least at the protein level. Similarly

Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats.

PubMed

Krieger, Jean-Philippe; Santos da Conceição, Ellen Paula; Sanchez-Watts, Graciela; Arnold, Myrtha; Pettersen, Klaus G; Mohammed, Mazher; Modica, Salvatore; Lossel, Pius; Morrison, Shaun F; Madden, Christopher J; Watts, Alan G; Langhans, Wolfgang; Lee, Shin J

2018-05-30

Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VAN). Recently, VAN have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is however unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE), and whether this VAN mechanism contributes to energy balance. First, we tested the effect of the GLP-1R agonist Exendin-4 (Ex4, 0.3 μg/kg IP) on EE and BAT thermogenesis, and whether these effects require VAN GLP-1R signaling, using a rat model with a selective Glp1r knockdown (kd) in VAN. Second, we examined the role of VAN GLP-1R in energy balance during chronic high-fat diet (HFD) feeding in VAN Glp1r kd rats. Lastly, we used viral transsynaptic tracers to identify the possible neuronal substrates of such a gut-BAT interaction. VAN Glp1r kd attenuated the acute suppressive effects of Ex4 on EE and BAT thermogenesis. Consistent with this finding, the VAN Glp1r kd increased EE and BAT activity, diminished body weight gain, and improved insulin sensitivity compared to HFD-fed controls. Anterograde transsynaptic viral tracing of VAN infected major hypothalamic and hindbrain areas involved in BAT sympathetic regulation. Moreover, retrograde tracing from BAT combined with laser capture microdissection revealed that a population of VAN expressing Glp1r is synaptically connected to the BAT. Our findings reveal a novel role of VAN GLP-1R signaling in the regulation of EE and BAT thermogenesis, and imply that through this gut-brain-BAT connection intestinal GLP-1 plays a role in HFD-induced metabolic syndrome.

New gene targets for glucagon-like peptide-1 during embryonic development and in undifferentiated pluripotent cells.

PubMed

Sanz, Carmen; Blázquez, Enrique

2011-09-01

In humans, glucagon-like peptide (GLP-1) functions during adult life as an incretin hormone with anorexigenic and antidiabetogenic properties. Also, the therapeutic potential of GLP-1 in preventing the adipocyte hyperplasia associated with obesity and in bolstering the maintenance of human mesenchymal stem cell (hMSC) stores by promoting the proliferation and cytoprotection of hMSC seems to be relevant. Since these observations suggest a role for GLP-1 during developmental processes, the aim of the present work was to characterize GLP-1 in early development as well as its gene targets in mouse embryonic stem (mES) cells. Mouse embryos E6, E8, and E10.5 and pluripotent mES were used for the inmunodetection of GLP-1 and GLP-1 receptor. Quantitative real-time PCR was used to determine the expression levels of GLP-1R in several tissues from E12.5 mouse embryos. Additionally, GLP-1 gene targets were studied in mES by multiple gene expression analyses. GLP-1 and its receptors were identified in mES and during embryonic development. In pluripotent mES, GLP-1 modified the expression of endodermal, ectodermal, and mesodermal gene markers as well as sonic hedgehog, noggin, members of the fibroblast and hepatic growth factor families, and others involved in pancreatic development. Additionally, GLP-1 promoted the expression of the antiapoptotic gene bcl2 and at the same time reduced proapoptotic caspase genes. Our results indicate that apart from the effects and therapeutic benefits of GLP-1 in adulthood, it may have additional gene targets in mES cells during embryonic life. Furthermore, the pathophysiological implications of GLP-1 imbalance in adulthood may have a counterpart during development.

A grape seed extract increases active glucagon-like peptide-1 levels after an oral glucose load in rats.

PubMed

González-Abuín, Noemi; Martínez-Micaelo, Neus; Margalef, Maria; Blay, Mayte; Arola-Arnal, Anna; Muguerza, Begoña; Ardévol, Anna; Pinent, Montserrat

2014-09-01

We have previously reported that procyanidins, a class of flavonoids, improve glycemia and exert an incretin-like effect, which was linked to their proven inhibitory effect on the dipeptidyl-peptidase 4 (DPP4) activity. However, their actual effect on incretin levels has not been reported yet. Therefore, in the present study we have evaluated whether a grape seed extract enriched in procyanidins (GSPE) modulates plasma incretin levels and attempted to determine the mechanisms involved. An acute GSPE treatment in healthy Wistar female rats prior to an oral glucose load induced an increase in plasma active glucagon-like peptide-1 (GLP-1), which was accompanied by an increase in the plasma insulin/glucose ratio and a simultaneous decrease in glucose levels. In agreement with our previous studies, the intestinal DPP4 activity was inhibited by the GSPE treatment. We have also assayed in vitro whether this inhibition occurs in inner intestinal tissues close to GLP-1-producing cells, such as the endothelium of the capillaries. We have found that the main compounds absorbed by intestinal CaCo-2 cells after an acute treatment with GSPE are catechin, epicatechin, B2 dimer and gallic acid, and that they inhibit the DPP4 activity in endothelial HUVEC cells in an additive way. Moreover, an increase in plasma total GLP-1 levels was found, suggesting an increase in GLP-1 secretion. In conclusion, our results show that GSPE improves glycemia through its action on GLP-1 secretion and on the inhibition of the inner intestinal DPP4 activity, leading to an increase in active GLP-1 levels, which, in turn, may affect the insulin release.

Non-invasive glucagon-like peptide-1 receptor imaging in pancreas with (18)F-Al labeled Cys(39)-exendin-4.

PubMed

Mi, Baoming; Xu, Yuping; Pan, Donghui; Wang, Lizhen; Yang, Runlin; Yu, Chunjing; Wan, Weixing; Wu, Yiwei; Yang, Min

2016-02-26

Glucagon-like peptide-1 receptor (GLP-1R) is abundantly expressed on beta cells and may be an ideal target for the pancreas imaging. Monitoring the GLP-1R of pancreas could be benefit for understanding the pathophysiology of diabetes. In the present study, (18)F-Al labeled exendin-4 analog, (18)F-Al-NOTA-MAL-Cys(39)-exendin-4, was evaluated for PET imaging GLP-1R in the pancreas. The targeting of (18)F-Al labeled exendin-4 analog was examined in healthy and streptozotocin induced diabetic rats. Rats were injected with (18)F-Al-NOTA-MAL-Cys(39)-exendin-4 and microPET imaging was performed at 1 h postinjection, followed by ex vivo biodistribution. GLP-1R expression in pancreas was determined through post mortern examinations. The pancreas of healthy rats was readily visualized after administration of (18)F-Al-NOTA-MAL-Cys(39)-exendin-4, whereas the pancreas of diabetic rats, as well as those from rats co-injected with excess of unlabeled peptides, was barely visible by microPET. At 60 min postinjection, the pancreatic uptakes were 1.02 ± 0.15%ID/g and 0.23 ± 0.05%ID/g in healthy and diabetic rats respectively. Under block, the pancreatic uptakes of non-diabetic rats reduced to 0.21 ± 0.07%ID/g at the same time point. Biodistribution data and IHC staining confirmed the findings of the microPET imaging. The favorable preclinical data indicated that (18)F-Al-NOTA-MAL-Cys(39)-exendin-4may be suitable for non-invasive monitoring functional pancreatic beta cells. Copyright © 2016 Elsevier Inc. All rights reserved.

Glucagon-like peptide-1 reduces pancreatic β-cell mass through hypothalamic neural pathways in high-fat diet-induced obese rats.

PubMed

Ando, Hisae; Gotoh, Koro; Fujiwara, Kansuke; Anai, Manabu; Chiba, Seiichi; Masaki, Takayuki; Kakuma, Tetsuya; Shibata, Hirotaka

2017-07-17

We examined whether glucagon-like peptide-1 (GLP-1) affects β-cell mass and proliferation through neural pathways, from hepatic afferent nerves to pancreatic efferent nerves via the central nervous system, in high-fat diet (HFD)-induced obese rats. The effects of chronic administration of GLP-1 (7-36) and liraglutide, a GLP-1 receptor agonist, on pancreatic morphological alterations, c-fos expression and brain-derived neurotrophic factor (BDNF) content in the hypothalamus, and glucose metabolism were investigated in HFD-induced obese rats that underwent hepatic afferent vagotomy (VgX) and/or pancreatic efferent sympathectomy (SpX). Chronic GLP-1 (7-36) administration to HFD-induced obese rats elevated c-fos expression and BDNF content in the hypothalamus, followed by a reduction in pancreatic β-cell hyperplasia and insulin content, thus resulting in improved glucose tolerance. These responses were abolished by VgX and SpX. Moreover, administration of liraglutide similarly activated the hypothalamic neural pathways, thus resulting in a more profound amelioration of glucose tolerance than native GLP-1 (7-36). These data suggest that GLP-1 normalizes the obesity-induced compensatory increase in β-cell mass and glucose intolerance through a neuronal relay system consisting of hepatic afferent nerves, the hypothalamus, and pancreatic efferent nerves.

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.

Mody-3: novel HNF1A mutation and the utility of glucagon-like peptide (GLP)-1 receptor agonist therapy.

PubMed

Docena, Maricor K; Faiman, Charles; Stanley, Christine M; Pantalone, Kevin M

2014-02-01

An estimated 1 to 2% of cases of diabetes mellitus have a monogenic basis; however, delayed diagnosis and misdiagnosis as type 1 and 2 diabetes are common. Correctly identifying the molecular basis of an individual's diabetes may significantly alter the management approach to both the patient and his or her relatives. We describe a case of mature onset diabetes of the young (MODY) with sufficient evidence to support the classification of a novel HNF1A (hepatocyte nuclear factor-1-α) mutation as a cause of MODY-3. A 21-year-old Caucasian female presented to our office with a diagnosis of noninsulin-dependent diabetes mellitus (NIDDM) at age 10; glycemia was initially managed with oral antidiabetic (OAD) agents and insulin detemir. The patient reported a strong family history of early-onset NIDDM in both her mother and maternal grandmother, both of whom eventually required insulin therapy to control glycemia. The patient's medical and family history were highly suggestive of maturity-onset diabetes of the young (MODY), and genetic testing was performed. Genetic screening detected a mutation p. Arg200Trp in the HNF1A gene in the patient, her mother, and maternal grandmother, suggesting a diagnosis of MODY-3. This finding resulted in a change of antidiabetic therapy in all 3 patients, including the addition of once-daily liraglutide therapy, which helped improve their glycemic control. Our case report supports the classification of the p. Arg200Trp mutation as a cause of MODY-3. The findings also suggest that glucagon-like peptide-1 (GLP-1) receptor agonist therapy may be of value in managing glycemia in patients with MODY-3.

[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. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Lipid Raft-dependent Glucagon-like Peptide-2 Receptor Trafficking Occurs Independently of Agonist-induced Desensitization

PubMed Central

Estall, Jennifer L.; Yusta, Bernardo; Drucker, Daniel J.

2004-01-01

The intestinotrophic and cytoprotective actions of glucagon-like peptide-2 (GLP-2) are mediated by the GLP-2 receptor (GLP-2R), a member of the class II glucagon-secretin G protein-coupled receptor superfamily. Although native GLP-2 exhibits a short circulating half-life, long-acting degradation-resistant GLP-2 analogues are being evaluated for therapeutic use in human subjects. Accordingly, we examined the mechanisms regulating signaling, internalization, and trafficking of the GLP-2R to identify determinants of receptor activation and desensitization. Heterologous cells expressing the transfected rat or human GLP-2R exhibited a rapid, dose-dependent, and prolonged desensitization of the GLP-2–stimulated cAMP response and a sustained GLP-2–induced decrease in levels of cell surface receptor. Surprisingly, inhibitors of clathrin-dependent endocytosis failed to significantly decrease GLP-2R internalization, whereas cholesterol sequestration inhibited ligand-induced receptor internalization and potentiated homologous desensitization. The hGLP-2R localized to both Triton X-100–soluble and –insoluble (lipid raft) cellular fractions and colocalized transiently with the lipid raft marker caveolin-1. Although GLP-2R endocytosis was dependent on lipid raft integrity, the receptor transiently associated with green fluorescent protein tagged-early endosome antigen 1–positive vesicles and inhibitors of endosomal acidification attenuated the reappearance of the GLP-2R on the cell surface. Our data demonstrate that GLP-2R desensitization and raft-dependent trafficking represent distinct and independent cellular mechanisms and provide new evidence implicating the importance of a clathrin- and dynamin-independent, lipid raft-dependent pathway for homologous G protein-coupled receptor internalization. PMID:15169869

Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve fibres in inflammatory bowel disease and functional effects in cultured neurons.

PubMed

Anand, Uma; Yiangou, Yiangos; Akbar, Ayesha; Quick, Tom; MacQuillan, Anthony; Fox, Mike; Sinisi, Marco; Korchev, Yuri E; Jones, Ben; Bloom, Steve R; Anand, Praveen

2018-01-01

Glucagon like-peptide 1 receptor (GLP-1R) agonists diminish appetite and may contribute to the weight loss in inflammatory bowel disease (IBD). The aim of this study was to determine, for the first time, the expression of GLP-1R by colon nerve fibres in patients with IBD, and functional effects of its agonists in cultured rat and human sensory neurons. GLP-1R and other nerve markers were studied by immunohistochemistry in colon biopsies from patients with IBD (n = 16) and controls (n = 8), human dorsal root ganglia (DRG) tissue, and in GLP-1R transfected HEK293 cells. The morphological effects of incretin hormones oxyntomodulin, exendin-4 and glucagon were studied on neurite extension in cultured DRG neurons, and their functional effects on capsaicin and ATP signalling, using calcium imaging. Significantly increased numbers of colonic mucosal nerve fibres were observed in IBD biopsies expressing GLP-1R (p = 0.0013), the pan-neuronal marker PGP9.5 (p = 0.0008), and sensory neuropeptide CGRP (p = 0.0014). An increase of GLP-1R positive nerve fibres in IBD colon was confirmed with a different antibody to GLP-1R (p = 0.016). GLP-1R immunostaining was intensely positive in small and medium-sized neurons in human DRG, and in human and rat DRG cultured neurons. Co-localization of GLP-1R expression with neuronal markers in colon and DRG confirmed the neural expression of GLP-1R, and antibody specificity was confirmed in HEK293 cells transfected with the GLP-1R. Treatment with oxyntomodulin, exendin-4 and GLP-1 increased neurite length in cultured neurons compared with controls, but did not stimulate calcium influx directly, or affect capsaicin responses. However, exendin-4 significantly enhanced ATP responses in human DRG neurons. Our results show that increased GLP-1R innervation in IBD bowel could mediate enhanced visceral afferent signalling, and provide a peripheral target for therapeutic intervention. The differential effect of GLP-1R agonists on capsaicin and ATP

Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve fibres in inflammatory bowel disease and functional effects in cultured neurons

PubMed Central

Yiangou, Yiangos; Akbar, Ayesha; Quick, Tom; MacQuillan, Anthony; Fox, Mike; Sinisi, Marco; Korchev, Yuri E.; Jones, Ben; Bloom, Steve R.; Anand, Praveen

2018-01-01

Introduction Glucagon like-peptide 1 receptor (GLP-1R) agonists diminish appetite and may contribute to the weight loss in inflammatory bowel disease (IBD). Objectives The aim of this study was to determine, for the first time, the expression of GLP-1R by colon nerve fibres in patients with IBD, and functional effects of its agonists in cultured rat and human sensory neurons. Methods GLP-1R and other nerve markers were studied by immunohistochemistry in colon biopsies from patients with IBD (n = 16) and controls (n = 8), human dorsal root ganglia (DRG) tissue, and in GLP-1R transfected HEK293 cells. The morphological effects of incretin hormones oxyntomodulin, exendin-4 and glucagon were studied on neurite extension in cultured DRG neurons, and their functional effects on capsaicin and ATP signalling, using calcium imaging. Results Significantly increased numbers of colonic mucosal nerve fibres were observed in IBD biopsies expressing GLP-1R (p = 0.0013), the pan-neuronal marker PGP9.5 (p = 0.0008), and sensory neuropeptide CGRP (p = 0.0014). An increase of GLP-1R positive nerve fibres in IBD colon was confirmed with a different antibody to GLP-1R (p = 0.016). GLP-1R immunostaining was intensely positive in small and medium-sized neurons in human DRG, and in human and rat DRG cultured neurons. Co-localization of GLP-1R expression with neuronal markers in colon and DRG confirmed the neural expression of GLP-1R, and antibody specificity was confirmed in HEK293 cells transfected with the GLP-1R. Treatment with oxyntomodulin, exendin-4 and GLP-1 increased neurite length in cultured neurons compared with controls, but did not stimulate calcium influx directly, or affect capsaicin responses. However, exendin-4 significantly enhanced ATP responses in human DRG neurons. Conclusion Our results show that increased GLP-1R innervation in IBD bowel could mediate enhanced visceral afferent signalling, and provide a peripheral target for therapeutic intervention. The differential

Anti-glucagon-like peptide-1 immunoreactivity in samples of blood and ileum obtained from neonatal and adult alpacas.

PubMed

Smith, Courtney C; Cebra, Christopher K; Heidel, Jerry R; Stang, Bernadette V

2013-11-01

To compare numbers of L cells in intestinal samples and blood concentrations of glucagon-like peptide (GLP)-1 between neonatal and mature alpacas. Intestinal samples from carcasses of 4 suckling crias and 4 postweaning alpacas for immunohistochemical analysis and blood samples from 32 suckling crias and 19 healthy adult alpacas for an ELISA. Immunohistochemical staining was conducted in accordance with Oregon State University Veterinary Diagnostic Laboratory standard procedures with a rabbit polyclonal anti-GLP-1 primary antibody. Stained cells with staining results in ileal tissue were counted in 20 fields by 2 investigators, and the mean value was calculated. For quantification of GLP-1 concentrations, blood samples were collected into tubes containing a dipeptidyl peptidase-4 inhibitor. Plasma samples were tested in duplicate with a commercial GLP-1 ELISA validated for use in alpacas. Counts of stained cells (mean ± SD, 50 ± 18 cells) and plasma GLP-1 concentrations (median, 0.086 ng/mL; interquartile range, 0.061 to 0.144 ng/mL) were higher for suckling alpacas than for postsuckling alpacas (stained cells, 26 ± 4 cells; plasma GLP-1 concentration, median, 0.034 ng/mL; interquartile range, 0.015 to 0.048 ng/mL). Older alpacas had lower numbers of L cells in intestinal tissues and lower blood concentrations of GLP-1 than those in neonates. These findings suggested that there may be a decrease in the contribution of GLP-1 to insulin production in adult alpacas, compared with the contribution in neonates.

Gαs regulates Glucagon-Like Peptide 1 Receptor-mediated cyclic AMP generation at Rab5 endosomal compartment.

PubMed

Girada, Shravan Babu; Kuna, Ramya S; Bele, Shilpak; Zhu, Zhimeng; Chakravarthi, N R; DiMarchi, Richard D; Mitra, Prasenjit

2017-10-01

Upon activation, G protein coupled receptors (GPCRs) associate with heterotrimeric G proteins at the plasma membrane to initiate second messenger signaling. Subsequently, the activated receptor experiences desensitization, internalization, and recycling back to the plasma membrane, or it undergoes lysosomal degradation. Recent reports highlight specific cases of persistent cyclic AMP generation by internalized GPCRs, although the functional significance and mechanistic details remain to be defined. Cyclic AMP generation from internalized Glucagon-Like Peptide-1 Receptor (GLP-1R) has previously been reported from our laboratory. This study aimed at deciphering the molecular mechanism by which internalized GLP-R supports sustained cyclic AMP generation upon receptor activation in pancreatic beta cells. We studied the time course of cyclic AMP generation following GLP-1R activation with particular emphasis on defining the location where cyclic AMP is generated. Detection involved a novel GLP-1 conjugate coupled with immunofluorescence using specific endosomal markers. Finally, we employed co-immunoprecipitation as well as immunofluorescence to assess the protein-protein interactions that regulate GLP-1R mediated cyclic AMP generation at endosomes. Our data reveal that prolonged association of G protein α subunit Gαs with activated GLP-1R contributed to sustained cyclic AMP generation at Rab 5 endosomal compartment. The findings provide the mechanism of endosomal cyclic AMP generation following GLP-1R activation. We identified the specific compartment that serves as an organizing center to generate endosomal cyclic AMP by internalized activated receptor complex. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

Enteroendocrine-derived glucagon-like peptide-2 controls intestinal amino acid transport.

PubMed

Lee, Jennifer; Koehler, Jacqueline; Yusta, Bernardo; Bahrami, Jasmine; Matthews, Dianne; Rafii, Mahroukh; Pencharz, Paul B; Drucker, Daniel J

2017-03-01

Glucagon-like peptide-2 (GLP-2) is co-secreted with GLP-1 from gut endocrine cells, and both peptides act as growth factors to expand the surface area of the mucosal epithelium. Notably, GLP-2 also enhances glucose and lipid transport in enterocytes; however, its actions on control of amino acid (AA) transport remain unclear. Here we examined the mechanisms linking gain and loss of GLP-2 receptor (GLP-2R) signaling to control of intestinal amino acid absorption in mice. Absorption, transport, and clearance of essential AAs, specifically lysine, were measured in vivo by Liquid Chromatography triple quadrupole Mass Spectrometry (LC-MS/MS) and ex vivo with Ussing chambers using intestinal preparations from Glp2 r +/+ and Glp2r - / - mice. Immunoblotting determined jejunal levels of protein components of signaling pathways (PI3K-AKT, and mTORC1-pS6-p4E-BP1) following administration of GLP-2, protein gavage, and rapamycin to fasted Glp2 r +/+ and Glp2r - / - mice. Expression of AA transporters from full thickness jejunum and 4F2hc from brush border membrane vesicles (BBMVs) was measured by real-time PCR and immunoblotting, respectively. Acute administration of GLP-2 increased basal AA absorption in vivo and augmented basal lysine transport ex vivo . GLP-2-stimulated lysine transport was attenuated by co-incubation with wortmannin, rapamycin, or tetrodotoxin ex vivo . Phosphorylation of mTORC1 effector proteins S6 and 4E-BP1 was significantly increased in wild-type mice in response to GLP-2 alone, or when co-administered with protein gavage, and abolished following oral gavage of rapamycin. In contrast, activation of GLP-1R signaling did not enhance S6 phosphorylation. Disruption of GLP-2 action in Glp2r -/- mice reduced lysine transport ex vivo and attenuated the phosphorylation of S6 and 4E-BP1 in response to oral protein. Moreover, the expression of cationic AA transporter slc7a9 in response to refeeding, and the abundance of 4F2hc in BBMVs following protein

Swim training restores glucagon-like peptide-1 insulinotropic action in pancreatic islets from monosodium glutamate-obese rats.

PubMed

Svidnicki, P V; de Carvalho Leite, N; Venturelli, A C; Camargo, R L; Vicari, M R; de Almeida, M C; Artoni, R F; Nogaroto, V; Grassiolli, S

2013-09-01

Glucagon-like peptide-1 (GLP-1) is an important modulator of insulin secretion by endocrine pancreas. In the present study, we investigated the effect of swim training on GLP-1 insulinotropic action in pancreatic islets from monosodium glutamate (MSG)-obese rats. Obesity was induced by neonatal MSG administration. MSG-obese and control (CON) exercised rats swam for 30 min (3 times week(-1) ) for 10 weeks. Pancreatic islets were isolated by colagenase technique and incubated with low (5.6 mM) or high (16.7 mM) glucose concentrations in the presence or absence of GLP-1 (10 nM). In addition, GLP-1 gene expression in ileum was quantified in fasting and glucose conditions. Exercise reduced obesity and hyperinsulinemia in MSG-obese rats. Swim training also inhibited glucose-induced insulin secretion in islets from both groups. Islets from MSG-obese rats maintained GLP-1 insulinotropic response in low glucose concentration. In contrast, in the presence of high glucose concentration, GLP-1 insulinotropic action was absent in islets from MSG-obese rats. Islets from MSG-exercised rats showed reduced GLP-1 insulinotropic action in the presence of low glucose. However, in high glucose concentration swim training restored GLP-1 insulinotropic response in islets from MSG-obese rats. In all groups, glucose intake increased GLP-1 immunoreactivity and gene expression in ileum cells in relation to fasting conditions. Swim training reduced these parameters only in ileum cells from CON-exercised rats. Neither MSG treatment nor exercise affected GLP-1 expression in the ileum. Exercise avoids insulin hypersecretion restoring GLP-1's insulinotropic action in pancreatic islets from MSG-obese rats. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta-analysis of randomized clinical trials.

PubMed

Mabilleau, Guillaume; Mieczkowska, Aleksandra; Chappard, Daniel

2014-05-01

Patients with type 2 diabetes mellitus (T2DM) are at a higher risk of bone fractures independent of the use of antidiabetic medications. Furthermore, antidiabetic medications could directly affect bone metabolism. Recently, the use of dipeptidyl peptidase-4 inhibitors has been associated with a lower rate of bone fracture. The aim of the present meta-analysis was to assess whether patients with T2DM treated with glucagon-like peptide-1 receptor agonists (GLP-1Ra) present a lower incidence of bone fracture compared with patients using other antidiabetic drugs. A search on Medline, Embase, and http://www.clinicaltrials.gov, as well as a manual search for randomized clinical trials of T2DM treated with either a GLP-1Ra or another antidiabetic drug for a duration of ≥24 weeks was conducted by two authors (GM, AM) independently. Although 28 eligible studies were identified, only seven trials reported the occurrence of at least a bone fracture in one arm of the trial. The total number of fractures was 19 (13 and six with GLP-1Ra and comparator, respectively). The pooled Mantel-Haenszel odds ratio for GLP-1Ra was 0.75 (95% confidence interval 0.28-2.02, P = 0.569) in trials versus other antidiabetic agents. Although preliminary, our study highlighted that the use of GLP-1Ra does not modify the risk of bone fracture in T2DM compared with the use of other antidiabetic medications. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Encapsulated Glucagon-Like Peptide-1-Producing Mesenchymal Stem Cells Have a Beneficial Effect on Failing Pig Hearts

PubMed Central

Wright, Elizabeth J.; Farrell, Kelly A.; Malik, Nadim; Kassem, Moustapha; Lewis, Andrew L.; Wallrapp, Christine

2012-01-01

Stem cell therapy is an exciting and emerging treatment option to promote post-myocardial infarction (post-MI) healing; however, cell retention and efficacy in the heart remain problematic. Glucagon-like peptide-1 (GLP-1) is an incretin hormone with cardioprotective properties but a short half-life in vivo. The effects of prolonged GLP-1 delivery from stromal cells post-MI were evaluated in a porcine model. Human mesenchymal stem cells immortalized and engineered to produce a GLP-1 fusion protein were encapsulated in alginate (bead-GLP-1 MSC) and delivered to coronary artery branches. Control groups were cell-free beads and beads containing unmodified MSCs (bead-MSC), n = 4–5 per group. Echocardiography confirmed left ventricular (LV) dysfunction at time of delivery in all groups. Four weeks after intervention, only the bead-GLP-1 MSC group demonstrated LV function improvement toward baseline and showed decreased infarction area compared with controls. Histological analysis showed reduced inflammation and a trend toward reduced apoptosis in the infarct zone. Increased collagen but fewer myofibroblasts were observed in infarcts of the bead-GLP-1 MSC and bead-MSC groups, and significantly more vessels per mm2 were noted in the infarct of the bead-GLP-1 MSC group. No differences were observed in myocyte cross-sectional area between groups. Post-MI delivery of GLP-1 encapsulated genetically modified MSCs provided a prolonged supply of GLP-1 and paracrine stem cell factors, which improved LV function and reduced epicardial infarct size. This was associated with increased angiogenesis and an altered remodeling response. Combined benefits of paracrine stem cell factors and GLP-1 were superior to those of stem cells alone. These results suggest that encapsulated genetically modified MSCs would be beneficial for recovery following MI. PMID:23197668

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. Copyright © 2016 Elsevier Inc. All rights reserved.

A novel GIP analogue, ZP4165, enhances glucagon-like peptide-1-induced body weight loss and improves glycaemic control in rodents.

PubMed

Nørregaard, Pia K; Deryabina, Maria A; Tofteng Shelton, Pernille; Fog, Jacob U; Daugaard, Jens R; Eriksson, Per-Olof; Larsen, Lone F; Jessen, Lene

2018-01-01

To investigate the effects of the novel glucose-dependent insulinotropic polypeptide (GIP) analogue, ZP4165, on body weight and glycaemic control in rodents, and to investigate if ZP4165 modulates the anti-obesity and anti-hyperglycaemic effects of a glucagon-like peptide-1 (GLP-1) agonist (liraglutide). The acute insulinotropic effect of ZP4165 was investigated in rats during an oral glucose tolerance test. The long-term effects of ZP4165 on body weight and glycaemic control, either alone or in combination with liraglutide, were assessed in diet-induced obese mice and diabetic db/db mice. ZP4165 showed insulinotropic action in rats. The GIP analogue did not alter the body weight of obese mice but enhanced GLP-1-induced weight loss. In diabetic mice, 4 weeks' dosing with ZP4165 reduced glycated haemoglobin levels vs vehicle by an extent similar to the GLP-1 agonist. ZP4165 potentiated the anti-obesity effect of a GLP-1 agonist in obese mice and improved glycaemic control in diabetic mice. These studies support further investigation of dual-incretin therapy as a more effective treatment option than mono GLP-1 medication for type 2 diabetes mellitus and obesity. © 2017 John Wiley & Sons Ltd.

Yield improvement of heterologous peptides expressed in yps1-disrupted Saccharomyces cerevisiae strains.

PubMed

Egel-Mitani; Andersen; Diers; Hach; Thim; Hastrup; Vad

2000-06-01

Heterologous protein expression levels in Saccharomyces cerevisiae fermentations are highly dependent on the susceptibility to endogenous yeast proteases. Small peptides, such as glucagon and glucagon-like-peptides (GLP-1 and GLP-2), featuring an open structure are particularly accessible for proteolytic degradation during fermentation. Therefore, homogeneous products cannot be obtained. The most sensitive residues are found at basic amino acid residues in the peptide sequence. These heterologous peptides are degraded mainly by the YPS1-encoded aspartic protease, yapsin1, when produced in the yeast. In this article, distinct degradation products were analyzed by HPLC and mass spectrometry, and high yield of the heterologous peptide production has been achieved by the disruption of the YPS1 gene (previously called YAP3). By this technique, high yield continuous fermentation of glucagon in S. cerevisiae is now possible.

Treatment Strategy for Type 2 Diabetes with Obesity: Focus on Glucagon-like Peptide-1 Receptor Agonists.

PubMed

Ji, Qiuhe

2017-06-01

The progressive nature of type 2 diabetes mellitus (T2DM) calls for step-wise intensification of therapy for maintaining normal glycemic levels and lowering cardiovascular (CV) risk. Because obesity is a prominent risk factor and comorbidity of T2DM, it further elevates the CV risk in T2DM. Therefore, it is vital to manage weight, obesity, and glycemic parameters for effective T2DM management. Few oral antidiabetic drugs (sulfonylureas and thiazolidinediones) and insulin are not suitable for obese patients with T2DM because these drugs cause weight gain. The present review discusses the place of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of obese patients with T2DM and the significance of these drugs in the prevention of future CV risk in patients with T2DM. A literature search of PubMed and EMBASE was conducted by using the search terms T2DM, GLP-1RAs, obesity, and cardiovascular complication. Randomized controlled trials measuring the effect of GLP-1RAs versus that of placebo on CV outcomes were included in the review. GLP-1RAs have emerged as a therapeutic alternative; these drugs exert their actions by providing glycemic control, improving insulin resistance and ö̇-cell function, and reducing weight. The risk of hypoglycemia with GLP-1RAs is minimal; however, GLP-1RAs are associated with gastrointestinal adverse events and raise concerns regarding pancreatitis. Combining GLP-1RAs with insulin analogues results in higher efficacy, a lowered insulin dose, and reduced insulin-related hypoglycemia and weight gain. Longer acting GLP-1RAs are also associated with improvement in medication adherence. Improvement in CV risk factors such as blood pressure and lipid profile further increases their usability for improving CV outcomes. Overall, the properties of GLP-1RAs make them suitable for combination with oral antidiabetic drugs in the early stages of T2DM and with insulins in the later stages for optimizing comprehensive management of the

Enhanced Glucose Control Following Vertical Sleeve Gastrectomy Does Not Require a β-Cell Glucagon-Like Peptide 1 Receptor.

PubMed

Douros, Jonathan D; Lewis, Alfor G; Smith, Eric P; Niu, JingJing; Capozzi, Megan; Wittmann, April; Campbell, Jonathan; Tong, Jenny; Wagner, Constance; Mahbod, Parinaz; Seeley, Randy; D'Alessio, David A

2018-05-14

Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell specific Glp1r knockdown ( Glp1r β-cell-ko ). Mice with VSG lost ∼20% of body weight over 30 days compared to sham-operated controls and had a ∼60% improvement in glucose tolerance. Isolated islets from VSG mice had significantly greater insulin responses to glucose than controls. Glp1r knockdown in β-cells caused glucose intolerance in diet-induced obese mice compared to obese controls, but VSG improved glycemic profiles to similar levels during oral and intraperitoneal glucose challenges in Glp1r βcell-ko and Glp1r WT mice. Therefore, while the β-cell GLP-1R seems to be important for maintaining glucose tolerance in obese mice, in these experiments it is dispensable for the improvement in glucose tolerance after VSG. Moreover, the metabolic physiology activated by VSG can overcome the deficits in glucose regulation caused by lack of β-cell GLP-1 signaling in obesity. © 2018 by the American Diabetes Association.

Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus.

PubMed

Hogan, Andrew E; Gaoatswe, Gadintshware; Lynch, Lydia; Corrigan, Michelle A; Woods, Conor; O'Connell, Jean; O'Shea, Donal

2014-04-01

Glucagon-like peptide 1 (GLP-1) is a gut hormone used in the treatment of type 2 diabetes mellitus. There is emerging evidence that GLP-1 has anti-inflammatory activity in humans, with murine studies suggesting an effect on macrophage polarisation. We hypothesised that GLP-1 analogue therapy in individuals with type 2 diabetes mellitus would affect the inflammatory macrophage molecule soluble CD163 (sCD163) and adipocytokine profile. We studied ten obese type 2 diabetes mellitus patients starting GLP-1 analogue therapy at a hospital-based diabetes service. We investigated levels of sCD163, TNF-α, IL-1β, IL-6, adiponectin and leptin by ELISA, before and after 8 weeks of GLP-1 analogue therapy. GLP-1 analogue therapy reduced levels of the inflammatory macrophage activation molecule sCD163 (220 ng/ml vs 171 ng/ml, p < 0.001). This occurred independent of changes in body weight, fructosamine and HbA1c. GLP-1 analogue therapy was associated with a decrease in levels of the inflammatory cytokines TNF-α (264 vs 149 pg/ml, p < 0.05), IL-1β (2,919 vs 748 pg/ml, p < 0.05) and IL-6 (1,379 vs 461 pg/ml p < 0.05) and an increase in levels of the anti-inflammatory adipokine adiponectin (4,480 vs 6,290 pg/ml, p < 0.002). In individuals with type 2 diabetes mellitus, GLP-1 analogue therapy reduces the frequency of inflammatory macrophages. This effect is not dependent on the glycaemic or body weight effects of GLP-1.

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.

GLP-1/glucagon receptor co-agonism for treatment of obesity.

PubMed

Sánchez-Garrido, Miguel A; Brandt, Sara J; Clemmensen, Christoffer; Müller, Timo D; DiMarchi, Richard D; Tschöp, Matthias H

2017-10-01

Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacological attempts to treat obesity have had limited success, with notable adverse effects, rendering bariatric surgery as the only current therapy for substantially improving body weight. Novel unimolecular, multifunctional peptides have emerged as one of the most promising medicinal approaches to enhance metabolic efficacy and restore normal body weight. In this review, we will mainly focus on the discovery and translational relevance of dual agonists that pharmacologically function at the receptors for glucagon and glucagon-like peptide-1. Such peptides have advanced to clinical evaluation and inspired the pursuit of multiple related approaches to achieving polypharmacy within single molecules.

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.

Feedback suppression of meal-induced glucagon-like peptide-1 (GLP-1) secretion mediated through elevations in intact GLP-1 caused by dipeptidyl peptidase-4 inhibition: a randomized, prospective comparison of sitagliptin and vildagliptin treatment.

PubMed

Baranov, Oleg; Kahle, Melanie; Deacon, Carolyn F; Holst, Jens J; Nauck, Michael A

2016-11-01

To compare directly the clinical effects of vildagliptin and sitagliptin in patients with type 2 diabetes, with a special emphasis on incretin hormones and L-cell feedback inhibition induced by dipeptidyl peptidase (DPP-4) inhibition. A total of 24 patients (12 on a diet/exercise regimen, 12 on metformin) were treated, in randomized order, for 7-9 days, with either vildagliptin (50 mg twice daily = 100 mg/d), sitagliptin (100 mg once daily in those on diet, 50 mg twice daily in those on metformin treatment = 100 mg/d) or placebo (twice daily). A mixed-meal test was performed. Intact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide concentrations were doubled by both DPP-4 inhibitors. Meal-related total GLP-1 responses were reduced by vildagliptin and sitagliptin treatment alike in the majority of patients (vildagliptin: p = 0.0005; sitagliptin: p = 0.019), but with substantial inter-individual variation. L-cell feedback appeared to be more pronounced in those whose intact GLP-1 relative to total GLP-1 increased more, and who had greater reductions in fasting plasma glucose after DPP-4 inhibition. K-cell feedback inhibition overall was not significant. There were no differences in any of the clinical variables (glycaemia, insulin and glucagon secretory responses) between vildagliptin and sitagliptin treatment. Vildagliptin and sitagliptin affected incretin hormones, glucose concentrations, insulin and glucagon secretion in a similar manner. Inter-individual variations in L-cell feedback inhibition may indicate heterogeneity in the clinical response to DPP-4 inhibition. © 2016 John Wiley & Sons Ltd.

Associations between changes in glucagon-like peptide-1 and bodyweight reduction in patients receiving acarbose or metformin treatment.

PubMed

Wang, Na; Zhang, Jin-Ping; Xing, Xiao-Yan; Yang, Zhao-Jun; Zhang, Bo; Wang, Xin; Yang, Wen-Ying

2017-08-01

The present post hoc analysis investigated whether changes in endogenous glucagon-like peptide-1 (∆GLP-1) levels are associated with weight loss in newly diagnosed diabetes patients. In all, 784 subjects from the Metformin and AcaRbose in Chinese as initial Hypoglycemic treatment (MARCH) study were stratified according to ∆GLP-1. Changes in clinical and physiological parameters were evaluated across ∆GLP-1 subgroups (low, medium, and high) to assess correlations between ∆GLP-1 and weight loss in acarbose- versus metformin-treated groups. After 24 weeks treatment, greater ∆GLP-1 was associated with significantly greater weight loss (-2 vs -1 kg in the medium/high vs low ∆GLP-1 groups, respectively) and reduction in body mass index (BMI; -0.88, -0.83, and -0.69 kg/m 2 in the high, medium, and low ∆GLP-1 groups, respectively). In the acarbose-treated group, there was a significant association between ∆GLP-1 and BMI reductions, and greater ∆GLP-1 across the high, medium, and low ∆GLP-1 groups was correlated with greater weight loss (-2.8, -2.1, and -1.9 kg, respectively) and reductions in fasting plasma glucose (-1.57, -1.28, and -1.02 mmol/L, respectively) at Week 24. No significant differences were found across ∆GLP-1 subgroups in metformin-treated patients (P > 0.05). Multivariate linear regression analysis revealed that gender, baseline BMI, and ∆GLP-1 at Week 24 were associated with weight loss. Baseline BMI and ∆GLP-1 in the acarbose-treated group and baseline BMI in the metformin-treated group predicted weight loss at Week 24. Changes in GLP-1 levels are associated with weight loss in newly diagnosed Chinese diabetes patients receiving acarbose. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

New screening strategy and analysis for identification of allosteric modulators for glucagon-like peptide-1 receptor using GLP-1 (9-36) amide.

PubMed

Nakane, Atsushi; Gotoh, Yusuke; Ichihara, Junji; Nagata, Hidetaka

2015-12-15

The glucagon-like peptide-1 receptor (GLP-1R) is an important physiologic regulator of insulin secretion and a major therapeutic target for diabetes mellitus. GLP-1 (7-36) amide (active form of GLP-1) is truncated to GLP-1 (9-36) amide, which has been described as a weak agonist of GLP-1R and the major form of GLP-1 in the circulation. New classes of positive allosteric modulators (PAMs) for GLP-1R may offer improved therapeutic profiles. To identify these new classes, we developed novel and robust primary and secondary high-throughput screening (HTS) systems in which PAMs were identified to enhance the GLP-1R signaling induced by GLP-1 (9-36) amide. Screening enabled identification of two compounds, HIT-465 and HIT-736, which possessed new patterns of modulation of GLP-1R. We investigated the ability of these compounds to modify GLP-1R signaling enhanced GLP-1 (9-36) amide- and/or GLP-1 (7-36) amide-mediated cyclic adenosine monophosphate (cAMP) accumulation. These compounds also had unique profiles with regard to allosteric modulation of multiple downstream signaling (PathHunter β-arrestin signaling, PathHunter internalization signaling, microscopy-based internalization assay). We found allosteric modulation patterns to be obviously different among HIT-465, HIT-736, and Novo Nordisk compound 2. This work may enable the design of new classes of drug candidates by targeting modulation of GLP-1 (7-36) amide and GLP-1 (9-36) amide. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of exogenous glucagon-like peptide-2 and distal bowel resection on intestinal and systemic adaptive responses in rats

PubMed Central

de Heuvel, Elaine; Wallace, Laurie E.; Hartmann, Bolette; Holst, Jens J.; Brindle, Mary E.; Chelikani, Prasanth K.; Sigalet, David L.

2017-01-01

Objective To determine the effects of exogenous glucagon-like peptide-2 (GLP-2), with or without massive distal bowel resection, on adaptation of jejunal mucosa, enteric neurons, gut hormones and tissue reserves in rats. Background GLP-2 is a gut hormone known to be trophic for small bowel mucosa, and to mimic intestinal adaptation in short bowel syndrome (SBS). However, the effects of exogenous GLP-2 and SBS on enteric neurons are unclear. Methods Sprague Dawley rats were randomized to four treatments: Transected Bowel (TB) (n = 8), TB + GLP-2 (2.5 nmol/kg/h, n = 8), SBS (n = 5), or SBS + GLP-2 (2.5 nmol/kg/h, n = 9). SBS groups underwent a 60% jejunoileal resection with cecectomy and jejunocolic anastomosis. All rats were maintained on parenteral nutrition for 7 d. Parameters measured included gut morphometry, qPCR for hexose transporter (SGLT-1, GLUT-2, GLUT-5) and GLP-2 receptor mRNA, whole mount immunohistochemistry for neurons (HuC/D, VIP, nNOS), plasma glucose, gut hormones, and body composition. Results Resection increased the proportion of nNOS immunopositive myenteric neurons, intestinal muscularis propria thickness and crypt cell proliferation, which were not recapitulated by GLP-2 therapy. Exogenous GLP-2 increased jejunal mucosal surface area without affecting enteric VIP or nNOS neuronal immunopositivity, attenuated resection-induced reductions in jejunal hexose transporter abundance (SGLT-1, GLUT-2), increased plasma amylin and decreased peptide YY concentrations. Exogenous GLP-2 attenuated resection-induced increases in blood glucose and body fat loss. Conclusions Exogenous GLP-2 stimulates jejunal adaptation independent of enteric neuronal VIP or nNOS changes, and has divergent effects on plasma amylin and peptide YY concentrations. The novel ability of exogenous GLP-2 to modulate resection-induced changes in peripheral glucose and lipid reserves may be important in understanding the whole-body response following intestinal resection, and is worthy

Non-invasive glucagon-like peptide-1 receptor imaging in pancreas with {sup 18}F-Al labeled Cys{sup 39}-exendin-4

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mi, Baoming; Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University; Xu, Yuping

Purpose: Glucagon-like peptide-1 receptor (GLP-1R) is abundantly expressed on beta cells and may be an ideal target for the pancreas imaging. Monitoring the GLP-1R of pancreas could be benefit for understanding the pathophysiology of diabetes. In the present study, {sup 18}F-Al labeled exendin-4 analog, {sup 18}F-Al-NOTA-MAL-Cys{sup 39}-exendin-4, was evaluated for PET imaging GLP-1R in the pancreas. Methods: The targeting of {sup 18}F-Al labeled exendin-4 analog was examined in healthy and streptozotocin induced diabetic rats. Rats were injected with {sup 18}F-Al-NOTA-MAL-Cys{sup 39}-exendin-4 and microPET imaging was performed at 1 h postinjection, followed by ex vivo biodistribution. GLP-1R expression in pancreas was determined throughmore » post mortern examinations. Results: The pancreas of healthy rats was readily visualized after administration of {sup 18}F-Al-NOTA-MAL-Cys{sup 39}-exendin-4, whereas the pancreas of diabetic rats, as well as those from rats co-injected with excess of unlabeled peptides, was barely visible by microPET. At 60 min postinjection, the pancreatic uptakes were 1.02 ± 0.15%ID/g and 0.23 ± 0.05%ID/g in healthy and diabetic rats respectively. Under block, the pancreatic uptakes of non-diabetic rats reduced to 0.21 ± 0.07%ID/g at the same time point. Biodistribution data and IHC staining confirmed the findings of the microPET imaging. Conclusion: The favorable preclinical data indicated that {sup 18}F-Al-NOTA-MAL-Cys{sup 39}-exendin-4may be suitable for non-invasive monitoring functional pancreatic beta cells.« less

The Impacts of Gastroileostomy Rat Model on Glucagon-like Peptide-1: a Promising Model to Control Type 2 Diabetes Mellitus.

PubMed

Keleidari, Behrouz; Mohammadi Mofrad, Rastin; Shahabi Shahmiri, Shahab; Sanei, Mohammad Hossein; Kolahdouzan, Mohsen; Sheikhbahaei, Erfan

2018-05-21

One of the new current treatment options for Diabetes Mellitus is about increasing glucagon-like peptide-1 (GLP-1) activity. GLP-1 with its incretin effect showed major role in glucose homeostasis. Gastroileostomy can increase GLP-1 secretion by rapid delivery of undigested food to the terminal ileum. We studied the early effects of a gastroileostomy on serum levels of GLP-1, glucose, and insulin in rats. Gastroileostomies with side-to-side anastomosis were performed on 15 male New Zealand rats. Blood samples were obtained before and 1 week after the gastroileostomy. Our results showed that the rats lost a lot of weight from start (330 ± 15 g) to the end (240 ± 25 g) of the experiment (p = 0.048). The data analysis showed that the gastroileostomy surgery elevates the level of GLP-1in plasma significantly (89.1852 vs. 177.440 respectively; p < 0.001) and caused a significant decrease in plasma glucose as well (92.00 and 66.29 mg/dL respectively; p < 0.001). However, the insulin state elevated after the surgery significantly (8.03 vs. 9.89; p < 0.001). In this study, we showed the effectiveness of gastroileostomy treatment to decrease body weight and plasma glucose with increased GLP-1 in rats. This small rat model suggests the potential of this surgery to treat type 2 diabetes mellitus.

Short communication: The effect of delayed colostrum feeding on plasma concentrations of glucagon-like peptide 1 and 2 in newborn calves.

PubMed

Inabu, Y; Fischer, A; Song, Y; Guan, L L; Oba, M; Steele, M A; Sugino, T

2018-07-01

Glucagon-like peptide (GLP)-1 is involved in glucose homeostasis via its role in stimulating insulin secretion, whereas GLP-2 increases mucosal growth of the small intestine. To our knowledge, the effect of delayed colostrum feeding on plasma GLP-1 and GLP-2 in neonatal calves has not been evaluated. To investigate the effect of delayed colostrum feeding on plasma concentrations of GLP-1 and GLP-2 in newborn calves, we randomly assigned 27 Holstein bull calves to 1 of 3 treatment groups: those fed colostrum within 1 h after birth (control), 6 h after birth (6H), and 12 h after birth (12H; n = 9 for each treatment). Blood samples were obtained before the colostrum feeding and every 3 h after each colostrum feeding for a 36-h period, and plasma concentrations of GLP-1, GLP-2, insulin, and glucose were measured. Plasma GLP-1 concentration at 12 h after colostrum feeding was lower in 12H than in control calves. In addition, plasma insulin concentration was lower in the 6H and 12H calves than in the controls. Plasma glucose and GLP-2 concentrations were, however, not affected by treatment. These results indicate that delayed colostrum feeding can decrease plasma GLP-1 and insulin concentrations without affecting glucose or GLP-2 concentration. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Intracoronary glucagon-like peptide 1 preferentially augments glucose uptake in ischemic myocardium independent of changes in coronary flow.

PubMed

Moberly, Steven P; Berwick, Zachary C; Kohr, Meredith; Svendsen, Mark; Mather, Kieren J; Tune, Johnathan D

2012-03-01

We examined the acute dose-dependent effects of intracoronary glucagon-like peptide (GLP)-1 (7-36) on coronary vascular tone, cardiac contractile function and metabolism in normal and ischemic myocardium. Experiments were conducted in open chest, anesthetized dogs at coronary perfusion pressures (CPP) of 100 and 40 mmHg before and during intracoronary GLP-1 (7-36) infusion (10 pmol/L to 1 nmol/L). Isometric tension studies were also conducted in isolated coronary arteries. Cardiac and coronary expression of GLP-1 receptors (GLP-1R) was assessed by Western blot and immunohistochemical analysis. GLP-1R was present in the myocardium and the coronary vasculature. The tension of intact and endothelium-denuded coronary artery rings was unaffected by GLP-1. At normal perfusion pressure (100 mmHg), intracoronary GLP-1 (7-36) (targeting plasma concentration 10 pmol/L to 1 nmol/L) did not affect blood pressure, coronary blood flow or myocardial oxygen consumption (MVO(2)); however, there were modest reductions in cardiac output and stroke volume. In untreated control hearts, reducing CPP to 40 mmHg produced marked reductions in coronary blood flow (0.50 ± 0.10 to 0.17 ± 0.03 mL/min/g; P < 0.001) and MVO(2) (27 ± 2.3 to 15 ± 2.7 μL O(2)/min/g; P < 0.001). At CPP = 40 mmHg, GLP-1 had no effect on coronary blood flow, MVO(2) or regional shortening, but dose-dependently increased myocardial glucose uptake from 0.11 ± 0.02 μmol/min/g at baseline to 0.17 ± 0.04 μmol/min/g at 1 nmol/L GLP-1 (P < 0.001). These data indicate that acute, intracoronary administration of GLP-1 (7-36) preferentially augments glucose metabolism in ischemic myocardium, independent of effects on cardiac contractile function or coronary blood flow.

SAD-A potentiates glucose-stimulated insulin secretion as a mediator of glucagon-like peptide 1 response in pancreatic β cells.

PubMed

Nie, Jia; Lilley, Brendan N; Pan, Y Albert; Faruque, Omar; Liu, Xiaolei; Zhang, Weiping; Sanes, Joshua R; Han, Xiao; Shi, Yuguang

2013-07-01

Type 2 diabetes is characterized by defective glucose-stimulated insulin secretion (GSIS) from pancreatic β cells, which can be restored by glucagon-like peptide 1 (GLP-1), an incretin hormone commonly used for the treatment of type 2 diabetes. However, molecular mechanisms by which GLP-1 affects glucose responsiveness in islet β cells remain poorly understood. Here we investigated a role of SAD-A, an AMP-activated protein kinase (AMPK)-related kinase, in regulating GSIS in mice with conditional SAD-A deletion. We show that selective deletion of SAD-A in pancreas impaired incretin's effect on GSIS, leading to glucose intolerance. Conversely, overexpression of SAD-A significantly enhanced GSIS and further potentiated GLP-1's effect on GSIS from isolated mouse islets. In support of SAD-A as a mediator of incretin response, SAD-A is expressed exclusively in pancreas and brain, the primary targeting tissues of GLP-1 action. Additionally, SAD-A kinase is activated in response to stimulation by GLP-1 through cyclic AMP (cAMP)/Ca(2+)-dependent signaling pathways in islet β cells. Furthermore, we identified Thr443 as a key autoinhibitory phosphorylation site which mediates SAD-A's effect on incretin response in islet β cells. Consequently, ablation of Thr443 significantly enhanced GLP-1's effect on GSIS from isolated mouse islets. Together, these findings identified SAD-A kinase as a pancreas-specific mediator of incretin response in islet β cells.

SAD-A Potentiates Glucose-Stimulated Insulin Secretion as a Mediator of Glucagon-Like Peptide 1 Response in Pancreatic β Cells

PubMed Central

Nie, Jia; Lilley, Brendan N.; Pan, Y. Albert; Faruque, Omar; Liu, Xiaolei; Zhang, Weiping; Sanes, Joshua R.

2013-01-01

Type 2 diabetes is characterized by defective glucose-stimulated insulin secretion (GSIS) from pancreatic β cells, which can be restored by glucagon-like peptide 1 (GLP-1), an incretin hormone commonly used for the treatment of type 2 diabetes. However, molecular mechanisms by which GLP-1 affects glucose responsiveness in islet β cells remain poorly understood. Here we investigated a role of SAD-A, an AMP-activated protein kinase (AMPK)-related kinase, in regulating GSIS in mice with conditional SAD-A deletion. We show that selective deletion of SAD-A in pancreas impaired incretin's effect on GSIS, leading to glucose intolerance. Conversely, overexpression of SAD-A significantly enhanced GSIS and further potentiated GLP-1's effect on GSIS from isolated mouse islets. In support of SAD-A as a mediator of incretin response, SAD-A is expressed exclusively in pancreas and brain, the primary targeting tissues of GLP-1 action. Additionally, SAD-A kinase is activated in response to stimulation by GLP-1 through cyclic AMP (cAMP)/Ca2+-dependent signaling pathways in islet β cells. Furthermore, we identified Thr443 as a key autoinhibitory phosphorylation site which mediates SAD-A's effect on incretin response in islet β cells. Consequently, ablation of Thr443 significantly enhanced GLP-1's effect on GSIS from isolated mouse islets. Together, these findings identified SAD-A kinase as a pancreas-specific mediator of incretin response in islet β cells. PMID:23629625

Obesity Alters Molecular and Functional Cardiac Responses to Ischemia-Reperfusion and Glucagon-Like Peptide-1 Receptor Agonism

PubMed Central

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

2016-01-01

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 (miR) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-min 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 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 Ca2+ 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

Prolonged survival and improved glycemia in BioBreeding diabetic rats after early sustained exposure to glucagon-like peptide 1.

PubMed

Yanay, Ofer; Moralejo, Daniel; Kernan, Kelly; Brzezinski, Margaret; Fuller, Jessica M; Barton, Randall W; Lernmark, Ake; Osborne, William R

2010-06-01

Type 1 diabetes (T1D) in both humans and BioBreeding (BB) rats is an autoimmune disease that results in complete destruction of islets and insulin dependency for life. Glucagon-like peptide 1 (GLP-1) promotes beta cell proliferation and neogenesis and has a potent insulinotropic effect. We hypothesized that the expression of GLP-1 before disease onset would increase islet mass, delay diabetes and prolong survival of BB rats. Vascular smooth muscle cells retrovirally transduced to secrete GLP-1 were seeded into TheraCyte encapsulation devices, implanted subcutaneously, and rats were monitored for diabetes. In untreated control rats, plasma GLP-1 levels were 34.5-39.5 pmol/l, whereas, in treated rats, plasma levels were elevated, in the range 90-250.4 pmol/l. Hypoglycemia was not detected and this was anticipated from the glucose-regulated action of GLP-1. Diabetes onset (mean + or - SEM) in untreated rats occurred at 56.5 + or - 0.6 days (n = 6) and, in GLP-1-treated rats, was delayed until 76.4 + or - 3.3 days (n = 5) (p < 0.001). After disease onset, untreated control rats showed a rapid weight loss and elevated blood glucose (>650 mg/dl) and did not survive beyond 11 days. At 5 days after diabetes onset, insulin-secreting islets were absent in untreated rats. By contrast, treated rats maintained weight for up to 143 days of age and showed insulin-secreting beta cells. Sustained GLP-1 expression delivered by encapsulated cells before diabetes onset in BB rats showed an improved clinical outcome, suggesting the potential for treating patients using long lasting GLP-1 analogs.

Effects of 24-week treatment with acarbose on glucagon-like peptide 1 in newly diagnosed type 2 diabetic patients: a preliminary report

PubMed Central

2013-01-01

Background Treatment with the alpha-glucosidase inhibitor (AGI) acarbose is associated with a significant reduction the risk of cardiovascular events. However, the underlying mechanisms of this effect are unclear. AGIs were recently suggested to participate in stimulating glucagon-like peptide 1 (GLP-1) secretion. We therefore examined the effects of a 24-week treatment of acarbose on endogenous GLP-1, nitric oxide (NO) levels, nitric oxide synthase (NOS) activity, and carotid intima-media thickness (CIMT) in newly diagnosed patients with type 2 diabetes (T2D). Methods Blood was drawn from 24 subjects (14 male, 10 female, age: 50.7 ± 7.36 years, BMI: 26.64 ± 3.38 kg/m2, GHbA1c: 7.00 ± 0.74%) with drug-naïve T2D at 0 and 120 min following a standard mixed meal for the measurements of active GLP-1, NO and NOS. The CIMT was measured prior to and following 24 weeks of acarbose monotherapy (mean dose: 268 mg daily). Results Following 24 weeks of acarbose treatment, both fasting and postprandial plasma GLP-1 levels were increased. In patients with increased postprandial GLP-1 levels, serum NO levels and NOS activities were also significantly increased and were positively related to GLP-1 levels. Although the CIMT was not significantly altered following treatment with acarbose, a decreased CIMT was negatively correlated with increased GLP-1 levels. Conclusions Twenty-four weeks of acarbose monotherapy in newly diagnosed patients with T2D is associated with significantly increased levels of both fasting and postprandial GLP-1 as well as significantly increased NO levels and NOS activity for those patients in whom postprandial GLP-1 levels were increased. Therefore, the benefits of acarbose on cardiovascular risk may be related to its stimulation of GLP-1 secretion. PMID:23642288

Suppression of Food Intake by Glucagon-Like Peptide-1 Receptor Agonists: Relative Potencies and Role of Dipeptidyl Peptidase-4

PubMed Central

Jessen, Lene; Aulinger, Benedikt A.; Hassel, Jonathan L.; Roy, Kyle J.; Smith, Eric P.; Greer, Todd M.; Woods, Stephen C.; Seeley, Randy J.

2012-01-01

Administration of the glucagon-like peptide-1 (GLP-1) receptor agonists GLP-1 and exendin-4 (Ex-4) directly into the central nervous system decreases food intake. But although Ex-4 potently suppresses food intake after peripheral administration, the effects of parenteral GLP-1 are variable and not as strong. A plausible explanation for these effects is the rapid inactivation of circulating GLP-1 by dipeptidyl peptidase-4 (DPP-4), an enzyme that does not alter Ex-4 activity. To test this hypothesis, we assessed the relative potency of Ex-4 and GLP-1 under conditions in which DPP-4 activity was reduced. Outbred rats, wild-type mice, and mice with a targeted deletion of DPP-4 (Dpp4−/−) were treated with GLP-1 alone or in combination with the DPP-4 inhibitor vildagliptin, Ex-4, or saline, and food intake was measured. GLP-1 alone, even at high doses, did not affect feeding in wild-type mice or rats but did reduce food intake when combined with vildagliptin or given to Dpp4−/− mice. Despite plasma clearance similar to DPP-4-protected GLP-1, equimolar Ex-4 caused greater anorexia than vildagliptin plus GLP-1. To determine whether supraphysiological levels of endogenous GLP-1 would suppress food intake if protected from DPP-4, rats with Roux-en-Y gastric bypass and significantly elevated postprandial plasma GLP-1 received vildagliptin or saline. Despite 5-fold greater postprandial GLP-1 in these animals, vildagliptin did not affect food intake in Roux-en-Y gastric bypass rats. Thus, in both mice and rats, peripheral GLP-1 reduces food intake significantly less than Ex-4, even when protected from DPP-4. These findings suggest distinct potencies of GLP-1 receptor agonists on food intake that cannot be explained by plasma pharmacokinetics. PMID:23033273

Mice Deficient for Glucagon Gene-Derived Peptides Display Normoglycemia and Hyperplasia of Islet α-Cells But Not of Intestinal L-Cells

PubMed Central

Hayashi, Yoshitaka; Yamamoto, Michiyo; Mizoguchi, Hiroyuki; Watanabe, Chika; Ito, Ryoichi; Yamamoto, Shiori; Sun, Xiao-yang; Murata, Yoshiharu

2009-01-01

Multiple bioactive peptides, including glucagon, glucagon-like peptide-1 (GLP-1), and GLP-2, are derived from the glucagon gene (Gcg). In the present study, we disrupted Gcg by introduction of GFP cDNA and established a knock-in mouse line. Gcggfp/gfp mice that lack most, if not all, of Gcg-derived peptides were born in an expected Mendelian ratio without gross abnormalities. Gcggfp/gfp mice showed lower blood glucose levels at 2 wk of age, but those in adult Gcggfp/gfp mice were not significantly different from those in Gcg+/+ and Gcggfp/+ mice, even after starvation for 16 h. Serum insulin levels in Gcggfp/gfp mice were lower than in Gcg+/+ and Gcggfp/+ on ad libitum feeding, but no significant differences were observed on starvation. Islet α-cells and intestinal L-cells were readily visualized in Gcggfp/gfp and Gcggfp/+ mice under fluorescence. The Gcggfp/gfp postnatally developed hyperplasia of islet α-cells, whereas the population of intestinal L-cells was not increased. In the Gcggfp/gfp, expression of Aristaless-related homeobox (Arx) was markedly increased in pancreas but not in intestine and suggested involvement of Arx in differential regulation of proliferation of Gcg-expressing cells. These results illustrated that Gcg-derived peptides are dispensable for survival and maintaining normoglycemia in adult mice and that Gcg-derived peptides differentially regulate proliferation/differentiation of α-cells and L-cells. The present model is useful for analyzing glucose/energy metabolism in the absence of Gcg-derived peptides. It is useful also for analysis of the development, differentiation, and function of Gcg-expressing cells, because such cells are readily visualized by fluorescence in this model. PMID:19819987

A Human Glucagon-Like Peptide-1-albumin Recombinant Protein with Prolonged Hypoglycemic Effect Provides Efficient and Beneficial Control of Glucose Metabolism in Diabetic Mice.

PubMed

Li, Caina; Yang, Miaomiao; Hou, Guojiang; Liu, Shuainan; Huan, Yi; Yu, Dongan; Sun, Sujuan; Liu, Quan; Yan, Shousheng; Shen, Zhufang

2017-09-01

GW002 is a recombinant protein engineered by fusing the C-terminal region of human glucagon-like peptide-1 (GLP-1) to the N-terminal region of human serum albumin (HSA) with a peptide linker. This study aims to evaluate its anti-diabetic effects both in vitro and in vivo. The GLP-1 receptor-dependent luciferase reporter plasmid was transiently transfected in NIT-1 cells to calculate the half-maximal concentration (EC 50 ) for GLP-1 receptor activation, and normal ICR mice and diabetic KKAy mice were acutely injected with GW002 (1, 3, 9 mg/kg) subcutaneously to evaluate the hypoglycemic action, while the diabetic KKAy and db/db mice were treated with GW002 once daily for 7 weeks to evaluate the effects on glucose metabolism. The results showed that GW002 activated GLP-1 receptor in NIT-1 cells with higher EC 50 versus exendin-4 (46.7 vs. 7.89 nM), and single subcutaneous injection of GW002 at doses of 1, 3 and 9 mg/kg efficiently restrained the glycemia variation after oral glucose loading in ICR mice for at least 4 d, as well as reducing the non-fasting blood glucose in KKAy mice for about 2 d, while repeated injections of GW002 significantly improved abnormal glycaemia, hemoglobin (Hb)A1c levels, oral glucose intolerance and β-cell function in diabetic db/db mice. These results suggested that GW002 showed prolonged hypoglycemic action by activating its cognate receptor and provided efficient control of glucose metabolism. Thus GW002 may be a potential treatment for the management of type 2 diabetes.

Lysophosphatidylinositol-induced activation of the cation channel TRPV2 triggers glucagon-like peptide-1 secretion in enteroendocrine L cells.

PubMed

Harada, Kazuki; Kitaguchi, Tetsuya; Kamiya, Taichi; Aung, Kyaw Htet; Nakamura, Kazuaki; Ohta, Kunihiro; Tsuboi, Takashi

2017-06-30

The lysophosphatidylinositol (LPI) has crucial roles in multiple physiological processes, including insulin exocytosis from pancreatic islets. However, the role of LPI in secretion of glucagon-like peptide-1 (GLP-1), a hormone that enhances glucose-induced insulin secretion, is unclear. Here, we used the murine enteroendocrine L cell line GLUTag and primary murine small intestinal cells to elucidate the mechanism of LPI-induced GLP-1 secretion. Exogenous LPI addition increased intracellular Ca 2+ concentrations ([Ca 2+ ] i ) in GLUTag cells and induced GLP-1 secretion from both GLUTag and acutely prepared primary intestinal cells. The [Ca 2+ ] i increase was suppressed by an antagonist for G protein-coupled receptor 55 (GPR55) and by silencing of GPR55 expression, indicating involvement of G q and G 12/13 signaling pathways in the LPI-induced increased [Ca 2+ ] i levels and GLP-1 secretion. However, GPR55 agonists did not mimic many of the effects of LPI. We also found that phospholipase C inhibitor and Rho-associated kinase inhibitor suppressed the [Ca 2+ ] i increase and that LPI increased the number of focal adhesions, indicating actin reorganization. Of note, blockage or silencing of transient receptor potential cation channel subfamily V member 2 (TRPV2) channels suppressed both the LPI-induced [Ca 2+ ] i increase and GLP-1 secretion. Furthermore, LPI accelerated TRPV2 translocation to the plasma membrane, which was significantly suppressed by a GPR55 antagonist. These findings suggest that TRPV2 activation via actin reorganization induced by G q and G 12/13 signaling is involved in LPI-stimulated GLP-1 secretion in enteroendocrine L cells. Because GPR55 agonists largely failed to mimic the effects of LPI, its actions on L cells are at least partially independent of GPR55 activation. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice.

PubMed

Pereira, M; Jeyabalan, J; Jørgensen, C S; Hopkinson, M; Al-Jazzar, A; Roux, J P; Chavassieux, P; Orriss, I R; Cleasby, M E; Chenu, C

2015-12-01

Some anti-diabetic therapies can have adverse effects on bone health and increase fracture risk. In this study, we tested the skeletal effects of chronic administration of two Glucagon-like peptide-1 receptor agonists (GLP-1RA), increasingly used for type 2 diabetes treatment, in a model of osteoporosis associated bone loss and examined the expression and activation of GLP-1R in bone cells. Mice were ovariectomised (OVX) to induce bone loss and four weeks later they were treated with Liraglutide (LIR) 0.3mg/kg/day, Exenatide (Ex-4) 10 μg/kg/day or saline for four weeks. Mice were injected with calcein and alizarin red prior to euthanasia, to label bone-mineralising surfaces. Tibial micro-architecture was determined by micro-CT and bone formation and resorption parameters measured by histomorphometric analysis. Serum was collected to measure calcitonin and sclerostin levels, inhibitors of bone resorption and formation, respectively. GLP-1R mRNA and protein expression were evaluated in the bone, bone marrow and bone cells using RT-PCR and immunohistochemistry. Primary osteoclasts and osteoblasts were cultured to evaluate the effect of GLP-1RA on bone resorption and formation in vitro. GLP-1RA significantly increased trabecular bone mass, connectivity and structure parameters but had no effect on cortical bone. There was no effect of GLP-1RA on bone formation in vivo but an increase in osteoclast number and osteoclast surfaces was observed with Ex-4. GLP-1R was expressed in bone marrow cells, primary osteoclasts and osteoblasts and in late osteocytic cell line. Both Ex-4 and LIR stimulated osteoclastic differentiation in vitro but slightly reduced the area resorbed per osteoclast. They had no effect on bone nodule formation in vitro. Serum calcitonin levels were increased and sclerostin levels decreased by Ex-4 but not by LIR. Thus, GLP-1RA can have beneficial effects on bone and the expression of GLP-1R in bone cells may imply that these effects are exerted directly

Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency☆ab

PubMed Central

Mokadem, Mohamad; Zechner, Juliet F.; Margolskee, Robert F.; Drucker, Daniel J.; Aguirre, Vincent

2013-01-01

Glucagon-like peptide-1 (GLP-1) secretion is greatly enhanced after Roux-en-Y gastric bypass (RYGB). While intact GLP-1exerts its metabolic effects via the classical GLP-1 receptor (GLP-1R), proteolytic processing of circulating GLP-1 yields metabolites such as GLP-1(9–36)amide/GLP-1(28–36)amide, that exert similar effects independent of the classical GLP-1R. We investigated the hypothesis that GLP-1, acting via these metabolites or through its known receptor, is required for the beneficial effects of RYGB using two models of functional GLP-1 deficiency – α-gustducin-deficient (α-Gust−/−) mice, which exhibit attenuated nutrient-stimulated GLP-1 secretion, and GLP-1R-deficient mice. We show that the effect of RYGB to enhance glucose-stimulated GLP-1 secretion was greatly attenuated in α-Gust−/− mice. In both genetic models, RYGB reduced body weight and improved glucose homeostasis to levels observed in lean control mice. Therefore, GLP-1, acting through its classical GLP-1R or its bioactive metabolites, does not seem to be involved in the effects of RYGB on body weight and glucose homeostasis. PMID:24634822

Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans.

PubMed

van Bloemendaal, L; Veltman, D J; Ten Kulve, J S; Groot, P F C; Ruhé, H G; Barkhof, F; Sloan, J H; Diamant, M; Ijzerman, R G

2015-09-01

To test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. As part of a larger study, we determined the effects of GLP-1 receptor activation on brain responses to anticipation and receipt of chocolate milk versus a tasteless solution, using functional MRI (fMRI). Obese subjects with type 2 diabetes, and obese and lean subjects with normoglycaemia (n = 48) underwent three fMRI sessions at separate visits with intravenous infusion of the GLP-1 receptor agonist exenatide, exenatide with prior GLP-1 receptor blockade by exendin-9-39 or placebo, during somatostatin pituitary-pancreatic clamps. Body mass index negatively correlated with brain responses to receipt of chocolate milk and positively correlated with anticipation of receipt of chocolate milk in brain areas regulating reward, appetite and motivation. Exenatide increased brain responses to receipt of chocolate milk and decreased anticipation of receipt of chocolate milk compared with placebo, paralleled by reductions in food intake. Exendin-9-39 largely prevented these effects. Our findings show that GLP-1 receptor activation decreases anticipatory food reward, which may reduce cravings for food and increases consummatory food reward, which may prevent overeating. © 2015 John Wiley & Sons Ltd.

The endocrine disrupting potential of monosodium glutamate (MSG) on secretion of the glucagon-like peptide-1 (GLP-1) gut hormone and GLP-1 receptor interaction.

PubMed

Shannon, Maeve; Green, Brian; Willars, Gary; Wilson, Jodie; Matthews, Natalie; Lamb, Joanna; Gillespie, Anna; Connolly, Lisa

2017-01-04

Monosodium glutamate (MSG) is a suspected obesogen with epidemiological evidence positively correlating consumption to increased body mass index and higher prevalence of metabolic syndrome. ELISA and high content analysis (HCA) were employed to examine the disruptive effects of MSG on the secretion of enteroendocrine hormone glucagon-like peptide-1 (GLP-1) and GLP-1 receptor (GLP-1R), respectively. Following 3h MSG exposure of the enteroendocrine pGIP/neo: STC-1 cell line model (500μg/ml) significantly increased GLP-1 secretion (1.8 fold; P≤0.001), however, 72h exposure (500μg/ml) caused a 1.8 fold decline (P≤0.05). Also, 3h MSG exposure (0.5-500μg/ml) did not induce any cytotoxicity (including multiple pre-lethal markers) but 72h exposure at 250-500μg/ml, decreased cell number (11.8-26.7%; P≤0.05), increased nuclear area (23.9-29.8%; P≤0.001) and decreased mitochondrial membrane potential (13-21.6%; P≤0.05). At 500μg/ml, MSG increased mitochondrial mass by 16.3% (P≤0.01). MSG did not agonise or antagonise internalisation of the GLP-1R expressed recombinantly in U2OS cells, following GLP-1 stimulation. In conclusion, 72h exposure of an enteroendocrine cell line at dietary levels of MSG, results in pre-lethal cytotoxicity and decline in GLP-1 secretion. These adverse events may play a role in the pathogenesis of obesity as outlined in the obesogen hypothesis by impairing GLP-1 secretion, related satiety responses and glucose-stimulated insulin release. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The glucagon-like peptide-1 receptor agonist liraglutide improves hypoxia-induced pulmonary hypertension in mice partly via normalization of reduced ET(B) receptor expression.

PubMed

Honda, J; Kimura, T; Sakai, S; Maruyama, H; Tajiri, K; Murakoshi, N; Homma, S; Miyauchi, T; Aonuma, K

2018-06-27

The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is an incretin hormone mimetic used in the treatment of diabetes. However, the effects of liraglutide on pulmonary hypertension (PH) and pulmonary endothelin (ET) system are unknown. Eight-week-old C57BL6/J mice were injected liraglutide or vehicle for 5 weeks. One week after injection, the mice were exposed to either room air (normoxia) or chronic hypoxia (10 % O(2)) for 4 weeks. The right ventricular systolic pressure (RVSP) was significantly higher in hypoxia + vehicle group than in normoxia + vehicle group. ET-1 mRNA expression in the lungs was comparable among all the groups. ET(B) mRNA and protein expression in the lungs was significantly lower in hypoxia + vehicle group than in normoxia + vehicle group. The above changes were normalized by liraglutide treatment. The expression of phospho-eNOS and phospho-AMPK proteins in the lungs was significantly higher in hypoxia + liraglutide group than in normoxia + vehicle group. We demonstrated for the first time that liraglutide effectively improved RVSP and RV hypertrophy in hypoxia-induced PH mice by activating eNOS through normalization of impaired ET(B) pathway and augmentation of AMPK pathway. Therefore, GLP-1R agonists can be promising therapeutic agents for PH.

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.

Characterization of glucagon-like peptide 2 pathway member expression in bovine gastrointestinal tract.

PubMed

Connor, E E; Baldwin, R L; Capuco, A V; Evock-Clover, C M; Ellis, S E; Sciabica, K S

2010-11-01

Glucagon-like peptide 2 (GLP-2), secreted by enteroendocrine cells, has several physiological effects on the intestine of monogastric species, including promotion of growth of intestinal epithelium, reduction of epithelial cell apoptosis, and enhancement of intestinal blood flow, nutrient absorption, and epithelial barrier function. The regulatory functions of GLP-2 in the ruminant gastrointestinal tract (GIT) have not been well studied. The objectives of this investigation were to characterize the mRNA expression of 4 members of the GLP-2 pathway throughout the bovine GIT, including (1) proglucagon (GCG), the parent peptide from which GLP-2 is derived through cleavage by prohormone convertase; (2) prohormone convertase (PCSK1); (3) GLP-2 receptor (GLP2R); and (4) dipeptidyl peptidase IV (DPP4), the enzyme that inactivates GLP-2. Gene expression was evaluated in rumen, reticulum, omasum, abomasum, duodenum, jejunum, ileum, cecum, and rectum collected at slaughter from prepubertal heifers, mature cows in early, mid, and late lactation, and nonlactating cows (n=3 per stage) by a gene expression profiling assay. In addition, mRNA expression of 14 genes involved in nutrient transport, enzyme activity, blood flow, apoptosis, and proliferation were evaluated in the 9 GIT tissues for their association with GCG and GLP2R mRNA expression. Immunohistochemistry was used to localize GLP2R protein in tissues of the lower GIT. Results indicated that mRNA expression of GCG, PCSK1, GLP2R, and DPP4 varies across the 9 GIT tissues, with greatest expression in small and large intestines, and generally nondetectable levels in forestomachs. Expression of DPP4 and GLP2R mRNA varied by developmental stage or lactational state in intestinal tissues. Expression of GCG or GLP2R mRNA was correlated with molecular markers of proliferation, apoptosis, blood flow, enzyme activity, and urea transport, depending on the tissue examined, which suggests a potential for involvement of GLP-2 in these

The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity.

PubMed

Burmeister, Melissa A; Brown, Jacob D; Ayala, Jennifer E; Stoffers, Doris A; Sandoval, Darleen A; Seeley, Randy J; Ayala, Julio E

2017-12-01

Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect. Furthermore, we found that Ex4-mediated anorexia in the VMH involved mTOR but not acetyl-CoA carboxylase, two downstream targets of AMPK. We support this by showing that Ex4 activates mTOR signaling in the VMH and Chinese hamster ovary (CHO)-K1 cells. In contrast to the clear acute pharmacological impact of the these receptors on food intake, knockdown of the VMH Glp1r conferred no changes in energy balance in either chow- or high-fat-diet-fed mice, and the acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA were preserved. These results show that the VMH GLP-1R regulates food intake by engaging key nutrient sensors but is dispensable for the effects of GLP-1RA on nutrient homeostasis. Copyright © 2017 the American Physiological Society.

The Vildagliptin Experience - 25 Years Since the Initiation of the Novartis Glucagon-like Peptide-1 Based Therapy Programme and 10 Years Since the First Vildagliptin Registration.

PubMed

Foley, James E; Ahrén, Bo

2017-08-01

The discovery of the incretin hormone glucagon like peptide-1 (GLP-1), and its usefulness in the treatment of type 2 diabetes mellitus (T2DM) followed by the finding that dipeptidyl peptidase-4 (DPP-4) inhibition prevents GLP-1 inactivation, led to the discovery of DPP-728. In 1999, studies with DPP-728 established the first proof-of-concept that DPP-4 inhibition improves glycaemic control in patients with T2DM. Further efforts to improve the binding kinetics of DPP-728 resulted in the discovery of vildagliptin (LAF237). In the last 20 years, a plethora of studies conducted by Novartis in collaboration with external investigators has demonstrated the mechanism of action of vildagliptin and its efficacy as monotherapy and as an add-on therapy for patients with T2DM. The studies establish that vildagliptin is a selective DPP-4 inhibitor that blocks GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) inactivation, thereby prolonging their action, resulting in improved glycaemic control. This review aims to discuss the discovery and development of vildagliptin, with an emphasis on mechanism of action and clinical efficacy.

“Living High-Training Low” improved weight loss and glucagon-like peptide-1 level in a 4-week weight loss program in adolescents with obesity

PubMed Central

Yang, Qin; Huang, Guoyuan; Tian, Qianqian; Liu, Wei; Sun, Xiangdong; Li, Na; Sun, Shunli; Zhou, Tang; Wu, Nana; Wei, Yuqin; Chen, Peijie; Wang, Ru

2018-01-01

Abstract Background: “Living High-Training Low” (LHTL) is effective for the improvement of athletic ability; however, little is known about the effect of LHTL on obese individuals. The present study determined whether LHTL would have favorable influence on body composition, rebalance the appetite hormones, and explore the underlying mechanism. Methods: Adolescents with obesity [body mass index (BMI) >30 kg/m2] were randomly assigned to “Living Low-Training Low” (LLTL, n = 19) group that slept in a normobaric normoxia condition and the LHTL (n = 16) group slept in a normobaric hypoxia room (14.7% PO2 ∼2700 m). Both groups underwent the same aerobic exercise training program. Morphological, blood lipids, and appetite hormones were measured and assessed. Results: After the intervention, the body composition improved in both groups, whereas reductions in body weight (BW), BMI, and lean body mass increased significantly in the LHTL group (all, P < .05). In the LLTL group, cholecystokinin (CCK) decreased remarkably (P < .05) and CCK changes were positively associated with changes in BW (r = 0.585, P = .011) and BMI (r = 0.587, P = .010). However, in the LHTL group, changes in plasma glucagon-like peptide-1 (GLP-1) and interleukin-6 (IL-6) levels, positively correlated with each other (r = 0.708, P = .015) but negatively with BW changes (r = −0.608, P = .027 and r = −0.518, P = .048, respectively). Conclusion: The results indicated that LHTL could induce more weight loss safely and efficiently as compared to LLTL and increase the plasma GLP-1 levels that may be mediated by IL-6 to rebalance the appetite. Thus, an efficient method to treat obesity and prevent weight regain by appetite rebalance in hypoxia condition was established. PMID:29465583

[Role of p38MAPK/eNOS signaling pathway in the inhibition of AGEs-induced apoptosis of human umbilical vein endothelial cells by glucagon-like peptide-1].

PubMed

Zeng, Hailong; Huang, Zhiqiu; Zhang, Yineng; Sun, Huilin

2016-01-01

To investigate the role of p38MAPK signaling pathway in the mechanism by which glucagon-like peptide-1 (GLP-1) inhibits endothelial cell damage induced by AGEs. Human umbilical vein endothelial cells were divided into control group, AGEs group, GLP-1 group, AGEs+GLP-1 group, AGEs+inhibitor group, and AGEs+GLP-1+inhibitor group. The expressions of p-p38MAPK/p38MAPK and p-eNOS/eNOS protein were examined by Western blotting, and the cell apoptosis rates were tested by flow cytometry. Compared with the control group, AGEs significantly enhanced the expression of p-p38 MAPK protein (P=0.001) while GLP-1 significantly inhibited its expression (P<0.001). AGEs significantly inhibited the expression of p-eNOS protein (P=0.007), which was enhanced by GLP-1 and p38 MAPK inhibitor (SB203580) (P=0.004). Both SB203580 and GLP-1 treatment decreased the apoptosis rate of AGEs-treated cells (P<0.001). GLP-1 can protect human umbilical vein endothelial cells against AGEs-induced apoptosis partially by inhibiting the phosphorylation of p38MAPK protein and promoting the expression of p-eNOS protein.

Linagliptin potentiates the effect of l-dopa on the behavioural, biochemical and immunohistochemical changes in experimentally-induced Parkinsonism: Role of toll-like receptor 4, TGF-β1, NF-κB and glucagon-like peptide 1.

PubMed

Kabel, Ahmed M; Omar, Mohamed S; Alhadhrami, A; Alharthi, Salman S; Alrobaian, Majed M

2018-05-01

Our aim was to assess the effect of different doses of linagliptin with or without l-dopa/Carbidopa on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in mice. Eighty Balb/c mice were divided into 8 equal groups: Control; MPTP; MPTP + l-dopa/Carbidopa; MPTP + linagliptin 3 mg/kg/day; MPTP + linagliptin 10 mg/kg/day; MPTP + Carboxymethyl cellulose; MPTP + l-dopa/Carbidopa + linagliptin 3 mg/kg/day and MPTP + l-dopa/Carbidopa + linagliptin 10 mg/kg/day. Striatal dopamine, tumor necrosis factor alpha (TNF-α), interleukin 10 (IL-10), transforming growth factor beta 1 (TGF-β1), toll-like receptor 4 (TLR4), antioxidant enzymes, adenosine triphosphate (ATP), glucagon-like peptide-1 (GLP-1), receptors of advanced glycation end products (RAGE), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), mitochondrial complex I activity, catalepsy and total swim scores were measured. Also, the substantia nigra was subjected to immunohistochemical examination. The combination of l-dopa/Carbidopa and linagliptin in a dose-dependent manner resulted in significant improvement of the behavioural changes, striatal dopamine, antioxidant parameters, Nrf2/HO-1 content, GLP-1, ATP and mitochondrial complex I activity with significant decrease in striatal RAGE, TGF-β1, TNF-α, IL-10, TLR4 and alleviated the immunohistochemical changes better than the groups that received either l-dopa/Carbidopa or linagliptin alone. The combination of l-dopa/Carbidopa and linagliptin might represent a promising therapeutic modality for management of parkinsonism. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of exogenous glucagon-like peptide-2 and distal bowel resection on intestinal and systemic adaptive responses in rats.

PubMed

Lai, Sarah W; de Heuvel, Elaine; Wallace, Laurie E; Hartmann, Bolette; Holst, Jens J; Brindle, Mary E; Chelikani, Prasanth K; Sigalet, David L

2017-01-01

To determine the effects of exogenous glucagon-like peptide-2 (GLP-2), with or without massive distal bowel resection, on adaptation of jejunal mucosa, enteric neurons, gut hormones and tissue reserves in rats. GLP-2 is a gut hormone known to be trophic for small bowel mucosa, and to mimic intestinal adaptation in short bowel syndrome (SBS). However, the effects of exogenous GLP-2 and SBS on enteric neurons are unclear. Sprague Dawley rats were randomized to four treatments: Transected Bowel (TB) (n = 8), TB + GLP-2 (2.5 nmol/kg/h, n = 8), SBS (n = 5), or SBS + GLP-2 (2.5 nmol/kg/h, n = 9). SBS groups underwent a 60% jejunoileal resection with cecectomy and jejunocolic anastomosis. All rats were maintained on parenteral nutrition for 7 d. Parameters measured included gut morphometry, qPCR for hexose transporter (SGLT-1, GLUT-2, GLUT-5) and GLP-2 receptor mRNA, whole mount immunohistochemistry for neurons (HuC/D, VIP, nNOS), plasma glucose, gut hormones, and body composition. Resection increased the proportion of nNOS immunopositive myenteric neurons, intestinal muscularis propria thickness and crypt cell proliferation, which were not recapitulated by GLP-2 therapy. Exogenous GLP-2 increased jejunal mucosal surface area without affecting enteric VIP or nNOS neuronal immunopositivity, attenuated resection-induced reductions in jejunal hexose transporter abundance (SGLT-1, GLUT-2), increased plasma amylin and decreased peptide YY concentrations. Exogenous GLP-2 attenuated resection-induced increases in blood glucose and body fat loss. Exogenous GLP-2 stimulates jejunal adaptation independent of enteric neuronal VIP or nNOS changes, and has divergent effects on plasma amylin and peptide YY concentrations. The novel ability of exogenous GLP-2 to modulate resection-induced changes in peripheral glucose and lipid reserves may be important in understanding the whole-body response following intestinal resection, and is worthy of further study.

Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy.

PubMed

Nikolaidis, Lazaros A; Elahi, Dariush; Hentosz, Teresa; Doverspike, Aaron; Huerbin, Rhonda; Zourelias, Lee; Stolarski, Carol; Shen, You-tang; Shannon, Richard P

2004-08-24

The failing heart demonstrates a preference for glucose as its metabolic substrate. Whether enhancing myocardial glucose uptake favorably influences left ventricular (LV) contractile performance in heart failure remains uncertain. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with potent insulinotropic effects the action of which is attenuated when glucose levels fall below 4 mmol. We examined the impact of recombinant GLP-1 (rGLP-1) on LV and systemic hemodynamics and myocardial substrate uptake in conscious dogs with advanced dilated cardiomyopathy (DCM) as a mechanism for overcoming myocardial insulin resistance and enhancing myocardial glucose uptake. Thirty-five dogs were instrumented and studied in the fully conscious state. Advanced DCM was induced by 28 days of rapid pacing. Sixteen dogs with advanced DCM received a 48-hour infusion of rGLP-1 (1.5 pmol x kg(-1) x min(-1)). Eight dogs with DCM served as controls and received 48 hours of a saline infusion (3 mL/d). Infusion of rGLP-1 was associated with significant (P<0.02) increases in LV dP/dt (98%), stroke volume (102%), and cardiac output (57%) and significant decreases in LV end-diastolic pressure, heart rate, and systemic vascular resistance. rGLP-1 increased myocardial insulin sensitivity and myocardial glucose uptake. There were no significant changes in the saline control group. rGLP-1 dramatically improved LV and systemic hemodynamics in conscious dogs with advanced DCM induced by rapid pacing. rGLP-1 has insulinomimetic and glucagonostatic properties, with resultant increases in myocardial glucose uptake. rGLP-1 may be a useful metabolic adjuvant in decompensated heart failure.

Expression of cholecystokinin2-receptor in rat and human L cells and the stimulation of glucagon-like peptide-1 secretion by gastrin treatment.

PubMed

Cao, Yang; Cao, Xun; Liu, Xiao-Min

2015-03-01

Gastrin is a gastrointestinal hormone secreted by G cells. Hypergastrinemia can improve blood glucose and glycosylated hemoglobin levels. These positive effects are primarily due to the trophic effects of gastrin on β-cells. In recent years, many receptors that regulate secretion of glucagon-like peptide 1 (GLP-1) have been identified in enteroendocrine L cell lines. This led us to hypothesize that, in addition to the trophic effects of gastrin on β-cells, L cells also express cholecystokinin2-receptor (CCK2R), which may regulate GLP-1 secretion and have synergistic effects on glucose homeostasis. Our research provides a preliminary analysis of CCK2R expression and the stimulating effect of gastrin treatment on GLP-1 secretion in a human endocrine L cell line, using RT-PCR, Western blot, immunocytochemistry, and ELISA analyses. The expression of proglucagon and prohormone convertase 3, which regulate GLP-1 biosynthesis, were also analyzed by real-time PCR. Double immunofluorescence labeling was utilized to assess the intracellular localization of CCK2R and GLP-1 in L cells harvested from rat colon tissue. Our results showed that CCK2R was expressed in both the human L cell line and the rat L cells. We also showed that treatment with gastrin, a CCK2R agonist, stimulated the secretion of GLP-1, and that this effect was likely due to increased expression of proglucagon and PCSK1 (also known as prohormone convertase 3 (PC3 gene)). These results not only provide a basis for the role gastrin may play in intestinal L cells, and may also provide the basis for the development of a method of gastrin-mediated glycemic regulation. Copyright © 2014 Elsevier GmbH. All rights reserved.

Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight.

PubMed

Anderberg, Rozita H; Richard, Jennifer E; Eerola, Kim; López-Ferreras, Lorena; Banke, Elin; Hansson, Caroline; Nissbrandt, Hans; Berqquist, Filip; Gribble, Fiona M; Reimann, Frank; Wernstedt Asterholm, Ingrid; Lamy, Christophe M; Skibicka, Karolina P

2017-04-01

Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT 2A ) and 5-HT 2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT 2A , but surprisingly not the 5-HT 2C , receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT 2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation. © 2017 by the American Diabetes Association.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Yunli, E-mail: chrisyu1255@yahoo.com.cn; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009; Wang, Xinting, E-mail: wxinting1986@yahoo.com.cn

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-daymore » 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

Glucagon-like peptide-2 treatment improves glucose dysmetabolism in mice fed a high-fat diet.

PubMed

Baldassano, Sara; Amato, Antonella; Caldara, Gaetano Felice; Mulè, Flavia

2016-12-01

Previous studies suggested that endogenous glucagon-like peptide 2 (GLP-2) is dispensable for the regulation of glucose homeostasis under normal conditions, while it can play a beneficial role in obesity conditions. The purpose of the present study was to investigate whether chronic treatment with Gly 2 -GLP-2, a stable analogue of GLP-2, can have an impact on glycaemic and lipid control in mice fed a high-fat diet (HFD), an animal model of human obesity and insulin resistance. HFD mice were treated once a day with Gly 2 -GLP-2 for 4 weeks. Body weight, food intake, fasting glucose, intraperitoneal glucose tolerance, insulin-induced glucose clearance, glucose-stimulated insulin secretion, β-cell mass, plasma lipid metabolic profile, and lipid deposition in the liver were examined. In untreated HFD mice, fasting glucose levels, glucose tolerance, glucose-stimulated plasma insulin and sensibility to exogenous insulin were deteriorating with time and β-cell mass increased. In Gly 2 -GLP-2-treated mice, we found significant increase in glucose tolerance and exogenous insulin sensitivity, reduction in glucose-stimulated plasma insulin and in the increase in β-cell mass in comparison with pair-aged HFD untreated animals. The chronic treatment with the peptide was not associated with remarkable improvements of dyslipidemia and it did not prevent liver fat accumulation and the presence of microvesicular steatosis. In conclusion, the results of the present study suggest, for the first time, that Gly 2 -GLP-2 may produce glucose metabolic benefits in mice with diet-induced obesity. The mechanisms underlying the beneficial impact of GLP-2 on glucose metabolism remain to be established.

Glucagon-like peptide-2 protects impaired intestinal mucosal barriers in obstructive jaundice rats.

PubMed

Chen, Jun; Dong, Jia-Tian; Li, Xiao-Jing; Gu, Ye; Cheng, Zhi-Jian; Cai, Yuan-Kun

2015-01-14

To observe the protective effect of glucagon-like peptide-2 (GLP-2) on the intestinal barrier of rats with obstructive jaundice and determine the possible mechanisms of action involved in the protective effect. Thirty-six Sprague-Dawley rats were randomly divided into a sham operation group, an obstructive jaundice group, and a GLP-2 group; each group consisted of 12 rats. The GLP-2 group was treated with GLP-2 after the day of surgery, whereas the other two groups were treated with the same concentration of normal saline. Alanine aminotransferase (ALT), total bilirubin, and endotoxin levels were recorded at 1, 3, 7, 10 and 14 d. Furthermore, on the 14(th) day, body weight, the wet weight of the small intestine, pathological changes of the small intestine and the immunoglobulin A (IgA) expressed by plasma cells located in the small intestinal lamina propria were recorded for each group. In the rat model, jaundice was obvious, and the rats' activity decreased 4-6 d post bile duct ligation. Compared with the sham operation group, the obstructive jaundice group displayed increased yellow staining of abdominal visceral serosa, decreased small intestine wet weight, thinning of the intestinal muscle layer and villi, villous atrophy, uneven height, fusion, partial villous epithelial cell shedding, substantial inflammatory cell infiltration and significantly reduced IgA expression. However, no significant gross changes were noted between the GLP-2 and sham groups. With time, the levels of ALT, endotoxin and bilirubin in the GLP-2 group were significantly increased compared with the sham group (P < 0.01). The increasing levels of the aforementioned markers were more significant in the obstructive jaundice group than in the GLP-2 group (P < 0.01). GLP-2 reduces intestinal mucosal injuries in obstructive jaundice rats, which might be attributed to increased intestinal IgA and reduced bilirubin and endotoxin.

HBA1C CONTROL AND COST-EFFECTIVENESS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS INITIATED ON CANAGLIFLOZIN OR A GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONIST IN A REAL-WORLD SETTING.

PubMed

Wysham, Carol H; Pilon, Dominic; Ingham, Mike; Lafeuille, Marie-Hélène; Emond, Bruno; Kamstra, Rhiannon; Pfeifer, Michael; Lefebvre, Patrick

2018-03-01

To compare glycated hemoglobin (HbA1c) control and medication costs between patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin 300 mg (CANA) or a glucagon-like peptide 1 receptor agonist (GLP-1 RA) in a real-world setting. Adults with T2DM newly initiated on CANA or a GLP-1 RA (index date) were identified from IQVIA ™ Real-World Data Electronic Medical Records U.S. database (March 29, 2012-April 30, 2016). Inverse probability of treatment weighting accounted for differences in baseline characteristics. HbA1c levels at 3-month intervals were compared using generalized estimating equations. Medication costs used wholesale acquisition costs. For both cohorts (CANA: n = 11,435; GLP-1 RA: n = 11,582), HbA1c levels decreased at 3 months postindex and remained lower through 30 months. Absolute changes in mean HbA1c from index to 3 months postindex for CANA and GLP-1 RA were -1.16% and -1.21% (patients with baseline HbA1c ≥7% [53 mmol/mol]); -1.54% and -1.51% (patients with baseline HbA1c ≥8% [64 mmol/mol]); and -2.13% and -1.99% (patients with baseline HbA1c ≥9% [75 mmol/mol]), respectively. Postindex, CANA patients with baseline HbA1c ≥7% had similar HbA1c levels at each interval versus GLP-1 RA patients, except 9 months (mean HbA1c, 7.75% [61 mmol/mol] vs. 7.86% [62 mmol/mol]; P = .0305). CANA patients with baseline HbA1c ≥8% and ≥9% had consistently lower HbA1c numerically versus GLP-1 RA patients and statistically lower HbA1c at 9 (baseline HbA1c ≥8% or ≥9%), 27, and 30 months (baseline HbA1c ≥9%). Continuous 12-month medication cost $3,326 less for CANA versus GLP-1 RA. This retrospective study demonstrated a similar evolution of HbA1c levels among CANA and GLP-1 RA patients in a real-world setting. Lower medication costs suggest CANA is economically dominant over GLP-1 RA (similar effectiveness, lower cost). AHA = antihyperglycemic agent BMI = body mass index CANA = canagliflozin 300 mg DCSI = diabetes complications severity

Plasma concentrations of glucagon-like peptide 1 and 2 in calves fed calf starters containing lactose.

PubMed

Inabu, Y; Saegusa, A; Inouchi, K; Koike, S; Oba, M; Sugino, T

2017-11-01

The objective of this study was to evaluate the effects of lactose inclusion in calf starters on plasma glucagon-like peptide (GLP)-1 and GLP-2 concentrations and gastrointestinal tract development in calves. Holstein bull calves (n = 45) were raised on an intensified nursing program using milk replacer containing 28.0% CP and 15.0% fat, and were fed a texturized calf starter containing 0 (control), 5.0 (LAC5), or 10.0% (LAC10; n = 15 for each treatment) lactose on a DM basis. Lactose was included in the starter by partially replacing dry ground corn in pelleted portion of the starter. All calf starters were formulated with 23.1% CP. The ethanol-soluble carbohydrate concentrations of the control, LAC5, and LAC10 starters were 7.3, 12.3, and 16.8% on a DM basis, respectively. Starch concentrations of the control, LAC5, and LAC10 starters were 29.7, 27.0, and 21.4% on a DM basis, respectively. All calves were fed treatment calf starters ad libitum. Blood samples were obtained weekly from 1 to 11 wk of age, and used to measure plasma GLP-1, GLP-2, and insulin concentrations, serum β-hydroxybutyrate (BHB) concentration, and blood glucose concentration. At 80 d of age, calves were euthanized, and weights of the reticulorumen, omasum, abomasum, small intestine, and large intestine tissue were measured. Serum BHB concentration was higher for calves fed the LAC10 (171 μmol/L) starter than for those fed the control (151 μmol/L) and LAC5 (145 μmol/L) starters. Plasma GLP-1 and GLP-2 concentrations did not differ between treatments. However, relative to the baseline (1 wk of age), the plasma GLP-1 concentration was higher for the LAC10 (125.9%) than for the LAC5 (68.2%) and control (36.8%), and for the LAC5 than for the control (36.8%). Moreover, similar differences between treatments were observed for GLP-2 concentration relative to the baseline (88.2, 76.9, and 74.9% for LAC10, LAC5, and control treatments, respectively). The serum BHB concentration was positively

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

Inhibition of dipeptidyl peptidase-4 augments insulin secretion in response to exogenously administered glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and gastrin-releasing peptide in mice.

PubMed

Ahrén, Bo; Hughes, Thomas E

2005-04-01

Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently being explored as a new approach to the treatment of type 2 diabetes. This concept has emerged from the powerful and rapid action of the enzyme to inactivate glucagon-like peptide-1 (GLP-1). However, other bioactive peptides with potential influence of islet function are also substrates of DPP-4. Whether this inactivation may add to the beneficial effects of DPP-4 inhibition is not known. In this study, we explored whether DPP-4 inhibition by valine-pyrrolidide (val-pyr; 100 micromol/kg administered through gastric gavage at t = -30 min) affects the insulin and glucose responses to iv glucose (1 g/kg) together with GLP-1 (10 nmol/kg), glucose-dependent insulinotropic polypeptide (GIP; 10 nmol/kg), pituitary adenylate cyclase-activating polypeptide 38 (PACAP38; 1.3 nmol/kg), or gastrin-releasing peptide (GRP; 20 nmol/kg) given at t = 0 in anesthetized C57BL/6J mice. It was found that the acute (1-5 min) insulin response to GLP-1 was augmented by val-pyr by 80% (4.2 +/- 0.4 vs. 7.6 +/- 0.8 nmol/liter), that to GIP by 40% (2.7 +/- 0.3 vs. 3.8 +/- 0.4 nmol/liter), that to PACAP38 by 75% (4.6 +/- 0.5 vs. 8.1 +/- 0.6 nmol/liter), and that to GRP by 25% (1.8 +/- 0.2 vs. 2.3 +/- 0.3 nmol/liter; all P < 0.05 or less). This was associated with enhanced glucose elimination rate after GLP-1 [glucose elimination constant (K(G)) 2.1 +/- 0.2 vs. 3.1 +/- 0.3%/min] and PACAP38 (2.1 +/- 0.3 vs. 3.2 +/- 0.3%/min; both P < 0.01), but not after GIP or GRP. The augmented insulin response to GRP by val-pyr was prevented by the GLP-1 receptor antagonist, exendin(3) (9-39), raising the possibility that GRP effects may occur secondary to stimulation of GLP-1 secretion. We conclude that DPP-4 inhibition augments the insulin response not only to GLP-1 but also to GIP, PACAP38, and GRP.

Effect of glucagon-like peptide-1 analogue; Exendin-4, on cognitive functions in type 2 diabetes mellitus; possible modulation of brain derived neurotrophic factor and brain Visfatin.

PubMed

Abdelwahed, O M; Tork, O M; Gamal El Din, M M; Rashed, L; Zickri, M

2018-05-01

Brain derived neurotrophic factor (BDNF) is one of the most essential neurotrophic factors in the brain. BDNF is involved in learning, memory and locomotion suggesting it as a target in type 2 diabetes mellitus (T2DM) associated cognitive changes. Visfatin; an adipokine discovered to be expressed in the brain; was found to have multiple effects including its participation in keeping energy supply to the cell and is consequentially involved in cell survival. Its role in cognitive functions in T2DM was not studied before. Recent studies point to the possible neuro-protective mechanisms of glucagon-like peptide 1 analogue: Exendin-4 (Ex-4) in many cognitive disorders, but whether BDNF or Visfatin are involved or not in its neuro-protective mechanisms; is still unknown. to study the changes in cognitive functions in T2DM, either not treated or treated with Glucagon-like peptide 1 (GLP-1) analogue: Ex-4, and to identify the possible underlying mechanisms of these changes and whether BDNF and brain Visfatin are involved. A total of 36 adult male wistar albino rats were divided into 4 groups; Control, Exendin-4 control, Diabetic and Exendin-4 treated groups. At the end of the study, Y-maze and open field tests were done the day before scarification to assess spatial working memory and locomotion, respectively. Fasting glucose and insulin, lipid profile and tumor necrosis factor- alpha (TNF-α) were measured in the serum. Homeostasis model assessment insulin resistance was calculated. In the brain tissue, malondialdehyde (MDA) level, gene expression and protein levels of BDNF and Visfatin, area of degenerated neurons, area of glial cells and area % of synaptophysin immunoexpression were assessed. Compared with the control, the untreated diabetic rats showed insulin resistance, dyslipidemia and elevation of serum TNF-α. The brain tissue showed down-regulation of BDNF gene expression and reduction of its protein level, up-regulation of Visfatin gene expression and elevation

Pancreatic glucagon-like peptide-1 receptor couples to multiple G proteins and activates mitogen-activated protein kinase pathways in Chinese hamster ovary cells.

PubMed

Montrose-Rafizadeh, C; Avdonin, P; Garant, M J; Rodgers, B D; Kole, S; Yang, H; Levine, M A; Schwindinger, W; Bernier, M

1999-03-01

Chinese hamster ovary (CHO) cells stably expressing the human insulin receptor and the rat glucagon-like peptide-1 (GLP-1) receptor (CHO/GLPR) were used to study the functional coupling of the GLP-1 receptor with G proteins and to examine the regulation of the mitogen-activated protein (MAP) kinase signaling pathway by GLP-1. We showed that ligand activation of GLP-1 receptor led to increased incorporation of GTP-azidoanilide into Gs alpha, Gq/11 alpha, and Gi1,2 alpha, but not Gi3 alpha. GLP-1 increased p38 MAP kinase activity 2.5- and 2.0-fold over the basal level in both CHO/GLPR cells and rat insulinoma cells (RIN 1046-38), respectively. Moreover, GLP-1 induced phosphorylation of the immediate upstream kinases of p38, MKK3/MKK6, in CHO/GLPR and RIN 1046-38 cells. Ligand-stimulated GLP-1 receptor produced 1.45- and 2.7-fold increases in tyrosine phosphorylation of 42-kDa extracellular signal-regulated kinase (ERK) in CHO/GLPR and RIN 1046-38 cells, respectively. In CHO/GLPR cells, these effects of GLP-1 on the ERK and p38 MAP kinase pathways were inhibited by pretreatment with cholera toxin (CTX), but not with pertussis toxin. The combination of insulin and GLP-1 resulted in an additive response (1.6-fold over insulin alone) that was attenuated by CTX. In contrast, the ability of insulin alone to activate these pathways was insensitive to either toxin. Our study indicates a direct coupling between the GLP-1 receptor and several G proteins, and that CTX-sensitive proteins are required for GLP-1-mediated activation of MAP kinases.

Effects of 24-week treatment with acarbose on glucagon-like peptide 1 in newly diagnosed type 2 diabetic patients: a preliminary report.

PubMed

Zheng, Miao-yan; Yang, Ju-hong; Shan, Chun-yan; Zhou, Hong-tao; Xu, Yan-guang; Wang, Ying; Ren, Hui-zhu; Chang, Bao-cheng; Chen, Li-ming

2013-05-04

Treatment with the alpha-glucosidase inhibitor (AGI) acarbose is associated with a significant reduction the risk of cardiovascular events. However, the underlying mechanisms of this effect are unclear. AGIs were recently suggested to participate in stimulating glucagon-like peptide 1 (GLP-1) secretion. We therefore examined the effects of a 24-week treatment of acarbose on endogenous GLP-1, nitric oxide (NO) levels, nitric oxide synthase (NOS) activity, and carotid intima-media thickness (CIMT) in newly diagnosed patients with type 2 diabetes (T2D). Blood was drawn from 24 subjects (14 male, 10 female, age: 50.7 ± 7.36 years, BMI: 26.64 ± 3.38 kg/m2, GHbA1c: 7.00 ± 0.74%) with drug-naïve T2D at 0 and 120 min following a standard mixed meal for the measurements of active GLP-1, NO and NOS. The CIMT was measured prior to and following 24 weeks of acarbose monotherapy (mean dose: 268 mg daily). Following 24 weeks of acarbose treatment, both fasting and postprandial plasma GLP-1 levels were increased. In patients with increased postprandial GLP-1 levels, serum NO levels and NOS activities were also significantly increased and were positively related to GLP-1 levels. Although the CIMT was not significantly altered following treatment with acarbose, a decreased CIMT was negatively correlated with increased GLP-1 levels. Twenty-four weeks of acarbose monotherapy in newly diagnosed patients with T2D is associated with significantly increased levels of both fasting and postprandial GLP-1 as well as significantly increased NO levels and NOS activity for those patients in whom postprandial GLP-1 levels were increased. Therefore, the benefits of acarbose on cardiovascular risk may be related to its stimulation of GLP-1 secretion.

[Effects of glucagon-like peptide 2 on the adaptation of residual small bowel in a rat model of short bowel syndrome].

PubMed

Wu, Guo-Hao; Chen, Ji; Li, Hang; Wu, Zhao-Han

2006-09-01

To investigate the effects of glucagon-like peptide 2 (GLP-2) on the morphology and functional adaptation of the residual small bowel in rat model of short bowel syndrome. Twenty rats with 75% of the midjejunoileum removed were randomly divided into two groups, and received intra-peritoneal injection of GLP-2(250 micro*gd*kg-1*d-1) or subcutaneous injection saline(0.5 ml, twice one day) after operation. On postoperative day 6, the morphological changes of the residual jejunum and ileum, the expression of proliferating cell nuclear antigen(PCNA), and the mRNA expressions of Na-D-glucose cotransporters (SGLT1) and peptide cotransporters (PEPT1) were determined. The intestinal glucose absorption data per unit length as well as per unit weight of ileum were measured by in vivo circulatory perfusion experiment. The morphological parameters of the residual gut such as the thickness of mucosa, height of villus, depth of crypt, and PCNA positive index were significantly higher, while the apoptosis rate per unit of mucosal square was significantly lower in GLP-2 treatment group than those in the control group. The expressions of mRNA SGTLl and PEPT1 in the residual ileum were significantly higher than those in the control group. There was no significant difference in glucose absorption rate per gram of mucosal wet weight between the two groups (P > 0.05). GLP-2 could improve morphological and functional adaptation of the residual small bowel by stimulating enterocyte proliferation and decreasing enterocyte apoptosis in short bowel syndrome.

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

PubMed

Thymann, Thomas; Stoll, Barbara; Mecklenburg, Lars; Burrin, Douglas G; Vegge, Andreas; Qvist, Niels; Eriksen, Thomas; Jeppesen, Palle B; Sangild, Per T

2014-06-01

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 objective was to test the efficacy of the long-acting synthetic human GLP-2 analogue, teduglutide (ALX-0600), in a neonatal piglet jejunostomy model. Two-day-old pigs were subjected to resection of 50% of the small intestine (distal part), and the remnant intestine was exteriorized on the abdominal wall as a jejunostomy. All pigs were given total parenteral nutrition for 7 days and a single daily injection of the following doses of teduglutide: 0.01 (n = 6), 0.02 (n = 6), 0.1 (n = 5), or 0.2 mg · kg · day (n = 6), and compared with placebo (n = 9). Body weight increment was similar for all 4 teduglutide groups but higher than placebo (P < 0.05). There was a dose-dependent increase in weight per length of the remnant intestine (P < 0.01) and fractional protein synthesis rate in the intestine was increased in the 0.2 mg · kg · day group versus placebo (P < 0.001); however, functional and structural endpoints including activity of digestive enzymes, absorption of enteral nutrients, and immunohistochemistry (Ki67, villin, FABP2, ChgA, and GLP-2R) were not affected by the treatment. Teduglutide induces trophicity on the remnant intestine but has limited acute effects on functional endpoints. Significant effects of teduglutide on gut function may require a longer adaptation period and/or a more frequent administration of the peptide. In perspective, GLP-2 or its analogues may be relevant to improve intestinal adaptation in pediatric patients with short bowel syndrome.

The effects of short-term continuous subcutaneous insulin infusion treatment on fasting glucagon-like peptide-1 concentrations in newly diagnosed type 2 diabetes.

PubMed

Huang, Xiaofei; Li, Sha; Yang, Mei; Fu, Xuquan; Li, Huaqi; Yan, Tong; Liu, Yidong; Chen, Lihong; Lan, Lingsheng; Li, Libo; Zhong, Xiaowei

2018-04-01

Early short-term intensive insulin therapy in newly diagnosed type 2 diabetes patients shows benefit in glycemic control and β-cell function. Glucagon-like peptide-1 (GLP-1) plays an important role in glucose metabolism and development of type 2 diabetes. We did a study to observe the changes of GLP-1 and β-cell function after short-term continuous subcutaneous insulin infusion (CSII) treatment. A total of 66 subjects were enrolled, including 30 normal glucose tolerance controls (NGT) and 36 patients with newly diagnosed type 2 diabetes between October 2015 and July 2016. Fasting plasma glucose (FPG), insulin, and GLP-1 were measured in each subject. The patients underwent CSII treatment for 2 weeks, and then FBG, insulin, and GLP-1 were measured. HOMA-IR and HOMA-B were then calculated. All patients achieved target glycemic control in two weeks. HOMA-IR and HOMA-B improved significantly after intensive interventions (p < 0.05). The GLP-1 concentration increased significantly in patients after treatment (p < 0.05). When grouped according to bodyweight and age in all patients, the HOMA-IR changed significantly in overweight and old age subgroups, the HOMA-B increased significantly in normal weight, overweight and middle age subgroups, and the GLP-1 concentration also increased significantly in overweight and middle age subgroups respectively (p < 0.05). Short-term CSII treatment can obtain glycemic control target and recover β-cell function and GLP-1 secretion in newly diagnosed type 2 diabetes patients. The overweight and middle-aged patients may get more benefit from this treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

Role of fatty acid transport protein 4 in oleic acid-induced glucagon-like peptide-1 secretion from murine intestinal L cells

PubMed Central

Poreba, M. A.; Dong, C. X.; Li, S. K.; Stahl, A.; Miner, J. H.

2012-01-01

The antidiabetic intestinal L cell hormone glucagon-like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion and inhibits gastric emptying. GLP-1 secretion is stimulated by luminal oleic acid (OA), which crosses the cell membrane by an unknown mechanism. We hypothesized that L cell fatty acid transport proteins (FATPs) are essential for OA-induced GLP-1 release. Therefore, the murine GLUTag L cell model was used for immunoblotting, [3H]OA uptake assay, and GLP-1 secretion assay as determined by radioimmunoassay following treatment with OA ± phloretin, sulfo-N-succinimidyl oleate, or siRNA against FATP4. FATP4−/− and cluster-of-differentiation 36 (CD36)−/− mice received intraileal OA, and plasma GLP-1 was measured by sandwich immunoassay. GLUTag cells were found to express CD36, FATP1, FATP3, and FATP4. The cells demonstrated specific 3H[OA] uptake that was dose-dependently inhibited by 500 and 1,000 μM unlabeled OA (P < 0.001). Cell viability was not altered by treatment with OA. Phloretin and sulfo-N-succinimidyl oleate, inhibitors of protein-mediated transport and CD36, respectively, also decreased [3H]OA uptake, as did knockdown of FATP4 by siRNA transfection (P < 0.05–0.001). OA dose-dependently increased GLP-1 secretion at 500 and 1,000 μM (P < 0.001), whereas phloretin, sulfo-N-succinimidyl oleate, and FATP4 knockdown decreased this response (P < 0.05–0.01). FATP4−/− mice displayed lower plasma GLP-1 at 60 min in response to intraileal OA (P < 0.05), whereas, unexpectedly, CD36−/− mice displayed higher basal GLP-1 levels (P < 0.01) but a normal response to intraileal OA. Together, these findings demonstrate a key role for FATP4 in OA-induced GLP-1 secretion from the murine L cell in vitro and in vivo, whereas the precise role of CD36 remains unclear. PMID:22871340

Induction of miR-132 and miR-212 Expression by Glucagon-Like Peptide 1 (GLP-1) in Rodent and Human Pancreatic β-Cells

PubMed Central

Li, Jing; Keller, Mark P.; Hohmeier, Hans E.; Wang, Yong; Feng, Yue; Zhou, Heather H.; Shen, Xiaolan; Rabaglia, Mary; Soni, Mufaddal; Attie, Alan D.; Newgard, Christopher B.; Thornberry, Nancy A.; Howard, Andrew D.; Zhou, Yun-Ping

2015-01-01

Better understanding how glucagon-like peptide 1 (GLP-1) promotes pancreatic β-cell function and/or mass may uncover new treatment for type 2 diabetes. In this study, we investigated the potential involvement of microRNAs (miRNAs) in the effect of GLP-1 on glucose-stimulated insulin secretion. miRNA levels in INS-1 cells and isolated rodent and human islets treated with GLP-1 in vitro and in vivo (with osmotic pumps) were measured by real-time quantitative PCR. The role of miRNAs on insulin secretion was studied by transfecting INS-1 cells with either precursors or antisense inhibitors of miRNAs. Among the 250 miRNAs surveyed, miR-132 and miR-212 were significantly up-regulated by GLP-1 by greater than 2-fold in INS-1 832/3 cells, which were subsequently reproduced in freshly isolated rat, mouse, and human islets, as well as the islets from GLP-1 infusion in vivo in mice. The inductions of miR-132 and miR-212 by GLP-1 were correlated with cAMP production and were blocked by the protein kinase A inhibitor H-89 but not affected by the exchange protein activated by cAMP activator 8-pCPT-2′-O-Me-cAMP-AM. GLP-1 failed to increase miR-132 or miR-212 expression levels in the 832/13 line of INS-1 cells, which lacks robust cAMP and insulin responses to GLP-1 treatment. Overexpression of miR-132 or miR-212 significantly enhanced glucose-stimulated insulin secretion in both 832/3 and 832/13 cells, and restored insulin responses to GLP-1 in INS-1 832/13 cells. GLP-1 increases the expression of miRNAs 132 and 212 via a cAMP/protein kinase A-dependent pathway in pancreatic β-cells. Overexpression of miR-132 or miR-212 enhances glucose and GLP-1-stimulated insulin secretion. PMID:26218441

Induction of miR-132 and miR-212 Expression by Glucagon-Like Peptide 1 (GLP-1) in Rodent and Human Pancreatic β-Cells.

PubMed

Shang, Jin; Li, Jing; Keller, Mark P; Hohmeier, Hans E; Wang, Yong; Feng, Yue; Zhou, Heather H; Shen, Xiaolan; Rabaglia, Mary; Soni, Mufaddal; Attie, Alan D; Newgard, Christopher B; Thornberry, Nancy A; Howard, Andrew D; Zhou, Yun-Ping

2015-09-01

Better understanding how glucagon-like peptide 1 (GLP-1) promotes pancreatic β-cell function and/or mass may uncover new treatment for type 2 diabetes. In this study, we investigated the potential involvement of microRNAs (miRNAs) in the effect of GLP-1 on glucose-stimulated insulin secretion. miRNA levels in INS-1 cells and isolated rodent and human islets treated with GLP-1 in vitro and in vivo (with osmotic pumps) were measured by real-time quantitative PCR. The role of miRNAs on insulin secretion was studied by transfecting INS-1 cells with either precursors or antisense inhibitors of miRNAs. Among the 250 miRNAs surveyed, miR-132 and miR-212 were significantly up-regulated by GLP-1 by greater than 2-fold in INS-1 832/3 cells, which were subsequently reproduced in freshly isolated rat, mouse, and human islets, as well as the islets from GLP-1 infusion in vivo in mice. The inductions of miR-132 and miR-212 by GLP-1 were correlated with cAMP production and were blocked by the protein kinase A inhibitor H-89 but not affected by the exchange protein activated by cAMP activator 8-pCPT-2'-O-Me-cAMP-AM. GLP-1 failed to increase miR-132 or miR-212 expression levels in the 832/13 line of INS-1 cells, which lacks robust cAMP and insulin responses to GLP-1 treatment. Overexpression of miR-132 or miR-212 significantly enhanced glucose-stimulated insulin secretion in both 832/3 and 832/13 cells, and restored insulin responses to GLP-1 in INS-1 832/13 cells. GLP-1 increases the expression of miRNAs 132 and 212 via a cAMP/protein kinase A-dependent pathway in pancreatic β-cells. Overexpression of miR-132 or miR-212 enhances glucose and GLP-1-stimulated insulin secretion.

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.

Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors.

PubMed

Ronn, Jonas; Jensen, Elisa P; Wewer Albrechtsen, Nicolai J; Holst, Jens Juul; Sorensen, Charlotte M

2017-12-01

Glucagon-like peptide-1 (GLP-1) is an incretin hormone increasing postprandial insulin release. GLP-1 also induces diuresis and natriuresis in humans and rodents. The GLP-1 receptor is extensively expressed in the renal vascular tree in normotensive rats where acute GLP-1 treatment leads to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP-1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP-1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect of acute intrarenal infusion of GLP-1. We hypothesized that GLP-1 would increase diuresis and natriuresis and reduce MAP in SHR. Immunohistochemical staining and in situ hybridization for the GLP-1 receptor were used to localize GLP-1 receptors in the kidney. Sevoflurane-anesthetized normotensive Sprague-Dawley rats and SHR received a 20 min intrarenal infusion of GLP-1 and changes in MAP, RBF, heart rate, dieresis, and natriuresis were measured. The vasodilatory effect of GLP-1 was assessed in isolated interlobar arteries from normo- and hypertensive rats. We found no expression of GLP-1 receptors in the kidney from SHR. However, acute intrarenal infusion of GLP-1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP-1 in SHR are caused either by extrarenal GLP-1 receptors activating other mechanisms (e.g., insulin) to induce the renal changes observed or possibly by an alternative renal GLP-1 receptor. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Glucagon-like peptide-1 receptor imaging with [Lys40(Ahx-HYNIC- 99mTc/EDDA)NH2]-exendin-4 for the detection of insulinoma.

PubMed

Sowa-Staszczak, Anna; Pach, Dorota; Mikołajczak, Renata; Mäcke, Helmut; Jabrocka-Hybel, Agata; Stefańska, Agnieszka; Tomaszuk, Monika; Janota, Barbara; Gilis-Januszewska, Aleksandra; Małecki, Maciej; Kamiński, Grzegorz; Kowalska, Aldona; Kulig, Jan; Matyja, Andrzej; Osuch, Czesław; Hubalewska-Dydejczyk, Alicja

2013-04-01

The objective of this article is to present a new method for the diagnosis of insulinoma with the use of [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH2]-exendin-4. Studies were performed in 11 patients with negative results of all available non-isotopic diagnostic methods (8 with symptoms of insulinoma, 2 with malignant insulinoma and 1 with nesidioblastosis). In all patients glucagon-like peptide-1 (GLP-1) receptor imaging (whole-body and single photon emission computed tomography/CT examinations) after the injection of 740 MBq of the tracer was performed. Both sensitivity and specificity of GLP-1 receptor imaging were assessed to be 100 % in patients with benign insulinoma. In all eight cases with suspicion of insulinoma a focal uptake in the pancreas was found. In six patients surgical excision of the tumour was performed (type G1 tumours were confirmed histopathologically). In one patient surgical treatment is planned. One patient was disqualified from surgery. In one case with malignant insulinoma pathological accumulation of the tracer was found only in the region of local recurrence. The GLP-1 study was negative in the other malignant insulinoma patient. In one case with suspicion of nesidioblastosis, a focal accumulation of the tracer was observed and histopathology revealed coexistence of insulinoma and nesidioblastosis. [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH2]-exendin-4 seems to be a promising diagnostic tool in the localization of small insulinoma tumours, but requires verification in a larger series of patients.

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.

Secretion of glucagon-like peptide-2 responds to nutrient intake but not glucose provision in milk-fed calves.

PubMed

Castro, J J; Morrison, S Y; Hosseinni, A; Loor, J J; Drackley, J K; Ipharraguerre, I R

2016-07-01

Glucagon-like peptide 2 (GLP-2) is a peptide released by the lower gut that has potent trophic and restorative effects on the intestinal epithelium. Two experiments were conducted to assess the effects of feeding rate and either metabolizable or nonmetabolizable glucose supplementation on GLP-2 concentrations in plasma and intestinal development in Holstein calves. In the first experiment, 48 newborn calves were assigned to 12 treatments (n=4) corresponding to the factorial combination of 4 milk feeding amounts [1.75, 1.32, 0.88, and 0.44% of body weight (BW) as dry matter (DM)] and 3 oral supplementation treatments (nonsupplemented, glucose-supplemented, and 3-O-methyl glucose-supplemented). In the second experiment 30 newborn calves (n=10) were fed milk at a fixed rate of 1.75% of BW as DM and assigned to the same glucose supplementation treatments used in experiment 1 to investigate effects on intestinal development. In the first experiment, we found a saturating response of plasma GLP-2 to increasing feeding levels. The feeding rate at which 50% of the maximal GLP-2 release occurred was estimated to be 0.53% of BW as DM or 30.3% of the maximum feeding rate (1.75% of BW as DM), whereas maximal secretion was estimated to be about 98.6 pmol/L. In turn, feeding 75, 50, or 25% of the maximal feeding rate (i.e., 1.75% BW as DM) resulted in plasma GLP-2 concentrations 87, 72, and 49% of that in fully fed calves, respectively. Neither metabolizable nor nonmetabolizable glucose supplementation affected GLP-2 secretion and no interaction with feed intake level was detected. In the second experiment, no effect of glucose supplementation was observed on intestinal growth, mucosal cell proliferation, or expression of genes related to the actions of GLP-2. Nonetheless, we observed that a pool of genes of the GLP-2 signaling pathway was more abundantly and coordinately regulated in the colon than in the ileum of these animals, indicating an opportunity for dietary induction

Glucagon-like peptide-2 protects impaired intestinal mucosal barriers in obstructive jaundice rats

PubMed Central

Chen, Jun; Dong, Jia-Tian; Li, Xiao-Jing; Gu, Ye; Cheng, Zhi-Jian; Cai, Yuan-Kun

2015-01-01

AIM: To observe the protective effect of glucagon-like peptide-2 (GLP-2) on the intestinal barrier of rats with obstructive jaundice and determine the possible mechanisms of action involved in the protective effect. METHODS: Thirty-six Sprague-Dawley rats were randomly divided into a sham operation group, an obstructive jaundice group, and a GLP-2 group; each group consisted of 12 rats. The GLP-2 group was treated with GLP-2 after the day of surgery, whereas the other two groups were treated with the same concentration of normal saline. Alanine aminotransferase (ALT), total bilirubin, and endotoxin levels were recorded at 1, 3, 7, 10 and 14 d. Furthermore, on the 14th day, body weight, the wet weight of the small intestine, pathological changes of the small intestine and the immunoglobulin A (IgA) expressed by plasma cells located in the small intestinal lamina propria were recorded for each group. RESULTS: In the rat model, jaundice was obvious, and the rats’ activity decreased 4-6 d post bile duct ligation. Compared with the sham operation group, the obstructive jaundice group displayed increased yellow staining of abdominal visceral serosa, decreased small intestine wet weight, thinning of the intestinal muscle layer and villi, villous atrophy, uneven height, fusion, partial villous epithelial cell shedding, substantial inflammatory cell infiltration and significantly reduced IgA expression. However, no significant gross changes were noted between the GLP-2 and sham groups. With time, the levels of ALT, endotoxin and bilirubin in the GLP-2 group were significantly increased compared with the sham group (P < 0.01). The increasing levels of the aforementioned markers were more significant in the obstructive jaundice group than in the GLP-2 group (P < 0.01). CONCLUSION: GLP-2 reduces intestinal mucosal injuries in obstructive jaundice rats, which might be attributed to increased intestinal IgA and reduced bilirubin and endotoxin. PMID:25593463

The glucagon-like peptide-1-based therapeutics exenatide and saxagliptin did not cause detrimental effects on the pancreas in mice, rats, dogs and monkeys.

PubMed

Roy, D; Chadwick, K D; Tatarkiewicz, K; LaCerte, C; Bergholm, A-M; Brodie, T; Mangipudy, R S; Parkes, D; Graziano, M J; Reilly, T P

2014-10-01

Recent reports in the literature have suggested that glucagon-like peptide-1 (GLP-1)-based therapies may lead to increased risk of pancreatic pathology leading to chronic pancreatic injury and pancreatic neoplasia. Extensive non-clinical and clinical safety testing was conducted to support the global development of exenatide twice daily, exenatide once weekly and saxagliptin. Our aim was to integrate these non-clinical data obtained with both mechanisms of GLP-1-based drugs to provide complementary data regarding the potential for drug-induced pancreatic safety signals. More than 70 regulated non-clinical toxicology studies in rodents and non-rodents were conducted in accordance with International Conference on Harmonisation and US Food and Drug Administration guidance documents, current industry standards, animal welfare regulations and in compliance with Good Laboratory Practice regulations. Treatment duration was up to 2 years in rodents and up to 12 months in non-rodents using high doses representing large multiples of human exposures (up to 130× for exenatide and 2200× for saxagliptin). Comprehensive pancreas assessments involved more than 2400 pancreata from animals exposed to exenatide and over 1700 pancreata from animals exposed to saxagliptin. Neither exenatide nor saxagliptin treatment resulted in drug-related microscopic changes indicative of acute or chronic adverse effects (including neoplasia) in the endocrine or exocrine pancreas, at doses far exceeding the maximum human systemic exposures. These data substantially add to the weight of evidence supporting the lack of non-clinical drug-induced pancreatic safety signals in animals exposed to GLP-1-based therapies. © 2014 John Wiley & Sons Ltd.

Development of novel ligands for peptide GPCRs.

PubMed

Moran, Brian M; McKillop, Aine M; O'Harte, Finbarr Pm

2016-12-01

Incretin based glucagon-like peptide-1 receptor (GLP-1R) agonists which target a G-protein coupled receptor (GPCR) are currently used in the treatment of type 2 diabetes. This review focuses on GPCRs from pancreatic β-cells, including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon, somatostatin, pancreatic polypeptide (PP), cholecystokinin (CCK), peptide YY (PYY), oxyntomodulin (OXM) and ghrelin receptors. In addition, fatty acids GPCRs are thought to have an increasing role in regulating peptide secretions namely short fatty acids GPCR (GPR41, GPR43), medium chain fatty acid GPCR (GPR84), long chain fatty acid GPCR (GPR40, GPR120) and cannabinoid-like GPCR (GPR55, GPR119). Several pre-clinical and clinical trials are currently ongoing in peptide GPCR based therapies, including dual and triple agonist peptides which activate two or more GPCRs simultaneously. Copyright © 2016 Elsevier Ltd. All rights reserved.

Elevations in growth hormone and glucagon-like peptide-2 levels on admission are associated with increased mortality in trauma patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rowan, Matthew P.; Beckman, Darrick J.; Rizzo, Julie A.

Burn and trauma patients present a clinical challenge due to metabolic derangements and hypermetabolism that result in a prolonged catabolic state with impaired healing and secondary complications, including ventilator dependence. Previous work has shown that circulating levels of growth hormone (GH) are predictive of mortality in critically ill adults, but few studies have examined the prognostic potential of GH levels in adult trauma patients. Here, our objective is to investigate the utility of GH and other endocrine responses in the prediction of outcomes, we conducted a prospective, observational study of adult burn and trauma patients. We evaluated the serum concentrationmore » of GH, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), and glucagon-like peptide-2 (GLP-2) weekly for up to 6 weeks in 36 adult burn and trauma patients admitted between 2010 and 2013. As a result, non-survivors had significantly higher levels of GH and GLP-2 on admission than survivors. This study demonstrates that GH has potential as a predictor of mortality in critically ill trauma and burn patients. Future studies will focus on not only the role of GH, but also GLP-2, which was shown to correlate with mortality in this study with a goal of offering early, targeted therapeutic interventions aimed at decreasing mortality in the critically injured. GH and GLP-2 may have clinical utility for outcome prediction in adult trauma patients.« less

Elevations in growth hormone and glucagon-like peptide-2 levels on admission are associated with increased mortality in trauma patients

DOE PAGES

Rowan, Matthew P.; Beckman, Darrick J.; Rizzo, Julie A.; ...

2016-10-04

Burn and trauma patients present a clinical challenge due to metabolic derangements and hypermetabolism that result in a prolonged catabolic state with impaired healing and secondary complications, including ventilator dependence. Previous work has shown that circulating levels of growth hormone (GH) are predictive of mortality in critically ill adults, but few studies have examined the prognostic potential of GH levels in adult trauma patients. Here, our objective is to investigate the utility of GH and other endocrine responses in the prediction of outcomes, we conducted a prospective, observational study of adult burn and trauma patients. We evaluated the serum concentrationmore » of GH, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), and glucagon-like peptide-2 (GLP-2) weekly for up to 6 weeks in 36 adult burn and trauma patients admitted between 2010 and 2013. As a result, non-survivors had significantly higher levels of GH and GLP-2 on admission than survivors. This study demonstrates that GH has potential as a predictor of mortality in critically ill trauma and burn patients. Future studies will focus on not only the role of GH, but also GLP-2, which was shown to correlate with mortality in this study with a goal of offering early, targeted therapeutic interventions aimed at decreasing mortality in the critically injured. GH and GLP-2 may have clinical utility for outcome prediction in adult trauma patients.« less

Glucagon orchestrates stress-induced hyperglycaemia.

PubMed

Harp, J B; Yancopoulos, G D; Gromada, J

2016-07-01

Hyperglycaemia is commonly observed on admission and during hospitalization for medical illness, traumatic injury, burn and surgical intervention. This transient hyperglycaemia is referred to as stress-induced hyperglycaemia (SIH) and frequently occurs in individuals without a history of diabetes. SIH has many of the same underlying hormonal disturbances as diabetes mellitus, specifically absolute or relative insulin deficiency and glucagon excess. SIH has the added features of elevated blood levels of catecholamines and cortisol, which are not typically present in people with diabetes who are not acutely ill. The seriousness of SIH is highlighted by its greater morbidity and mortality rates compared with those of hospitalized patients with normal glucose levels, and this increased risk is particularly high in those without pre-existing diabetes. Insulin is the treatment standard for SIH, but new therapies that reduce glucose variability and hypoglycaemia are desired. In the present review, we focus on the key role of glucagon in SIH and discuss the potential use of glucagon receptor blockers and glucagon-like peptide-1 receptor agonists in SIH to achieve target glucose control. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Efficacy and safety of glucagon-like peptide-1 agonists on macrovascular and microvascular events in type 2 diabetes mellitus: A meta-analysis.

PubMed

Gargiulo, P; Savarese, G; D'Amore, C; De Martino, F; Lund, L H; Marsico, F; Dellegrottaglie, S; Marciano, C; Trimarco, B; Perrone-Filardi, P

2017-12-01

Glucagon-like peptide-1 (GLP-1) agonists improve glycaemic control in type 2 diabetes mellitus (DM). Outcome trials investigating macro and microvascular effects of GLP-1 agonists reported conflicting results. The aim of this study was to assess, in a meta-analysis, the effects of GLP-1 agonists on mortality, major nonfatal cardiovascular (CV) events, renal and retinal events. MEDLINE, Cochrane, ISI Web of Science, SCOPUS and ClinicalTrial.gov databases were searched for articles published until June 2017. Randomized trials enrolling more than 200 patients, comparing GLP-1 versus placebo or active treatments in patients with DM, and assessing outcomes among all-cause death, CV death, MI, stroke, HF, diabetic retinopathy and nephropathy were included. 77 randomized trials enrolling 60,434 patients were included. Compared to control, treatment with GLP-1 significantly reduced the risk of all-cause death (RR: 0.888; CI: 0.804-0.979; p = 0.018) and the risk of CV death (RR: 0.858; CI: 0.757-0.973; p = 0.017). GLP-1 agonists did not affect the risk of MI (RR: 0.917; CI: 0.830-1.014; p = 0.092) as well as the risk of stroke (RR: 0.882; CI: 0.759-1.023; p = 0.097), HF (RR: 0.967; CI: 0.803-1.165; p = 0.725), retinopathy (RR: 1.000; CI: 0.807-1.238; p = 0.997) and nephropathy (RR: 0.866; CI: 0.625-1.199; p = 0.385). Treatment with GLP-1 agonists in DM patients is associated with a significant reduction of all cause and CV mortality. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

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

Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice.

PubMed

Hou, Shaocong; Li, Caina; Huan, Yi; Liu, Shuainan; Liu, Quan; Sun, Sujuan; Jiang, Qian; Jia, Chunming; Shen, Zhufang

2015-01-01

Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice

PubMed Central

Hou, Shaocong; Li, Caina; Liu, Shuainan; Liu, Quan; Sun, Sujuan; Jia, Chunming; Shen, Zhufang

2015-01-01

Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes. PMID:26351642

Residues within the Transmembrane Domain of the Glucagon-Like Peptide-1 Receptor Involved in Ligand Binding and Receptor Activation: Modelling the Ligand-Bound Receptor

PubMed Central

Coopman, K.; Wallis, R.; Robb, G.; Brown, A. J. H.; Wilkinson, G. F.; Timms, D.

2011-01-01

The C-terminal regions of glucagon-like peptide-1 (GLP-1) bind to the N terminus of the GLP-1 receptor (GLP-1R), facilitating interaction of the ligand N terminus with the receptor transmembrane domain. In contrast, the agonist exendin-4 relies less on the transmembrane domain, and truncated antagonist analogs (e.g. exendin 9–39) may interact solely with the receptor N terminus. Here we used mutagenesis to explore the role of residues highly conserved in the predicted transmembrane helices of mammalian GLP-1Rs and conserved in family B G protein coupled receptors in ligand binding and GLP-1R activation. By iteration using information from the mutagenesis, along with the available crystal structure of the receptor N terminus and a model of the active opsin transmembrane domain, we developed a structural receptor model with GLP-1 bound and used this to better understand consequences of mutations. Mutation at Y152 [transmembrane helix (TM) 1], R190 (TM2), Y235 (TM3), H363 (TM6), and E364 (TM6) produced similar reductions in affinity for GLP-1 and exendin 9–39. In contrast, other mutations either preferentially [K197 (TM2), Q234 (TM3), and W284 (extracellular loop 2)] or solely [D198 (TM2) and R310 (TM5)] reduced GLP-1 affinity. Reduced agonist affinity was always associated with reduced potency. However, reductions in potency exceeded reductions in agonist affinity for K197A, W284A, and R310A, while H363A was uncoupled from cAMP generation, highlighting critical roles of these residues in translating binding to activation. Data show important roles in ligand binding and receptor activation of conserved residues within the transmembrane domain of the GLP-1R. The receptor structural model provides insight into the roles of these residues. PMID:21868452

Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice.

PubMed

Jouihan, Hani; Will, Sarah; Guionaud, Silvia; Boland, Michelle L; Oldham, Stephanie; Ravn, Peter; Celeste, Anthony; Trevaskis, James L

2017-11-01

Nonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice. OCA and IP118 alone and in combination were sub-chronically administered to Lep ob /Lep ob mice with diet-induced NASH or diet-induced obese (DIO) mice. Metabolic (body weight and glucose) and liver (biochemical and histological) endpoints were assessed. NASH severity in Lep ob /Lep ob mice was graded using a customized integrated scoring system. OCA reduced liver weight and lipid in NASH mice (both by -17%) but had no effect on plasma ALT or AST levels. In contrast, IP118 significantly reduced liver weight (-21%), liver lipid (-15%), ALT (-29%), and AST (-27%). The combination of OCA + IP118 further reduced liver weight (-29%), liver lipid (-22%), ALT (-39%), and AST (-36%). Combination therapy was superior to monotherapies in reducing hepatic steatosis, inflammation, and fibrosis. Hepatic improvements with IP118 and OCA + IP118 were associated with reduced body weight (-4.3% and -3.5% respectively) and improved glycemic control in OCA + IP118-treated mice. In DIO mice, OCA + IP118 co-administration reduced body weight (-25.3%) to a greater degree than IP118 alone (-12.5%) and further improved glucose tolerance and reduced hepatic lipid. Our data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

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

Effects of 1 and 3 g cinnamon on gastric emptying, satiety, and postprandial blood glucose, insulin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and ghrelin concentrations in healthy subjects.

PubMed

Hlebowicz, Joanna; Hlebowicz, Anna; Lindstedt, Sandra; Björgell, Ola; Höglund, Peter; Holst, Jens J; Darwiche, Gassan; Almér, Lars-Olof

2009-03-01

A previous study of healthy subjects showed that intake of 6 g cinnamon with rice pudding reduced postprandial blood glucose and the gastric emptying rate (GER) without affecting satiety. The objective was to study the effect of 1 and 3 g cinnamon on GER, postprandial blood glucose, plasma concentrations of insulin and incretin hormones [glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)], the ghrelin response, and satiety in healthy subjects. GER was measured by using real-time ultrasonography after ingestion of rice pudding with and without 1 or 3 g cinnamon. Fifteen healthy subjects were assessed in a crossover trial. The addition of 1 or 3 g cinnamon had no significant effect on GER, satiety, glucose, GIP, or the ghrelin response. The insulin response at 60 min and the area under the curve (AUC) at 120 min were significantly lower after ingestion of rice pudding with 3 g cinnamon (P = 0.05 and P = 0.036, respectively, after Bonferroni correction). The change in GLP-1 response (DeltaAUC) and the change in the maximum concentration (DeltaC(max)) were both significantly higher after ingestion of rice pudding with 3 g cinnamon (P = 0.0082 and P = 0.0138, respectively, after Bonferroni correction). Ingestion of 3 g cinnamon reduced postprandial serum insulin and increased GLP-1 concentrations without significantly affecting blood glucose, GIP, the ghrelin concentration, satiety, or GER in healthy subjects. The results indicate a relation between the amount of cinnamon consumed and the decrease in insulin concentration.

Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces Alzheimer disease-associated tau hyperphosphorylation in the hippocampus of rats with type 2 diabetes.

PubMed

Xu, Weijie; Yang, Yan; Yuan, Gang; Zhu, Wenjun; Ma, Delin; Hu, Shuhong

2015-02-01

Impaired insulin signaling pathway in the brain in type 2 diabetes (T2D) is a risk factor for Alzheimer disease (AD). Glucagon-like peptide-1 (GLP-1) and its receptor agonist are widely used for treatment of T2D. Here we studied whether the effects of exendin-4 (EX-4), a long-lasting GLP-1 receptor agonist, could reduce the risk of AD in T2D. Type 2 diabetes rats were injected with EX-4 for 28 consecutive days. Blood glucose and insulin levels, as well as GLP-1 and insulin in cerebrospinal fluid, were determined during the experiment. The phosphorylation level of tau at individual phosphorylation sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and glycogen synthase kinase-3β (GSK-3β) were analyzed with Western blots. The levels of phosphorylated tau protein at site Ser199/202 and Thr217 level in the hippocampus of T2D rats were found to be raised notably and evidently decreased after EX-4 intervention. In addition, brain insulin signaling pathway was ameliorated after EX-4 treatment, and this result was reflected by a decreased activity of PI3K/AKT and an increased activity of GSK-3β in the hippocampus of T2D rats as well as a rise in PI3K/AKT activity and a decline in GSK-3β activity after 4 weeks intervention of EX-4. These results demonstrate that multiple days with EX-4 appears to prevent the hyperphosphorylation of AD-associated tau protein due to increased insulin signaling pathway in the brain. These findings support the potential use of GLP-1 for the prevention and treatment of AD in individuals with T2D.

Roles of increased glycaemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass

PubMed Central

Tharakan, George; Behary, Preeshila; Wewer Albrechtsen, Nicolai J; Chahal, Harvinder; Kenkre, Julia; Miras, Alexander D; Ahmed, Ahmed R; Holst, Jens J; Bloom, Stephen R

2017-01-01

Objective Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized and highly disabling complication of RYGB is postprandial hypoglycaemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like peptide-1 (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments are proposed, including dietary modification, GLP-1 antagonism, GLP-1 analogues and even surgical reversal, with none showing a more decided advantage over the others. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies. Methods We studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycaemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations. Results We found increased glycaemic variability in our cohort of PPH patients, specifically a higher mean amplitude glucose excursion (MAGE) score of 4.9. We observed significantly greater and earlier increases in insulin, GLP-1 and glucagon in patients who had hypoglycaemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups. Conclusion An early peak in GLP-1 and glucagon may together trigger an exaggerated insulinotropic response to eating and consequent hypoglycaemia in patients with PPH. PMID:28855269

Val8-glucagon-like peptide-1 protects against Aβ1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats.

PubMed

Wang, X H; Li, L; Hölscher, C; Pan, Y F; Chen, X R; Qi, J S

2010-11-10

Amyloid β protein (Aβ) is considered to be partly responsible for the impairment of learning and memory in Alzheimer disease (AD). In addition, it has been found recently that type 2 diabetes mellitus (T2DM) is a risk factor for developing AD. One promising treatment for AD is using analogues for the insulin-release facilitating gut hormone glucagon-like peptide-1 (GLP-1) that has been developed as a T2DM therapy. GLP-1 has been shown to have neuroprotective properties. However, if GLP-1 can protect the late phase-long term potentiation (L-LTP) and related cognitive function against Aβ-induced impairment it is still an open question. To further characterize the neuroprotective function of GLP-1 in the brain, we investigated the effects of i.c.v. injected Val(8)-GLP-1(7-36) on the Aβ fragment-induced impairment of in vivo hippocampal L-LTP and spatial learning and memory in rats. The results showed that (1) Aβ1-40 (5 nmol) injection did not affect the baseline field excitatory postsynaptic potentials (fEPSPs), but significantly suppressed multiple high frequency stimulation (HFS)-induced L-LTP in hippocampal CA1 region; (2) Val(8)-GLP-1(7-36) (0.05 pmol) administration alone did not affect the baseline synaptic transmission and the maintenance of L-LTP; (3) pretreatment with Val(8)-GLP-1(7-36) (0.05 pmol) effectively prevented Aβ1-40-induced deficit of L-LTP; (4) i.c.v. injection of 5 nmol Aβ1-40 resulted in a significant decline learning a spatial Morris water maze (MWM) test; (5) Val(8)-GLP-1(7-36) (0.05 pmol) administration alone did not affect spatial learning in this task, while pretreatment with Val(8)-GLP-1(7-36) effectively reversed the impairment of spatial learning and memory induced by Aβ1-40. At the same time, the swim speeds and escape latencies of rats among all groups in the visible platform tests did not show any difference. These results suggest that increase of GLP-1 signalling in the brain may be a promising strategy to ameliorate the

Population pharmacokinetics of lyophilized recombinant glucagon-like peptide-1 receptor agonist (recombinant exendin-4, rE-4) in Chinese patients with type 2 diabetes mellitus
.

PubMed

Zang, Yan-Nan; Zhang, Min-Jie; Wang, Yi-Tong; Wang, Chen; Wang, Qian; Zheng, Qing-Shan; Ji, Li-Nong; Guo, Wei; Fang, Yi

2017-08-01

To investigate the population pharmacokinetics of lyophilized recombinant glucagon-like peptide-1 receptor agonist (rE-4) in Chinese patients with type 2 diabetes mellitus (T2DM) for plasma concentration estimation and individualized treatment. Twelve patients with T2DM were enrolled to receive subcutaneous injections of rE-4 at 5 µg twice daily for 84 days. Administration dosage was adjusted from 5 µg to 10 µg twice daily at day 29 in case of glycated albumin (GA) ≥ 17%. The population pharmacokinetic model was developed in the nonlinear mixed-effects modeling software NONMEM. The data were best described by a two-compartment model with first-order absorption and elimination. The outcome parameters were as follows: apparent clearance (CL/F) 6.67 L/h, apparent distribution volume of central compartment (V_c/F) 19.4 L, absorption rate constant (K_a) 1.39 h^-1, apparent distribution volume of peripheral compartment (V_p/F) 22.6 L, intercompartmental clearance (Q/F) 1.28 L/h. The interindividual variabilities for CL/F, V_c/F, K_a, and Q/F were 64.4%, 57.7%, 45.5%, and 153.3%, respectively. The intra-individual variability of proportional error model was 41.7%. No covariate was screened out that showed significant influence on the model parameters. The established two-compartment model with first-order absorption and elimination successfully described the pharmacokinetic characteristics of rE-4 in Chinese patients with T2DM.
.

Nutrient-intake-level-dependent regulation of intestinal development in newborn intrauterine growth-restricted piglets via glucagon-like peptide-2.

PubMed

Liu, J; Liu, Z; Gao, L; Chen, L; Zhang, H

2016-10-01

The objective of the present study was to investigate the intestinal development of newborn intrauterine growth-restricted (IUGR) piglets subjected to normal nutrient intake (NNI) or restricted nutrient intake (RNI). Newborn normal birth weight (NBW) and IUGR piglets were allotted to NNI or RNI levels for 4 weeks from day 8 postnatal. IUGR piglets receiving NNI had similar growth performance compared with that of NBW piglets. Small intestine length and villous height were greater in IUGR piglets fed the NNI than that of piglets fed the RNI. Lactase activity was increased in piglets fed the NNI compared with piglets fed the RNI. Absorptive function, represented by active glucose transport by the Ussing chamber method and messenger RNA (mRNA) expressions of two main intestinal glucose transporters, Na+-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), were greater in IUGR piglets fed the NNI compared with piglets fed the RNI regimen. The apoptotic process, characterized by caspase-3 activity (a sign of activated apoptotic cells) and mRNA expressions of p53 (pro-apoptotic), bcl-2-like protein 4 (Bax) (pro-apoptotic) and B-cell lymphoma-2 (Bcl-2) (anti-apoptotic), were improved in IUGR piglets fed the NNI regimen. To test the hypothesis that improvements in intestinal development of IUGR piglets fed NNI might be mediated through circulating glucagon-like peptide-2 (GLP-2), GLP-2 was injected subcutaneously to IUGR piglets fed the RNI from day 8 to day 15 postnatal. Although the intestinal development of IUGR piglets fed the RNI regimen was suppressed compared with those fed the NNI regimen, an exogenous injection of GLP-2 was able to bring intestinal development to similar levels as NNI-fed IUGR piglets. Collectively, our results demonstrate that IUGR neonates that have NNI levels could improve intestinal function via the regulation of GLP-2.

Correlation between plasma glucagon-like peptide 2 levels and proliferative makers in small intestinal injury in rats induced by methotrexate administration.

PubMed

Hirotani, Yoshihiko; Yamamoto, Kaoru; Ikeda, Kenji; Arakawa, Yukio; Li, Jun; Kitamura, Kazuyuki; Kurokawa, Nobuo; Tanaka, Kazuhiko

2006-11-01

Glucagon-like peptide 2 (GLP-2) is a potent intestinal epithelium-specific growth factor that has been shown to reduce the severity of inflammatory disorders of the intestine in rodent models. We examined whether a relationship exists between plasma level of GLP-2 and the degree of intestinal injury induced by chemotherapeutic agents in the rat. Methotrexate (MTX) was administrated orally for 6 consecutive days at doses of 1.25, 2.5, and 5.0 mg/kg body weight per day. Mucosal samples of rat duodenum, jejunum, and ileum were used for assessment of mucosal weight, DNA and protein content. Plasma GLP-2 levels were measured on day 8. MTX significantly reduced body weight. The values of all indices tended to decrease in all segments with increases in MTX dose. Plasma GLP-2 levels were significantly higher in the MTX 2.5 mg/kg/d group (p<0.05) and the MTX 5.0 mg/kg/d group (p<0.01) than in the control group. Correlations were found between plasma GLP-2 levels and mucosal weight, DNA and protein content. We concluded that plasma GLP-2 levels reflect the degree of intestinal injury following MTX administration in this preclinical model.

Glucagon-like peptide-1 receptor agonists compared with basal insulins for the treatment of type 2 diabetes mellitus: a systematic review and meta-analysis.

PubMed

Singh, Sonal; Wright, Eugene E; Kwan, Anita Y M; Thompson, Juliette C; Syed, Iqra A; Korol, Ellen E; Waser, Nathalie A; Yu, Maria B; Juneja, Rattan

2017-02-01

Since 2005, several glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been approved to treat people with type 2 diabetes. These agents are considered for use at the same point in the treatment paradigm as basal insulins. A comprehensive comparison of these drug classes, therefore, can help inform treatment decisions. This systematic review and meta-analysis assessed the clinical efficacy and safety of GLP-1 RAs compared with basal insulins. MEDLINE, EMBASE, CENTRAL and PubMed databases were searched. Randomized clinical trials (RCTs) of ≥16 weeks' duration comparing GLP-1 RAs vs basal insulins in adults with type 2 diabetes inadequately controlled with oral antihyperglycemic drugs were included. Data on the change from baseline to 26 weeks (±10 weeks) of treatment in hemoglobin A1c (HbA1c) and weight, as well as the proportion of patients experiencing hypoglycaemia, were extracted. Fixed-effect pairwise meta-analyses were conducted where data were available from ≥2 studies. Fifteen RCTs were identified and 11 were meta-analysed. The once-weekly GLP-1 RAs, exenatide long acting release (LAR) and dulaglutide, led to greater, statistically significant mean HbA1c reductions vs basal insulins (exenatide: -0.31% [95% confidence interval -0.42, -0.19], dulaglutide: -0.39% [-0.49, -0.29]) whilst once-daily liraglutide and twice-daily exenatide did not (liraglutide: 0.06% [-0.06, 0.18], exenatide: 0.01% [-0.11, 0.13]). Mean weight reduction was seen with all GLP-1 RAs while mean weight gain was seen with basal insulins. Interpretation of the analysis of hypoglycaemia was limited by inconsistent definitions and reporting. Because of the limited number of available studies sensitivity analyses to explore heterogeneity could not be conducted. Although weight reduction is seen with all GLP-1 RA's, only the once-weekly agents, exenatide LAR and dulaglutide, demonstrate significant HbA1c reductions when compared to basal insulins. © 2016 The Authors. Diabetes

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. © 2015 The Authors

The effect of endogenously released glucose, insulin, glucagon-like peptide 1, ghrelin on cardiac output, heart rate, stroke volume, and blood pressure.

PubMed

Hlebowicz, Joanna; Lindstedt, Sandra; Björgell, Ola; Dencker, Magnus

2011-12-29

Ingestion of a meal increases the blood flow to the gastrointestinal organs and affects the heart rate (HR), blood pressure and cardiac output (CO), although the mechanisms are not known. The aim of this study was to evaluate the effect of endogenously released glucose, insulin, glucagon-like peptide 1 (GLP-1), ghrelin on CO, HR, stroke volume (SV), and blood pressure. Eleven healthy men and twelve healthy women ((mean ± SEM) aged: 26 ± 0.2 y; body mass index: 21.8 ± 0.1 kg/m(2))) were included in this study. The CO, HR, SV, systolic and diastolic blood pressure, antral area, gastric emptying rate, and glucose, insulin, GLP-1 and ghrelin levels were measured. The CO and SV at 30 min were significantly higher, and the diastolic blood pressure was significantly lower, than the fasting in both men and women (P < 0.05). In men, significant correlations were found between GLP-1 level at 30 min and SV at 30 min (P = 0.015, r = 0.946), and between ghrelin levels and HR (P = 0.013, r = 0.951) at 110 min. Significant correlations were also found between the change in glucose level at 30 min and the change in systolic blood pressure (P = 0.021, r = -0.681), and the change in SV (P = 0.008, r = -0.748) relative to the fasting in men. The insulin 0-30 min AUC was significantly correlated to the CO 0-30 min AUC (P = 0.002, r = 0.814) in men. Significant correlations were also found between the 0-120 min ghrelin and HR AUCs (P = 0.007, r = 0.966) in men. No statistically significant correlations were seen in women. Physiological changes in the levels of glucose, insulin, GLP-1 and ghrelin may influence the activity of the heart and the blood pressure. There may also be gender-related differences in the haemodynamic responses to postprandial changes in hormone levels. The results of this study show that subjects should not eat immediately prior to, or during, the evaluation of cardiovascular interventions as postprandial affects may affect the results, leading to erroneous

Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies.

PubMed

Li, Ling; Li, Sheyu; Liu, Jiali; Deng, Ke; Busse, Jason W; Vandvik, Per Olav; Wong, Evelyn; Sohani, Zahra N; Bala, Malgorzata M; Rios, Lorena P; Malaga, German; Ebrahim, Shanil; Shen, Jiantong; Zhang, Longhao; Zhao, Pujing; Chen, Qunfei; Wang, Yingqiang; Guyatt, Gordon H; Sun, Xin

2016-05-11

The effect of glucagon-like peptide-1(GLP-1) receptor agonists on heart failure remains uncertain. We therefore conducted a systematic review to assess the possible impact of GLP-1 agonists on heart failure or hospitalization for heart failure in patients with type 2 diabetes. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov to identify randomized controlled trials (RCTs) and observational studies that addressed the effect of GLP-1 receptor agonists in adults with type 2 diabetes, and explicitly reported heart failure or hospitalization for heart failure. Two paired reviewers screened reports, collected data, and assessed the risk of bias. We pooled data from RCTs and observational studies separately, and used the GRADE approach to rate the quality of evidence. We identified 25 studies that were eligible for our review; 21 RCTs (n = 18,270) and 4 observational studies (n = 111,029). Low quality evidence from 20 RCTs suggested, if anything, a lower incidence of heart failure between GLP-1 agonists versus control (17/7,441 vs. 19/4,317; odds ratio (OR) 0.62, 95 % confidence interval (CI) 0.31 to 1.22; risk difference (RD) 19 fewer, 95 % CI 34 fewer to 11 more per 1000 over 5 years). Three cohort studies comparing GLP-1 agonists to alternative agents provided very low quality evidence that GLP-1 agonists do not increase the incidence of heart failure. One RCT provided moderate quality evidence that GLP-1 agonists were not associated with hospitalization for heart failure (lixisenatide vs placebo: 122/3,034 vs. 127/3,034; adjusted hazard ratio 0.96, 95 % CI 0.75 to 1.23; RD 4 fewer, 95 % CI 25 fewer to 23 more per 1000 over 5 years) and a case-control study provided very low quality evidence also suggesting no association (GLP-1 agonists vs. other anti-hyperglycemic drugs: 1118 cases and 17,626 controls, adjusted OR 0.67, 95 % CI 0.32 to 1.42). The current evidence suggests that GLP-1 agonists do not

Structure of the glucagon receptor in complex with a glucagon analogue.

PubMed

Zhang, Haonan; Qiao, Anna; Yang, Linlin; Van Eps, Ned; Frederiksen, Klaus S; Yang, Dehua; Dai, Antao; Cai, Xiaoqing; Zhang, Hui; Yi, Cuiying; Cao, Can; He, Lingli; Yang, Huaiyu; Lau, Jesper; Ernst, Oliver P; Hanson, Michael A; Stevens, Raymond C; Wang, Ming-Wei; Reedtz-Runge, Steffen; Jiang, Hualiang; Zhao, Qiang; Wu, Beili

2018-01-03

Class B G-protein-coupled receptors (GPCRs), which consist of an extracellular domain (ECD) and a transmembrane domain (TMD), respond to secretin peptides to play a key part in hormonal homeostasis, and are important therapeutic targets for a variety of diseases. Previous work has suggested that peptide ligands bind to class B GPCRs according to a two-domain binding model, in which the C-terminal region of the peptide targets the ECD and the N-terminal region of the peptide binds to the TMD binding pocket. Recently, three structures of class B GPCRs in complex with peptide ligands have been solved. These structures provide essential insights into peptide ligand recognition by class B GPCRs. However, owing to resolution limitations, the specific molecular interactions for peptide binding to class B GPCRs remain ambiguous. Moreover, these previously solved structures have different ECD conformations relative to the TMD, which introduces questions regarding inter-domain conformational flexibility and the changes required for receptor activation. Here we report the 3.0 Å-resolution crystal structure of the full-length human glucagon receptor (GCGR) in complex with a glucagon analogue and partial agonist, NNC1702. This structure provides molecular details of the interactions between GCGR and the peptide ligand. It reveals a marked change in the relative orientation between the ECD and TMD of GCGR compared to the previously solved structure of the inactive GCGR-NNC0640-mAb1 complex. Notably, the stalk region and the first extracellular loop undergo major conformational changes in secondary structure during peptide binding, forming key interactions with the peptide. We further propose a dual-binding-site trigger model for GCGR activation-which requires conformational changes of the stalk, first extracellular loop and TMD-that extends our understanding of the previously established two-domain peptide-binding model of class B GPCRs.

The glucagon-miniglucagon interplay: a new level in the metabolic regulation.

PubMed

Bataille, Dominique; Fontés, Ghislaine; Costes, Safia; Longuet, Christine; Dalle, Stéphane

2006-07-01

Miniglucagon (glucagon 19-29) is the ultimate processing product of proglucagon, present in the glucagon-secreting granules of the alpha cells, at a close vicinity of the insulin-secreting beta cells. Co-released with glucagon and thanks to its original mode of action and its huge potency, it suppresses, inside the islet of Langerhans, the detrimental effect of glucagon on insulin secretion, while it leaves untouched the beneficial effect of glucagon on glucose competence of the beta cell. At the periphery, miniglucagon is processed at the surface of glucagon- and insulin-sensitive cells from circulating glucagon. At that level, it acts via a cellular pathway which uses initial molecular steps distinct from that of insulin which, when impaired, are involved in insulin resistence. This bypass allows miniglucagon to act as an insulin-like component, a characteristic which makes this peptide of particular interest from a pathophysiological and pharmacological point of views in understanding and treating metabolic diseases, such as the type 2 diabetes.

Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy.

PubMed

Bhashyam, Siva; Fields, Anjali V; Patterson, Brandy; Testani, Jeffrey M; Chen, Li; Shen, You-Tang; Shannon, Richard P

2010-07-01

We have shown that glucagon-like peptide-1 (GLP-1[7-36] amide) stimulates myocardial glucose uptake in dilated cardiomyopathy (DCM) independent of an insulinotropic effect. The cellular mechanisms of GLP-1-induced myocardial glucose uptake are unknown. Myocardial substrates and glucoregulatory hormones were measured in conscious, chronically instrumented dogs at control (n=6), DCM (n=9) and DCM after treatment with a 48-hour infusion of GLP-1 (7-36) amide (n=9) or vehicle (n=6). GLP-1 receptors and cellular pathways implicated in myocardial glucose uptake were measured in sarcolemmal membranes harvested from the 4 groups. GLP-1 stimulated myocardial glucose uptake (DCM: 20+/-7 nmol/min/g; DCM+GLP-1: 61+/-12 nmol/min/g; P=0.001) independent of increased plasma insulin levels. The GLP-1 receptors were upregulated in the sarcolemmal membranes (control: 98+/-2 density units; DCM: 256+/-58 density units; P=0.046) and were expressed in their activated (65 kDa) form in DCM. The GLP-1-induced increases in myocardial glucose uptake did not involve adenylyl cyclase or Akt activation but was associated with marked increases in p38alpha MAP kinase activity (DCM+vehicle: 97+/-22 pmol ATP/mg/min; DCM+GLP-1: 170+/-36 pmol ATP/mg/min; P=0.051), induction of nitric oxide synthase 2 (DCM+vehicle: 151+/-13 density units; DCM+GLP-1: 306+/-12 density units; P=0.001), and GLUT-1 translocation (DCM+vehicle: 21+/-3% membrane bound; DCM+GLP-1: 39+/-3% membrane bound; P=0.005). The effects of GLP-1 on myocardial glucose uptake were blocked by pretreatment with the p38alpha MAP kinase inhibitor or the nonspecific nitric oxide synthase inhibitor nitro-l-arginine. GLP-1 stimulates myocardial glucose uptake through a non-Akt-1-dependent mechanism by activating cellular pathways that have been identified in mediating chronic hibernation and the late phase of ischemic preconditioning.

Insulin and proglucagon-derived peptides from the horned frog, Ceratophrys ornata (Anura:Leptodactylidae).

PubMed

White, A M; Secor, S M; Conlon, J M

1999-07-01

Insulin and peptides derived from the processing of proglucagon have been isolated from an extract of the pancreas of the South American horned frog, Ceratophrys ornata (Leptodactylidae). Ceratophrys insulin is identical to the insulin previously isolated from the toad, Bufo marinus (Bufonidae). Ceratophrys glucagon was isolated in two molecular forms with 29- and 36-amino acid residues in approximately equal amounts. Glucagon-29 is identical to glucagon from B. marinus and from the bullfrog, Rana catesbeiana (Ranidae) and contains only 1 amino acid substitution (Thr29 --> Ser) compared with glucagon from Xenopus laevis (Pipidae). Glucagon-36 comprises glucagon-29 extended from its C-terminus by Lys-Arg-Ser-Gly-Gly-Met-Ser. This extension is structurally dissimilar to the C-terminal octapeptide of mammalian oxyntomodulin and resembles more closely that found in C-terminally extended glucagons isolated from fish pancreata. Ceratophrys glucagon-like peptide-1 (GLP-1) (His-Ala-Asp-Gly-Thr-Tyr-Gln-Asn-Asp-Val10-Gln-Gln-Phe-Leu-Glu- Glu-Lys-Ala-Ala-Lys20-Glu-Phe-Ile-Asp-Trp-Leu-Ile-Lys-Gly- Lys30-Pro-Lys-Lys-Gln-Arg-Leu-Ser) contains 3 amino acid substitutions compared with the corresponding peptide from B. marinus, 8 substitutions compared with GLP-1 from R. catesbeiana, and between 4 and 11 substitutions compared with the three GLP-1 peptides identified in X. laevis proglucagon. GLP-2 was not identified in the extract of Ceratophrys pancreas. The data indicate that, despite its importance in the regulation of glucose metabolism, the primary structure of GLP-1 has been very poorly conserved during evolution, even among a single order such as the Anura. Copyright 1999 Academic Press.

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

Gastrin-Releasing Peptide and Glucose Metabolism Following Pancreatitis

PubMed Central

Pendharkar, Sayali A.; Drury, Marie; Walia, Monika; Korc, Murray; Petrov, Maxim S.

2017-01-01

Background Gastrin-releasing peptide (GRP) is a pluripotent peptide that has been implicated in both gastrointestinal inflammatory states and classical chronic metabolic diseases such as diabetes. Abnormal glucose metabolism (AGM) after pancreatitis, an exemplar inflammatory disease involving the gastrointestinal tract, is associated with persistent low-grade inflammation and altered secretion of pancreatic and gut hormones as well as cytokines. While GRP is involved in secretion of many of them, it is not known whether GRP has a role in AGM. Therefore, we aimed to investigate the association between GRP and AGM following pancreatitis. Methods Fasting blood samples were collected to measure GRP, blood glucose, insulin, amylin, glucagon, pancreatic polypeptide (PP), somatostatin, cholecystokinin, gastric-inhibitory peptide (GIP), gastrin, ghrelin, glicentin, glucagon-like peptide-1 and 2, oxyntomodulin, peptide YY (PYY), secretin, vasoactive intestinal peptide, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein (MCP)-1, and interleukin-6. Modified Poisson regression analysis and linear regression analyses were conducted. Four statistical models were used to adjust for demographic, metabolic, and pancreatitis-related risk factors. Results A total of 83 individuals after an episode of pancreatitis were recruited. GRP was significantly associated with AGM, consistently in all four models (P -trend < 0.05), and fasting blood glucose contributed 17% to the variance of GRP. Further, GRP was significantly associated with glucagon (P < 0.003), MCP-1 (P < 0.025), and TNF-α (P < 0.025) - consistently in all four models. GRP was also significantly associated with PP and PYY in three models (P < 0.030 for both), and with GIP and glicentin in one model (P = 0.001 and 0.024, respectively). Associations between GRP and other pancreatic and gut hormones were not significant. Conclusion GRP is significantly increased in patients with AGM after pancreatitis and is

Insulin and Glucagon-Like Peptide 1 Receptor Agonist Combination Therapy in Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

PubMed

Maiorino, Maria Ida; Chiodini, Paolo; Bellastella, Giuseppe; Capuano, Annalisa; Esposito, Katherine; Giugliano, Dario

2017-04-01

The combination of basal insulin plus a glucagon-like peptide 1 receptor agonist (GLP-1RA) has been proposed as a treatment option to intensify insulin therapy in type 2 diabetes. We performed a meta-analysis of randomized controlled trials (RCTs) comparing this combination strategy to other injectable antidiabetes treatments on metabolic control in adult patients with type 2 diabetes. We conducted an electronic search until November 2016 on many electronic databases to identify RCTs assessing changes in HbA 1c , proportion of patients at HbA 1c target ≤7% (53 mmol/mol), hypoglycemia, and weight change. We used a random-effect model to calculate the weighted mean difference (WMD) or relative risk (RR) with the 95% CI. We identified 26 RCTs, lasting 12-52 weeks, and involving 11,425 patients. When the combination strategy was compared with other injectable treatments (overall data), there were reductions in HbA 1c (WMD = -0.47%, 95% CI -0.59 to -0.35), more patients at HbA 1c target (RR = 1.65, 95% CI 1.44-1.88), similar hypoglycemic events (RR = 1.14, 95% CI 0.93-1.39) and a reduction in weight (WMD = -2.5 kg, 95% CI -3.3 to -1.7), with high heterogeneity ( I 2 > 89%, P < 0.001) and a significant publication bias for three outcomes. In preplanned subgroup analyses, the combination treatment was similar to basal-bolus insulin regimens for glycemic control, with less hypoglycemia (RR = 0.66, 95% CI 0.46-0.93) and reduced weight (WMD = -4.7 kg, 95% CI -6.9 to -2.4). Fixed-ratio combinations yielded results similar to the overall analysis (HbA 1c WMD = -0.56%, 95% CI -0.72 to -0.40). GLP-1RAs alone or as titratable fixed-ratio combinations with basal insulin may represent a promising option to advance basal insulin therapy or to initiate injectable therapy in patients with type 2 diabetes inadequately controlled on oral agents. Longer studies are needed to assess durability and tolerability. © 2017 by the American Diabetes Association.

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

Li, Zhixia; Zhang, Yuan; Quan, Xiaochi; Yang, Zhirong; Zeng, Xiantao; Ji, Linong; Sun, Feng; Zhan, Siyan

2016-01-01

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. Systematic review and network meta-analysis. Literature search (Medline, Embase, the Cochrane library), website of clinical trial, bibliographies of published systematic reviews. Randomized controlled trials with available data comparing GLP-1 RAs with placebo or traditional anti-diabetic drugs in patients with type 2 diabetes. 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. 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 impact on glycemic level among 13 treatments. Among 13 treatments, GLP-1 RAs

Signals for glucagon secretion.

PubMed

Bloom, S R

1977-01-01

The normal physiological role of glucagon is in controlling hepatic glucose output. Glucagon subserves the role of homeostasis by maintaining plasma glucose and of a stress hormone by producing hyperglycaemia. While control of glucagon release by circulating metabolites and also other hormones is clearly important, it seems likely that the nervous system exerts an over-riding influence. The parasympathetic nervous system maintains homeostasis and the sympathetic acts in stress. Glucagon levels are found to be high in cirrhosis and also after acute hepatic failure. It is likely that these changes in glucagon concentration are secondary to metabolic abnormalities. While some glucagon is cleared by the liver, a similar clearance is seen by many other tissues and it is not likely that the elevation of glucagon seen in liver failure is due solely to a gross deficiency of glucagon clearance. No liver abnormality is seen in the glucagonoma syndrome, where glucagon concentration are chronically high, or in patients who have had a total pancreatectomy, where plasma glucagon is undetectably low. It thus seems unlikely that liver mass is importantly controlled by glucagon.

Inhibiting receptor for advanced glycation end product (AGE) and oxidative stress involved in the protective effect mediated by glucagon-like peptide-1 receptor on AGE induced neuronal apoptosis.

PubMed

Chen, Song; Yin, Lei; Xu, Zheng; An, Feng-Mao; Liu, Ai-Ran; Wang, Ying; Yao, Wen-Bing; Gao, Xiang-Dong

2016-01-26

Our previous study has demonstrated that glucagon-like peptide-1 (GLP-1) receptor agonist could protect neurons from advanced glycation end products (AGEs) toxicity in vitro. However, further studies are still needed to clarify the molecular mechanism of this GLP-1 receptor -dependent action. The present study mainly focused on the effect of GLP-1 receptor agonists against the receptor for advanced glycation end products (RAGE) signal pathway and the mechanism underlying this effect of GLP-1. Firstly the data based on the SH-GLP-1R(+) and SH-SY5Y cells confirmed our previous finding that GLP-1 receptor could mediate the protective effect against AGEs. The assays of the protein activity and of the mRNA level revealed that apoptosis-related proteins such as caspase-3, caspase-9, Bax and Bcl-2 were involved. Additionally, we found that both GLP-1 and exendin-4 could reduce AGEs-induced reactive oxygen species (ROS) accumulation by suppressing the activity of nicotinamide adenine dinucleotide phosphate-oxidase. Interestingly, we also found that GLP-1 receptor activation could attenuate the abnormal expression of the RAGE in vitro and in vivo. Furthermore, based on the analysis of the protein expression and translocation level of transcription factor nuclear factor-κB (NF-κB), and the use of GLP-1 receptor antagonist exendin(9-39) and NF-κB inhibitor pyrrolidine dithiocarbamate, we found that the effect mediated by GLP-1 receptor could alleviate the over expression of RAGE induced by ligand via the suppression of NF-κB. In summary, the results indicated that inhibiting RAGE/oxidative stress was involved in the protective effect of GLP-1 on neuron cells against AGEs induced apoptosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Short communication: Promotion of glucagon-like peptide-2 secretion in dairy calves with a bioactive extract from Olea europaea.

PubMed

Morrison, S Y; Pastor, J J; Quintela, J C; Holst, J J; Hartmann, B; Drackley, J K; Ipharraguerre, I R

2017-03-01

Diarrhea episodes in dairy calves involve profound alterations in the mechanism controlling gut barrier function that ultimately compromise intestinal permeability to macromolecules, including pathogenic bacteria. Intestinal dysfunction models suggest that a key element of intestinal adaptation during the neonatal phase is the nutrient-induced secretion of glucagon-like peptide (GLP)-2 and associated effects on mucosal cell proliferation, barrier function, and inflammatory response. Bioactive molecules found in Olea europaea have been shown to induce the release of regulatory peptides from model enteroendocrine cells. The ability to enhance GLP-2 secretion via the feeding of putative GLP-2 secretagogues is untested in newborn calves. The objectives of this study were to determine whether feeding a bioactive extract from Olea europaea (OBE) mixed in the milk replacer (1) can stimulate GLP-2 secretion beyond the response elicited by enteral nutrients and, thereby, (2) improve intestinal permeability and animal growth as well as (3) reduce the incidence of diarrhea in preweaning dairy calves. Holstein heifer calves (n = 60) were purchased, transported to the research facility, and blocked by body weight and total serum protein and assigned to 1 of 3 treatments. Treatments were control (CON), standard milk replacer (MR) and ad libitum starter; CON plus OBE added into MR at 30 mg/kg of body weight (OBE30); and CON plus OBE added into MR at 60 mg/kg of body weight (OBE60). The concentration of GLP-2 was measured at the end of wk 2. Intestinal permeability was measured at the onset of the study and the end of wk 2 and 6, with lactulose and d-mannitol as markers. Treatments did not affect calf growth and starter intake. Compared with CON, administration of OBE60 increased the nutrient-induced response in GLP-2 by about 1 fold and reduced MR intake during the second week of study. Throughout the study, however, all calves had compromised intestinal permeability and a high

Proglucagon-Derived Peptides Do Not Significantly Affect Acute Exocrine Pancreas in Rats

PubMed Central

Akalestou, Elina; Christakis, Ioannis; Solomou, Antonia M.; Minnion, James S.; Rutter, Guy A.; Bloom, Stephen R.

2015-01-01

Objectives Reports have suggested a link between treatment with glucagon-like peptide 1 (GLP-1) analogues and an increased risk of pancreatitis. Oxyntomodulin, a dual agonist of both GLP-1 and glucagon receptors, is currently being investigated as a potential anti-obesity therapy, but little is known about its pancreatic safety. The aim of this study was to investigate the acute effect of oxyntomodulin and other proglucagon-derived peptides on the rat exocrine pancreas. Methods GLP-1, oxyntomodulin, glucagon and exendin-4 were infused into anaesthetised rats to measure plasma amylase concentration changes. Additionally, the effect of each peptide on both amylase release and proliferation in rat pancreatic acinar (AR42J) and primary isolated ductal cells was determined. Results Plasma amylase did not increase post peptide infusion, compared to vehicle and cholecystokinin (CCK); however, oxyntomodulin inhibited plasma amylase when co-administered with CCK. None of the peptides caused a significant increase in proliferation rate or amylase secretion from acinar and ductal cells. Conclusions The investigated peptides do not have an acute effect on the exocrine pancreas with regard to proliferation and plasma amylase, when administered individually. Oxyntomodulin appears to be a potent inhibitor of amylase release, potentially making it a safer anti-obesity agent regarding pancreatitis, compared to GLP-1 agonists. PMID:26731187

Acute effect on satiety, resting energy expenditure, respiratory quotient, glucagon-like peptide-1, free fatty acids, and glycerol following consumption of a combination of bioactive food ingredients in overweight subjects.

PubMed

Rondanelli, Mariangela; Opizzi, Annalisa; Perna, Simone; Faliva, Milena; Solerte, Sebastiano Bruno; Fioravanti, Marisa; Klersy, Catherine; Edda, Cava; Maddalena, Paolini; Luciano, Scavone; Paola, Ceccarelli; Emanuela, Castellaneta; Claudia, Savina; Donini, Lorenzo Maria

2013-01-01

A combination of bioactive food ingredients (capsaicinoids, epigallocatechin gallate, piperin, and l-carnitine, CBFI) may promote satiety and thermogenesis. The study was conducted in order to assess whether there is any effect on satiety, resting energy expenditure (REE), respiratory quotient, glucagon-like peptide-1 (GLP-1), free fatty acids (FFA) and glycerol release, following a standardized mixed meal with or without single consumption of a CBFI. An 8-week randomized double-blind placebo-controlled trial. Dietetic and Metabolic Unit, Azienda di Servizi alla Persona, University of Pavia and "Villa delle Querce" Clinical Rehabilitation Institute, Rome, Italy. Thirty-seven overweight adults (body mass index [BMI]: 25-35). Nineteen overweight subjects were included in the supplemented group (14 women, 5 men; age 46.4 ± 6.4; BMI: 30.5 ± 3.3) and 18 in the placebo group (13 women, 5 men; age 40.8 ± 11.5; BMI: 30.1 ± 2.6). Satiety was assessed using 100-mm visual analogue scales (VAS) and the area under the curve was calculated. All measured parameters increased significantly in comparison with baseline in response to meal, both with CBFI and with placebo. However, throughout the study day, the supplemented group experienced a significantly greater increase than the placebo group in their sensation of satiety following acute administration of the supplement. CBFI may therefore be of great value in the treatment of overweight patients by increasing satiety and stimulating thermogenesis.

Glucagon-like peptide-1 exerts anti-inflammatory effects on mouse colon smooth muscle cells through the cyclic adenosine monophosphate/nuclear factor-κB pathway in vitro.

PubMed

Al-Dwairi, Ahmed; Alqudah, Tamara E; Al-Shboul, Othman; Alqudah, Mohammad; Mustafa, Ayman G; Alfaqih, Mahmoud A

2018-01-01

Intestinal smooth muscle cells (SMCs) undergo substantial morphological, phenotypic, and contractile changes during inflammatory bowel disease (IBD). SMCs act as a source and target for different inflammatory mediators, however their role in IBD pathogenesis is usually overlooked. Glucagon-like peptide-1 (GLP-1) is an incretin hormone reported to exert multiple anti-inflammatory effects in different tissues including the gastrointestinal tract through various mechanisms. The aim of this research is to explore the effect of GLP-1 analog exendin-4 on the expression and secretion of inflammatory markers from mouse colon smooth muscle cells (CSMCs) after stimulation with lipopolysaccharide (LPS). Freshly isolated CSMCs from male BALB/c mice were cultured in DMEM and treated with vehicle, LPS (1 μg/mL), LPS+exendin-4 (50 nM), or LPS+exendin-4 (100 nM) for 24 h. Expression of inflammatory cytokines was then evaluated by antibody array membrane. CSMCs showed basal expression of several cytokines which was enhanced with the induction of inflammation by LPS. However, exendin-4 (50 and 100 nM) significantly ( p <0.05) reduced the expression of multiple cytokines including tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), T cell activation gene-3 (TCA-3), stromal cell-derived factor-1 (SDF-1), and macrophage colony stimulating factor (M-CSF). To confirm these results, expression of these cytokines was further assessed by enzyme-linked immunosorbent assay and real-time polymerase chain reaction and similar results were also observed. Moreover, secretion of TNF-α and IL1-α into the conditioned media was significantly downregulated by exendin-4 when compared to LPS-treated cells. Furthermore, LPS increased NF-κB phosphorylation, while exendin-4 significantly reduced levels of NF-κB phosphorylation. These data indicate that GLP-1 analogs can exert significant anti-inflammatory effects on CSMCs and can potentially be used as an adjunct treatment for inflammatory

Glucagon-Like Peptide-1 Receptor Imaging with [Lys (40) (Ahx-HYNIC- (99 m) Tc/EDDA)NH 2 ]-Exendin-4 for the Diagnosis of Recurrence or Dissemination of Medullary Thyroid Cancer: A Preliminary Report.

PubMed

Pach, D; Sowa-Staszczak, A; Jabrocka-Hybel, A; Stefańska, A; Tomaszuk, M; Mikołajczak, R; Janota, B; Trofimiuk-Müldner, M; Przybylik-Mazurek, E; Hubalewska-Dydejczyk, A

2013-01-01

Introduction. Epidemiological studies on medullary thyroid cancer (MTC) have shown that neither a change in stage at diagnosis nor improvement in survival has occurred during the past 30 years. In patients with detectable serum calcitonin and no clinically apparent disease, a careful search for local recurrence, and nodal or distant metastases, should be performed. Conventional imaging modalities will not show any disease until basal serum calcitonin is at least 150 pg/mL. The objective of the study was to present the first experience with labelled glucagon-like peptide-1 (GLP-1) analogue [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH2]-exendin-4 in the visualisation of MTC in humans. Material and Method. Four patients aged 22-74 years (two with sporadic and two with MEN2 syndrome-related disseminated MTC) were enrolled in the study. In all patients, GLP-1 receptor imaging was performed. Results. High-quality images were obtained in all patients. All previously known MTC lesions have been confirmed in GLP-1 scintigraphy. Moreover, one additional liver lesion was detected in sporadic MTC male patient. Conclusions. GLP-1 receptor imaging with [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH2]-exendin-4 is able to detect MTC lesions. GLP-1 scintigraphy can serve as a confirmatory test in MTC patients, in whom other imaging procedures are inconsistent.

Glucagon-Like Peptide-1 Receptor Imaging with [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-Exendin-4 for the Diagnosis of Recurrence or Dissemination of Medullary Thyroid Cancer: A Preliminary Report

PubMed Central

Pach, D.; Sowa-Staszczak, A.; Jabrocka-Hybel, A.; Stefańska, A.; Tomaszuk, M.; Mikołajczak, R.; Janota, B.; Trofimiuk-Müldner, M.; Przybylik-Mazurek, E.; Hubalewska-Dydejczyk, A.

2013-01-01

Introduction. Epidemiological studies on medullary thyroid cancer (MTC) have shown that neither a change in stage at diagnosis nor improvement in survival has occurred during the past 30 years. In patients with detectable serum calcitonin and no clinically apparent disease, a careful search for local recurrence, and nodal or distant metastases, should be performed. Conventional imaging modalities will not show any disease until basal serum calcitonin is at least 150 pg/mL. The objective of the study was to present the first experience with labelled glucagon-like peptide-1 (GLP-1) analogue [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 in the visualisation of MTC in humans. Material and Method. Four patients aged 22–74 years (two with sporadic and two with MEN2 syndrome-related disseminated MTC) were enrolled in the study. In all patients, GLP-1 receptor imaging was performed. Results. High-quality images were obtained in all patients. All previously known MTC lesions have been confirmed in GLP-1 scintigraphy. Moreover, one additional liver lesion was detected in sporadic MTC male patient. Conclusions. GLP-1 receptor imaging with [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 is able to detect MTC lesions. GLP-1 scintigraphy can serve as a confirmatory test in MTC patients, in whom other imaging procedures are inconsistent. PMID:23606839

Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.

PubMed

Kazierad, D J; Bergman, A; Tan, B; Erion, D M; Somayaji, V; Lee, D S; Rolph, T

2016-08-01

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia. © 2016 John Wiley & Sons Ltd.

Saxagliptin improves glycemic control by modulating postprandial glucagon and C-peptide levels in Chinese patients with type 2 diabetes.

PubMed

Sjöstrand, Mikaela; Iqbal, Nayyar; Lu, Jane; Hirshberg, Boaz

2014-08-01

Saxagliptin reduced glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial glucose (PPG) in Asian patients with type 2 diabetes mellitus (T2DM). To understand the physiology of this effect, indices of α- and β-cell function were measured in a subpopulation of Chinese patients following a noodle mixed-meal tolerance test. Data from Chinese patients were pooled from two phase 3, 24-week studies of saxagliptin 5mg/d as monotherapy in drug-naive patients and as add-on to metformin in patients inadequately controlled with metformin alone. The end points for β- and α-cell function were change from baseline in C-peptide, insulin, and glucagon areas under the curve from 0 to 180 min (AUC0-180), insulinogenic index, and insulin sensitivity from Matsuda index after a mixed meal. Also glycemic variables, HbA1c, FPG, and PPG (AUC0-180), and homeostasis model assessment (HOMA) 2β were measured. At 24 weeks, greater improvements in adjusted mean change from baseline HbA1c (difference vs placebo [95% CI], -0.33% [-0.50%, -0.17%], [-4 (-5.5, -1.9) mmol/mol], P<0.0001), FPG (-0.41 [-0.78, -0.03] mmol/L, P=0.03), PPG AUC0-180 (-168 [-245, -91.8] mmol min/L, P<0.0001), C-peptide AUC0-180 (19.7 [5.2, 34.2] nmol min/L, P=0.008), insulinogenic index (0.06% [0.02%, 0.09%], P=0.002), and greater suppression of glucagon secretion (glucagon AUC0-180, -322 [-493.6, -150.7] pmol min/L, P=0.0003) were observed with saxagliptin versus placebo. In Chinese patients with T2DM, saxagliptin as monotherapy or as add-on to metformin improved glycemic control by modulating α- and β-cell function. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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. © 2016 John Wiley & Sons Ltd.

"Living High-Training Low" improved weight loss and glucagon-like peptide-1 level in a 4-week weight loss program in adolescents with obesity: A pilot study.

PubMed

Yang, Qin; Huang, Guoyuan; Tian, Qianqian; Liu, Wei; Sun, Xiangdong; Li, Na; Sun, Shunli; Zhou, Tang; Wu, Nana; Wei, Yuqin; Chen, Peijie; Wang, Ru

2018-02-01

"Living High-Training Low" (LHTL) is effective for the improvement of athletic ability; however, little is known about the effect of LHTL on obese individuals. The present study determined whether LHTL would have favorable influence on body composition, rebalance the appetite hormones, and explore the underlying mechanism. Adolescents with obesity [body mass index (BMI) >30 kg/m] were randomly assigned to "Living Low-Training Low" (LLTL, n = 19) group that slept in a normobaric normoxia condition and the LHTL (n = 16) group slept in a normobaric hypoxia room (14.7% PO2 ∼2700 m). Both groups underwent the same aerobic exercise training program. Morphological, blood lipids, and appetite hormones were measured and assessed. After the intervention, the body composition improved in both groups, whereas reductions in body weight (BW), BMI, and lean body mass increased significantly in the LHTL group (all, P < .05). In the LLTL group, cholecystokinin (CCK) decreased remarkably (P < .05) and CCK changes were positively associated with changes in BW (r = 0.585, P = .011) and BMI (r = 0.587, P = .010). However, in the LHTL group, changes in plasma glucagon-like peptide-1 (GLP-1) and interleukin-6 (IL-6) levels, positively correlated with each other (r = 0.708, P = .015) but negatively with BW changes (r = -0.608, P = .027 and r = -0.518, P = .048, respectively). The results indicated that LHTL could induce more weight loss safely and efficiently as compared to LLTL and increase the plasma GLP-1 levels that may be mediated by IL-6 to rebalance the appetite. Thus, an efficient method to treat obesity and prevent weight regain by appetite rebalance in hypoxia condition was established.

Postmeal increment in intact glucagon-like peptide 1 level, but not intact glucose-dependent insulinotropic polypeptide levels, is inversely associated with metabolic syndrome in patients with type 2 diabetes.

PubMed

Yoo, Soyeon; Yang, Eun-Jin; Lee, Sang Ah; Koh, Gwanpyo

2018-02-01

Metabolic syndrome increases the risk of cardiovascular disease. Recently glucagon-like peptide 1 (GLP-1) agonists proved to be effective in preventing cardiovascular disease (CVD) in patients with type 2 diabetes. We investigated the association of blood incretin levels with metabolic syndrome in patients with type 2 diabetes. This is a cross-sectional study involving 334 people with type 2 diabetes. Intact GLP-1 (iGLP-1) and intact glucose-dependent insulinotropic polypeptide (iGIP) levels were measured in a fasted state and 30 min after ingestion of a standard mixed meal. Metabolic syndrome was diagnosed based on the criteria of the International Diabetes Federation. Two hundred twenty-five (69%) of the subjects have metabolic syndrome. The fasting iGLP-1 level was no different between groups. Thirty-min postprandial iGLP-1 was non-significantly lower in the subjects who had metabolic syndrome. Incremental iGLP-1 (ΔiGLP-1, the difference between 30-min postmeal and fasting iGLP-1 levels) was significantly lower in those with metabolic syndrome. There were no significant differences in fasting iGIP, postprandial iGIP, and ΔiGIP between groups. The ΔiGLP-1, but not ΔiGIP levels decreased significantly as the number of metabolic syndrome components increased. In hierarchical logistic regression analysis, the ΔiGLP-1 level was found to be a significant contributor to metabolic syndrome even after adjusting for other covariates. Taken together, the iGLP-1 increment in the 30 min after meal ingestion is inversely associated with metabolic syndrome in patients with type 2 diabetes. This suggests that postmeal iGLP-1 increment could be useful in assessing cardiovascular risk in type 2 diabetes.

Evidence for a potential role of glucagon during eye growth regulation in chicks.

PubMed

Feldkaemper, Marita P; Schaeffel, Frank

2002-01-01

Eye growth and refraction are regulated by visual processing in the retina. Until now, the messengers released by the retina to induce these changes are largely unknown. Previously, it was found that glucagon amacrine cells respond to defocus in the retinal image and even to its sign. The expression of the immediate-early gene product ZENK increased in this cell population in eyes wearing plus lenses and decreased in minus lens-treated chicks. Moreover, it was shown that the amount of retinal glucagon mRNA increased during treatment with positive lenses. Therefore, it seems likely that these cells contribute to the visual regulation of ocular growth and that glucagon may act as a stop signal for eye growth. The purpose of the present study was to accumulate further evidence for a role of glucagon in the visual control of eye growth. Chicks were treated with plus and minus lenses after injection of different amounts of the glucagon antagonist des-His1-Glu1-glucagon-amide or the agonist Lys17,18,Glu21-glucagon, respectively. Refractive development and eye growth were recorded by automated infrared photorefraction and A-scan ultrasound, respectively. The glucagon antagonist inhibited hyperopia development, albeit only in a narrow concentration range, and at most by 50%, but not myopia development. In contrast, the agonist inhibited myopia development in a dose-dependent fashion. At high concentrations, it also prevented hyperopia development. The amount of glucagon peptide in the retinae and choroids of lens-treated chicks and its diurnal variation was measured by using a radio-immunoassay. Retinal glucagon content decreased after minus lens treatment and choroidal glucagon content increased after plus lens treatment. No diurnal variation in the retinal amount of glucagon was detected. In addition, using an optokinetic nystagmus paradigm, the effect of glucagon and the antagonist des-His1-Glu9-glucagon-amide on suprathreshold contrast sensitivity was studied. Glucagon

Study on interaction of mangiferin to insulin and glucagon in ternary system

NASA Astrophysics Data System (ADS)

Lin, Hui; Chen, Rui; Liu, Xiaoyan; Sheng, Fenling; Zhang, Haixia

2010-05-01

The binding of mangiferin to insulin and glucagon was investigated in the presence and absence of another Peptide by optical spectroscopy. Fluorescence titration experiments revealed that mangiferin quenched the intrinsic fluorescence of insulin and glucagon by static quenching. The ratios of binding constants of glucagon-mangiferin to insulin-mangiferin at different temperatures were calculated in "pure" and ternary system, respectively. The results indicated that the Peptides were competitive with each other to act on mangiferin. Values of the thermodynamic parameters and the experiments of pH effect proved that the key interacting forces between mangiferin and the Peptides were hydrophobic interaction. In addition, UV-vis absorption, synchronous fluorescence and Fourier transform infrared measurements showed that the conformation of insulin and glucagon were changed after adding mangiferin.

Early loss of the glucagon response to hypoglycemia in adolescents with type 1 diabetes.

PubMed

Siafarikas, Aris; Johnston, Robert J; Bulsara, Max K; O'Leary, Peter; Jones, Timothy W; Davis, Elizabeth A

2012-08-01

To assess the glucagon response to hypoglycemia and identify influencing factors in patients with type 1 diabetes compared with nondiabetic control subjects. Hyperinsulinemic hypoglycemic clamp studies were performed in all participants. The glucagon response to both hypoglycemia and arginine was measured, as well as epinephrine, cortisol, and growth hormone responses to hypoglycemia. Residual β-cell function was assessed using fasting and stimulated C-peptide. Twenty-eight nonobese adolescents with type 1 diabetes (14 female, mean age 14.9 years [range 11.2-19.8]) and 12 healthy control subjects (6 female, 15.3 years [12.8-18.7]) participated in the study. Median duration of type 1 diabetes was 0.66 years (range 0.01-9.9). The glucagon peak to arginine stimulation was similar between groups (P = 0.27). In contrast, the glucagon peak to hypoglycemia was reduced in the group with diabetes (95% CI): 68 (62-74) vs. 96 (87-115) pg/mL (P < 0.001). This response was greater than 3 SDs from baseline for only 7% of subjects with type 1 diabetes in comparison with 83% of control subjects and was lost at a median duration of diabetes of 8 months and as early as 1 month after diagnosis (R = -0.41, P < 0.01). There was no correlation in response with height, weight, BMI, and HbA(1c). Epinephrine, cortisol, and growth hormone responses to hypoglycemia were present in both groups. The glucagon response to hypoglycemia in adolescents with type 1 diabetes is influenced by the duration of diabetes and can be lost early in the course of the disease.

Preoperative weight loss with glucagon-like peptide-1 receptor agonist treatment predicts greater weight loss achieved by the combination of medical weight management and bariatric surgery in patients with type 2 diabetes: A longitudinal analysis.

PubMed

Tang, Tien; Abbott, Sally; le Roux, Carel W; Wilson, Violet; Singhal, Rishi; Bellary, Srikanth; Tahrani, Abd A

2018-03-01

We examined the relationship between weight changes after preoperative glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and weight changes from the start of medical weight management (MWM) until 12 months after bariatric surgery in patients with type 2 diabetes in a retrospective cohort study. A total of 45 patients (64.4% women, median [interquartile range] age 49 [45-60] years) were included. The median (interquartile range) weight loss from start of MWM until 12 months post-surgery was 17.9% (13.0%-29.3%). GLP-1RA treatment during MWM resulted in 5.0% (1.9%-7.7%) weight loss. Weight loss during GLP-1RA treatment predicted weight loss from the start of MWM until 12 months post-surgery, but not postoperative weight loss after adjustment. The proportion of weight loss from start of MWM to 12 months post-surgery attributed to GLP-1RA treatment was negatively associated with that attributed to surgery, after adjustment. In conclusion, weight change after GLP-1RA treatment predicted the weight loss achieved by a combination of MWM and bariatric surgery, but not weight loss induced by surgery only. Failure to lose weight after GLP-1RA treatment should not be considered a barrier to undergoing bariatric surgery. © 2017 John Wiley & Sons Ltd.

A 12-week treatment with the long-acting glucagon-like peptide 1 receptor agonist liraglutide leads to significant weight loss in a subset of obese women with newly diagnosed polycystic ovary syndrome.

PubMed

Jensterle, Mojca; Kravos, Nika Aleksandra; Pfeifer, Marija; Kocjan, Tomaz; Janez, Andrej

2015-01-01

The long-acting glucagon-like peptide 1 receptor agonist liraglutide is linked to progressive and sustained weight loss in obese people with diabetes. However, its efficacy and safety in women with polycystic ovary syndrome (PCOS) has not yet been addressed. Thirty-two obese women (aged 27.6±7.2 years, BMI 39.5±6.2 kg/m(2)) with newly diagnosed PCOS were randomized to receive either liraglutide 1.2 mg QD sc (n=17) or metformin 1000 mg BID po (n=15) for 12 weeks; 28 patients completed the study (14 on liraglutide and 14 on metformin). The main outcome was change in body weight. Intention-to-treat analysis showed significant BMI (-0.98 kg/m(2); p<0.001), body weight (-2.52 kg; p<0.001), waist circumference (-3.38 cm; p<0.001) and whole-body fat mass (-1.26%; p<0.001) reduction in both treatment arms without significant differences between therapeutic groups. However, in a subgroup of patients (n=9) with insulin resistance (HOMA(IR) >2), severe obesity and higher odds ratio for the metabolic syndrome (OR=3.9), the patients fared much better with liraglutide than with metformin (mean BMI decreased 2.13 kg/m(2) vs. 0.62 kg/m(2), respectively). Short-term liraglutide treatment was associated with significant weight loss in a subset of obese patients with newly diagnosed PCOS and a higher metabolic risk profile.

Glucagon‐related peptides and the regulation of food intake in chickens

PubMed Central

2016-01-01

Abstract The regulatory mechanisms underlying food intake in chickens have been a focus of research in recent decades to improve production efficiency when raising chickens. Lines of evidence have revealed that a number of brain‐gut peptides function as a neurotransmitter or peripheral satiety hormone in the regulation of food intake both in mammals and chickens. Glucagon, a 29 amino acid peptide hormone, has long been known to play important roles in maintaining glucose homeostasis in mammals and birds. However, the glucagon gene encodes various peptides that are produced by tissue‐specific proglucagon processing: glucagon is produced in the pancreas, whereas oxyntomodulin (OXM), glucagon‐like peptide (GLP)‐1 and GLP‐2 are produced in the intestine and brain. Better understanding of the roles of these peptides in the regulation of energy homeostasis has led to various physiological roles being proposed in mammals. For example, GLP‐1 functions as an anorexigenic neurotransmitter in the brain and as a postprandial satiety hormone in the peripheral circulation. There is evidence that OXM and GLP‐2 also induce anorexia in mammals. Therefore, it is possible that the brain‐gut peptides OXM, GLP‐1 and GLP‐2 play physiological roles in the regulation of food intake in chickens. More recently, a novel GLP and its specific receptor were identified in the chicken brain. This review summarizes current knowledge about the role of glucagon‐related peptides in the regulation of food intake in chickens. PMID:27150835

The glucagon-like peptide-2 receptor C terminus modulates beta-arrestin-2 association but is dispensable for ligand-induced desensitization, endocytosis, and G-protein-dependent effector activation.

PubMed

Estall, Jennifer L; Koehler, Jacqueline A; Yusta, Bernardo; Drucker, Daniel J

2005-06-10

Classic models of receptor desensitization and internalization have been largely based on the behavior of Family A G-protein-coupled receptors (GPCRs). The glucagon-like peptide-2 receptor (GLP-2R) is a member of the Family B glucagon-secretin GPCR family, which exhibit significant sequence and structural differences from the Family A receptors in their intracellular and extracellular domains. To identify structural motifs that regulate GLP-2R signaling and cell surface receptor expression, we analyzed the functional properties of a series of mutant GLP-2Rs. The majority of the C-terminal receptor tail was dispensable for GLP-2-induced cAMP accumulation, ERK1/2 activation, and endocytosis in transfected cells. However, progressive truncation of the C terminus reduced cell surface receptor expression, altered agonist-induced GLP-2R trafficking, and abrogated protein kinase A-mediated heterologous receptor desensitization. Elimination of the distal 21 amino acids of the receptor was sufficient to promote constitutive receptor internalization and prevent agonist-induced recruitment of beta-arrestin-2. Site-directed mutagenesis identified specific amino acid residues within the distal GLP-2R C terminus that mediate the stable association with beta-arrestin-2. Surprisingly, although the truncated mutant receptors failed to interact with beta-arrestin-2, they underwent homologous desensitization and subsequent resensitization with kinetics similar to that observed with the wild-type GLP-2R. Our data suggest that, although the GLP-2R C terminus is not required for coupling to cellular machinery regulating signaling or desensitization, it may serve as a sorting signal for intracellular trafficking. Taken together with the previously demonstrated clathrin and dynamin-independent, lipid-raft-dependent pathways for internalization, our data suggest that GLP-2 receptor signaling has evolved unique structural and functional mechanisms for control of receptor trafficking

RAMP2 Influences Glucagon Receptor Pharmacology via Trafficking and Signaling.

PubMed

Cegla, Jaimini; Jones, Ben J; Gardiner, James V; Hodson, David J; Marjot, Thomas; McGlone, Emma R; Tan, Tricia M; Bloom, Stephen R

2017-08-01

Endogenous satiety hormones provide an attractive target for obesity drugs. Glucagon causes weight loss by reducing food intake and increasing energy expenditure. To further understand the cellular mechanisms by which glucagon and related ligands activate the glucagon receptor (GCGR), we investigated the interaction of the GCGR with receptor activity modifying protein (RAMP)2, a member of the family of receptor activity modifying proteins. We used a combination of competition binding experiments, cell surface enzyme-linked immunosorbent assay, functional assays assessing the Gαs and Gαq pathways and β-arrestin recruitment, and small interfering RNA knockdown to examine the effect of RAMP2 on the GCGR. Ligands tested were glucagon; glucagonlike peptide-1 (GLP-1); oxyntomodulin; and analog G(X), a GLP-1/glucagon coagonist developed in-house. Confocal microscopy was used to assess whether RAMP2 affects the subcellular distribution of GCGR. Here we demonstrate that coexpression of RAMP2 and the GCGR results in reduced cell surface expression of the GCGR. This was confirmed by confocal microscopy, which demonstrated that RAMP2 colocalizes with the GCGR and causes significant GCGR cellular redistribution. Furthermore, the presence of RAMP2 influences signaling through the Gαs and Gαq pathways, as well as recruitment of β-arrestin. This work suggests that RAMP2 may modify the agonist activity and trafficking of the GCGR, with potential relevance to production of new peptide analogs with selective agonist activities.

Mechanisms of Glucagon Degradation at Alkaline pH

PubMed Central

Caputo, Nicholas; Castle, Jessica R.; Bergstrom, Colin P.; Carroll, Julie M.; Bakhtiani, Parkash A.; Jackson, Melanie A.; Roberts, Charles T.; David, Larry L.; Ward, W. Kenneth

2014-01-01

Glucagon is unstable and undergoes degradation and aggregation in aqueous solution. For this reason, its use in portable pumps for closed loop management of diabetes is limited to very short periods. In this study, we sought to identify the degradation mechanisms and the bioactivity of specific degradation products. We studied degradation in the alkaline range, a range at which aggregation is minimized. Native glucagon and analogs identical to glucagon degradation products were synthesized. To quantify biological activity in glucagon and in the degradation peptides, a protein kinase A-based bioassay was used. Aged, fresh, and modified peptides were analyzed by liquid chromatography with mass spectrometry (LCMS). Oxidation of glucagon at the Met residue was common but did not reduce bioactivity. Deamidation and isomerization were also common and were more prevalent at pH 10 than 9. The biological effects of deamidation and isomerization were unpredictable; deamidation at some sites did not reduce bioactivity. Deamidation of Gln 3, isomerization of Asp 9, and deamidation with isomerization at Asn 28 all caused marked potency loss. Studies with molecular-weight-cutoff membranes and LCMS revealed much greater fibrillation at pH 9 than 10. Further work is necessary to determine formulations of glucagon that minimize degradation and fibrillation. PMID:23651991

Mechanisms of glucagon degradation at alkaline pH.

PubMed

Caputo, Nicholas; Castle, Jessica R; Bergstrom, Colin P; Carroll, Julie M; Bakhtiani, Parkash A; Jackson, Melanie A; Roberts, Charles T; David, Larry L; Ward, W Kenneth

2013-07-01

Glucagon is unstable and undergoes degradation and aggregation in aqueous solution. For this reason, its use in portable pumps for closed loop management of diabetes is limited to very short periods. In this study, we sought to identify the degradation mechanisms and the bioactivity of specific degradation products. We studied degradation in the alkaline range, a range at which aggregation is minimized. Native glucagon and analogs identical to glucagon degradation products were synthesized. To quantify biological activity in glucagon and in the degradation peptides, a protein kinase A-based bioassay was used. Aged, fresh, and modified peptides were analyzed by liquid chromatography with mass spectrometry (LCMS). Oxidation of glucagon at the Met residue was common but did not reduce bioactivity. Deamidation and isomerization were also common and were more prevalent at pH 10 than 9. The biological effects of deamidation and isomerization were unpredictable; deamidation at some sites did not reduce bioactivity. Deamidation of Gln 3, isomerization of Asp 9, and deamidation with isomerization at Asn 28 all caused marked potency loss. Studies with molecular-weight-cutoff membranes and LCMS revealed much greater fibrillation at pH 9 than 10. Further work is necessary to determine formulations of glucagon that minimize degradation and fibrillation. Copyright © 2013 Elsevier Inc. All rights reserved.

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

Appetite-related peptides in childhood and adolescence: role of ghrelin, PYY, and GLP-1.

PubMed

Horner, Katy; Lee, SoJung

2015-11-01

During childhood and adolescence, a number of factors, including age, puberty, sex, race, and body composition, may contribute to differences in satiety, food intake, and appetite-related peptides. These peptides include the orexigenic peptide ghrelin and anorexigenic gut peptides peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). For example, lower fasting ghrelin levels, lower postprandial ghrelin suppression, and blunted PYY and GLP-1 responses to food intake could contribute to a dysregulation of appetite in already obese children and adolescents. Whereas, changes in these peptides observed during puberty could facilitate growth. A greater understanding of the major moderating factors of appetite-related peptides in the pediatric population is essential to improve interpretation of study findings and for effective tailoring of strategies targeting appetite control to individuals. While more studies are needed, there is some evidence to suggest that exercise-based lifestyle interventions could be a potential therapeutic strategy to improve appetite-peptide profiles in overweight and obese children and adolescents. The aim of this review is (i) to discuss the potential moderating factors of ghrelin, PYY, and GLP-1, including age and puberty, sex, race and body composition; and (ii) to examine the effects of exercise interventions on these appetite-related gut peptides in children and adolescents.

Characterization of seed nuclei in glucagon aggregation using light scattering methods and field-flow fractionation

PubMed Central

Hoppe, Cindy C; Nguyen, Lida T; Kirsch, Lee E; Wiencek, John M

2008-01-01

Background Glucagon is a peptide hormone with many uses as a therapeutic agent, including the emergency treatment of hypoglycemia. Physical instability of glucagon in solution leads to problems with the manufacture, formulation, and delivery of this pharmaceutical product. Glucagon has been shown to aggregate and form fibrils and gels in vitro. Small oligomeric precursors serve to initiate and nucleate the aggregation process. In this study, these initial aggregates, or seed nuclei, are characterized in bulk solution using light scattering methods and field-flow fractionation. Results High molecular weight aggregates of glucagon were detected in otherwise monomeric solutions using light scattering techniques. These aggregates were detected upon initial mixing of glucagon powder in dilute HCl and NaOH. In the pharmaceutically relevant case of acidic glucagon, the removal of aggregates by filtration significantly slowed the aggregation process. Field-flow fractionation was used to separate aggregates from monomeric glucagon and determine relative mass. The molar mass of the large aggregates was shown to grow appreciably over time as the glucagon solutions gelled. Conclusion The results of this study indicate that initial glucagon solutions are predominantly monomeric, but contain small quantities of large aggregates. These results suggest that the initial aggregates are seed nuclei, or intermediates which catalyze the aggregation process, even at low concentrations. PMID:18613970

Glucagon Decreases IGF-1 Bioactivity in Humans, Independently of Insulin, by Modulating Its Binding Proteins.

PubMed

Sarem, Zeinab; Bumke-Vogt, Christiane; Mahmoud, Ayman M; Assefa, Biruhalem; Weickert, Martin O; Adamidou, Aikatarini; Bähr, Volker; Frystyk, Jan; Möhlig, Matthias; Spranger, Joachim; Lieske, Stefanie; Birkenfeld, Andreas L; Pfeiffer, Andreas F H; Arafat, Ayman M

2017-09-01

Depending on its lipolytic activity, glucagon plays a promising role in obesity treatment. Glucagon-induced growth hormone (GH) release can promote its effect on lipid metabolism, although the underlying mechanisms have not been well-defined. The present study highlights the glucagon effect on the GH/insulinlike growth factor 1 (IGF-1)/IGF-binding protein (IGFBP) axis in vivo and in vitro, taking into consideration insulin as a confounding factor. In a double-blind, placebo-controlled study, we investigated changes in GH, IGFBP, and IGF-1 bioactivity after intramuscular glucagon administration in 13 lean controls, 11 obese participants, and 13 patients with type 1 diabetes mellitus (T1DM). The effect of glucagon on the transcription factor forkhead box protein O1 (FOXO1) translocation, the transcription of GH/IGF-1 system members, and phosphorylation of protein kinase B (Akt) was further investigated in vitro. Despite unchanged total IGF-1 and IGFBP-3 levels, glucagon decreased IGF-1 bioactivity in all study groups by increasing IGFBP-1 and IGFBP-2. The reduction in IGF-1 bioactivity occurred before the glucagon-induced surge in GH. In contrast to the transient increase in circulating insulin in obese and lean participants, no change was observed in those with T1DM. In vitro, glucagon dose dependently induced a substantial nuclear translocation of FOXO1 in human osteosarcoma cells and tended to increase IGFBP-1 and IGFBP-2 gene expression in mouse primary hepatocytes, despite absent Akt phosphorylation. Our data point to the glucagon-induced decrease in bioactive IGF-1 levels as a mechanism through which glucagon induces GH secretion. This insulin-independent reduction is related to increased IGFBP-1 and IGFBP-2 levels, which are most likely mediated via activation of the FOXO/mTOR (mechanistic target of rapamycin) pathway. Copyright © 2017 Endocrine Society

Superactive amidated COOH-terminal glucagon analogues with no methionine or tryptophan.

PubMed

Murphy, W A; Coy, D H; Lance, V A

1986-01-01

The functions of the Trp-25 and Met-27 residues and the free carboxy terminus of glucagon have been debated for many years. Despite some semi-synthetic data to the contrary, comparison of the glucagon sequence with the other 5 members of this family of peptides, all of them amides and particularly growth hormone-releasing factor(1-29) amide and its recently described analogues, suggests that alterations to these positions should be quite well tolerated in terms of biological activity. To test this prediction, [Phe-25,Leu-27]-glucagon amide was synthesized in high yield and was found to actually have superior glycogenolytic activity (196%) to glucagon in the rat. Replacement of Gly-4 by D-Phe, which has been shown to give much enhanced glycogenolytic activity than glucagon itself, also increased the activity of [D-Phe-4,Phe-25,Leu-27]-glucagon amide (518%). The L-Phe-4-analogue, [Phe-4,25,Leu-27]-glucagon amide, in contrast, was 20 times less active (30%), strongly suggesting the presence of a beta-bend in this N-terminal region of glucagon. This was supported by Chou-Fasman structural predictions which indicate extensive folding in the 1-15 region. Indeed, additional conformational restriction by substitution of D-Ser in position 2 of glucagon also increased activity to 226%. [D-Gln-3]-glucagon was slightly less active (74%) than glucagon. Chou-Fasman calculations on glucagon were compared to similar treatments of the VIP, secretin, PHI, and GRF(1-29) sequences.

Glucagon Like Peptide-1 (GLP-1) Modulates OVA-Induced Airway Inflammation and Mucus Secretion Involving a Protein Kinase A (PKA)-Dependent Nuclear Factor-κB (NF-κB) Signaling Pathway in Mice.

PubMed

Zhu, Tao; Wu, Xiao-Ling; Zhang, Wei; Xiao, Min

2015-08-26

Asthma is a common chronic pulmonary inflammatory disease, featured with mucus hyper-secretion in the airway. Recent studies found that glucagon like peptide-1 (GLP-1) analogs, including liraglutide and exenatide, possessed a potent anti-inflammatory property through a protein kinase A (PKA)-dependent signaling pathway. Therefore, the aim of current study was to investigate the value of GLP-1 analog therapy liraglutide in airway inflammation and mucus secretion in a murine model of ovalbumin (OVA)-induced asthma, and its underlying molecular mechanism. In our study, BALB/c mice were sensitized and challenged by OVA to induce chronic asthma. Pathological alterations, the number of cells and the content of inflammatory mediators in bronchoalveolar lavage fluid (BALF), and mucus secretion were observed and measured. In addition, the mRNA and protein expression of E-selectin and MUC5AC were analyzed by qPCR and Western blotting. Then, the phosphorylation of PKA and nuclear factor-κB (NF-κB) p65 were also measured by Western blotting. Further, NF-κB p65 DNA binding activity was detected by ELISA. OVA-induced airway inflammation, airway mucus hyper-secretion, the up-regulation of E-selectin and MUC5AC were remarkably inhibited by GLP-1 in mice (all p < 0.01). Then, we also found that OVA-reduced phosphorylation of PKA, and OVA-enhanced NF-κB p65 activation and NF-κB p65 DNA binding activity were markedly improved by GLP-1 (all p < 0.01). Furthermore, our data also figured out that these effects of GLP-1 were largely abrogated by the PKA inhibitor H-89 (all p < 0.01). Taken together, our results suggest that OVA-induced asthma were potently ameliorated by GLP-1 possibly through a PKA-dependent inactivation of NF-κB in mice, indicating that GLP-1 analogs may be considered an effective and safe drug for the potential treatment of asthma in the future.

HMC-1 human mast cells synthesize neurotensin (NT) precursor, secrete bioactive NT-like peptide(s) and express NT receptor NTS1.

PubMed

Cochrane, David E; Carraway, Robert E; Harrington, Kimberly; Laudano, Melissa; Rawlings, Stephen; Feldberg, Ross S

2011-12-01

To determine if mast cells synthesize the inflammatory peptide, neurotensin (NT), secrete immunoreactive and bioactive NT, and express the NT receptor NTS1. HMC-1 cells, pleural mast cells from Sprague-Dawley rats, LAD2 mast cells, and human cord blood mast cells were used. HMC-1 cells were stimulated with NT, C48/80, mastoparan, or PGE(2). For changes in cutaneous vascular permeability, anesthetized rats were injected intravenously with Evans Blue dye and intradermally with saline, NT, histamine, diphenhydramine, and C48/80. RT-PCR was used to identify RNA transcripts. Histamine was measured by fluorometric assay. In vivo cutaneous vascular permeability assays, radio-immunoassays for NT, Western blotting for the NT precursor protein and NTS1 protein from HMC-1 cells and tissues from rats were used. Immunohistochemistry was used to identify NT precursor-like proteins in HMC-1 mast cells. HMC-1 cells express mRNAs for NT precursor, PC5A processing enzyme and NTS1 receptor. Human cord blood mast cells and LAD2 mast cells express mRNA transcripts for NT precursor and NTS1. Western blotting showed NT precursor and NTS1 receptor in HMC1. Rat tissues with high numbers of mast cells contained NT precursor proteins. NT-like peptides from HMC-1 displayed NT-like bioactivity. HMC-1 mast cells synthesize and secrete immunoreactive and bioactive NT-like peptide(s) and express the NT receptor, suggesting that NT from mast cells might serve autocrine and paracrine roles.

The importance of using the optimal plastic and glassware in studies involving peptides

PubMed Central

Goebel-Stengel, Miriam; Stengel, Andreas; Taché, Yvette; Reeve, Joseph R.

2011-01-01

Background The unpredictable nature of peptide binding to surfaces requires optimization of experimental containers to be utilized. Objective To demonstrate the variable recoveries of peptides from multiple surfaces commonly employed in peptide research by testing the recovery of radiolabeled 125I-endocrine peptides under different conditions and provide guidelines for determining the surfaces to use for other peptides. Methods 125I-labeled peptides (ghrelin, sulfated cholecystokinin-8, corticotropin releasing factor, glucagon-like peptide-1 (GLP-1), insulin, leptin, nesfatin-1, peptide YY) representing a wide spectrum in net charge, size, end groups and modifications were incubated for 48h in glass and plastic tubes untreated or coated with siliconizing fluid. Best surfaces were chosen and peptides incubated with bovine serum albumin (BSA, 1%) with or without subsequent lyophilization. Recovery of 125I-peptides was determined by γ-counting. Results Important differences in 125I-peptide binding capacities to various types of surfaces exist. Siliconization decreased while addition of BSA improved recovery from surfaces tested. Lyophilizing solutions containing 125I-peptides and BSA in the tubes best suited for individual peptides rendered >89% recovery for all peptides. Ghrelin specifically displaced 125I-ghrelin from borosilicate glass while GLP-1 and Fmoc-arginine did not. Conclusion Choosing the appropriate experimental container avoids unpredictable peptide loss resulting in inaccurate measurements and false conclusions. PMID:21315060

Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure

PubMed Central

Brinkman, Adam S.; Murali, Sangita G.; Hitt, Stacy; Solverson, Patrick M.; Holst, Jens J.

2012-01-01

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that shows promise for the treatment of short bowel syndrome (SBS). Our objective was to investigate how combination GLP-2 + enteral nutrients (EN) affects intestinal adaption in a rat model that mimics severe human SBS and requires parenteral nutrition (PN). Male Sprague-Dawley rats were assigned to one of five groups and maintained with PN for 18 days: total parenteral nutrition (TPN) alone, TPN + GLP-2 (100 μg·kg−1·day−1), PN + EN + GLP-2(7 days), PN + EN + GLP-2(18 days), and a nonsurgical oral reference group. Animals underwent massive distal bowel resection followed by jejunocolic anastomosis and placement of jugular catheters. Starting on postoperative day 4, rats in the EN groups were allowed ad libitum access to EN. Groups provided PN + EN + GLP-2 had their rate of PN reduced by 0.25 ml/day starting on postoperative day 6. Groups provided PN + EN + GLP-2 demonstrated significantly greater body weight gain with similar energy intake and a safe 80% reduction in PN compared with TPN ± GLP-2. Groups provided PN + EN + GLP-2 for 7 or 18 days showed similar body weight gain, residual jejunal length, and digestive capacity. Groups provided PN + EN + GLP-2 showed increased jejunal GLP-2 receptor (GLP-2R), insulin-like growth factor-I (IGF-I), and IGF-binding protein-5 (IGFBP-5) expression. Treatment with TPN + GLP-2 demonstrated increased jejunal expression of epidermal growth factor. Cessation of GLP-2 after 7 days with continued EN sustained the majority of intestinal adaption and significantly increased expression of colonic proglucagon compared with PN + EN + GLP-2 for 18 days, and increased plasma GLP-2 concentrations compared with TPN alone. In summary, EN potentiate the intestinotrophic actions of GLP-2 by improving body weight gain allowing for a safe 80% reduction in PN with increased jejunal expression of GLP-2R, IGF-I, and IGFBP-5 following distal bowel

A monomer-trimer model supports intermittent glucagon fibril growth

NASA Astrophysics Data System (ADS)

Košmrlj, Andrej; Cordsen, Pia; Kyrsting, Anders; Otzen, Daniel E.; Oddershede, Lene B.; Jensen, Mogens H.

2015-03-01

We investigate in vitro fibrillation kinetics of the hormone peptide glucagon at various concentrations using confocal microscopy and determine the glucagon fibril persistence length 60μm. At all concentrations we observe that periods of individual fibril growth are interrupted by periods of stasis. The growth probability is large at high and low concentrations and is reduced for intermediate glucagon concentrations. To explain this behavior we propose a simple model, where fibrils come in two forms, one built entirely from glucagon monomers and one entirely from glucagon trimers. The opposite building blocks act as fibril growth blockers, and this generic model reproduces experimental behavior well.

Development of Stable Liquid Glucagon Formulations for Use in Artificial Pancreas

PubMed Central

Li, Ming; Krasner, Alan; De Souza, Errol

2014-01-01

Background: A promising approach to treat diabetes is the development of fully automated artificial/bionic pancreas systems that use both insulin and glucagon to maintain euglycemia. A physically and chemically stable liquid formulation of glucagon does not currently exist. Our goal is to develop a glucagon formulation that is stable as a clear and gel-free solution, free of fibrils and that has the requisite long-term shelf life for storage in the supply chain, short-term stability for at least 7 days at 37°C, and pump compatibility for use in a bihormonal pump. Methods: We report the development of two distinct families of stable liquid glucagon formulations which utilize surfactant or surfactant-like excipients (LMPC and DDM) to “immobilize” the glucagon in solution potentially through the formation of micelles and prevention of interaction between glucagon molecules. Results: Data are presented that demonstrate long-term physical and chemical stability (~2 years) at 5°C, short-term stability (up to 1 month) under accelerated 37°C testing conditions, pump compatibility for up to 9 days, and adequate glucose responses in dogs and diabetic swine. Conclusions: These stable glucagon formulations show utility and promise for further development in artificial pancreas systems. PMID:25352634

Exogenous glucagon-like peptide-2 improves outcomes of intestinal adaptation in a distal-intestinal resection neonatal piglet model of short bowel syndrome.

PubMed

Suri, Megha; Turner, Justine M; Sigalet, David L; Wizzard, Pamela R; Nation, Patrick N; Ball, Ron O; Pencharz, Paul B; Brubaker, Patricia L; Wales, Paul W

2014-10-01

Endogenous glucagon-like peptide-2 (GLP-2) levels and intestinal adaptation are reduced in distal-intestinal resection animal models of short bowel syndrome (SBS) that lack remnant ileum. We hypothesized that exogenous GLP-2 would improve intestinal adaptation in a distal-intestinal resection neonatal piglet model of SBS. In all, 35 piglets were randomized to 2 treatment and 3 surgical groups: control (sham), 75% mid-intestinal resection (JI), and 75% distal-intestinal resection (JC). Parenteral nutrition (PN) commenced on day 1 and was weaned as enteral nutrition (EN) advanced. IV GLP-2 (11 nmol/kg/d) or saline was initiated on day 2. Piglets were maintained for 14 d. Clinical, functional, morphological, and histological outcomes were obtained. JC-GLP-2 piglets had fewer days on PN (10.0 ± 0.6 vs. 13.8 ± 0.2), more days on EN (4.0 ± 0.6 vs. 0.2 ± 0.2), a higher percentage of EN at termination (92 ± 5 vs. 52 ± 10%), fewer days of diarrhea (8.0 ± 0.7 vs. 12.3 ± 0.4), increased intestinal length (19 ± 4 vs. -5 ± 3%), and deeper jejunal crypts (248 ± 21 vs. 172 ± 12 μm), compared with saline piglets. GLP-2 therapy improves clinical, morphological, and histological outcomes of intestinal adaptation in a distal-intestinal resection model of SBS. Since this anatomical subtype represents the majority of clinical cases of neonatal SBS, these results support a potential role for GLP-2 therapy in pediatric SBS.

Bioactivity of food peptides: biological response of rats to bovine milk whey peptides following acute exercise

PubMed Central

Moura, Carolina Soares; Lollo, Pablo Christiano Barboza; Morato, Priscila Neder; Risso, Eder Muller; Amaya-Farfan, Jaime

2017-01-01

ABSTRACT Background: Several physiologically beneficial effects of consuming a whey protein hydrolysate (WPH) have been attributed to the greater availability of bioactive peptides. Aims: The aim was to investigate the effect of four branched-chain amino acid- (BCAA-)containing dipeptides, present in WPH, on immune modulation, stimulation of HSP expression, muscle protein synthesis, glycogen content, satiety signals and the impact of these peptides on the plasma free amino acid profiles. Methods: The animals were divided in groups: control (rest, without gavage), vehicle (water), L-isoleucyl-L-leucine (lle-Leu), L-leucyl-L-isoleucine (Leu-lle), L-valyl-Lleucine (Val-Leu), L-leucyl-L-valine (Leu-Val) and WPH. All animals were submitted to acute exercise, except for control. Results: lle-Leu stimulated immune response, hepatic and muscle glycogen and HSP60 expression, whereas Leu-Val enhanced HSP90 expression. All dipeptides reduced glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, no changes were observed on leptin. All peptides inhibited NF-kB expression. The plasma amino acid time-course showed peptide-specific and isomer-specific metabolic features, including increases of the BCAAs. Conclusion: The data indicate that lle-Leu was effective to attenuate immune-suppression exercise-induced, promoted glycogen content and stimulated anti-stress effect (HSP). Furthermore, Leu-Val increased HSP90, p-4EBP1, p-mTOR and p-AMPK expression. The data suggest the involvement of these peptides in various beneficial functions of WPH consumption. PMID:28326005

Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT 2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart.

PubMed

Zhang, Li-Hui; Pang, Xue-Fen; Bai, Feng; Wang, Ning-Ping; Shah, Ahmed Ijaz; McKallip, Robert J; Li, Xue-Wen; Wang, Xiong; Zhao, Zhi-Qing

2015-06-01

The glucagon-like peptide-1 (GLP-1) has been shown to exert cardioprotective effects in animals and patients. This study tests the hypothesis that preservation of GLP-1 by the GLP-1 receptor agonist liraglutide or the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is associated with a reduction of angiotensin (Ang) II-induced cardiac fibrosis. Sprague-Dawley rats were subjected to Ang II (500 ng/kg/min) infusion using osmotic minipumps for 4 weeks. Liraglutide (0.3 mg/kg) was subcutaneously injected twice daily or linagliptin (8 mg/kg) was administered via oral gavage daily during Ang II infusion. Relative to the control, liraglutide, but not linagliptin decreased MAP (124 ± 4 vs. 200 ± 7 mmHg in control, p < 0.003). Liraglutide and linagliptin comparatively reduced the protein level of the Ang II AT1 receptor and up-regulated the AT2 receptor as identified by a reduced AT1/AT2 ratio (0.4 ± 0.02 and 0.7 ± 0.01 vs. 1.4 ± 0.2 in control, p < 0.05), coincident with the less locally-expressed AT1 receptor and enhanced AT2 receptor in the myocardium and peri-coronary vessels. Both drugs significantly reduced the populations of macrophages (16 ± 6 and 19 ± 7 vs. 61 ± 29 number/HPF in control, p < 0.05) and α-SMA expressing myofibroblasts (17 ± 7 and 13 ± 4 vs. 66 ± 29 number/HPF in control, p < 0.05), consistent with the reduction in expression of TGFβ1 and phospho-Smad2/3, and up-regulation of Smad7. Furthermore, ACE2 activity (334 ± 43 and 417 ± 51 vs. 288 ± 19 RFU/min/μg protein in control, p < 0.05) and GLP-1 receptor expression were significantly up-regulated. Along with these modulations, the synthesis of collagen I and tissue fibrosis were inhibited as determined by the smaller collagen-rich area and more viable myocardium. These results demonstrate for the first time that preservation of GLP-1 using liraglutide or linagliptin is effective in inhibiting Ang II-induced cardiac fibrosis, suggesting that these drugs could be selected as an

Insulin deficiency with and without glucagon: A comparative study between total pancreatectomy and type 1 diabetes.

PubMed

Niwano, Fumimaru; Hiromine, Yoshihisa; Noso, Shinsuke; Babaya, Naru; Ito, Hiroyuki; Yasutake, Sara; Matsumoto, Ippei; Takeyama, Yoshifumi; Kawabata, Yumiko; Ikegami, Hiroshi

2017-12-30

Patients with a total pancreatectomy and type 1 diabetes are similar in regard to absolute insulin deficiency, but different in regard to glucagon, providing a unique opportunity to study the contribution of glucagon to glucose metabolism in an insulin-dependent state. The aim of the present study was to investigate the contribution of glucagon to glucose homeostasis in complete insulin deficiency in vivo. A total of 38 individuals with a complete lack of endogenous insulin (fasting C-peptide <0.0066 nmol/L) and whose glycemic control was optimized with an insulin pump during hospitalization were retrospectively studied. The basal insulin requirement, time-to-time adjustment of the basal insulin infusion rate, prandial insulin requirement and fasting plasma glucagon were compared between patients with a total pancreatectomy (n = 10) and those with type 1 diabetes (n = 28) after achievement of optimal glycemic control. Total daily insulin (P = 0.03) and basal insulin (P = 0.000006), but not prandial insulin requirements, were significantly lower in total pancreatectomy patients than in type 1 diabetes patients. The basal percentage (basal insulin/total daily insulin) was also significantly lower in total pancreatectomy patients than in type 1 diabetes patients (15.8 ± 7.8 vs 32.9 ± 10.1%, P = 0.00003). An increase in the insulin infusion rate early in the morning was not necessary in most patients with a pancreatectomy. The fasting plasma glucagon concentration was significantly lower in total pancreatectomy patients than in type 1 diabetes patients (P = 0.00007), and was positively correlated with the basal insulin requirement (P = 0.038). The difference in insulin requirements between total pancreatectomy and type 1 diabetes patients suggests a contribution of glucagon to the basal insulin requirement and dawn phenomenon. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and

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

High-fidelity Glucagon-CreER mouse line generated by CRISPR-Cas9 assisted gene targeting.

PubMed

Ackermann, Amanda M; Zhang, Jia; Heller, Aryel; Briker, Anna; Kaestner, Klaus H

2017-03-01

α-cells are the second most prominent cell type in pancreatic islets and are responsible for producing glucagon to increase plasma glucose levels in times of fasting. α-cell dysfunction and inappropriate glucagon secretion occur in both type 1 and type 2 diabetes. Thus, there is growing interest in studying both normal function and pathophysiology of α-cells. However, tools to target gene ablation or activation specifically of α-cells have been limited, compared to those available for β-cells. Previous Glucagon-Cre and Glucagon-CreER transgenic mouse lines have suffered from transgene silencing, and the only available Glucagon-CreER "knock-in" mouse line results in glucagon haploinsufficiency, which can confound the interpretation of gene deletion analyses. Therefore, we sought to develop a Glucagon-CreER T2 mouse line that would maintain normal glucagon expression and would be less susceptible to transgene silencing. We utilized CRISPR-Cas9 technology to insert an IRES-CreER T2 sequence into the 3' UTR of the Glucagon ( Gcg ) locus in mouse embryonic stem cells (ESCs). Targeted ESC clones were then injected into mouse blastocysts to obtain Gcg-CreER T2 mice. Recombination efficiency in GCG + pancreatic α-cells and glucagon-like peptide 1 positive (GLP1 + ) enteroendocrine L-cells was measured in Gcg-CreER T2 ; Rosa26-LSL-YFP mice injected with tamoxifen during fetal development and adulthood. Tamoxifen injection of Gcg-CreER T2 ; Rosa26-LSL-YFP mice induced high recombination efficiency of the Rosa26-LSL-YFP locus in perinatal and adult α-cells (88% and 95%, respectively), as well as in first-wave fetal α-cells (36%) and adult enteroendocrine L-cells (33%). Mice homozygous for the Gcg-CreER T2 allele were phenotypically normal. We successfully derived a Gcg-CreER T2 mouse line that expresses CreER T2 in pancreatic α-cells and enteroendocrine L-cells without disrupting preproglucagon gene expression. These mice will be a useful tool for performing

Blood Glucagon Levels Predict the Hemoglobin A1c Response to Saxagliptin in Patients with Type 2 Diabetes Inadequately Controlled with Metformin.

PubMed

Liu, Hao; Hu, Yun; Li, Feng-Fei; Liu, Bing-Li; Su, Xiao-Fei; Ma, Jian-Hua

2016-12-01

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as second-option medications when metformin fails. Variance of the glycated hemoglobin (HbA1c) response to DPP-4 inhibitions in patients with type 2 diabetes mellitus (T2DM) has been observed, but the characteristics which predict the response to DPP-4 inhibitor therapy are unclear. The aim of this study was to investigate the characteristics of α- and β-cell functions which might predict the efficacy of saxagliptin and facilitate personalization of treatment. We studied 60 patients with T2DM who had inadequate glycemic control [HbA1c7.0-13.0% (53-119 mmol/mol)) with metformin alone. The patients were treated with saxagliptin (5 mg, daily) and metformin (1000-2000 mg as former) for 12 weeks. Oral glucose tolerance tests were carried out at baseline and endpoint to evaluate α- and β-cell functions, and blood C-peptide, insulin, glucagon levels were tested. Blood glucose, HbA1c and weight were also observed. Significant reduction of weight, HbA1c and glucagon was observed after 12-week treatment, while C-peptide, insulin and homeostasis model assessment-β increased (P < 0.05). Linear regression and receiver operating characteristic analysis showed that baseline HbA1c and 30 min-glucagon were correlated with the HbA1c response to saxagliptin, while the weight loss was correlated with gender, age and fasting-insulin level. Further analysis showed the 30 min-glucagon of 49.1 pmol/L was the optimal cutoff value to predict the efficacy of saxagliptin. Saxagliptin added to metformin significantly improved glycemic control and α- and β-cell function. Blood glucagon level was a good predicting factor for the HbA1c response to saxagliptin, and it will help appropriate patient selection. Chinese Clinical Trial Register identifier, ChiCTR-PPR-15007045.

Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells.

PubMed

Schlatter, P; Beglinger, C; Drewe, J; Gutmann, H

2007-06-07

GLP-1 is secreted into the circulation after food intake. The main biological effects of GLP-1 include stimulation of glucose dependent insulin secretion and induction of satiety feelings. Recently, it was demonstrated in rats and humans that GLP-1 can stimulate renal excretion of sodium. Based on these data, the existence of a renal GLP-1 receptor (GLP-1R) was postulated. However, the exact localization of the GLP-1R and the mechanism of this GLP-1 action have not yet been investigated. Primary porcine proximal tubular cells were isolated from porcine kidneys. Expression of GLP-1R was measured at the mRNA level by quantitative RT-PCR. Protein expression of GLP-1R was verified with immunocytochemistry, immunohistochemistry and Western blot analysis. Functional studies included transport assessments of sodium and glucose using three different GLP-1 concentrations (200 pM, 2 nM and 20 nM), 200 pM exendin-4 (GLP-1 analogue) and an inhibitor of the dipeptidylpeptidase IV (DPPIV) enzyme (P32/98 at 10 microM). Finally, the expression of NHE3, the predominant Na(+)/H(+) exchanger in proximal tubular cells, was also investigated. GLP-1R, NHE3 and DPPIV were expressed at the mRNA level in porcine proximal tubular kidney cells. GLP-1R expression was confirmed at the protein level. Staining of human and pig kidney cortex revealed that GLP-1R was predominantly expressed in proximal tubular cells. Functional assays demonstrated an inhibition of sodium re-absorption with GLP-1 after 3 h of incubation. Exendin-4 and GLP-1 in combination with P32/98 co-administration had no clear influence on glucose and sodium uptake and transport. GLP-1R is functionally expressed in porcine proximal tubular kidney cells. Addition of GLP-1 to these cells resulted in a reduced sodium re-absorption. GLP-1 had no effect on glucose re-absorption. We conclude that GLP-1 modulates sodium homeostasis in the kidney most likely through a direct action via its GLP-1R in proximal tubular cells.

Treatment patterns in patients with type 2 diabetes mellitus treated with glucagon-like peptide-1 receptor agonists: Higher adherence and persistence with dulaglutide compared with once-weekly exenatide and liraglutide.

PubMed

Alatorre, Carlos; Fernández Landó, Laura; Yu, Maria; Brown, Katelyn; Montejano, Leslie; Juneau, Paul; Mody, Reema; Swindle, Ralph

2017-07-01

To compare adherence (proportion of days covered [PDC]), persistence, and treatment patterns among patients with type 2 diabetes mellitus (T2DM) newly initiating glucagon-like peptide-1 receptor agonists (GLP-1RAs). More specifically, the main objectives were to compare dulaglutide vs exenatide once weekly and dulaglutide vs liraglutide. Patients with T2DM newly initiating dulaglutide, albiglutide, exenatide once weekly, exenatide twice daily and liraglutide between November 2014 and April 2015 were hierarchically selected from Truven Health's MarketScan Research Databases. Propensity score matching was used to account for selection bias. Adherence to and persistence with the index GLP-1RA, and switching and augmentation patterns were assessed during the 6-month post-index period. Mean adherence for the matched cohorts was significantly higher for dulaglutide than for exenatide once weekly (0.72 vs 0.61; P  < .0001) and liraglutide (0.71 vs 0.67; P  < .0001). The percentage of patients achieving PDC ≥ 0.80 was significantly higher for dulaglutide compared with exenatide once weekly (54.2% vs 37.9%; P  < .0001) and liraglutide (53.5% vs 44.3%; P  < .0001). The mean (standard deviation) days on treatment for all matched patients was significantly higher for patients in the dulaglutide cohort compared with those in the exenatide once-weekly (148.4 [55.4] vs 123.6 [61.6]; P  < .0001) and liraglutide cohorts (146.0 [56.9] vs 137.4 [60.1]; P  < .0001). A significantly lower proportion of patients on dulaglutide discontinued treatment compared with those on exenatide once weekly (26.2% vs 48.4%; P  < .0001) and those on liraglutide (28.0% vs 35.6%; P  < .0001). Dulaglutide initiators had significantly higher adherence, were more persistent, and had lower discontinuation rates compared with initiators of exenatide once weekly or liraglutide during the 6-month follow-up period. © 2017 Eli Lilly and Company. Diabetes, Obesity and

Delivering heparin-binding insulin-like growth factor 1 with self-assembling peptide hydrogels.

PubMed

Florine, Emily M; Miller, Rachel E; Liebesny, Paul H; Mroszczyk, Keri A; Lee, Richard T; Patwari, Parth; Grodzinsky, Alan J

2015-02-01

Heparin-binding insulin-like growth factor 1 (HB-IGF-1) is a fusion protein of IGF-1 with the HB domain of heparin-binding epidermal growth factor-like growth factor. A single dose of HB-IGF-1 has been shown to bind specifically to cartilage and to promote sustained upregulation of proteoglycan synthesis in cartilage explants. Achieving strong integration between native cartilage and tissue-engineered cartilage remains challenging. We hypothesize that if a growth factor delivered by the tissue engineering scaffold could stimulate enhanced matrix synthesis by both the cells within the scaffold and the adjacent native cartilage, integration could be enhanced. In this work, we investigated methods for adsorbing HB-IGF-1 to self-assembling peptide hydrogels to deliver the growth factor to encapsulated chondrocytes and cartilage explants cultured with growth factor-loaded hydrogels. We tested multiple methods for adsorbing HB-IGF-1 in self-assembling peptide hydrogels, including adsorption prior to peptide assembly, following peptide assembly, and with/without heparan sulfate (HS, a potential linker between peptide molecules and HB-IGF-1). We found that HB-IGF-1 and HS were retained in the peptide for all tested conditions. A subset of these conditions was then studied for their ability to stimulate increased matrix production by gel-encapsulated chondrocytes and by chondrocytes within adjacent native cartilage. Adsorbing HB-IGF-1 or IGF-1 prior to peptide assembly was found to stimulate increased sulfated glycosaminoglycan per DNA and hydroxyproline content of chondrocyte-seeded hydrogels compared with basal controls at day 10. Cartilage explants cultured adjacent to functionalized hydrogels had increased proteoglycan synthesis at day 10 when HB-IGF-1 was adsorbed, but not IGF-1. We conclude that delivery of HB-IGF-1 to focal defects in cartilage using self-assembling peptide hydrogels is a promising technique that could aid cartilage repair via enhanced matrix

Calcitonin gene-related peptide: neuroendocrine communication between the pancreas, gut, and brain in regulation of blood glucose.

PubMed

Pendharkar, Sayali A; Walia, Monika; Drury, Marie; Petrov, Maxim S

2017-11-01

Calcitonin gene-related peptide (CGRP), a ubiquitous neuropeptide, plays a diverse and intricate role in chronic low-grade inflammation, including conditions such as obesity, type 2 diabetes, and diabetes of the exocrine pancreas. Diabetes of exocrine pancreas is characterised by chronic hyperglycemia and is associated with persistent low-grade inflammation and altered secretion of certain pancreatic and gut hormones. While CGRP may regulate glucose homeostasis and the secretion of pancreatic and gut hormones, its role in chronic hyperglycemia after acute pancreatitis (CHAP) is not known. The aim of this study was to investigate the association between CGRP and CHAP. Fasting blood samples were collected to measure insulin, HbA1c, CGRP, amylin, C-peptide, glucagon, pancreatic polypeptide (PP), somatostatin, gastric inhibitory peptide, glicentin, glucagon-like peptide-1 and 2, and oxyntomodulin. Modified Poisson regression analysis and linear regression analyses were conducted. Five statistical models were used to adjust for demographic, metabolic, and pancreatitis-related risk factors. A total of 83 patients were recruited. CGRP was significantly associated with CHAP in all five models (P-trend <0.005). Further, it was significantly associated with oxyntomodulin (P<0.005) and glucagon (P<0.030). Oxyntomodulin and glucagon independently contributed 9.7% and 7%, respectively, to circulating CGRP variance. Other pancreatic and gut hormones were not significantly associated with CGRP. CGRP is involved in regulation of blood glucose in individuals after acute pancreatitis. This may have translational implications in prevention and treatment of diabetes of the exocrine pancreas.

Gastrin-Releasing Peptide and Glucose Metabolism Following Pancreatitis.

PubMed

Pendharkar, Sayali A; Drury, Marie; Walia, Monika; Korc, Murray; Petrov, Maxim S

2017-08-01

Gastrin-releasing peptide (GRP) is a pluripotent peptide that has been implicated in both gastrointestinal inflammatory states and classical chronic metabolic diseases such as diabetes. Abnormal glucose metabolism (AGM) after pancreatitis, an exemplar inflammatory disease involving the gastrointestinal tract, is associated with persistent low-grade inflammation and altered secretion of pancreatic and gut hormones as well as cytokines. While GRP is involved in secretion of many of them, it is not known whether GRP has a role in AGM. Therefore, we aimed to investigate the association between GRP and AGM following pancreatitis. Fasting blood samples were collected to measure GRP, blood glucose, insulin, amylin, glucagon, pancreatic polypeptide (PP), somatostatin, cholecystokinin, gastric-inhibitory peptide (GIP), gastrin, ghrelin, glicentin, glucagon-like peptide-1 and 2, oxyntomodulin, peptide YY (PYY), secretin, vasoactive intestinal peptide, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein (MCP)-1, and interleukin-6. Modified Poisson regression analysis and linear regression analyses were conducted. Four statistical models were used to adjust for demographic, metabolic, and pancreatitis-related risk factors. A total of 83 individuals after an episode of pancreatitis were recruited. GRP was significantly associated with AGM, consistently in all four models (P -trend < 0.05), and fasting blood glucose contributed 17% to the variance of GRP. Further, GRP was significantly associated with glucagon (P < 0.003), MCP-1 (P < 0.025), and TNF-α (P < 0.025) - consistently in all four models. GRP was also significantly associated with PP and PYY in three models (P < 0.030 for both), and with GIP and glicentin in one model (P = 0.001 and 0.024, respectively). Associations between GRP and other pancreatic and gut hormones were not significant. GRP is significantly increased in patients with AGM after pancreatitis and is associated with increased levels of pro

Conformational states of the full-length glucagon receptor

PubMed Central

Yang, Linlin; Yang, Dehua; de Graaf, Chris; Moeller, Arne; West, Graham M.; Dharmarajan, Venkatasubramanian; Wang, Chong; Siu, Fai Y.; Song, Gaojie; Reedtz-Runge, Steffen; Pascal, Bruce D.; Wu, Beili; Potter, Clinton S.; Zhou, Hu; Griffin, Patrick R.; Carragher, Bridget; Yang, Huaiyu; Wang, Ming-Wei; Stevens, Raymond C.; Jiang, Hualiang

2015-01-01

Class B G protein-coupled receptors are composed of an extracellular domain (ECD) and a seven-transmembrane (7TM) domain, and their signalling is regulated by peptide hormones. Using a hybrid structural biology approach together with the ECD and 7TM domain crystal structures of the glucagon receptor (GCGR), we examine the relationship between full-length receptor conformation and peptide ligand binding. Molecular dynamics (MD) and disulfide crosslinking studies suggest that apo-GCGR can adopt both an open and closed conformation associated with extensive contacts between the ECD and 7TM domain. The electron microscopy (EM) map of the full-length GCGR shows how a monoclonal antibody stabilizes the ECD and 7TM domain in an elongated conformation. Hydrogen/deuterium exchange (HDX) studies and MD simulations indicate that an open conformation is also stabilized by peptide ligand binding. The combined studies reveal the open/closed states of GCGR and suggest that glucagon binds to GCGR by a conformational selection mechanism. PMID:26227798

Control of Food Intake by Gastrointestinal Peptides: Mechanisms of Action and Possible Modulation in the Treatment of Obesity

PubMed Central

Prinz, Philip; Stengel, Andreas

2017-01-01

This review focuses on the control of appetite by food intake-regulatory peptides secreted from the gastrointestinal tract, namely cholecystokinin, glucagon-like peptide 1, peptide YY, ghrelin, and the recently discovered nesfatin-1 via the gut-brain axis. Additionally, we describe the impact of external factors such as intake of different nutrients or stress on the secretion of gastrointestinal peptides. Finally, we highlight possible conservative—physical activity and pharmacotherapy—treatment strategies for obesity as well as surgical techniques such as deep brain stimulation and bariatric surgery also altering these peptidergic pathways. PMID:28096522

Brain GLP-1 and insulin sensitivity

USDA-ARS?s Scientific Manuscript database

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....

Evaluation of long-term treatment effect in a type 1 diabetes intervention trial: differences after stimulation with glucagon or a mixed meal.

PubMed

Pozzilli, Paolo; Raz, Itamar; Peled, Dana; Elias, Dana; Avron, Ann; Tamir, Merana; Eren, Rachel; Dagan, Shlomo; Cohen, Irun R

2014-01-01

Endogenous insulin secretion, measured by C-peptide area under the curve (AUC), can be tested using both the glucagon stimulation test (GST) and the mixed-meal tolerance test (MMTT). This study compares these two stimulation methods using long-term data from patients newly diagnosed with type 1 diabetes or with latent autoimmune diabetes. A recently completed phase 3 intervention study with DiaPep277 demonstrated improved glycemic control and a significant treatment effect of glucagon-stimulated C-peptide secretion. Unexpectedly, MMTT failed to detect differences between the treated and control groups. Data from 343 patients in two balanced-randomized, double-blind, placebo-controlled, parallel-group trials of DiaPep277 were used to compare and correlate between GST- and MMTT-derived C-peptide AUC. Pearson's correlations were calculated for absolute C-peptide AUC at baseline and 12 and 24 months and for long-term changes in AUC (AUC). The absolute AUC values obtained at any single time point by the two tests were well correlated in both data sets (r = 0.74-0.9). However, the correlations between the AUC were much weaker (r = 0.39-0.58). GST-stimulated C-peptide secretion was stable over the fasting glucose range permitted for the test (4-11.1 mmol/L), but MMTT-stimulated C-peptide secretion decreased over the same range, implying differences in sensitivity to glucose. Measurement of long-term changes in stimulated C-peptide, reflecting endogenous insulin secretion, during the course of intervention trials may be affected by the method of stimulation, possibly reflecting different sensitivities to the physiological status of the tested subject.

A second glucagon in the pancreatic islets of the daddy sculpin Cottus scorpius.

PubMed

Cutfield, S M; Cutfield, J F

1993-09-01

The peptide hormone glucagon has been isolated from the islet tissue (Brockmann bodies) of the teleost Cottus scorpius (daddy sculpin) and sequenced. The sequence is HSEGTSNDYSKYLEDRKAQDFVQWLMNN differing at four positions from the glucagon found earlier in the same species by Conlon and coworkers (1987b, Eur. J. Biochem, 164, 117-122). Thus sculpin, in common with anglerfish, possesses two distinct glucagons. Comparative sequence data are presented as a phylogenetic tree.

Gut satiety hormones cholecystokinin and glucagon-like Peptide-17-36 amide mediate anorexia induction by trichothecenes T-2 toxin, HT-2 toxin, diacetoxyscirpenol and neosolaniol.

PubMed

Zhang, Jie; Liu, Shengli; Zhang, Hua; Li, Yuanyuan; Wu, Wenda; Zhang, Haibin

2017-11-15

The food-borne trichothecene mycotoxins have been documented to cause human and animal food poisoning. Anorexia is a hallmark of the trichothecene mycotoxins-induced adverse effects. Type B trichothecenes have been previously demonstrated to elicit robust anorectic responses, and this response has been directly linked to secretion of the gut satiety hormones cholecystokinin (CCK) and glucagon-like peptide-1 7-36 amide (GLP-1). However, less is known about the anorectic effects and underlying mechanisms of the type A trichothecenes, including T-2 toxin (T-2), HT-2 toxin (HT-2), diacetoxyscirpenol (DAS), neosolaniol (NEO). The purpose of this study was to relate type A trichothecenes T-2, HT-2, DAS and NEO-induced anorectic response to changes plasma concentrations of CCK and GLP-1. Following both oral gavage and intraperitoneal (IP) administration of 1mg/kg bw T-2, HT-2, DAS and NEO evoked robust anorectic response and secretion of CCK and GLP-1. Elevations of plasma CCK markedly corresponded to anorexia induction by T-2, HT-2, DAS and NEO. Following oral exposure, plasma CCK was peaked at 6h, 6h, 2h, 2h and lasted up to 24h, 24h, > 6h, > 6h for T-2, HT-2, DAS and NEO, respectively. IP exposed to four toxins all induced elevation of CCK with peak point and duration at 6h and >24h, respectively. In contrast to CCK, GLP-1 was moderately elevated by these toxins. Following both oral and IP exposure, T-2 and HT-2 evoked plasma GLP-1 elevation with peak point and duration at 2h and 6h, respectively. Plasma GLP-1 was peaked at 2h and still increased at 6h for IP and oral administration with DAS and NEO, respectively. In conclusion, CCK plays a contributory role in anorexia induction but GLP-1 might play a lesser role in this response. Copyright © 2017 Elsevier Inc. All rights reserved.

Gastric inhibitory peptide, serotonin, and glucagon are unexpected chloride secretagogues in the rectal gland of the skate (Leucoraja erinacea).

PubMed

Kelley, Catherine A; Decker, Sarah E; Silva, Patricio; Forrest, John N

2014-05-01

Since the discovery of the rectal gland of the dogfish shark 50 years ago, experiments with this tissue have greatly aided our understanding of secondary active chloride secretion and the secretagogues responsible for this function. In contrast, very little is known about the rectal gland of skates. In the present experiments, we performed the first studies in the perfused rectal gland of the little skate (Leucoraja erinacea), an organ weighing less than one-tenth of the shark rectal gland. Our results indicate that the skate gland can be studied by modified perfusion techniques and in primary culture monolayers, and that secretion is blocked by the inhibitors of membrane proteins required for secondary active chloride secretion. Our major finding is that three G protein-coupled receptor agonists, the incretin gastric inhibitory polypeptide (GIP), also known as glucose-dependent insulinotropic peptide, as well as glucagon and serotonin, are unexpected potent chloride secretagogues in the skate but not the shark. Glucagon stimulated chloride secretion to a mean value of 1,661 ± 587 μeq·h(-1)·g(-1) and serotonin stimulated to 2,893 ± 699 μeq·h(-1)·g(-1). GIP stimulated chloride secretion to 3,733 ± 679 μeq·h(-1)·g(-1) and significantly increased tissue cAMP content compared with basal conditions. This is the first report of GIP functioning as a chloride secretagogue in any species or tissue.

Gastric inhibitory peptide, serotonin, and glucagon are unexpected chloride secretagogues in the rectal gland of the skate (Leucoraja erinacea)

PubMed Central

Kelley, Catherine A.; Decker, Sarah E.; Silva, Patricio

2014-01-01

Since the discovery of the rectal gland of the dogfish shark 50 years ago, experiments with this tissue have greatly aided our understanding of secondary active chloride secretion and the secretagogues responsible for this function. In contrast, very little is known about the rectal gland of skates. In the present experiments, we performed the first studies in the perfused rectal gland of the little skate (Leucoraja erinacea), an organ weighing less than one-tenth of the shark rectal gland. Our results indicate that the skate gland can be studied by modified perfusion techniques and in primary culture monolayers, and that secretion is blocked by the inhibitors of membrane proteins required for secondary active chloride secretion. Our major finding is that three G protein-coupled receptor agonists, the incretin gastric inhibitory polypeptide (GIP), also known as glucose-dependent insulinotropic peptide, as well as glucagon and serotonin, are unexpected potent chloride secretagogues in the skate but not the shark. Glucagon stimulated chloride secretion to a mean value of 1,661 ± 587 μeq·h−1·g−1 and serotonin stimulated to 2,893 ± 699 μeq·h−1·g−1. GIP stimulated chloride secretion to 3,733 ± 679 μeq·h−1·g−1 and significantly increased tissue cAMP content compared with basal conditions. This is the first report of GIP functioning as a chloride secretagogue in any species or tissue. PMID:24553297

Dysregulated Plasma Glucagon Levels in Japanese Young-adult Type 1 Diabetes Patients.

PubMed

Kawamori, Dan; Katakami, Naoto; Takahara, Mitsuyoshi; Miyashita, Kazuyuki; Sakamoto, Fumie; Yasuda, Tetsuyuki; Matsuoka, Taka-Aki; Shimomura, Iichiro

2018-05-16

Currently, the clinical dynamics of glucagon needs to be revised based on previous data obtained from conventional glucagon radioimmunoassays. In this study, we evaluated plasma glucagon levels in type 1 diabetes patients using a newly-developed sandwich enzyme-linked immunosorbent assay (ELISA), and its association with clinical parameters and markers of diabetes complications were statistically assessed. The plasma glucagon level in 77 Japanese type 1 diabetes patients was 28.1±17.7 pg/mL, and comparable to that reported previously for type 2 diabetes patients. However, the values were widely spread and did not correlate with plasma glucose values. Additionally, the average glucagon levels in patients in a hypoglycemic state (glucose level <80 mg/dL) did not increase (21.7±12.2 pg/mL). The average glucagon level of patients experiencing hypoglycemia unawareness was significantly lower. Plasma glucagon levels evaluated using the new ELISA were dysregulated in type 1 diabetes patients in respect of plasma glucose levels, suggesting dysregulation of secretion. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

GLP-1 Elicits an Intrinsic Gut-Liver Metabolic Signal to Ameliorate Diet-Induced VLDL Overproduction and Insulin Resistance.

PubMed

Khound, Rituraj; Taher, Jennifer; Baker, Christopher; Adeli, Khosrow; Su, Qiaozhu

2017-12-01

Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance. By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a high-fat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes. Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism. © 2017 American Heart Association, Inc.

Impact of Sleeve Gastrectomy on Type 2 Diabetes Mellitus, Gastric Emptying Time, Glucagon-Like Peptide 1 (GLP-1), Ghrelin and Leptin in Non-morbidly Obese Subjects with BMI 30-35.0 kg/m2: a Prospective Study.

PubMed

Vigneshwaran, B; Wahal, Akshat; Aggarwal, Sandeep; Priyadarshini, Pratyusha; Bhattacharjee, Hemanga; Khadgawat, Rajesh; Yadav, Rajkumar

2016-12-01

The study was conducted to evaluate the impact of laparoscopic sleeve gastrectomy (LSG) on type 2 diabetes mellitus (T2DM) in patients with a body mass index (BMI) of 30.0-35.0 kg/m 2 . Possible mechanisms, including alterations in gastric emptying time (GET), glucagon-like peptide 1 (GLP-1), ghrelin and leptin, were evaluated. Twenty obese patients with T2DM and with a BMI of 30.0-35.0 kg/m 2 underwent LSG during March 2012 to February 2015. Glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG) and GET were measured at baseline, 3 months, 6 months, 12 months and 24 months after surgery. Fasting and post-prandial levels of serum GLP-1, ghrelin and leptin were measured pre-operatively and after 3 and 6 months. The average duration of follow-up was 17.6 months, and 10 patients had completed 2 years of follow-up. After 2 years, the average BMI decreased from 33.4 ± 1.2 to 26.7 ± 1.8 kg/m 2 . The mean HbA1c decreased from 8.7 ± 1.6 to 6.7 ± 1.5 %, respectively. Ten patients achieved complete remission. Insulin could be stopped in all six patients who were on it pre-operatively. Meal-stimulated GLP-1 response and serum insulin at 30 min showed a significant increase following surgery. There was a significant decrease in GET. This prospective study confirms the positive impact of LSG on diabetic status of non-morbidly obese patients. The possible mechanisms include the rise in post-prandial GLP-1 level induced by accelerated gastric emptying, leading to an increase in insulin secretion. LSG also leads to decreased ghrelin and leptin levels which may have a role in improving glucose homeostasis after surgery.