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Sample records for gut incretin hormones

  1. [Incretin hormones].

    PubMed

    Cáp, J

    2011-04-01

    Incretin hormones are peptides that are secreted from endocrine cell of gastrointestinal tract after nutrient ingestion and stimulate insulin secretion. Glucosodependent Insulinotropic Peptide--GIP is released from K-cells of duodenum and proximal jejunum, recently GIP synthesis has been proved in pancreatic alpha cells. Besides the incretin effect causes GIP increased lipogenesis and decreased lipolysis in fat tissue, increased bone formation and decreased resorption and has protective and proliferative effect on CNS neurons. Both GIP agonists (to treat diabetes) and antagonist (to treat obesity) are being studied. Another incretin hormone is derived in intestinal I-cells by posttranslational processing of proglucagon--glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). GLP-1 stimulates insuline production and inhibits glucagon secretion, exerts proliferative and antiapoptotic effect on beta-cells. Via receptors on vagal nerve and central mechanisms decreases food intake and decreases body weight. By deceleration of gastric emptying it attenuates increases in meal-associated blood glucose levels. It exerts cardioprotective effects. GLP-1 receptors have been proved in liver recently but decreased liver glucose production and increased glucose uptake by liver and muscle are mediated indirectly by altering insulin and glucagons levels. GLP-2 stimulates enterocytes proliferation, up-regulates intestinal nutrient transport, improves intestinal barrier function, and inhibits gastric and intestinal motility. GLP-2 also reduces bone resorption.

  2. Influence of diabetes surgery on gut hormones and incretins.

    PubMed

    Papamargaritis, D; Miras, A D; le Roux, Carel W

    2013-03-01

    The dramatic rise in the prevalence of obesity and type 2 diabetes mellitus (T2DM) has become a major global public health issue. There is increasing evidence that metabolic surgery is more effective than diet and exercise for diabetes remission and weight loss. Moreover, the rapid time course and disproportional degree of T2DM improvement after metabolic procedures compared with equivalent weight loss with conservative treatment, suggest surgery-specific, weight-independent effects on glucose homeostasis. Gut hormones has been proposed as one of the potential mechanisms for the weight-independent diabetes remission and long-term weight loss after these procedures. In this review we discuss the available current metabolic procedures and we review the current human data on changes in gut hormones after each metabolic procedure.

  3. Nutrient detection by incretin hormone secreting cells

    PubMed Central

    Diakogiannaki, Eleftheria; Gribble, Fiona M.; Reimann, Frank

    2012-01-01

    The hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulintropic polypeptide (GIP) are secreted after a meal. Like other enteroendocrine hormones they help to orchestrate the bodies' response to the availability of newly absorbable nutrients and are noteworthy as they stimulate postprandial insulin secretion, underlying what is known as the incretin effect. GLP-1-mimetics are now widely used in the treatment of type 2 diabetes and advantages over older insulinotropic therapies include weight loss. An alternative treatment regime might be the recruitment of endogenous GLP-1, however, very little is known about the physiological control of enteroendocrine responses. This review focuses on the molecular mechanisms to detect nutrient arrival in the gut that have been implicated within the incretin secreting cells. PMID:22182802

  4. Bone: Incretin Hormones Perceiver or Receiver?

    PubMed Central

    Dicembrini, Ilaria; Mannucci, Edoardo; Rotella, Carlo Maria

    2012-01-01

    Novel incretin-based drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), have been last introduced in the pharmacological treatment of type 2 diabetes. In the last few years, the interest on the relationship of gut hormones with bone metabolism in diabetes has been increasing. The aim of present paper is to examine in vitro and in vivo evidence on the connections between incretin hormones and bone metabolism. We also discuss results of clinical trials and metaanalysis, explore the effects of incretin drugs in vitro on osteogenic cells and osteoclasts, and speculate on the possibility of different effects of GLP-1 RA and DPP-4i on the risk of bone fractures risk in humans. Although existing preliminary evidence suggests a protective effect on the bone, at least for DPP-4i, further controlled, long-term studies with measurement of bone markers, bone density, and clinical fractures rates are needed to substantiate and confirm those findings. PMID:22761607

  5. Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo.

    PubMed

    Fujita, Yukihiro; Wideman, Rhonda D; Speck, Madeleine; Asadi, Ali; King, David S; Webber, Travis D; Haneda, Masakazu; Kieffer, Timothy J

    2009-03-01

    Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are released during meals from endocrine cells located in the gut mucosa and stimulate insulin secretion from pancreatic beta-cells in a glucose-dependent manner. Although the gut epithelium senses luminal sugars, the mechanism of sugar sensing and its downstream events coupled to the release of the incretin hormones are not clearly elucidated. Recently, it was reported that sucralose, a sweetener that activates the sweet receptors of taste buds, triggers incretin release from a murine enteroendocrine cell line in vitro. We confirmed that immunoreactivity of alpha-gustducin, a key G-coupled protein involved in taste sensing, is sometimes colocalized with GIP in rat duodenum. We investigated whether secretion of incretins in response to carbohydrates is mediated via taste receptors by feeding rats the sweet-tasting compounds saccharin, acesulfame potassium, d-tryptophan, sucralose, or stevia. Oral gavage of these sweeteners did not reduce the blood glucose excursion to a subsequent intraperitoneal glucose tolerance test. Neither oral sucralose nor oral stevia reduced blood glucose levels in Zucker diabetic fatty rats. Finally, whereas oral glucose increased plasma GIP levels approximately 4-fold and GLP-1 levels approximately 2.5-fold postadministration, none of the sweeteners tested significantly increased levels of these incretins. Collectively, our findings do not support the concept that release of incretins from enteroendocrine cells is triggered by carbohydrates via a pathway identical to the sensation of "sweet taste" in the tongue.

  6. Hormonal Signaling in the Gut*

    PubMed Central

    Côté, Clémence D.; Zadeh-Tahmasebi, Melika; Rasmussen, Brittany A.; Duca, Frank A.; Lam, Tony K. T.

    2014-01-01

    The gut is anatomically positioned to play a critical role in the regulation of metabolic homeostasis, providing negative feedback via nutrient sensing and local hormonal signaling. Gut hormones, such as cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), are released following a meal and act on local receptors to regulate glycemia via a neuronal gut-brain axis. Additionally, jejunal nutrient sensing and leptin action are demonstrated to suppress glucose production, and both are required for the rapid antidiabetic effect of duodenal jejunal bypass surgery. Strategies aimed at targeting local gut hormonal signaling pathways may prove to be efficacious therapeutic options to improve glucose control in diabetes. PMID:24577102

  7. Hormonal signaling in the gut.

    PubMed

    Côté, Clémence D; Zadeh-Tahmasebi, Melika; Rasmussen, Brittany A; Duca, Frank A; Lam, Tony K T

    2014-04-25

    The gut is anatomically positioned to play a critical role in the regulation of metabolic homeostasis, providing negative feedback via nutrient sensing and local hormonal signaling. Gut hormones, such as cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), are released following a meal and act on local receptors to regulate glycemia via a neuronal gut-brain axis. Additionally, jejunal nutrient sensing and leptin action are demonstrated to suppress glucose production, and both are required for the rapid antidiabetic effect of duodenal jejunal bypass surgery. Strategies aimed at targeting local gut hormonal signaling pathways may prove to be efficacious therapeutic options to improve glucose control in diabetes.

  8. Unraveling the science of incretin biology.

    PubMed

    Nauck, Michael A

    2009-07-01

    Type 2 diabetes mellitus has become an enormous and worldwide healthcare problem that is almost certain to worsen. Current therapies, which address glycemia and insulin resistance, have not adequately addressed the complications and treatment failures associated with this disease. New treatments based on the incretin hormones provide a novel approach to address some components of the complex pathophysiology of type 2 diabetes. The purpose of this review is to elucidate the science of the incretin hormones and describe the incretin effect and its regulatory role in beta-cell function, insulin secretion, and glucose metabolism. The key endogenous hormones of incretin system are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1); a key enzymatic regulator of these hormones is dipeptidyl peptidase-4, which rapidly inactivates/degrades the incretin hormones. The roles of the incretin hormones in the regulation of glucose metabolism and other related physiologic processes such as gut motility and food intake are disturbed in type 2 diabetes. These disturbances--defects in the incretin system--contribute to the pathophysiology of type 2 diabetes in manifold ways. Consequently, therapies designed to address impairments to the effects of the incretin hormones have the potential to improve glucose regulation and other abnormalities (e.g., weight gain, loss of beta-cell function) associated with type 2 diabetes.

  9. Unraveling the science of incretin biology.

    PubMed

    Nauck, Michael A

    2009-06-01

    Type 2 diabetes mellitus has become an enormous and worldwide healthcare problem that is almost certain to worsen. Current therapies, which address glycemia and insulin resistance, have not adequately addressed the complications and treatment failures associated with this disease. New treatments based on the incretin hormones provide a novel approach to address some components of the complex pathophysiology of type 2 diabetes. The purpose of this review is to elucidate the science of the incretin hormones and describe the incretin effect and its regulatory role in beta-cell function, insulin secretion, and glucose metabolism. The key endogenous hormones of incretin system are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1); a key enzymatic regulator of these hormones is dipeptidyl peptidase-4, which rapidly inactivates/degrades the incretin hormones. The roles of the incretin hormones in the regulation of glucose metabolism and other related physiologic processes such as gut motility and food intake are disturbed in type 2 diabetes. These disturbances--defects in the incretin system--contribute to the pathophysiology of type 2 diabetes in manifold ways. Consequently, therapies designed to address impairments to the effects of the incretin hormones have the potential to improve glucose regulation and other abnormalities (e.g., weight gain, loss of beta-cell function) associated with type 2 diabetes.

  10. Incretin hormone receptors are required for normal beta cell development and function in female mice.

    PubMed

    Omar, Bilal; Ahlkvist, Linda; Yamada, Yuchiro; Seino, Yutaka; Ahrén, Bo

    2016-05-01

    The incretin hormones, glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), potentiate insulin secretion and are responsible for the majority of insulin secretion that occurs after a meal. They may also, however, have a fundamental role in pancreatic beta cell development and function, independently of their role in potentiating insulin secretion after a meal. This has led to observations that a loss of GIP or GLP-1 action affects normal beta cell function, however each one of the incretin hormones may compensate when the action of the other is lost and therefore the overall impact of the incretin hormones on beta cell function is not known. We therefore utilized a mouse line deficient in both the GLP-1 and GIP receptor genes, the double incretin receptor knockout (DIRKO), to determine the consequences of a lifelong, complete lack of incretin hormone action on beta cell function, in vivo, in intact animals. We found that DIRKO mice displayed impaired glucose tolerance and insulin secretion in response to both oral glucose and mixed meal tolerance tests compared to wild-type mice. Assessment of beta cell function using the hyperglycemic clamp technique revealed an 80% decrease in first phase insulin response in DIRKO mice, but a normal second phase insulin secretion. A similar decline was seen when wild-type mice were given acute intravenous injection of glucose together with the GLP-1 receptor antagonist Ex9-39. Ex vivo assessments of the pancreas revealed significantly fewer islets in the pancreata of DIRKO mice despite no differences in total pancreatic mass. Insulin secretion from isolated islets of DIRKO mice was impaired to a similar extent to that seen during the hyperglycemic clamp. Insulin secretion in wild-type islets was impaired by acute treatment with Ex9-39 to a similar extent as the in vivo intravenous glucose tolerance tests. In conclusion, a loss of the action of both incretin hormones results in direct impairment

  11. Stimulation of incretin secreting cells

    PubMed Central

    Pais, Ramona; Gribble, Fiona M.; Reimann, Frank

    2016-01-01

    The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (GLP-1) are secreted from enteroendocrine cells in the gut and regulate physiological and homeostatic functions related to glucose control, metabolism and food intake. This review provides a systematic summary of the molecular mechanisms underlying secretion from incretin cells, and an understanding of how they sense and interact with lumen and vascular factors and the enteric nervous system through transporters and G-protein coupled receptors (GPCRs) present on their surface to ultimately culminate in hormone release. Some of the molecules described below such as sodium coupled glucose transporter 1 (SGLT1), G-protein coupled receptor (GPR) 119 and GPR40 are targets of novel therapeutics designed to enhance endogenous gut hormone release. Synthetic ligands at these receptors aimed at treating obesity and type 2 diabetes are currently under investigation. PMID:26885360

  12. Postprandial Plasma Incretin Hormones in Exercise-Trained versus Untrained Subjects

    PubMed Central

    Weiss, Edward P.; Royer, Nathaniel K.; Fisher, Jonathan S.; Holloszy, John O.; Fontana, Luigi

    2014-01-01

    Introduction After food ingestion, the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted by the intestines into circulation where they act on the pancreas to promote insulin secretion. We evaluated the hypothesis that low postprandial plasma insulin levels in lean exercise-trained individuals are associated with low concentrations of incretin hormones. Methods A cross-sectional study was performed to compare postprandial incretin hormone levels in lean endurance exercise-trained individuals (EX; n=14, ≥40 yr) and age- and sex-matched, non-obese, sedentary control subjects (CON, n=14). The main outcome measures were GLP-1, GIP, insulin, and glucose incremental areas under the curve (AUC) as measured in plasma samples collected during a 2-hr,75-g oral glucose tolerance test (OGTT). Results The EX group had lower body fat percentage (14.6±1.1% vs. 23.3±1.7%, p=0.0002) and higher maximal oxygen uptake (53±2 vs. 34±2, p<0.0001) than CON. Glucose AUC did not differ between groups (p=0.20). Insulin AUC was lower in EX (2.5±0.5 vs. 4.2±1.2 μU/mL·min·1000, p=0.02). No differences were observed between groups (EX and CON, respectively) for GLP-1 AUC (3.5±0.7 vs. 4.1±1.1 pmol·min/L·100, p=0.61) or GIP AUC (19.2±1.4 vs. 18.0±1.4 pg·min/mL·1000; p=0.56). In CON, insulin AUC was correlated with AUCs for GLP-1 (r=0.53, p=0.05) and GIP (r=0.71, p=0.004) but no such correlations were observed in EX (both p≥0.67). Conclusion Low postprandial insulin levels in lean exercise-trained individuals are not attributable to lower incretin hormone concentrations. However, exercise may decrease the dependency of postprandial insulin levels on incretin hormones. PMID:24576859

  13. Gut hormones and obesity: physiology and therapies.

    PubMed

    Scott, Rebecca; Tan, Tricia; Bloom, Stephen

    2013-01-01

    Over the past 30 years, it has been established that hormones produced by the gut, pancreas, and adipose tissue are key players in the control of body weight. These hormones act through a complex neuroendocrine system, including the hypothalamus, to regulate metabolism and energy homeostasis. In obesity, this homeostatic balance is disrupted, either through alterations in the levels of these hormones or through resistance to their actions. Alterations in gut hormone secretion following gastric bypass surgery are likely to underlie the dramatic and persistent loss of weight following this procedure, as well as the observed amelioration in type 2 diabetes mellitus. Medications based on the gut hormone GLP-1 are currently in clinical use to treat type 2 diabetes mellitus and have been shown to produce weight loss. Further therapies for obesity based on other gut hormones are currently in development. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. 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.

  15. Accelerated intestinal glucose absorption in morbidly obese humans: relationship to glucose transporters, incretin hormones, and glycemia.

    PubMed

    Nguyen, Nam Q; Debreceni, Tamara L; Bambrick, Jenna E; Chia, Bridgette; Wishart, Judith; Deane, Adam M; Rayner, Chris K; Horowitz, Michael; Young, Richard L

    2015-03-01

    Intestinal glucose absorption is mediated by sodium-dependent glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2), which are linked to sweet taste receptor (STR) signaling and incretin responses. This study aimed to examine intestinal glucose absorption in morbidly obese humans and its relationship to the expression of STR and glucose transporters, glycemia, and incretin responses. Seventeen nondiabetic, morbidly obese subjects (body mass index [BMI], 48 ± 4 kg/m(2)) and 11 lean controls (BMI, 25 ± 1 kg/m(2)) underwent endoscopic duodenal biopsies before and after a 30-minute intraduodenal glucose infusion (30 g glucose and 3 g 3-O-methylglucose [3-OMG]). Blood glucose and plasma concentrations of 3-OMG, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), insulin, and glucagon were measured over 270 minutes. Expression of duodenal SGLT-1, GLUT2, and STR (T1R2) was quantified by PCR. The increase in plasma 3-OMG (P < .001) and blood glucose (P < .0001) were greater in obese than lean subjects. Plasma 3-OMG correlated directly with blood glucose (r = 0.78, P < .01). In response to intraduodenal glucose, plasma GIP (P < .001), glucagon (P < .001), and insulin (P < .001) were higher, but GLP-1 (P < .001) was less in the obese compared with lean. Expression of SGLT-1 (P = .035), but not GLUT2 or T1R2, was higher in the obese, and related to peak plasma 3-OMG (r = 0.60, P = .01), GIP (r = 0.67, P = .003), and insulin (r = 0.58, P = .02). In morbid obesity, proximal intestine glucose absorption is accelerated and related to increased SGLT-1 expression, leading to an incretin-glucagon profile promoting hyperinsulinemia and hyperglycemia. These findings are consistent with the concept that accelerated glucose absorption in the proximal gut underlies the foregut theory of obesity and type 2 diabetes.

  16. Gut hormones: the future of obesity treatment?

    PubMed Central

    McGavigan, Anne K; Murphy, Kevin G

    2012-01-01

    Obesity is a major worldwide health problem. The treatment options are severely limited. The development of novel anti-obesity drugs is fraught with efficacy and safety issues. Consequently, several investigational anti-obesity drugs have failed to gain marketing approval in recent years. Anorectic gut hormones offer a potentially safe and viable option for the treatment of obesity. The prospective utility of gut hormones has improved drastically in recent years with the development of longer acting analogues. Additionally, specific combinations of gut hormones have been demonstrated to have additive anorectic effects. This article reviews the current stage of anti-obesity drugs in development, focusing on gut hormone-based therapies. PMID:22452339

  17. Gut hormones: the future of obesity treatment?

    PubMed

    McGavigan, Anne K; Murphy, Kevin G

    2012-12-01

    Obesity is a major worldwide health problem. The treatment options are severely limited. The development of novel anti-obesity drugs is fraught with efficacy and safety issues. Consequently, several investigational anti-obesity drugs have failed to gain marketing approval in recent years. Anorectic gut hormones offer a potentially safe and viable option for the treatment of obesity. The prospective utility of gut hormones has improved drastically in recent years with the development of longer acting analogues. Additionally, specific combinations of gut hormones have been demonstrated to have additive anorectic effects. This article reviews the current stage of anti-obesity drugs in development, focusing on gut hormone-based therapies. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  18. Postprandial gut hormone responses and glucose metabolism in cholecystectomized patients.

    PubMed

    Sonne, David P; Hare, Kristine J; Martens, Pernille; Rehfeld, Jens F; Holst, Jens J; Vilsbøll, Tina; Knop, Filip K

    2013-02-15

    Preclinical studies suggest that gallbladder emptying, via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells, may play a significant role in the secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) and, hence, postprandial glucose homeostasis. We examined the secretion of gut hormones in cholecystectomized subjects to test the hypothesis that gallbladder emptying potentiates postprandial release of GLP-1. Ten cholecystectomized subjects and 10 healthy, age-, gender-, and body mass index-matched control subjects received a standardized fat-rich liquid meal (2,200 kJ). Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), cholecystokinin (CCK), and gastrin were measured. Furthermore, gastric emptying and duodenal and serum bile acids were measured. We found similar basal glucose concentrations in the two groups, whereas cholecystectomized subjects had elevated postprandial glucose excursions. Cholecystectomized subjects had reduced postprandial concentrations of duodenal bile acids, but preserved postprandial plasma GLP-1 responses, compared with control subjects. Also, cholecystectomized patients exhibited augmented fasting glucagon. Basal plasma CCK concentrations were lower and peak concentrations were higher in cholecystectomized patients. The concentrations of GIP, GLP-2, and gastrin were similar in the two groups. In conclusion, cholecystectomized subjects had preserved postprandial GLP-1 responses in spite of decreased duodenal bile delivery, suggesting that gallbladder emptying is not a prerequisite for GLP-1 release. Cholecystectomized patients demonstrated a slight deterioration of postprandial glycemic control, probably because of metabolic changes unrelated to incretin secretion.

  19. The Gut Hormones in Appetite Regulation

    PubMed Central

    Suzuki, Keisuke; Jayasena, Channa N.; Bloom, Stephen R.

    2011-01-01

    Obesity has received much attention worldwide in association with an increased risk of cardiovascular diseases, diabetes, and cancer. At present, bariatric surgery is the only effective treatment for obesity in which long-term weight loss is achieved in patients. By contrast, pharmacological interventions for obesity are usually followed by weight regain. Although the exact mechanisms of long-term weight loss following bariatric surgery are yet to be fully elucidated, several gut hormones have been implicated. Gut hormones play a critical role in relaying signals of nutritional and energy status from the gut to the central nervous system, in order to regulate food intake. Cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide-1, and oxyntomodulin act through distinct yet synergistic mechanisms to suppress appetite, whereas ghrelin stimulates food intake. Here, we discuss the role of gut hormones in the regulation of food intake and body weight. PMID:21949903

  20. Effects of sitagliptin and metformin treatment on incretin hormone and insulin secretory responses to oral and "isoglycemic" intravenous glucose.

    PubMed

    Vardarli, Irfan; Arndt, Elisabeth; Deacon, Carolyn F; Holst, Jens J; Nauck, Michael A

    2014-02-01

    Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent degradation of incretin hormones (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), whereas metformin may increase GLP-1 levels. We examined, in a four-period crossover trial, the influence of metformin (2,000 mg/day), sitagliptin (100 mg/day), or their combination, on GLP-1 responses and on the incretin effect in 20 patients with type 2 diabetes, comparing an oral glucose challenge (75 g, day 5) and an "isoglycemic" intravenous glucose infusion (day 6). Fasting total GLP-1 was significantly increased by metformin and not changed by sitagliptin. After oral glucose, metformin increased and sitagliptin significantly decreased (by 53%) total GLP-1. Fasting and postload intact GLP-1 increased with sitagliptin but not with metformin. After oral glucose, only sitagliptin, but not metformin, significantly augmented insulin secretion, in monotherapy and as an add-on to metformin. The incretin effect was not changed numerically with any of the treatments. In conclusion, sitagliptin increased intact GLP-1 and GIP through DPP-4 inhibition but reduced total GLP-1 and GIP (feedback inhibition) without affecting the numerical contribution of the incretin effect. Insulin secretion with sitagliptin treatment was similarly stimulated with oral and "isoglycemic" intravenous glucose. This points to an important contribution of small changes in incretin concentrations within the basal range or to additional insulinotropic agents besides GLP mediating the antidiabetic effects of DPP-4 inhibition.

  1. Novel therapeutics for type 2 diabetes: incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors.

    PubMed

    Verspohl, E J

    2009-10-01

    Known treatments of type 2 diabetes mellitus have limitations such as weight gain, and hypoglycaemias. A new perspective is the use of incretin hormones and incretin enhancers. Incretins are defined as being responsible for the higher insulin release after an oral glucose load compared to an intravenous glucose load. The delicate balance of glucose homeostasis, in which incretin hormones are involved, is disturbed in type 2 diabetes mellitus. The incretin GLP-1 helps to maintain glucose homeostasis through stimulation of insulin secretion and inhibition of glucagon release in a glucose-dependent manner. This is associated with reductions in body weight, and no risk of hypoglycaemias. When classical oral agents have failed to maintain adequate glycaemic control, incretin mimetics may be of particular value for obese patients and those who have little control over meal sizes. Exenatide was marketed as a GLP-1 analogue and longer acting incretin mimetics such as liraglutide, albiglutide and others have the same pharmacological profile. In addition to incretin mimetics incretin enhancers which inhibit/delay degradation of incretins were developed: so-called DPP-4 inhibitors such as sitagliptin and vildagliptin are approved in Europe. Their differences from incretin mimetics include: oral bioavailability, less side effects with overdose, no direct CNS effects (nausea and vomiting) and no effect on weight. In rodent models of diabetes, but not yet in humans, GLP-1 receptor agonists and DPP-4 inhibitors increase islet mass and preserve beta-cell function. Incretin mimetics and enhancers expand type 2 diabetes treatment, are still not first line therapy and it is discussed if they are to be prophylactically used.

  2. Detailed characterisation of STC-1 cells and the pGIP/Neo sub-clone suggests the incretin hormones are translationally regulated.

    PubMed

    Gillespie, Anna L; Pan, Xiaobei; Marco-Ramell, Anna; Meharg, Caroline; Green, Brian D

    2017-10-01

    STC-1 is a heterogeneous plurihormonal cell line producing several prominent gut peptide hormones. pGIP/Neo is a genetically selected sub-clone of STC-1 with augmented levels of glucose-dependent insulinotropic peptide (GIP). Morphometric parameters, hormone concentrations, mRNA transcripts, hormone immunocytochemistry and nutrient utilisation/production of these two cell lines were compared. Proglucagon-derived peptides (Glucagon-like peptide-1 (GLP-1) and - 2(GLP-2)) were lower in sub-clone cells than progenitor cells. High Content Analysis found altered intracellular GLP-1, GIP, cholecystokinin (CCK) and peptide YY (PYY) levels and differing hormone co-localisation. The proportion pGIP/Neo cells containing GIP immunoreactivity (82%) was greater than STC-1 (65%), as were the proportion with 'GIP only', 'GLP-1+GIP' or 'GIP+PYY' immunoreactivity. Most surprisingly mRNA transcripts of the proglucagon and GIP genes were inversely correlated to the levels of their translated peptides. This strongly suggests that proglucagon and GIP are encoded on 'translationally regulated genes' - a characteristic possessed by other endocrine hormones. Metabolomic profiling revealed differences in cellular nutrient utilisation/production and that under normal culture conditions both cell lines exhibit signs of overflow metabolism. These studies provide an insight into the metabolism and properties of these valuable cells, suggesting for the first time that incretin hormone genes are translationally regulated. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. [The incretin effect and type 2 diabetes].

    PubMed

    Quintanilla-García, Cristina; Zúñiga-Guajardo, Sergio

    2010-01-01

    In the gastrointestinal tract we produce hormones, called incretins, in response to food ingestion with a direct effect on pancreatic β and α cell improving the insulin and glucagon response to glucose. The effect consisting in a greater secretion of insulin with a glucose stimulus from the gut or IV injection is called "the incretin effect." The main incretins are: glucagon like peptide-1 (GLP1) and glucose-dependent insulinotropic peptide (GIP). The action of both incretins is very short due to a rapid inhibition in the circulation by an enzyme dipeptylpeptidase IV (DPP4). In type 2 diabetics, the incretin effect is altered and can be improved by elaboration of a GLP1 resistant to the action of DPP4 (GLP1 analogs) or by direct inhibition of DPP4 producing better effect of native GLP1 and GIP. We have exenatide a derivative from exendin 4, and liraglutide very similar to the native human GLP1. Three inhibitors of DPP4: sitagliptin, and vildagliptin and saxagliptin produce a prolonged inhibition of DPP4 and as a consequence increased effect of native incretins with better control of fasting and postprandial glucose and improve on A1c with a very few hypoglycemic events.

  4. On the role of gallbladder emptying and incretin hormones for nutrient-mediated TSH suppression in patients with type 2 diabetes.

    PubMed

    Sonne, David P; Lund, Asger; Faber, Jens; Holst, Jens J; Vilsbøll, Tina; Knop, Filip K

    2014-12-01

    Bile acids are possible candidate agents in newly identified pathways through which energy expenditure may be regulated. Preclinical studies suggest that bile acids activate the enzyme type 2 iodothyronine deiodinase, which deiodinates thyroxine (T4) to the biologically active triiodothyronine (T3). We aimed to evaluate the influence of bile acid exposure and incretin hormones on thyroid function parameters in patients with type 2 diabetes. Thyroid-stimulating hormone (TSH) and thyroid hormones (total T3 and free T4) were measured in plasma from two human studies: i) 75 g-oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals with increasing fat content with concomitant ultrasonographic evaluation of gallbladder emptying in 15 patients with type 2 diabetes and 15 healthy age, gender and BMI-matched controls (meal-study) and ii) 50 g-OGTT and isoglycaemic intravenous glucose infusions (IIGI) alone or in combination with glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and/or GLP2, in ten patients with type 2 diabetes (IIGI-study). In both studies, TSH levels declined (P<0.01) similarly following all meal and infusion stimuli. T3 and T4 concentrations did not change in response to any of the applied stimuli. TSH levels declined independently of the degree of gallbladder emptying (meal-study), route of nutrient administration and infusion of gut hormones. In conclusion, intestinal bile flow and i.v. infusions of the gut hormones, GIP, GLP1 and/or GLP2, do not seem to affect thyroid function parameters. Thus, the presence of a 'gut-thyroid-pituitary' axis seems questionable.

  5. Gut hormone GPCRs: structure, function, drug discovery.

    PubMed

    Cordomí, Arnau; Fourmy, Daniel; Tikhonova, Irina G

    2016-12-01

    Crystallization and determination of the high resolution three-dimensional structure of the β2-adrenergic receptor in 2007 was followed by structure elucidation of a number of other receptors, including those for neurotensin and glucagon. These major advances foster the understanding of structure-activity relationship of these receptors and structure-based rational design of new ligands having more predictable activity. At present, structure determination of gut hormone receptors in complex with their ligands (natural, synthetic) and interacting signalling proteins, for example, G-proteins, arrestins, represents a challenge which promises to revolutionize gut hormone endocrinonology.

  6. Gut hormones and endothelial dysfunction in patients with obesity and diabetes.

    PubMed

    Iantorno, M; Campia, U; Di Daniele, N; Nistico, S; Forleo, G B; Cardillo, C; Tesauro, M

    2014-01-01

    Overweight and obesity are the fifth leading risk for global deaths and its prevalence has doubled since 1980. At least 2.8 million adults, worldwide, die each year as a result of being overweight or obese. The deleterious effects of obesity are tightly related to diabetes, as they are often clinically present in combination to confer increased cardiovascular mortality. Thus, patients with diabetes and obesity are known to develop accelerated atherosclerosis characterized by a dysfunctional endothelium and decreased nitric oxide bioavailability. Recent clinical studies support, indeed, the use of incretin-based antidiabetic therapies for vascular protection. Thus, attention has been focusing on gut hormones and their role, not only in the regulation of appetite but also in vascular health. Intervention directed at modulating these molecules has the potential to decrease mortality of patients with diabetes and obesity. This review will cover part of the ongoing research to understand the role of gut hormones on endothelial function and vascular health.

  7. Incretins and amylin: neuroendocrine communication between the gut, pancreas, and brain in control of food intake and blood glucose.

    PubMed

    Hayes, Matthew R; Mietlicki-Baase, Elizabeth G; Kanoski, Scott E; De Jonghe, Bart C

    2014-01-01

    Arguably the most fundamental physiological systems for all eukaryotic life are those governing energy balance. Without sufficient energy, an individual is unable to survive and reproduce. Thus, an ever-growing appreciation is that mammalian physiology developed a redundant set of neuroendocrine signals that regulate energy intake and expenditure, which maintains sufficient circulating energy, predominantly in the form of glucose, to ensure that energy needs are met throughout the body. This orchestrated control requires cross talk between the gastrointestinal tract, which senses the incoming meal; the pancreas, which produces glycemic counterregulatory hormones; and the brain, which controls autonomic and behavioral processes regulating energy balance. Therefore, this review highlights the physiological, pharmacological, and pathophysiological effects of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide, as well as the pancreatic hormone amylin, on energy balance and glycemic control.

  8. Incretins and Amylin: Neuroendocrine Communication between the Gut, Pancreas, and Brain in Control of Food Intake and Blood Glucose

    PubMed Central

    Hayes, Matthew R.; Mietlicki-Baase, Elizabeth G.; Kanoski, Scott E.; De Jonghe, Bart C.

    2015-01-01

    Arguably the most fundamental physiological systems for all eukaryotic life are those governing energy balance. Without sufficient energy, an individual is unable to survive and reproduce. Thus, an ever-growing appreciation is that mammalian physiology developed a redundant set of neuroendocrine signals that regulate energy intake and expenditure, which maintains sufficient circulating energy, predominantly in the form of glucose, to ensure that energy needs are met throughout the body. This orchestrated control requires cross-talk between the gastrointestinal tract which senses the incoming meal, the pancreas which produces glycemic counterregulatory hormones, and the brain which controls autonomic and behavioral processes regulating energy balance. Therefore, this review highlights the physiological, pharmacological, and pathophysiological effects of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), as well as the pancreatic hormone amylin, on energy balance and glycemic control. PMID:24819325

  9. Gut hormone release after intestinal resection.

    PubMed Central

    Besterman, H S; Adrian, T E; Mallinson, C N; Christofides, N D; Sarson, D L; Pera, A; Lombardo, L; Modigliani, R; Bloom, S R

    1982-01-01

    To investigate the possible role of gut and pancreatic hormones in the adaptive responses to gut resection, plasma concentrations of the circulating hormones were measured, in response to a test breakfast, in patients with either small or large intestinal resection and in healthy control subjects. In 18 patients with partial ileal resection a significant threefold rise was found in basal and postprandial levels of pancreatic polypeptide, a fourfold increase in motilin, and more than a twofold increase in gastrin and enteroglucagon levels compared with healthy controls. In contrast, nine patients with colonic resection had a threefold rise in levels of pancreatic polypeptide only. One or more of these peptides may have a role in stimulating the adaptive changes found after gut resection. PMID:7117905

  10. Gut hormones and the control of appetite.

    PubMed

    Small, Caroline J; Bloom, Stephen R

    2004-08-01

    Obesity is the main cause of premature death in the UK. Worldwide its prevalence is accelerating. It has been hypothesized that a gut nutriment sensor signals to appetite centres in the brain to reduce food intake after meals. Gut hormones have been identified as an important mechanism for this. Ghrelin stimulates, and glucagon like peptide-1, oxyntomodulin, peptide YY (PYY), cholecystokinin and pancreatic polypeptide inhibit, appetite. At physiological postprandial concentrations they can alter food intake markedly in humans and rodents. In addition, in obese humans fasting levels of PYY are suppressed and postprandial release is reduced. Administration of gut hormones might provide a novel and physiological approach in anti-obesity therapy. Here, we summarize some of the recent advances in this field.

  11. Bowels control brain: gut hormones and obesity.

    PubMed

    Bewick, Gavin A

    2012-01-01

    Peptide hormones are released from the gastrointestinal tract in response to nutrients and communicate information regarding the current state of energy balance to the brain. These hormones regulate appetite, energy expenditure and glucose homeostasis. They can act either via the circulation at target peripheral tissues, by activation of the vagus nerve or by acting on key brain regions implicated in energy homeostasis such as the hypothalamus and brainstem. This review gives an overview of the main gut hormones implicated in the regulation of food intake and how some of these are being targeted to develop anti obesity treatments.

  12. Bowels control brain: gut hormones and obesity

    PubMed Central

    Bewick, Gavin A.

    2012-01-01

    Peptide hormones are released from the gastrointestinal tract in response to nutrients and communicate information regarding the current state of energy balance to the brain. These hormones regulate appetite, energy expenditure and glucose homeostasis. They can act either via the circulation at target peripheral tissues, by activation of the vagus nerve or by acting on key brain regions implicated in energy homeostasis such as the hypothalamus and brainstem. This review gives an overview of the main gut hormones implicated in the regulation of food intake and how some of these are being targeted to develop anti obesity treatments. PMID:23092061

  13. Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects

    PubMed Central

    Ma, Jing; Bellon, Max; Wishart, Judith M.; Young, Richard; Blackshaw, L. Ashley; Jones, Karen L.; Horowitz, Michael; Rayner, Christopher K.

    2009-01-01

    The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play an important role in glucose homeostasis in both health and diabetes. In mice, sucralose, an artificial sweetener, stimulates GLP-1 release via sweet taste receptors on enteroendocrine cells. We studied blood glucose, plasma levels of insulin, GLP-1, and GIP, and gastric emptying (by a breath test) in 7 healthy humans after intragastric infusions of 1) 50 g sucrose in water to a total volume of 500 ml (∼290 mosmol/l), 2) 80 mg sucralose in 500 ml normal saline (∼300 mosmol/l, 0.4 mM sucralose), 3) 800 mg sucralose in 500 ml normal saline (∼300 mosmol/l, 4 mM sucralose), and 4) 500 ml normal saline (∼300 mosmol/l), all labeled with 150 mg 13C-acetate. Blood glucose increased only in response to sucrose (P < 0.05). GLP-1, GIP, and insulin also increased after sucrose (P = 0.0001) but not after either load of sucralose or saline. Gastric emptying of sucrose was slower than that of saline (t50: 87.4 ± 4.1 min vs. 74.7 ± 3.2 min, P < 0.005), whereas there were no differences in t50 between sucralose 0.4 mM (73.7 ± 3.1 min) or 4 mM (76.7 ± 3.1 min) and saline. We conclude that sucralose, delivered by intragastric infusion, does not stimulate insulin, GLP-1, or GIP release or slow gastric emptying in healthy humans. PMID:19221011

  14. Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects.

    PubMed

    Ma, Jing; Bellon, Max; Wishart, Judith M; Young, Richard; Blackshaw, L Ashley; Jones, Karen L; Horowitz, Michael; Rayner, Christopher K

    2009-04-01

    The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play an important role in glucose homeostasis in both health and diabetes. In mice, sucralose, an artificial sweetener, stimulates GLP-1 release via sweet taste receptors on enteroendocrine cells. We studied blood glucose, plasma levels of insulin, GLP-1, and GIP, and gastric emptying (by a breath test) in 7 healthy humans after intragastric infusions of 1) 50 g sucrose in water to a total volume of 500 ml (approximately 290 mosmol/l), 2) 80 mg sucralose in 500 ml normal saline (approximately 300 mosmol/l, 0.4 mM sucralose), 3) 800 mg sucralose in 500 ml normal saline (approximately 300 mosmol/l, 4 mM sucralose), and 4) 500 ml normal saline (approximately 300 mosmol/l), all labeled with 150 mg 13C-acetate. Blood glucose increased only in response to sucrose (P<0.05). GLP-1, GIP, and insulin also increased after sucrose (P=0.0001) but not after either load of sucralose or saline. Gastric emptying of sucrose was slower than that of saline (t50: 87.4+/-4.1 min vs. 74.7+/-3.2 min, P<0.005), whereas there were no differences in t50 between sucralose 0.4 mM (73.7+/-3.1 min) or 4 mM (76.7+/-3.1 min) and saline. We conclude that sucralose, delivered by intragastric infusion, does not stimulate insulin, GLP-1, or GIP release or slow gastric emptying in healthy humans.

  15. T1R and T2R receptors: the modulation of incretin hormones and potential targets for the treatment of type 2 diabetes mellitus.

    PubMed

    Dotson, Cedrick D; Vigues, Stephan; Steinle, Nanette I; Munger, Steven D

    2010-04-01

    Type 2 diabetes mellitus (T2DM), which is characterized by insulin and glucose dysregulation, is a major contributor to the development of cardiovascular disease, renal failure and premature death. Incretin hormones are released from the intestines upon nutrient ingestion and contribute to glucose homeostasis in part by promoting insulin secretion from the pancreas. Drugs that enhance the incretin response have emerged as effective treatments for T2DM. Several recent studies have revealed that incretin secretion from enteroendocrine cells in the intestines can be modulated by T1R and T2R receptors, proteins that have been demonstrated to function as taste receptors. This review focuses on the intriguing finding that taste receptors may be involved in modulating the incretin response, and considers T1Rs and T2Rs as potential targets for new hypoglycemic drugs.

  16. Cooking enhances beneficial effects of pea seed coat consumption on glucose tolerance, incretin, and pancreatic hormones in high-fat-diet-fed rats.

    PubMed

    Hashemi, Zohre; Yang, Kaiyuan; Yang, Han; Jin, Alena; Ozga, Jocelyn; Chan, Catherine B

    2015-04-01

    Pulses, including dried peas, are nutrient- and fibre-rich foods that improve glucose control in diabetic subjects compared with other fibre sources. We hypothesized feeding cooked pea seed coats to insulin-resistant rats would improve glucose tolerance by modifying gut responses to glucose and reducing stress on pancreatic islets. Glucose intolerance induced in male Sprague-Dawley rats with high-fat diet (HFD; 10% cellulose as fibre) was followed by 3 weeks of HFD with fibre (10%) provided by cellulose, raw-pea seed coat (RP), or cooked-pea seed coat (CP). A fourth group consumed low-fat diet with 10% cellulose. Oral and intraperitoneal glucose tolerance tests (oGTT, ipGTT) were done. CP rats had 30% and 50% lower glucose and insulin responses in oGTT, respectively, compared with the HFD group (P < 0.05) but ipGTT was not different. Plasma islet and incretin hormone concentrations were measured. α- and β-cell areas in the pancreas and density of K- and L-cells in jejunum and ileum were quantified. Jejunal expression of hexose transporters was measured. CP feeding increased fasting glucagon-like peptide 1 and glucose-stimulated gastric inhibitory polypeptide responses (P < 0.05), but K- and L-cells densities were comparable to HFD, as was abundance of SGLT1 and GLUT2 mRNA. No significant difference in β-cell area between diet groups was observed. α-cell area was significantly smaller in CP compared with RP rats (P < 0.05). Overall, our results demonstrate that CP feeding can reverse adverse effects of HFD on glucose homeostasis and is associated with enhanced incretin secretion and reduced α-cell abundance.

  17. Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1.

    PubMed

    Gromada, J; Holst, J J; Rorsman, P

    1998-04-01

    Glucagon-like peptide 1 is a gastrointestinally derived hormone with profound effects on nutrient-induced pancreatic hormone release. GLP-1 modulates insulin, glucagon and somatostatin secretion by binding to guanine nucleotide binding protein-coupled receptors resulting in the activation of adenylate cyclase and generation of cyclic adenosine monophosphate (cAMP). In the B-cell, cAMP, via activation of protein kinase A, interacts with a plethora of signal transduction processes including ion channel activity, intracellular Ca2+ handling and exocytosis of the insulin-containing granules. The stimulatory action of GLP-1 on insulin secretion, contrary to that of the currently used hypoglycaemic sulphonylureas, is glucose dependent and requires the presence of normal or elevated concentrations of the sugar. For this reason, GLP-1 attracts much interest as a possible novel principle for the treatment of human type-2 diabetes. Here we review the actions of GLP-1 on islet cell function and attempt to integrate current knowledge into a working model for the control of pancreatic hormone secretion.

  18. Fructose intervention for 12 weeks does not impair glycemic control or incretin hormone responses during oral glucose or mixed meal tests in obese men.

    PubMed

    Matikainen, N; Söderlund, S; Björnson, E; Bogl, L H; Pietiläinen, K H; Hakkarainen, A; Lundbom, N; Eliasson, B; Räsänen, S M; Rivellese, A; Patti, L; Prinster, A; Riccardi, G; Després, J-P; Alméras, N; Holst, J J; Deacon, C F; Borén, J; Taskinen, M-R

    2017-06-01

    Incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are affected early on in the pathogenesis of metabolic syndrome and type 2 diabetes. Epidemiologic studies consistently link high fructose consumption to insulin resistance but whether fructose consumption impairs the incretin response remains unknown. As many as 66 obese (BMI 26-40 kg/m(2)) male subjects consumed fructose-sweetened beverages containing 75 g fructose/day for 12 weeks while continuing their usual lifestyle. Glucose, insulin, GLP-1 and GIP were measured during oral glucose tolerance test (OGTT) and triglycerides (TG), GLP-1, GIP and PYY during a mixed meal test before and after fructose intervention. Fructose intervention did not worsen glucose and insulin responses during OGTT, and GLP-1 and GIP responses during OGTT and fat-rich meal were unchanged. Postprandial TG response increased significantly, p = 0.004, and we observed small but significant increases in weight and liver fat content, but not in visceral or subcutaneous fat depots. However, even the subgroups who gained weight or liver fat during fructose intervention did not worsen their glucose, insulin, GLP-1 or PYY responses. A minor increase in GIP response during OGTT occurred in subjects who gained liver fat (p = 0.049). In obese males with features of metabolic syndrome, 12 weeks fructose intervention 75 g/day did not change glucose, insulin, GLP-1 or GIP responses during OGTT or GLP-1, GIP or PYY responses during a mixed meal. Therefore, fructose intake, even accompanied with mild weight gain, increases in liver fat and worsening of postprandial TG profile, does not impair glucose tolerance or gut incretin response to oral glucose or mixed meal challenge. 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

  19. Incretin hormones and maturity onset diabetes of the young--pathophysiological implications and anti-diabetic treatment potential.

    PubMed

    Østoft, Signe Harring

    2015-09-01

    Maturity onset diabetes of the young (MODY) designates monogenic forms of non-autoimmune diabetes characterised by autosomal dominant inheritance, non-insulin dependent diabetes at onset and diagnosis often before 25 years of age. MODY constitutes genetically and clinically heterogeneous forms of diabetes. More than 8 different genes are known to cause MODY, among which hepatocyte nuclear factor 1 alpha (HNF1A) (MODY3) and glucokinase (GCK) (MODY2) mutations are the most common. Both forms of MODY are characterised by specific beta cell dysfunction, with patients with HNF1A-diabetes having a reduced insulin secretory capacity, while patients with GCK-diabetes have a glucose-sensing defect, but preserved insulin secretory capacity. Patients with MODY are effectively treated with sulphonylurea (SU) due to very high sensitivity to these drugs, but they are also prone to develop hypoglycaemia. The objectives of this thesis were to study the pathophysiology of GCK-diabetes and HNF1A-diabetes by investigating the incretin effect, the physiological response to food ingestion and to estimate the treatment potential of a glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with HNF1A-diabetes. In Study I we investigated the incretin effect and the responses of islet hormones and incretin hormones to oral glucose tolerance test (OGTT) and isoglycaemic IV glucose infusion (IIGI) in patients with GCK-diabetes, in patients with HNF1A-diabetes, and in BMI and age matched healthy individuals (CTRLs). In Study II we investigated responses of islet hormones and incretin hormones to a more physiological stimulus consisting of a standardised meal test in patients with GCK-diabetes, in patients with HNF1A--diabetes, and in BMI and age matched CTRLs. In Study III we conducted a randomised, double-blind, crossover trial investigating the glucose lowering effect and risk of hypoglycaemia during 6 weeks of treatment with the GLP-1RA, liraglutide compared to the SU, glimepiride

  20. The [pre-] history of the incretin concept.

    PubMed

    Creutzfeldt, Werner

    2005-06-15

    The discoverers of secretin already thought of the existence of a chemical excitant for the internal secretion of the pancreas. Numerous experiments have been performed and published between 1906 and 1935 testing the effect of injected or ingested duodenal ("secretin") extracts on fasting or elevated blood glucose levels of normal or diabetic animals and humans with contradictory results. In 1940, after a series of negative dog experiments performed by an opinion leader, the existence of an incretin was considered questionable and further research stopped for more than 20 years. However, after the development of the radio-immunoassay, the incretin-concept has been revived in 1964, showing that significantly more insulin was released after ingestion of glucose than after intravenous injection. The possibility that nerves or one of the known gut hormones were responsible for the incretin effect could be ruled out. In 1970, glucose dependent insulinotropic polypeptide (GIP), and finally, in 1985 glucagon-like peptide 1 (GLP-1) and its truncated form GLP-1(7-36) were recognized as true incretins. Thereafter, multiple antidiabetic qualities and the therapeutic perspectives of GLP-1(7-36) and its analogues and mimetics have been demonstratred.

  1. Can Bayliss and Starling gut hormones cure a worldwide pandemic?

    PubMed

    Scott, R V; Tan, T M; Bloom, S R

    2014-12-01

    Bayliss and Starling first coined the term 'hormone' with reference to secretin, a substance they found that was produced by the gut, but released into the blood stream to act at a distance. The intestine is now known as the largest endocrine organ in the body, and it produces numerous hormones with a wide range of functions. These include controlling appetite and energy homeostasis. Obesity is one of the greatest health threats facing the world today. At present, the only successful treatment is surgery. Bariatric procedures such as the Roux-en-Y bypass work by elevating gut hormones that induce satiety. Significant research has gone into producing versions of these hormones that can be delivered therapeutically to treat obesity. This review looks at the role of gut hormones in obesity, and the development of gut hormone-derived obesity treatments. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

  2. Enteroendocrine secretion of gut hormones in diabetes, obesity and after bariatric surgery.

    PubMed

    Holst, Jens Juul

    2013-12-01

    Gastric bypass surgery is associated with a major weight loss and often causes remission in patients with type 2 diabetes. Surgery is also associated with dramatic increases in the secretion of the gut hormones, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), both of which regulate appetite and food intake, while GLP-1 in addition functions as an incretin hormone, stimulating insulin secretion. It has been possible to probe the role of GLP-1 for the diabetes resolution after gastric bypass using a GLP-1 receptor antagonist, and it is clear that the enhanced beta cell sensitivity to glucose which underlies the enhanced insulin secretion in the patients after the operation depends critically on the increased GLP-1 secretion. Both hormones seem to contribute importantly to the reduction in food intake after bypass and, therefore, to the weight loss. Currently, there are no data to indicate that decreased secretion of the hormones is involved in the pathogenesis of obesity and/or diabetes, but impaired secretion generally observed in obesity (and hence also in diabetes) may contribute to the development. Because of these effects receptor agonists for both hormones are currently being developed for the treatment of obesity and diabetes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Can Bayliss and Starling gut hormones cure a worldwide pandemic?

    PubMed Central

    Scott, R V; Tan, T M; Bloom, S R

    2014-01-01

    Bayliss and Starling first coined the term ‘hormone’ with reference to secretin, a substance they found that was produced by the gut, but released into the blood stream to act at a distance. The intestine is now known as the largest endocrine organ in the body, and it produces numerous hormones with a wide range of functions. These include controlling appetite and energy homeostasis. Obesity is one of the greatest health threats facing the world today. At present, the only successful treatment is surgery. Bariatric procedures such as the Roux-en-Y bypass work by elevating gut hormones that induce satiety. Significant research has gone into producing versions of these hormones that can be delivered therapeutically to treat obesity. This review looks at the role of gut hormones in obesity, and the development of gut hormone-derived obesity treatments. PMID:25217372

  4. Beta-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to Type 2 diabetes

    USDA-ARS?s Scientific Manuscript database

    Using the hyperglycemic and euglycemic clamp, we demonstrated impaired Beta-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled Beta-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. Bet...

  5. Pancreatic β-cell prosurvival effects of the incretin hormones involve post-translational modification of Kv2.1 delayed rectifier channels

    PubMed Central

    Kim, S-J; Widenmaier, S B; Choi, W S; Nian, C; Ao, Z; Warnock, G; McIntosh, C H S

    2012-01-01

    Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the major incretin hormones that exert insulinotropic and anti-apoptotic actions on pancreatic β-cells. Insulinotropic actions of the incretins involve modulation of voltage-gated potassium (Kv) channels. In multiple cell types, Kv channel activity has been implicated in cell volume changes accompanying initiation of the apoptotic program. Focusing on Kv2.1, we examined whether regulation of Kv channels in β-cells contributes to the prosurvival effects of incretins. Overexpression of Kv2.1 in INS-1 β-cells potentiated apoptosis in response to mitochondrial and ER stress and, conversely, co-stimulation with GIP/GLP-1 uncoupled this potentiation, suppressing apoptosis. In parallel, incretins promoted phosphorylation and acetylation of Kv2.1 via pathways involving protein kinase A (PKA)/mitogen- and stress-activated kinase-1 (MSK-1) and histone acetyltransferase (HAT)/histone deacetylase (HDAC). Further studies demonstrated that acetylation of Kv2.1 was mediated by incretin actions on nuclear/cytoplasmic shuttling of CREB binding protein (CBP) and its interaction with Kv2.1. Regulation of β-cell survival by GIP and GLP-1 therefore involves post-translational modifications (PTMs) of Kv channels by PKA/MSK-1 and HAT/HDAC. This appears to be the first demonstration of modulation of delayed rectifier Kv channels contributing to the β-cell prosurvival effects of incretins and of 7-transmembrane G protein-coupled receptor (GPCR)-stimulated export of a nuclear lysine acetyltransferase that regulates cell surface ion channel function. PMID:21818121

  6. The relationship between gut and adipose hormones, and reproduction.

    PubMed

    Comninos, Alexander N; Jayasena, Channa N; Dhillo, Waljit S

    2014-01-01

    Reproductive function is tightly regulated by nutritional status. Indeed, it has been well described that undernutrition or obesity can lead to subfertility or infertility in humans. The common regulatory pathways which control energy homeostasis and reproductive function have, to date, been poorly understood due to limited studies or inconclusive data. However, gut hormones and adipose tissue hormones have recently emerged as potential regulators of both energy homeostasis and reproductive function. A PubMed search was performed using keywords related to gut and adipose hormones and associated with keywords related to reproduction. Currently available evidence that gut (ghrelin, obestatin, insulin, peptide YY, glucagon-like peptide-1, glucose-dependent insulinotropic peptide, oxyntomodulin, cholecystokinin) and adipose hormones (leptin, adiponectin, resistin, omentin, chemerin) interact with the reproductive axis is presented. The extent, site and direction of their effects on the reproductive axis are variable and also vary depending on species, sex and pubertal stage. Gut and adipose hormones interact with the reproductive axis as well as with each other. While leptin and insulin have stimulatory effects and ghrelin has inhibitory effects on hypothalamic GnRH secretion, there is increasing evidence for their roles in other sites of the reproductive axis as well as evidence for the roles of other gut and adipose hormones in the complex interplay between nutrition and reproduction. As our understanding improves, so will our ability to identify and design novel therapeutic options for reproductive disorders and accompanying metabolic disorders.

  7. [Incretin and bone].

    PubMed

    Yamada, Yuichiro

    2009-09-01

    Gastrointestinal hormones including gastric inhibitory polypeptide (GIP) and glucagon-like peptide (GLP) -1 are incretin, which are secreted immediately after meal ingestion and stimulate insulin secretion from pancreatic beta-cells. Characterization of extra-pancreatic GIP and GLP-1 receptors has revealed that these hormones regulate bone turnover. GIP intermittently stimulates osteoblasts and GLP-1 suppresses osteoclasts through a calcitonin-dependent pathway to increase the bone volume.

  8. The role of gut hormones in appetite regulation (review).

    PubMed

    Marić, G; Gazibara, T; Zaletel, I; Labudović Borović, M; Tomanović, N; Ćirić, M; Puškaš, Nela

    2014-12-01

    Eating process is an aggregate of complex and different forms of behavior. Its regulation is based on energy homeostasis and appetite control which includes two components: the homeostatic and the hedonistic control. Important signals in appetite regulation are gut-derived hormones. They are produced by enteroendocrine cells in response to nutrient and energy intake, and achieve their effects by influencing brain structures involved in food intake regulation. The key brain structure involved in this process is the hypothalamus. Gut hormones reach the hypothalamus from the circulation or by the vagal nerve via the nucleus of the solitary tract. Among gut peptides, ghrelin is the only orexigenic hormone, leading to an increase in food intake and body weight. All others, such as cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine or pancreatic polypeptide, are anorexigenic, leading to decrease in food intake. Also, gut-derived endocannabinoids exert orexigenic effect on appetite. Keeping in mind the growing problem of obesity, the crucial issue when considering gut derived peptides is to understand their mechanisms of acting because of potential role in clinical therapy, and discovering long-lasting gut peptides or their analogues, with no or minimal side effects.

  9. The antidiabetic action of camel milk in experimental type 2 diabetes mellitus: an overview on the changes in incretin hormones, insulin resistance, and inflammatory cytokines.

    PubMed

    Korish, A A

    2014-06-01

    Folk medicine stories accredited the aptitude of camel milk (CMK) as a hypoglycemic agent and recent studies have confirmed this in the diabetic patients and experimental animals. However, the mechanism(s) by which CMK influences glucose homeostasis is yet unclear. The current study investigated the changes in the glucose homeostatic parameters, the incretin hormones, and the inflammatory cytokines in the CMK-treated diabetic animals. A model of type 2 diabetes mellitus was induced in rats by intraperitoneal injection of streptozotocin 40 mg/kg/day for 4 repeated doses. Camel milk treatment was administered for 8 weeks. The changes in glucagon like peptide-1 (GLP-1), glucose dependent insulinotropic peptide (GIP), glucose tolerance, fasting and glucose-stimulated insulin secretion, insulin resistance (IR), TNF-α, TGF-β1, lipid profile, atherogenic index (AI), and body weight were investigated. The untreated diabetic animals showed hyperglycemia, increased HOMA-IR, hyperlipidemia, elevated AI, high serum incretins [GLP-1 and GIP], TNF-α, and TGF-β1 levels and weight loss as compared with the control group. Camel milk treatment to the diabetic animals resulted in significant lowered fasting glucose level, hypolipidemia, decreased HOMA-IR, recovery of insulin secretion, weight gain, and no mortality during the study. Additionally, CMK inhibits the diabetes-induced elevation in incretin hormones, TNF-α and TGF-β1 levels. The increase in glucose-stimulated insulin secretion, decreased HOMA-IR, modulation of the secretion and/or the action of incretins, and the anti-inflammatory effect are anticipated mechanisms to the antidiabetic effect of CMK and suggest it as a valuable adjuvant antidiabetic therapy.

  10. The Role of Incretins in Glucose Homeostasis and Diabetes Treatment

    PubMed Central

    Kim, Wook; Egan, Josephine M.

    2009-01-01

    Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d’être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to β-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their

  11. Gastrointestinal hormones and the dialogue between gut and brain.

    PubMed

    Dockray, Graham J

    2014-07-15

    The landmark discovery by Bayliss and Starling in 1902 of the first hormone, secretin, emerged from earlier observations that a response (pancreatic secretion) following a stimulus (intestinal acidification) occurred after section of the relevant afferent nerve pathway. Nearly 80 years elapsed before it became clear that visceral afferent neurons could themselves also be targets for gut and other hormones. The action of gut hormones on vagal afferent neurons is now recognised to be an early step in controlling nutrient delivery to the intestine by regulating food intake and gastric emptying. Interest in these mechanisms has grown rapidly in view of the alarming global increase in obesity. Several of the gut hormones (cholecystokinin (CCK); peptide YY3-36 (PYY3-36); glucagon-like peptide-1 (GLP-1)) excite vagal afferent neurons to activate an ascending pathway leading to inhibition of food intake. Conversely others, e.g. ghrelin, that are released in the inter-digestive period, inhibit vagal afferent neurons leading to increased food intake. Nutrient status determines the neurochemical phenotype of vagal afferent neurons by regulating a switch between states that promote orexigenic or anorexigenic signalling through mechanisms mediated, at least partly, by CCK. Gut-brain signalling is also influenced by leptin, by gut inflammation and by shifts in the gut microbiota including those that occur in obesity. Moreover, there is emerging evidence that diet-induced obesity locks the phenotype of vagal afferent neurons in a state similar to that normally occurring during fasting. Vagal afferent neurons are therefore early integrators of peripheral signals underling homeostatic mechanisms controlling nutrient intake. They may also provide new targets in developing treatments for obesity and feeding disorders. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

  12. Gastrointestinal hormones and the dialogue between gut and brain

    PubMed Central

    Dockray, Graham J

    2014-01-01

    The landmark discovery by Bayliss and Starling in 1902 of the first hormone, secretin, emerged from earlier observations that a response (pancreatic secretion) following a stimulus (intestinal acidification) occurred after section of the relevant afferent nerve pathway. Nearly 80 years elapsed before it became clear that visceral afferent neurons could themselves also be targets for gut and other hormones. The action of gut hormones on vagal afferent neurons is now recognised to be an early step in controlling nutrient delivery to the intestine by regulating food intake and gastric emptying. Interest in these mechanisms has grown rapidly in view of the alarming global increase in obesity. Several of the gut hormones (cholecystokinin (CCK); peptide YY3–36 (PYY3–36); glucagon-like peptide-1 (GLP-1)) excite vagal afferent neurons to activate an ascending pathway leading to inhibition of food intake. Conversely others, e.g. ghrelin, that are released in the inter-digestive period, inhibit vagal afferent neurons leading to increased food intake. Nutrient status determines the neurochemical phenotype of vagal afferent neurons by regulating a switch between states that promote orexigenic or anorexigenic signalling through mechanisms mediated, at least partly, by CCK. Gut–brain signalling is also influenced by leptin, by gut inflammation and by shifts in the gut microbiota including those that occur in obesity. Moreover, there is emerging evidence that diet-induced obesity locks the phenotype of vagal afferent neurons in a state similar to that normally occurring during fasting. Vagal afferent neurons are therefore early integrators of peripheral signals underling homeostatic mechanisms controlling nutrient intake. They may also provide new targets in developing treatments for obesity and feeding disorders. PMID:24566540

  13. Differential responses of the incretin hormones GIP and GLP-1 to increasing doses of dietary carbohydrate but not dietary protein in lean rats

    PubMed Central

    Yang, Qing; Kindel, Tammy L.; Tso, Patrick

    2010-01-01

    Previous studies have shown that oral ingestion of nutrients stimulates secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1); however, it is unclear whether there is a dose-dependent response between the amount of nutrient ingested and the secretion of the hormones in vivo. Using our lymph fistula rat model, we previously demonstrated that both GIP and GLP-1 responded dose dependently to increasing amounts of infused dietary lipid and that the GLP-1-secreting cells were more sensitive to changes in intestinal lipid content. In the present study, we investigated the dose-dependent relationships between incretin secretion and the two remaining macronutrients, carbohydrate and protein. To accomplish this objective, the major mesenteric lymphatic duct of male Sprague-Dawley rats was cannulated. Each animal received a single bolus (3 ml) of saline, dextrin, whey protein, or casein hydrolysate (0.275, 0.55, 1.1, 2.2, 4.4 kcal) via a surgically inserted duodenal or ileal feeding tube. Lymph was continuously collected for 3 h and analyzed for GIP and GLP-1 content. Both GIP and GLP-1 outputs responded dose dependently to increasing amounts of dietary carbohydrate but not protein. Additionally, we found that the GIP-secreting cells were more sensitive than the GLP-1-secreting cells to changes in intestinal carbohydrate content. PMID:20522638

  14. New insights into the role of cAMP in the production and function of the incretin hormone glucagon-like peptide-1 (GLP-1).

    PubMed

    Yu, Zhiwen; Jin, Tianru

    2010-01-01

    The proglucagon gene (gcg) encodes both glucagon and glucagon-like peptide-1 (GLP-1), produced in pancreatic alpha cells and intestinal endocrine L cells, respectively. The incretin hormone GLP-1 stimulates insulin secretion and pro-insulin gene transcription. GLP-1 also enhances pancreatic beta-cell proliferation, inhibits cell apoptosis, and has been utilized in the trans-differentiation of insulin producing cells. A long-term effective GLP-1 receptor agonist, Byetta, has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders. 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, and the crosstalk between PKA and the Wnt signaling pathway, are involved in cAMP-stimulated gcg transcription and GLP-1 production as well. Finally, functions of GLP-1 in pancreatic beta cells are also mediated by PKA, Epac, as well as the effector of the Wnt signaling pathway. Together, these novel findings bring us a new insight into the role of cAMP in the production and function of the incretin hormone GLP-1.

  15. Gut hormone secretion, gastric emptying, and glycemic responses to erythritol and xylitol in lean and obese subjects.

    PubMed

    Wölnerhanssen, Bettina K; Cajacob, Lucian; Keller, Nino; Doody, Alison; Rehfeld, Jens F; Drewe, Juergen; Peterli, Ralph; Beglinger, Christoph; Meyer-Gerspach, Anne Christin

    2016-06-01

    With the increasing prevalence of obesity and a possible association with increasing sucrose consumption, nonnutritive sweeteners are gaining popularity. Given that some studies indicate that artificial sweeteners might have adverse effects, alternative solutions are sought. Xylitol and erythritol have been known for a long time and their beneficial effects on caries prevention and potential health benefits in diabetic patients have been demonstrated in several studies. Glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) are released from the gut in response to food intake, promote satiation, reduce gastric emptying (GE), and modulate glucose homeostasis. Although glucose ingestion stimulates sweet taste receptors in the gut and leads to incretin and gastrointestinal hormone release, the effects of xylitol and erythritol have not been well studied. Ten lean and 10 obese volunteers were given 75 g of glucose, 50 g of xylitol, or 75 g of erythritol in 300 ml of water or placebo (water) by a nasogastric tube. We examined plasma glucose, insulin, active GLP-1, CCK, and GE with a [(13)C]sodium acetate breath test and assessed subjective feelings of satiation. Xylitol and erythritol led to a marked increase in CCK and GLP-1, whereas insulin and plasma glucose were not (erythritol) or only slightly (xylitol) affected. Both xylitol and erythritol induced a significant retardation in GE. Subjective feelings of appetite were not significantly different after carbohydrate intake compared with placebo. In conclusion, acute ingestion of erythritol and xylitol stimulates gut hormone release and slows down gastric emptying, whereas there is no or only little effect on insulin release. Copyright © 2016 the American Physiological Society.

  16. Obesity: An overview of possible role(s) of gut hormones, lipid sensing and gut microbiota.

    PubMed

    Mishra, Alok Kumar; Dubey, Vinay; Ghosh, Asit Ranjan

    2016-01-01

    Obesity is one of the major challenges for public health in 21st century, with 1.9 billion people being considered as overweight and 600 million as obese. There are certain diseases such as type 2 diabetes, hypertension, cardiovascular disease, and several forms of cancer which were found to be associated with obesity. Therefore, understanding the key molecular mechanisms involved in the pathogenesis of obesity could be beneficial for the development of a therapeutic approach. Hormones such as ghrelin, glucagon like peptide 1 (GLP-1) peptide YY (PYY), pancreatic polypeptide (PP), cholecystokinin (CCK) secreted by an endocrine organ gut, have an intense impact on energy balance and maintenance of homeostasis by inducing satiety and meal termination. Glucose and energy homeostasis are also affected by lipid sensing in which different organs respond in different ways. However, there is one common mechanism i.e. formation of esterified lipids (long chain fatty acyl CoAs) and the activation of protein kinase C δ (PKC δ) involved in all these organs. The possible role of gut microbiota and obesity has been addressed by several researchers in recent years, indicating the possible therapeutic approach toward the management of obesity by the introduction of an external living system such as a probiotic. The proposed mechanism behind this activity is attributed by metabolites produced by gut microbial organisms. Thus, this review summarizes the role of various physiological factors such as gut hormone and lipid sensing involved in various tissues and organ and most important by the role of gut microbiota in weight management.

  17. Effects of Diet Soda on Gut Hormones in Youths With Diabetes

    PubMed Central

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

    2012-01-01

    OBJECTIVE In patients with type 2 diabetes, but not type 1 diabetes, abnormal secretion of incretins in response to oral nutrients has been described. In healthy youths, we recently reported accentuated glucagon-like peptide 1 (GLP-1) secretion in response to a diet soda sweetened with sucralose and acesulfame-K. In this study, we examined the effect of diet soda on gut hormones in youths with diabetes. RESEARCH DESIGN AND METHODS Subjects aged 12–25 years with type 1 diabetes (n = 9) or type 2 diabetes (n = 10), or healthy control participants (n = 25) drank 240 mL cola-flavored caffeine-free diet soda or carbonated water, followed by a 75-g glucose load, in a randomized, cross-over design. Glucose, C-peptide, GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide Tyr-Tyr (PYY) were measured for 180 min. Glucose and GLP-1 have previously been reported for the healthy control subjects. RESULTS GLP-1 area under the curve (AUC) was 43% higher after ingestion of diet soda versus carbonated water in individuals with type 1 diabetes (P = 0.020), similar to control subjects (34% higher, P = 0.029), but was unaffected by diet soda in patients with type 2 diabetes (P = 0.92). Glucose, C-peptide, GIP, and PYY AUC were not statistically different between the two conditions in any group. CONCLUSIONS Ingestion of diet soda before a glucose load augmented GLP-1 secretion in type 1 diabetic and control subjects but not type 2 diabetic subjects. GIP and PYY secretion were not affected by diet soda. The clinical significance of this increased GLP-1 secretion, and its absence in youths with type 2 diabetes, needs to be determined. PMID:22410815

  18. Effects of diet soda on gut hormones in youths with diabetes.

    PubMed

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

    2012-05-01

    In patients with type 2 diabetes, but not type 1 diabetes, abnormal secretion of incretins in response to oral nutrients has been described. In healthy youths, we recently reported accentuated glucagon-like peptide 1 (GLP-1) secretion in response to a diet soda sweetened with sucralose and acesulfame-K. In this study, we examined the effect of diet soda on gut hormones in youths with diabetes. Subjects aged 12-25 years with type 1 diabetes (n = 9) or type 2 diabetes (n = 10), or healthy control participants (n = 25) drank 240 mL cola-flavored caffeine-free diet soda or carbonated water, followed by a 75-g glucose load, in a randomized, cross-over design. Glucose, C-peptide, GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide Tyr-Tyr (PYY) were measured for 180 min. Glucose and GLP-1 have previously been reported for the healthy control subjects. GLP-1 area under the curve (AUC) was 43% higher after ingestion of diet soda versus carbonated water in individuals with type 1 diabetes (P = 0.020), similar to control subjects (34% higher, P = 0.029), but was unaffected by diet soda in patients with type 2 diabetes (P = 0.92). Glucose, C-peptide, GIP, and PYY AUC were not statistically different between the two conditions in any group. Ingestion of diet soda before a glucose load augmented GLP-1 secretion in type 1 diabetic and control subjects but not type 2 diabetic subjects. GIP and PYY secretion were not affected by diet soda. The clinical significance of this increased GLP-1 secretion, and its absence in youths with type 2 diabetes, needs to be determined.

  19. The incretin system and its role in type 2 diabetes mellitus.

    PubMed

    Holst, Jens Juul; Vilsbøll, Tina; Deacon, Carolyn F

    2009-01-15

    The incretin hormones are released during meals from gut endocrine cells. They potentiate glucose-induced insulin secretion and may be responsible for up to 70% of postprandial insulin secretion. The incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the incretin hormones is due to the fact that the incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. However, in supraphysiological doses, GLP-1 administration may completely normalize beta as well as alpha cell sensitivity to glucose. The impaired action of GLP-1 and GIP in T2DM may be at least partly restored by improved glycaemic control, as shown in studies involving 4 weeks of intensive insulin therapy. The reduced incretin effect is believed to contribute to impaired regulation of insulin and glucagon secretion in T2DM, and, in support of this, exogenous GLP-1 administration may restore blood glucose regulation to near normal levels. Thus, the pathogenesis of T2DM seems to involve a dysfunction of both

  20. Postprandial incretin and islet hormone responses and dipeptidyl-peptidase 4 enzymatic activity in patients with maturity onset diabetes of the young.

    PubMed

    Østoft, Signe Harring; Bagger, Jonatan Ising; Hansen, Torben; Hartmann, Bolette; Pedersen, Oluf; Holst, Jens Juul; Knop, Filip Krag; Vilsbøll, Tina

    2015-08-01

    The role of the incretin hormones in the pathophysiology of maturity onset diabetes of the young (MODY) is unclear. We studied the postprandial plasma responses of glucagon, incretin hormones (glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)) and dipeptidyl-peptidase 4 (DPP4) enzymatic activity in patients with glucokinase (GCK) diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A) diabetes (MODY3) as well as in matched healthy individuals (CTRLs). Ten patients with MODY2 (mean age ± S.E.M. 43 ± 5 years; BMI 24 ± 2 kg/m(2); fasting plasma glucose (FPG) 7.1 ± 0.3 mmol/l: HbA1c 6.6 ± 0.2%), ten patients with MODY3 (age 31 ± 3 years; BMI 24 ± 1 kg/m(2); FPG 8.9 ± 0.8 mmol/l; HbA1c 7.0 ± 0.3%) and ten CTRLs (age 40 ± 5 years; BMI 24 ± 1 kg/m(2); FPG 5.1 ± 0.1 mmol/l; HbA1c 5.3 ± 0.1%) were examined with a liquid test meal. All of the groups exhibited similar baseline values of glucagon (MODY2: 7 ± 1 pmol/l; MODY3: 6 ± 1 pmol/l; CTRLs: 8 ± 2 pmol/l, P=0.787), but patients with MODY3 exhibited postprandial hyperglucagonaemia (area under the curve (AUC) 838 ± 108 min × pmol/l) as compared to CTRLs (182 ± 176 min × pmol/l, P=0.005) and tended to have a greater response than did patients with MODY2 (410 ± 154 min × pmol/l, P=0.063). Similar peak concentrations and AUCs for plasma GIP and plasma GLP1 were observed across the groups. Increased fasting DPP4 activity was seen in patients with MODY3 (17.7 ± 1.2 mU/ml) vs CTRLs (13.6 ± 0.8 mU/ml, P=0.011), but the amount of activity was similar to that in patients with MODY2 (15.0 ± 0.7 mU/ml, P=0.133). The pathophysiology of MODY3 includes exaggerated postprandial glucagon responses and increased fasting DPP4 enzymatic activity but normal postprandial incretin responses both in patients with MODY2 and in patients with MODY3. © 2015 European Society of Endocrinology.

  1. Effect of Acarbose, Sitagliptin and combination therapy on blood glucose, insulin, and incretin hormone concentrations in experimentally induced postprandial hyperglycemia of healthy cats.

    PubMed

    Mori, Akihiro; Ueda, Kaori; Lee, Peter; Oda, Hitomi; Ishioka, Katsumi; Arai, Toshiro; Sako, Toshinori

    2016-06-01

    Acarbose (AC) and Sitagliptin (STGP) are oral hypoglycemic agents currently used either alone or in conjunction with human diabetic (Type 2) patients. AC has been used with diabetic cats, but not STGP thus far. Therefore, the objective of this study was to determine the potential use of AC or STGP alone and in combination for diabetic cats, by observing their effect on short-term post-prandial serum glucose, insulin, and incretin hormone (active glucagon-like peptide-1 (GLP-1) and total glucose dependent insulinotropic polypeptide (GIP)) concentrations in five healthy cats, following ingestion of a meal with maltose. All treatments tended (p<0.10; 5-7.5% reduction) to reduce postprandial glucose area under the curve (AUC), with an accompanying significant reduction (p<0.05, 35-45%) in postprandial insulin AUC as compared to no treatment. Meanwhile, a significant increase (p<0.05) in postprandial active GLP-1 AUC was observed with STGP (100% higher) and combined treatment (130% greater), as compared to either AC or no treatment. Lastly, a significant reduction (p<0.05) in postprandial total GIP AUC was observed with STGP (21% reduction) and combined treatment (7% reduction) as compared to control. Overall, AC, STGP, or combined treatment can significantly induce positive post-prandial changes to insulin and incretin hormone levels of healthy cats. Increasing active GLP-1 and reducing postprandial hyperglycemia appear to be the principal mechanisms of combined treatment. Considering the different, but complementary mechanisms of action by which AC and STGP induce lower glucose and insulin levels, combination therapy with both these agents offers great potential for treating diabetic cats in the future.

  2. Hormonal abnormalities of the pancreas and gut in cystic fibrosis.

    PubMed

    Adrian, T E; McKiernan, J; Johnstone, D I; Hiller, E J; Vyas, H; Sarson, D L; Bloom, S R

    1980-09-01

    We have investigated the effect of cystic fibrosis on alimentary hormones in 10 children by measuring the pancreatic and gut hormone rsponse to a milk drink. Plasma insulin and gastric inhibitory peptide were both significantly reduced (P < 0.05 and P < 0.005, respectively, at 15 min) in the patients with cystic fibrosis, compared with controls, even though the early glucose rise was greater in the former group (P < 0.05 at 15 min). Fasting levels of pancreatic polypeptide were significantly lower in the fibrocystic children (P < 0.01), and the normal response to milk was completely abolished in these patients (P < 0.001). Fasting plasma enteroglucagon concentrations were grossly abolished in the cystic fibrosis patients (P < 0.001) and these remained elevated throughout the test. No significant differences were seen in basal or postmilk responses of plasma glucagon, gastrin, secretin, vasoactive intestinal peptide, or motilin in cystic fibrosis. It would thus appear that the pancreatic polypeptide cell is more susceptible to the effects of the disease process than the beta or alpha cell in cystic fibrosis. Some aspects of the abnormalities in the gastrointestinal endocrine system were similar to those seen in celiac disease and tropical sprue and may, therefore, effect a similar hormonal response in these patients with cystic fibrosis to those with mucosal damage.

  3. Effect of dietary macronutrients on postprandial incretin hormone release and satiety in obese and normal-weight women.

    PubMed

    Wikarek, Tomasz; Chudek, Jerzy; Owczarek, Aleksander; Olszanecka-Glinianowicz, Magdalena

    2014-01-28

    The aim of the present study was to assess the effect of dietary macronutrients on postprandial incretin responses and satiety and hunger sensation in obese and normal-weight women. A total of eleven obese and nine normal-weight women were recruited for the assessment of plasma concentrations of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and insulin and the sensation of satiety and hunger using a visual analogue scale before and during a 6 h period after administration of three different macronutrient test meals. The AUCtotal GLP-1 and AUCtotal GIP values were decreased in obese women after the consumption of a fatty meal and all the test meals, respectively. However, the AUCtotal insulin value after a carbohydrate meal was greater in the obese group. The AUCtotal satiety value was decreased only after the intake of the protein meal in obese women when compared with normal-weight women. After the consumption of the fatty meal, a significant positive correlation between maximum satiety sensation and the AUCtotal GLP-1 value in the obese group and that between minimum hunger sensation and the AUCtotal GLP-1 value in the normal-weight group were observed. In conclusion, the findings of the present study suggest that: (1) satiety sensation after consumption of carbohydrate and protein meals in the obese group is related to the postprandial insulin response, while after consumption of a fatty meal, it is related to the postprandial GLP-1 release; (2) the postprandial GIP response does not influence the sensation of satiety and hunger; (3) the reduced GLP-1 release after the intake of a fatty meal in obese individuals may explain impaired satiety sensation; (4) the impaired postprandial GIP response is not related to the consumption of macronutrients and may be the early indicator of incretin axis dysfunction in obese women.

  4. The effect of bariatric surgery on gut hormones that alter appetite.

    PubMed

    Pournaras, D-J; Le Roux, C-W

    2009-12-01

    Bariatric surgery is the only effective treatment for morbid obesity in the long term. Gut hormones are key players in the metabolic mechanisms causing obesity. Furthermore gut hormones are involved in the signalling process of hunger and satiety which leads to the control of nutrient intake. In this review, the role of these hormones as facilitators of appetite control after bariatric and metabolic surgery will be explored.

  5. Glutamate Acts as a Key Signal Linking Glucose Metabolism to Incretin/cAMP Action to Amplify Insulin Secretion

    PubMed Central

    Gheni, Ghupurjan; Ogura, Masahito; Iwasaki, Masahiro; Yokoi, Norihide; Minami, Kohtaro; Nakayama, Yasumune; Harada, Kazuo; Hastoy, Benoit; Wu, Xichen; Takahashi, Harumi; Kimura, Kazushi; Matsubara, Toshiya; Hoshikawa, Ritsuko; Hatano, Naoya; Sugawara, Kenji; Shibasaki, Tadao; Inagaki, Nobuya; Bamba, Takeshi; Mizoguchi, Akira; Fukusaki, Eiichiro; Rorsman, Patrik; Seino, Susumu

    2014-01-01

    Summary Incretins, hormones released by the gut after meal ingestion, are essential for maintaining systemic glucose homeostasis by stimulating insulin secretion. The effect of incretins on insulin secretion occurs only at elevated glucose concentrations and is mediated by cAMP signaling, but the mechanism linking glucose metabolism and cAMP action in insulin secretion is unknown. We show here, using a metabolomics-based approach, that cytosolic glutamate derived from the malate-aspartate shuttle upon glucose stimulation underlies the stimulatory effect of incretins and that glutamate uptake into insulin granules mediated by cAMP/PKA signaling amplifies insulin release. Glutamate production is diminished in an incretin-unresponsive, insulin-secreting β cell line and pancreatic islets of animal models of human diabetes and obesity. Conversely, a membrane-permeable glutamate precursor restores amplification of insulin secretion in these models. Thus, cytosolic glutamate represents the elusive link between glucose metabolism and cAMP action in incretin-induced insulin secretion. PMID:25373904

  6. Gut hormones as therapeutic agents in treatment of diabetes and obesity.

    PubMed

    Tan, Tricia; Bloom, Stephen

    2013-12-01

    Obesity and Type 2 Diabetes Mellitus (T2DM) present an ever-increasing threat to global health. Although bariatric surgery is an effective treatment, it cannot be applied to the vast majority of patients. The beneficial effects of bariatric surgery are related to complex alterations in the secretion of gut hormones. By recapitulation of the changes of gut hormone secretion after bariatric surgery, drugs based on gut hormones represent an exciting possibility for the treatment of T2DM and obesity. We review the rapidly emerging role of GLP-1 based treatments as well as the future for new drugs based on other gut hormones such as GIP, ghrelin, oxyntomodulin and peptide YY. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. (−)-Epigallocatechin-3-gallate induces secretion of anorexigenic gut hormones

    PubMed Central

    Song, Won-Young; Aihara, Yoshiko; Hashimoto, Takashi; Kanazawa, Kazuki; Mizuno, Masashi

    2015-01-01

    The anorexigenic gut hormones, cholecystokinin (CCK), glucagon-like peptide (GLP)-1 and peptide tyrosine-tyrosine (PYY), are released in response to food intake from the intestines. Dietary nutrients have been shown to stimulate these hormones. Some non-nutrients such as polyphenols show anorexigenic effects on humans. In the present study, we examined whether dietary polyphenols can stimulate secretion of these gut hormones. Caco-2 cells expressed mRNA of the gut hormones, CCK, PC1 (prohormone convertase 1), GCG (glucagon) and PYY. CCK, GLP-1 and PYY were secreted from Caco-2 cells after adding sugars, amino acids or fatty acids. Using Caco-2 cells, epigallocatechin-3-gallate (EGCG), chlorogenic acid and ferulic acid induced secretion of anorexigenic gut hormones. Particularly, EGCG induced secretion of all three hormones. In an ex vivo assay using murine intestines, EGCG also released CCK from the duodenum, and GLP-1 from the ileum. These results suggest that EGCG may affect appetite via gut hormones. PMID:26388676

  8. Cardiovascular Effects of Incretin-Based Therapies.

    PubMed

    White, William B; Baker, William L

    2016-01-01

    The incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, are important new classes of therapy for type 2 diabetes mellitus (T2DM). These agents prolong the action of the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting their breakdown. The incretin hormones improve glycemic control in T2DM by increasing insulin secretion and suppressing glucagon levels. The cardiovascular (CV) effects of the incretin-based therapies have been of substantial interest since 2008, when the US Food and Drug Administration began to require that all new therapies for diabetes undergo rigorous assessment of CV safety through large-scale CV outcome trials. This article reviews the most recent CV outcome trials of the DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) as evidence that the incretin-based therapies have acceptable CV safety profiles for patients with T2DM. The studies differ with regard to patient population, trial duration, and heart failure outcomes but show similar findings for CV death, nonfatal myocardial infarction, and stroke, as well as hospitalization for unstable angina.

  9. Could the improvement of obesity-related co-morbidities depend on modified gut hormones secretion?

    PubMed

    Finelli, Carmine; Padula, Maria Carmela; Martelli, Giuseppe; Tarantino, Giovanni

    2014-11-28

    Obesity and its associated diseases are a worldwide epidemic disease. Usual weight loss cures - as diets, physical activity, behavior therapy and pharmacotherapy - have been continuously implemented but still have relatively poor long-term success and mainly scarce adherence. Bariatric surgery is to date the most effective long term treatment for morbid obesity and it has been proven to reduce obesity-related co-morbidities, among them nonalcoholic fatty liver disease, and mortality. This article summarizes such variations in gut hormones following the current metabolic surgery procedures. The profile of gut hormonal changes after bariatric surgery represents a strategy for the individuation of the most performing surgical procedures to achieve clinical results. About this topic, experts suggest that the individuation of the crosslink among the gut hormones, microbiome, the obesity and the bariatric surgery could lead to new and more specific therapeutic interventions for severe obesity and its co-morbidities, also non surgical.

  10. Could the improvement of obesity-related co-morbidities depend on modified gut hormones secretion?

    PubMed Central

    Finelli, Carmine; Padula, Maria Carmela; Martelli, Giuseppe; Tarantino, Giovanni

    2014-01-01

    Obesity and its associated diseases are a worldwide epidemic disease. Usual weight loss cures - as diets, physical activity, behavior therapy and pharmacotherapy - have been continuously implemented but still have relatively poor long-term success and mainly scarce adherence. Bariatric surgery is to date the most effective long term treatment for morbid obesity and it has been proven to reduce obesity-related co-morbidities, among them nonalcoholic fatty liver disease, and mortality. This article summarizes such variations in gut hormones following the current metabolic surgery procedures. The profile of gut hormonal changes after bariatric surgery represents a strategy for the individuation of the most performing surgical procedures to achieve clinical results. About this topic, experts suggest that the individuation of the crosslink among the gut hormones, microbiome, the obesity and the bariatric surgery could lead to new and more specific therapeutic interventions for severe obesity and its co-morbidities, also non surgical. PMID:25469034

  11. Incretin therapies: effects beyond glycemic control.

    PubMed

    Mudaliar, Sunder; Henry, Robert R

    2009-07-01

    Impaired insulin secretion plays a major role in the pathogenesis of type 2 diabetes mellitus, and progressive loss of beta-cell function is a pathophysiologic hallmark of type 2 diabetes. Recent science has elaborated on the role of the incretin hormones on beta-cell function and insulin secretion, as well as the role that incretin-based pharmacotherapies may have on glycemic control and beta-cell function, possibly altering the progressive loss of beta-cell function and possibly reversing/halting disease progression. However, incretin-based therapies may also have benefits extending beyond glycemic control and insulin secretion. In this review we examine some of those "beyond-glycemic" benefits, including presentation of data on weight reduction, blood pressure lowering, beneficial changes in the lipid profile, and improvements in myocardial and endothelial function. We investigate how those effects may help ameliorate the cardiovascular burden in patients with diabetes.

  12. Incretin-based therapies for obesity treatment.

    PubMed

    de Mello, Aline Haas; Prá, Morgana; Cardoso, Larissa Colonetti; de Bona Schraiber, Rosiane; Rezin, Gislaine Tezza

    2015-09-01

    Currently, obesity and its associated complications are considered major public health problems worldwide. Because the causes are multifactorial and complex, different treatment methods are used, which include diet and exercise, as well as the use of drugs, although they can have adverse side effects. A new target for the treatment of obesity may be the incretin system, which consists of hormones that seem to contribute to weight loss. In this sense, some studies have shown a relationship between weight loss and drugs related to incretin system, including glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. The objective of this review is to summarize the association between the incretin system and obesity treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Burns: where are we standing with propranolol, oxandrolone, recombinant human growth hormone, and the new incretin analogs?

    PubMed

    Gauglitz, Gerd G; Williams, Felicia N; Herndon, David N; Jeschke, Marc G

    2011-03-01

    The hypermetabolic response in critically ill patients is characterized by hyperdynamic circulatory, physiologic, catabolic and immune system responses. Failure to satisfy overwhelming energy and protein requirements after, and during critical illness, results in multiorgan dysfunction, increased susceptibility to infection, and death. Attenuation of the hypermetabolic response by various pharmacologic modalities is emerging as an essential component of the management of severe burn patients. This review focuses on the more recent advances in therapeutic strategies to attenuate the hypermetabolic response and its associated insulin resistance postburn. At present, beta-adrenergic blockade with propranolol represents probably the most efficacious anticatabolic therapy in the treatment of burns. Other pharmacological strategies include growth hormone, insulin-like growth factor, oxandrolone and intensive insulin therapy. Novel approaches to the management of critical illness by judicious glucose control and the use of pharmacologic modulators to the hypercatabolic response to critical illness have emerged. Investigation of alternative strategies, including the use of metformin, glucagon-like-peptide-1 and the PPAR-γ agonists are under current investigation.

  14. Incretin actions and consequences of incretin-based therapies: lessons from complementary animal models.

    PubMed

    Renner, Simone; Blutke, Andreas; Streckel, Elisabeth; Wanke, Rüdiger; Wolf, Eckhard

    2016-01-01

    The two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1), were discovered 45 and 30 years ago. Initially, only their insulinotropic effect on pancreatic β cells was known. Over the years, physiological and pharmacological effects of GIP and GLP1 in numerous extrapancreatic tissues were discovered which partially overlap, but may also be specific for GIP or GLP1 in certain target tissues. While the insulinotropic effect of GIP was found to be blunted in patients with type 2 diabetes, the function of GLP1 is preserved and GLP1 receptor agonists and dipeptidyl-peptidase 4 (DPP4) inhibitors, which prolong the half-life of incretins, are widely used in diabetes therapy. Wild-type and genetically modified rodent models have provided important mechanistic insights into the incretin system, but may have limitations in predicting the clinical efficacy and safety of incretin-based therapies. This review summarizes insights from rodent and non-rodent models (pig, non-human primate) into physiological and pharmacological incretin effects, with a focus on the pancreas. Similarities and differences between species are discussed and the increasing potential of genetically engineered pig models for translational incretin research is highlighted.

  15. Effect of glycemia on plasma incretins and the incretin effect during oral glucose tolerance test.

    PubMed

    Salehi, Marzieh; Aulinger, Benedict; D'Alessio, David A

    2012-11-01

    The incretin effect, reflecting the enhancement of postprandial insulin secretion by factors including the intestinal hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, increases in proportion to meal size. However, it is unknown whether the incretin effect is dependent on ambient glucose. The goal of this study was to determine the effect of plasma glycemia on the incretin effect. Thirteen healthy subjects consumed 50 g oral glucose solution mixed with d-xylose during fixed hyperglycemia at 8 and 10.5 mmol/L, on 3 separate days, twice at lower glycemia (LOW) and once at higher values (HIGH). The relative increase in insulin release after glucose ingestion at fixed hyperglycemia, a surrogate for the incretin effect, was similar among all three studies. The GLP-1 response to oral glucose was significantly lower at higher plasma glycemia, as was the appearance of d-xylose after the meal. Between the two LOW studies, the reproducibility of insulin release in response to intravenous glucose alone and intravenous plus ingested glucose was similar. These findings indicate that the incretin contribution to postprandial insulin release is independent of glycemia in healthy individuals, despite differences in GLP-1 secretion. The incretin effect is a reproducible trait among humans with normal glucose tolerance.

  16. Obesity: Lifestyle management, bariatric surgery, drugs, and the therapeutic exploitation of gut hormones.

    PubMed

    Behary, Preeshila; Cegla, Jaimini; Tan, Tricia M; Bloom, Stephen R

    2015-06-01

    Obesity is on the rise and the pursuit of efficient and safe treatment is ongoing. Available anti-obesity medical therapies have so far proved to be disappointing, whereas bariatric surgery is leading the way and offers long-term health benefits. Part of the success of bariatric surgery is thought to be mediated by gut hormones. A better understanding of the role of gut hormones within the gut-brain signaling pathway in the control of hunger, satiety, and energy homeostasis, has led to their therapeutic exploitation as possible anti-obesity drugs. In this review, we provide a summary of currently available treatment options for obesity from simple lifestyle modifications and bariatric surgery to traditional and novel medical therapies.

  17. Vagal and hormonal gut-brain communication: from satiation to satisfaction.

    PubMed

    Berthoud, H-R

    2008-05-01

    Studying communication between the gut and the brain is as relevant and exciting as it has been since Pavlov's discoveries a century ago. Although the efferent limb of this communication has witnessed significant advances, it is the afferent, or sensory, limb that has recently made for exciting news. It is now clear that signals from the gut are crucial for the control of appetite and the regulation of energy balance, glucose homeostasis, and more. Ghrelin, discovered just a few years ago, is the first gut hormone that increases appetite, and it may be involved in eating disorders. The stable analogue of glucagon-like peptide-1 has rapidly advanced to one of the most promising treatment options for type-2 diabetes. Changes in the signalling patterns of these and other gut hormones best explain the remarkable capacity of gastric bypass surgery to lower food intake and excess body weight. Given the enormous societal implications of the obesity epidemic, these are no small feats. Together with the older gut hormone cholecystokinin and abundant vagal mechanosensors, the gut continuously sends information to the brain regarding the quality and quantity of ingested nutrients, not only important for satiation and meal termination, but also for the appetitive phase of ingestive behaviour and the patterning of meals within given environmental constraints. By acting not only on brainstem and hypothalamus, this stream of sensory information from the gut to the brain is in a position to generate a feeling of satisfaction and happiness as observed after a satiating meal and exploited in vagal afferent stimulation for depression.

  18. Systemic administration of anorexic gut peptide hormones impairs hedonic-driven sucrose consumption in mice.

    PubMed

    Yamaguchi, Erina; Yasoshima, Yasunobu; Shimura, Tsuyoshi

    2017-03-15

    A number of reports suggest that gut hormones such as cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY(3-36) (PYY3-36), which are released postprandially, suppress homeostatic food intake and result in satiety and the termination of feeding. However, it remains unclear whether these peptide hormones also suppress non-homeostatic consumption of palatable foods or fluids. To examine whether gut hormones reduce hedonically motivated sugar consumption, we assessed the effects of intraperitoneal administration of these gut hormones on the consumption of a highly palatable sucrose solution, using a mouse model we previously established for binge-like sucrose overconsumption (Yasoshima and Shimura, 2015). To reduce homeostatic hunger, chow was available at nighttime prior to testing. After a limited-access training procedure for 10days, during which access to both sucrose and chow were controlled, on the test day, control mice injected with saline consumed significantly more sucrose than during the pre-training period. In contrast, sucrose consumption on the test day in the mice injected with CCK-8 (2 and 4μg/kg), GLP-1 (500 and 1000nmol/kg), or PYY3-36 (12.5 and 25nmol/kg) was significantly less than that in saline-injected mice. In a separate cohort of mice, the higher doses of CCK-8 and GLP-1 and a greater dose of PYY3-36 (50nmol/kg) did not produce conditioned taste aversion to saccharin, suggesting that the doses of exogenous hormones in the present study do not cause aversive visceral distress. The present findings suggest that the systemic administration of these three gut hormones suppresses hedonic-driven sugar consumption due to the anorexic, but not aversive-visceral, effects of these hormones. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Physiological mechanisms of action of incretin and insulin in regulating skeletal muscle metabolism.

    PubMed

    Abdulla, Haitham; Phillips, Bethan; Smith, Kenneth; Wilkinson, Daniel; Atherton, Philip J; Idris, Iskandar

    2014-01-01

    Type II diabetes (T2D) is a progressive condition affecting approximately 350 million adults worldwide. Whilst skeletal muscle insulin resistance and beta-cell dysfunction are recognised causes of T2D, progressive loss of lean muscle mass (reducing surface area for glucose disposal area) in tandem with ageing-related adiposity (i.e. sarcopenic obesity) also plays an important role in driving hyperglycaemia progression. The anabolic effects of nutrition on the muscle are driven by the uptake of amino acids, into skeletal muscle protein, and insulin plays a crucial role in regulating this. Meanwhile glucagon-like peptide (GLP-1) and glucose- dependent insulinotropic peptide (GIP) are incretin hormones released from the gut into the bloodstream in response to macronutrients, and have an established role in enhancing insulin secretion. Intriguingly, endocrine functions of incretins were recently shown to extend beyond classical insulinotropic effects, with GLP-1/GIP receptors being found in extra-pancreatic cells i.e., skeletal muscle and peripheral (muscle) microvasculature. Since, incretins have been shown to modulate blood flow and muscle glucose uptake in an insulin-independent manner, incretins may play a role in regulating nutrient-mediated modulation of muscle metabolism and microvascular tone, independently of their insulinotropic effects. In this review we will discuss the role of skeletal muscle in glucose homeostasis, disturbances related to insulin resistance, regulation of skeletal muscle metabolism, muscle microvascular abnormalities and disturbances of protein (PRO) metabolism seen in old age and T2D. We will also discuss the emerging non-insulinotropic role of GLP-1 in modulating skeletal muscle metabolism and microvascular blood flow.

  20. Gut Hormone Suppression Increases Food Intake After Esophagectomy With Gastric Conduit Reconstruction.

    PubMed

    Elliott, Jessie A; Jackson, Sabrina; King, Sinead; McHugh, Ruth; Docherty, Neil G; Reynolds, John V; le Roux, Carel W

    2015-11-01

    To characterize the gut hormone profile and determine the effect of satiety gut hormone blockade on food intake in disease-free postesophagectomy patients. Improved oncologic outcomes for esophageal cancer have resulted in increased survivorship and a focus on health-related quality of life. Anorexia and early satiety are common, but putative causative factors, in particular the gut-brain hormonal axis, have not been systematically studied. In a double-blind, placebo-controlled, randomized crossover study, disease-free patients at least 1 year postresection and gastric conduit reconstruction received either 1 mL 0.9% saline or 1 mL (100 μg) octreotide acetate subcutaneously followed by a standardized ad libitum meal on each of two assessments. Fasting and postprandial plasma glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin immunoreactivity were measured. Gut hormone responses and calorie intake postsaline versus octreotide were compared between experimental and control groups. Eighteen subjects [esophagectomy (ES), n = 10, 2.4 ± 0.75 years postresection; and unoperated control subjects, n = 8] were studied. ES demonstrated significant weight loss at 3, 6, 12, and 24 months postoperatively (all P < 0.05). Ghrelin levels were similar (P = 0.58) for both groups, but postprandial GLP-1 and PYY responses were significantly (P < 0.001) greater among ES as compared with controls. After octreotide, ad libitum calorie intake increased among ES (1.5 ± 0.2 fold-change, P = 0.02) but not controls (1.1 ± 0.1 fold-change, P = 0.30). ES demonstrated an exaggerated postprandial satiety gut hormone response that was attenuated by octreotide, thus identifying a potential therapeutic target to modulate in the ES patient with early satiety.

  1. Altered gut and adipose tissue hormones in overweight and obese individuals: cause or consequence?

    PubMed

    Lean, M E J; Malkova, D

    2016-04-01

    The aim of this article is to review the research into the main peripheral appetite signals altered in human obesity, together with their modifications after body weight loss with diet and exercise and after bariatric surgery, which may be relevant to strategies for obesity treatment. Body weight homeostasis involves the gut-brain axis, a complex and highly coordinated system of peripheral appetite hormones and centrally mediated neuronal regulation. The list of peripheral anorexigenic and orexigenic physiological factors in both animals and humans is intimidating and expanding, but anorexigenic glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), peptide YY (PYY) and orexigenic ghrelin from the gastrointestinal tract, pancreatic polypeptide (PP) from the pancreas and anorexigenic leptin from adiposites remain the most widely studied hormones. Homeostatic control of food intake occurs in humans, although its relative importance for eating behaviour is uncertain, compared with social and environmental influences. There are perturbations in the gut-brain axis in obese compared with lean individuals, as well as in weight-reduced obese individuals. Fasting and postprandial levels of gut hormones change when obese individuals lose weight, either with surgical or with dietary and/or exercise interventions. Diet-induced weight loss results in long-term changes in appetite gut hormones, postulated to favour increased appetite and weight regain while exercise programmes modify responses in a direction expected to enhance satiety and permit weight loss and/or maintenance. Sustained weight loss achieved by bariatric surgery may in part be mediated via favourable changes to gut hormones. Future work will be necessary to fully elucidate the role of each element of the axis, and whether modifying these signals can reduce the risk of obesity.

  2. The role of gut hormones in the regulation of body weight and energy homeostasis.

    PubMed

    Karra, Efthimia; Batterham, Rachel L

    2010-03-25

    Obesity is one of the greatest public health challenges of the 21st century with 1.6 billion adults currently classified as being overweight and 400 million as obese. Obesity is causally associated with type 2 diabetes, hypertension, cardiovascular disease, obstructive sleep apnoea and certain forms of cancer and is now one of the leading causes of mortality and morbidity worldwide. The gastrointestinal tract is the largest endocrine organ in the body producing hormones that have important sensing and signaling roles in regulating body weight and energy expenditure. The last decade has witnessed a marked increase in our understanding of the role of gut hormones in energy homeostasis. Consequently, strategies aimed at modulating circulating gut hormone concentrations or targeting their receptors are being developed as potential pharmacotherapies for obesity. This review summarizes the current knowledge regarding the mechanisms, sites of action and effects of the anorectic gut hormones peptide tyrosine-tyrosine (PYY), pancreatic polypeptide (PP), oxyntomodulin, and amylin and of the unique orexigenic hormone, ghrelin.

  3. [Incretin mimetic drugs: therapeutic positioning].

    PubMed

    López Simarro, F

    2014-07-01

    Type 2 diabetes is a chronic and complex disease, due to the differences among affected individuals, which affect choice of treatment. The number of drug families has increased in the last few years, and these families have widely differing mechanisms of action, which contributes greatly to the individualization of treatment according to the patient's characteristics and comorbidities. The present article discusses incretin mimetic drugs. Their development has been based on knowledge of the effects of natural incretin hormones: GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and dipeptidyl peptidase enzyme 4 (DPP4), which rapidly degrade them in the systemic circulation. This group is composed of 2 different types of molecules: GLP-1 analogs and DPP4 enzyme inhibitors. The benefits of these molecules include a reduction in plasma glucose without the risk of hypoglycemias or weight gain. There are a series of questions that require new studies to establish a possible association between the use of these drugs and notification of cases of pancreatitis, as well as their relationship with pancreatic and thyroid cancer. Also awaited is the publication of several studies that will provide information on the relationship between these drugs and cardiovascular risk in people with diabetes. All these questions will probably be progressively elucidated with greater experience in the use of these drugs. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Medicina Rural y Generalista (SEMERGEN). All rights reserved.

  4. Molecular mechanisms underlying nutrient detection by incretin-secreting cells

    PubMed Central

    Reimann, Frank

    2010-01-01

    The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted postprandially from intestinal K- and L-cells, respectively. As incretins, these hormones stimulate insulin secretion from the pancreatic β-cell, and have independently been implicated in the control of food intake and lipid metabolism. Whilst the enteroendocrine cells producing GIP and GLP-1 are therefore attractive targets for the treatment of diabetes and obesity, our understanding of their physiology is fairly limited. The mechanisms employed to sense the arrival of carbohydrate, fat and protein in the gut lumen have been investigated using organ perfusion techniques, primary epithelial cultures and cell line models. The recent development of mice with fluorescently labeled GIP or GLP-1-expressing cells is now enabling the use of single cell techniques to investigate stimulus-secretion coupling mechanisms. This review will focus on the current knowledge of the molecular machinery underlying nutrient sensing within K- and L-cells. PMID:20204054

  5. Receptors and effects of gut hormones in three osteoblastic cell lines

    PubMed Central

    2011-01-01

    Background In recent years the interest on the relationship of gut hormones to bone processes has increased and represents one of the most interesting aspects in skeletal research. The proportion of bone mass to soft tissue is a relationship that seems to be controlled by delicate and subtle regulations that imply "cross-talks" between the nutrient intake and tissues like fat. Thus, recognition of the mechanisms that integrate a gastrointestinal-fat-bone axis and its application to several aspects of human health is vital for improving treatments related to bone diseases. This work analysed the effects of gut hormones in cell cultures of three osteoblastic cell lines which represent different stages in osteoblastic development. Also, this is the first time that there is a report on the direct effects of glucagon-like peptide 2, and obestatin on osteoblast-like cells. Methods mRNA expression levels of five gut hormone receptors (glucose-dependent insulinotropic peptide [GIP], glucagon-like peptide 1 [GLP-1], glucagon-like peptide 2 [GLP-2], ghrelin [GHR] and obestatin [OB]) were analysed in three osteoblastic cell lines (Saos-2, TE-85 and MG-63) showing different stages of osteoblast development using reverse transcription and real time polymerase chain reaction. The responses to the gut peptides were studied using assays for cell viability, and biochemical bone markers: alkaline phosphatase (ALP), procollagen type 1 amino-terminal propeptides (P1NP), and osteocalcin production. Results The gut hormone receptor mRNA displayed the highest levels for GIP in Saos-2 and the lowest levels in MG-63, whereas GHR and GPR39 (the putative obestatin receptor) expression was higher in TE-85 and MG-63 and lower in Saos-2. GLP-1 and GLP-2 were expressed only in MG-63 and TE-85. Treatment of gut hormones to cell lines showed differential responses: higher levels in cell viability in Saos-2 after GIP, in TE-85 and MG-63 after GLP-1, GLP-2, ghrelin and obestatin. ALP showed higher

  6. Autonomous regulation of the insect gut by circadian genes acting downstream of juvenile hormone signaling

    PubMed Central

    Bajgar, Adam; Jindra, Marek; Dolezel, David

    2013-01-01

    In temperate regions, the shortening day length informs many insect species to prepare for winter by inducing diapause. The adult diapause of the linden bug, Pyrrhocoris apterus, involves a reproductive arrest accompanied by energy storage, reduction of metabolic needs, and preparation to withstand low temperatures. By contrast, nondiapause animals direct nutrient energy to muscle activity and reproduction. The photoperiod-dependent switch from diapause to reproduction is systemically transmitted throughout the organism by juvenile hormone (JH). Here, we show that, at the organ-autonomous level of the insect gut, the decision between reproduction and diapause relies on an interaction between JH signaling and circadian clock genes acting independently of the daily cycle. The JH receptor Methoprene-tolerant and the circadian proteins Clock and Cycle are all required in the gut to activate the Par domain protein 1 gene during reproduction and to simultaneously suppress a mammalian-type cryptochrome 2 gene that promotes the diapause program. A nonperiodic, organ-autonomous feedback between Par domain protein 1 and Cryptochrome 2 then orchestrates expression of downstream genes that mark the diapause vs. reproductive states of the gut. These results show that hormonal signaling through Methoprene-tolerant and circadian proteins controls gut-specific gene activity that is independent of circadian oscillations but differs between reproductive and diapausing animals. PMID:23442387

  7. The incretin hormone glucagon‐like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage‐dependent potassium channel

    PubMed Central

    Llewellyn‐Smith, Ida J.; Gribble, Fiona; Reimann, Frank; Trapp, Stefan; Fadool, Debra Ann

    2016-01-01

    Key points The gut hormone called glucagon‐like peptide 1 (GLP‐1) is a strong moderator of energy homeostasis and communication between the peripheral organs and the brain.GLP‐1 signalling occurs in the brain; using a newly developed genetic reporter line of mice, we have discovered GLP‐synthesizing cells in the olfactory bulb.GLP‐1 increases the firing frequency of neurons (mitral cells) that encode olfactory information by decreasing activity of voltage‐dependent K channels (Kv1.3).Modifying GLP‐1 levels, either therapeutically or following the ingestion of food, could alter the excitability of neurons in the olfactory bulb in a nutrition or energy state‐dependent manner to influence olfactory detection or metabolic sensing.The results of the present study uncover a new function for an olfactory bulb neuron (deep short axon cells, Cajal cells) that could be capable of modifying mitral cell activity through the release of GLP‐1. This might be of relevance for the action of GLP‐1 mimetics now widely used in the treatment of diabetes. Abstract The olfactory system is intricately linked with the endocrine system where it may serve as a detector of the internal metabolic state or energy homeostasis in addition to its classical function as a sensor of external olfactory information. The recent development of transgenic mGLU‐yellow fluorescent protein mice that express a genetic reporter under the control of the preproglucagon reporter suggested the presence of the gut hormone, glucagon‐like peptide (GLP‐1), in deep short axon cells (Cajal cells) of the olfactory bulb and its neuromodulatory effect on mitral cell (MC) first‐order neurons. A MC target for the peptide was determined using GLP‐1 receptor binding assays, immunocytochemistry for the receptor and injection of fluorescence‐labelled GLP‐1 analogue exendin‐4. Using patch clamp recording of olfactory bulb slices in the whole‐cell configuration, we report that GLP‐1 and its

  8. The incretin hormone glucagon-like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage-dependent potassium channel.

    PubMed

    Thiebaud, Nicolas; Llewellyn-Smith, Ida J; Gribble, Fiona; Reimann, Frank; Trapp, Stefan; Fadool, Debra Ann

    2016-05-15

    The gut hormone called glucagon-like peptide 1 (GLP-1) is a strong moderator of energy homeostasis and communication between the peripheral organs and the brain. GLP-1 signalling occurs in the brain; using a newly developed genetic reporter line of mice, we have discovered GLP-synthesizing cells in the olfactory bulb. GLP-1 increases the firing frequency of neurons (mitral cells) that encode olfactory information by decreasing activity of voltage-dependent K channels (Kv1.3). Modifying GLP-1 levels, either therapeutically or following the ingestion of food, could alter the excitability of neurons in the olfactory bulb in a nutrition or energy state-dependent manner to influence olfactory detection or metabolic sensing. The results of the present study uncover a new function for an olfactory bulb neuron (deep short axon cells, Cajal cells) that could be capable of modifying mitral cell activity through the release of GLP-1. This might be of relevance for the action of GLP-1 mimetics now widely used in the treatment of diabetes. The olfactory system is intricately linked with the endocrine system where it may serve as a detector of the internal metabolic state or energy homeostasis in addition to its classical function as a sensor of external olfactory information. The recent development of transgenic mGLU-yellow fluorescent protein mice that express a genetic reporter under the control of the preproglucagon reporter suggested the presence of the gut hormone, glucagon-like peptide (GLP-1), in deep short axon cells (Cajal cells) of the olfactory bulb and its neuromodulatory effect on mitral cell (MC) first-order neurons. A MC target for the peptide was determined using GLP-1 receptor binding assays, immunocytochemistry for the receptor and injection of fluorescence-labelled GLP-1 analogue exendin-4. Using patch clamp recording of olfactory bulb slices in the whole-cell configuration, we report that GLP-1 and its stable analogue exendin-4 increase the action potential

  9. Altered gut and adipose tissue hormones in overweight and obese individuals: cause or consequence?

    PubMed Central

    Lean, M E J; Malkova, D

    2016-01-01

    The aim of this article is to review the research into the main peripheral appetite signals altered in human obesity, together with their modifications after body weight loss with diet and exercise and after bariatric surgery, which may be relevant to strategies for obesity treatment. Body weight homeostasis involves the gut–brain axis, a complex and highly coordinated system of peripheral appetite hormones and centrally mediated neuronal regulation. The list of peripheral anorexigenic and orexigenic physiological factors in both animals and humans is intimidating and expanding, but anorexigenic glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), peptide YY (PYY) and orexigenic ghrelin from the gastrointestinal tract, pancreatic polypeptide (PP) from the pancreas and anorexigenic leptin from adiposites remain the most widely studied hormones. Homeostatic control of food intake occurs in humans, although its relative importance for eating behaviour is uncertain, compared with social and environmental influences. There are perturbations in the gut–brain axis in obese compared with lean individuals, as well as in weight-reduced obese individuals. Fasting and postprandial levels of gut hormones change when obese individuals lose weight, either with surgical or with dietary and/or exercise interventions. Diet-induced weight loss results in long-term changes in appetite gut hormones, postulated to favour increased appetite and weight regain while exercise programmes modify responses in a direction expected to enhance satiety and permit weight loss and/or maintenance. Sustained weight loss achieved by bariatric surgery may in part be mediated via favourable changes to gut hormones. Future work will be necessary to fully elucidate the role of each element of the axis, and whether modifying these signals can reduce the risk of obesity. PMID:26499438

  10. Soya milk exerts different effects on plasma amino acid responses and incretin hormone secretion compared with cows' milk in healthy, young men.

    PubMed

    Sun, Lijuan; Tan, Kevin Wei Jie; Siow, Phei Ching; Henry, Christiani Jeyakumar

    2016-10-01

    Apart from the well-known action of insulin, the mechanism by which soya and cows' milk improve postprandial glycaemia control was examined. In total, twelve healthy, young, Chinese men were studied on three separate occasions, in random order with isovolumetric (322 ml) control water, soya milk and cows' milk. Plasma total amino acid concentrations increased 30 min after test meals consumption and were higher after soya milk (230 %) and cow milk (240 %) consumption compared with water. Cows' milk ingestion induced higher branched-chain amino acids (BCAA) (40 %) than soya milk. Postprandial incretin concentrations increased after meal consumption. Cows' milk meal was accompanied by higher incremental AUC (iAUC) (170 %) for glucagon-like peptide-1 (GLP-1) compared with soya milk and control (P=0·06). However, glucose-dependent insulinotropic polypeptide (GIP) concentrations increased to significantly greater levels after soya milk consumption (iAUC 60 % higher) compared with cows' milk and control. Consumption of both soya and cows' milk with carbohydrates induced a similar reduction in glycaemic response through a different mechanism, beyond insulin action. Plasma amino acids (alanine and arginine), and incretins in particular (GIP was stimulated), may be involved in the hyperinsulinaemia after soya milk meals. However, BCAA and GLP-1 release may be responsible for the reduced glycaemia after cows' milk consumption by delaying gastric emptying. This could be the result of different milk protein/amino acid composition, but also differences in milk carbohydrate composition (i.e. lactose v. sucrose). It can be concluded that soya milk is a good alternative to cows' milk with regard to glycaemic regulation, with different mechanisms involved.

  11. Gastric emptying, mouth-to-cecum transit, and glycemic, insulin, incretin, and energy intake responses to a mixed-nutrient liquid in lean, overweight, and obese males.

    PubMed

    Seimon, Radhika V; Brennan, Ixchel M; Russo, Antonietta; Little, Tanya J; Jones, Karen L; Standfield, Scott; Wishart, Judith M; Horowitz, Michael; Feinle-Bisset, Christine

    2013-02-01

    Observations relating to the impact of obesity on gastric emptying (GE) and the secretion of gut hormones are inconsistent, probably because of a lack of studies in which GE, gastrointestinal hormone release, and energy intake (EI) have been evaluated concurrently with previous patterns of nutrient intake. GE is known to be a major determinant of postprandial glycemia and incretin secretion in health and type 2 diabetes. The aims of this study were to determine the effects of a mixed-nutrient drink on GE, oro-cecal transit, blood glucose, insulin and incretin concentrations and EI, and the relationship between the glycemic response to the drink with GE in lean, overweight, and obese subjects. Twenty lean, 20 overweight, and 20 obese males had measurements of GE, oro-cecal transit, and blood glucose, insulin, GLP-1, and GIP concentrations for 5 h after ingestion of a mixed-nutrient drink (500 ml, 532 kcal); EI at a subsequent buffet lunch was determined. Habitual EI was also quantified. Glycemic and insulinemic responses to the drink were greater in the obese (both P < 0.05) when compared with both lean and overweight, with no significant differences in GE, intragastric distribution, oro-cecal transit, incretins, or EI (buffet lunch or habitual) between groups. The magnitude of the rise in blood glucose after the drink was greater when GE was relatively more rapid (r = -0.55, P < 0.05). In conclusion, in the absence of differences in habitual EI, both GE and incretin hormones are unaffected in the obese despite greater glucose and insulin responses, and GE is a determinant of postprandial glycemia.

  12. Systematic Review: The emerging interplay between bile acids, gastrointestinal tract, and incretins in the pathogenesis of diabetes and nonalcoholic fatty liver disease

    PubMed Central

    Zarrinpar, Amir; Loomba, Rohit

    2012-01-01

    SUMMARY Background Recent research has led to an interest in the role of the gut and liver in type 2 diabetes mellitus (T2DM). Aim To review the role of the gastrointestinal system in glucose homeostasis, with particular focus on the effects of incretin hormones, hepatic steatosis, and bile acids. Methods PubMed and Google Scholar were searched using terms such as incretin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4), hepatic steatosis, bile acid, and gastric bypass. Additional relevant references were identified by reviewing the reference lists of articles. Results Perturbations of incretin hormones and bile acid secretion contribute to the pathogenesis of T2DM, leading to their potential as therapeutic targets. The incretin hormones (GIP and GLP-1) are deactivated by DPP-4. GLP-1 agonists and DPP-4 inhibitors improve glycemic control in patients with T2DM. Hepatic steatosis, along with insulin resistance, may precede the development of T2DM, and may benefit from antidiabetes medications. Bile acids play an important role in glucose homeostasis, with effects mediated via the farnesoid X receptor (FXR) and the cell surface G protein-coupled receptor TGR5. The bile acid sequestrant colesevelam has been shown to be effective in improving glycemic control in patients with T2DM. Altered gastrointestinal anatomy after gastric bypass surgery may also affect enterohepatic recirculation of bile acids and contribute to improved glycemic control. Conclusions: Research in recent years has led to new pathways and processes with a role in glucose homeostasis, and new therapeutic targets and options for T2DM. PMID:23057494

  13. Gut chemosensing: interactions between gut endocrine cells and visceral afferents.

    PubMed

    Raybould, Helen E

    2010-02-16

    Chemosensing in the gastrointestinal tract is less well understood than many aspects of gut mechanosensitivity; however, it is important in the overall function of the GI tract and indeed the organism as a whole. Chemosensing in the gut represents a complex interplay between the function of enteroendocrine (EEC) cells and visceral (primarily vagal) afferent neurons. In this brief review, I will concentrate on a new data on endocrine cells in chemosensing in the GI tract, in particular on new findings on glucose-sensing by gut EEC cells and the importance of incretin peptides and vagal afferents in glucose homeostasis, on the role of G protein coupled receptors in gut chemosensing, and on the possibility that gut endocrine cells may be involved in the detection of a luminal constituent other than nutrients, the microbiota. The role of vagal afferent pathways as a downstream target of EEC cell products will be considered and, in particular, exciting new data on the plasticity of the vagal afferent pathway with respect to expression of receptors for GI hormones and how this may play a role in energy homeostasis will also be discussed.

  14. Changes in gut hormone levels and negative energy balance during aerobic exercise in obese young males.

    PubMed

    Ueda, Shin-ya; Yoshikawa, Takahiro; Katsura, Yoshihiro; Usui, Tatsuya; Nakao, Hayato; Fujimoto, Shigeo

    2009-04-01

    We examined whether changes in gut hormone levels due to a single bout of aerobic exercise differ between obese young males and normal controls, and attempted to determine the involvement of hormonal changes during exercise in the regulation of energy balance (EB) in these obese subjects. Seven obese and seven age-matched subjects of normal weight participated in exercise and rest sessions. Subjects consumed a standardized breakfast that was followed by constant cycling exercise at 50% VO(2max) or rest for 60 min. At lunch, a test meal was presented, and energy intake (EI) and relative energy intake (REI) were calculated. Blood samples were obtained at 30 min intervals during both sessions for measurement of glucose, insulin, glucagon, ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Plasma levels of PYY and GLP-1 were increased by exercise, whereas plasma ghrelin levels were unaffected by exercise. The areas under the curve (AUC) of the time courses of PYY and GLP-1 levels did not significantly differ between the two groups. In contrast, EI and REI were decreased by exercise in both groups, and energy deficit was significantly larger in obese subjects than in normal controls. The present findings suggest that short-term EB during a single exercise session might be regulated not by increased amounts of these gut hormones per se.

  15. The CTRB1/2 Locus Affects Diabetes Susceptibility and Treatment via the Incretin Pathway

    PubMed Central

    ‘t Hart, Leen M.; Fritsche, Andreas; Nijpels, Giel; van Leeuwen, Nienke; Donnelly, Louise A.; Dekker, Jacqueline M.; Alssema, Marjan; Fadista, Joao; Carlotti, Françoise; Gjesing, Anette P.; Palmer, Colin N.A.; van Haeften, Timon W.; Herzberg-Schäfer, Silke A.; Simonis-Bik, Annemarie M.C.; Houwing-Duistermaat, Jeanine J.; Helmer, Quinta; Deelen, Joris; Guigas, Bruno; Hansen, Torben; Machicao, Fausto; Willemsen, Gonneke; Heine, Robert J.; Kramer, Mark H.H.; Holst, Jens J.; de Koning, Eelco J.P.; Häring, Hans-Ulrich; Pedersen, Oluf; Groop, Leif; de Geus, Eco J.C.; Slagboom, P. Eline; Boomsma, Dorret I.; Eekhoff, Elisabeth M.W.; Pearson, Ewan R.; Diamant, Michaela

    2013-01-01

    The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances β-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30–40%) on GLP-1–stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤ 8.8 × 10−7). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment. PMID:23674605

  16. Interactive effects of oligofructose and obesity predisposition on gut hormones and microbiota in diet-induced obese rats.

    PubMed

    Cluny, Nina L; Eller, Lindsay K; Keenan, Catherine M; Reimer, Raylene A; Sharkey, Keith A

    2015-04-01

    Oligofructose (OFS) is a prebiotic that reduces energy intake and fat mass via changes in gut satiety hormones and microbiota. The effects of OFS may vary depending on predisposition to obesity. The aim of this study was to examine the effect of OFS in diet-induced obese (DIO) and diet-resistant (DR) rats. Adult, male DIO, and DR rats were randomized to: high-fat/high-sucrose (HFS) diet or HFS diet + 10% OFS for 6 weeks. Body composition, food intake, gut microbiota, plasma gut hormones, and cannabinoid CB(1) receptor expression in the nodose ganglia were measured. OFS reduced body weight, energy intake, and fat mass in both phenotypes (P < 0.05). Select gut microbiota differed in DIO versus DR rats (P < 0.05), the differences being eliminated by OFS. OFS did not modify plasma ghrelin or CB(1) expression in nodose ganglia, but plasma levels of GIP were reduced and PYY were elevated (P < 0.05) by OFS. OFS was able to reduce body weight and adiposity in both prone and resistant obese phenotypes. OFS-induced changes in gut microbiota profiles in DIO and DR rats, along with changes in gut hormone levels, likely contribute to the sustained lower body weights. © 2015 The Obesity Society.

  17. Comparative effects of intraduodenal whey protein hydrolysate on antropyloroduodenal motility, gut hormones, glycemia, appetite, and energy intake in lean and obese men.

    PubMed

    Hutchison, Amy T; Feinle-Bisset, Christine; Fitzgerald, Penelope C E; Standfield, Scott; Horowitz, Michael; Clifton, Peter M; Luscombe-Marsh, Natalie D

    2015-12-01

    In lean individuals, intraduodenal protein and lipid modulate gastrointestinal motor and hormone functions and reduce energy intake in a load-dependent manner; protein also stimulates insulin, with modest effects on reducing blood glucose. The effect of intraduodenal lipid on gastrointestinal motor and hormone responses is diminished in obesity; whether the effects of protein are also attenuated remains unclear. The objectives of this study were to characterize the load-dependent effects of intraduodenal whey protein hydrolysate on antropyloroduodenal pressures, gut hormones, glycemia, appetite, and energy intake in obese subjects and to compare the responses to the higher protein load with those in lean subjects. We measured antropyloroduodenal pressures, plasma cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, insulin, blood glucose, appetite, and energy intake in 12 nondiabetic obese men on 3 separate occasions, in a double-blind, randomized order, during 60-min intraduodenal infusions of hydrolyzed whey protein at either 0 (saline control), 1.5, or 3 kcal/min. Twelve age-matched lean individuals received a 3-kcal/min infusion only. Immediately after the infusions, energy intake from a buffet lunch was quantified. In obese subjects, protein suppressed antral and duodenal pressures; stimulated plasma CCK, GLP-1, GIP, insulin, and glucagon (all r > 0.57, P < 0.01); and tended to reduce energy intake (r = -10.38, P = 0.057) in a dose-dependent manner. In response to the 3-kcal/min protein load, antropyloroduodenal pressures, CCK, GLP-1, and glucagon did not differ between lean and obese subjects. Insulin release was greater, and GIP release less, in obese than in lean subjects (both P < 0.05), whereas the reduction in glucose was comparable. Energy intake tended to be higher in obese subjects (P = 0.08). The gastrointestinal effects of hydrolyzed whey protein remain relatively intact in obesity

  18. Changes in gut hormones and leptin in military personnel during operational deployment in Afghanistan.

    PubMed

    Hill, Neil E; Fallowfield, Joanne L; Delves, Simon K; Ardley, Christian; Stacey, Michael; Ghatei, Mohammad; Bloom, Stephen R; Frost, Gary; Brett, Stephen J; Wilson, Duncan R; Murphy, Kevin G

    2015-03-01

    Understanding the mechanisms that drive weight loss in a lean population may elucidate systems that regulate normal energy homeostasis. This prospective study of British military volunteers investigated the effects of a 6-month deployment to Afghanistan on energy balance and circulating concentrations of specific appetite-regulating hormones. Measurements were obtained twice in the UK (during the Pre-deployment period) and once in Afghanistan, at Mid-deployment. Body mass, body composition, food intake, and appetite-regulatory hormones (leptin, active and total ghrelin, PYY, PP, GLP-1) were measured. Repeated measures analysis of 105 volunteers showed body mass decreased by 4.9% ± 3.7% (P < 0.0001) during the first half of the deployment. Leptin concentrations were significantly correlated with percentage body fat at each time point. The reduction in percentage body fat between Pre-deployment and Mid-deployment was 8.6%, with a corresponding 48% decrease in mean circulating leptin. Pre-deployment leptin and total and active ghrelin levels correlated with subsequent change in body mass; however. no changes were observed in the anorectic gut hormones GLP-1, PP, or PYY. These data suggest that changes in appetite-regulating hormones in front line military personnel occur in response to, but do not drive, reductions in body mass. © 2015 The Obesity Society.

  19. Effects of Dietary Bacillus licheniformis on Gut Physical Barrier, Immunity, and Reproductive Hormones of Laying Hens.

    PubMed

    Wang, Yang; Du, Wei; Lei, Kai; Wang, Baikui; Wang, Yuanyuan; Zhou, Yingshan; Li, Weifen

    2017-01-13

    Previous study showed that dietary Bacillus licheniformis (B. licheniformis) administration contributes to the improvement of laying performance and egg quality in laying hens. In this study, we aimed to further evaluate its underlying mechanisms. Three hundred sixty Hy-Line Variety W-36 hens (28 weeks of age) were randomized into four groups, each group with six replications (n = 15). The control group received the basal diet and the treatment groups received the same basal diets supplemented with 0.01, 0.03, and 0.06% B. licheniformis powder (2 × 10(10) cfu/g) for an 8-week trial. The results demonstrate that B. licheniformis significantly enhance the intestinal barrier functions via decreasing gut permeability, promoting mucin-2 transcription, and regulating inflammatory cytokines. The systemic immunity of layers in B. licheniformis treatment groups is improved through modulating the specific and non-specific immunity. In addition, gene expressions of hormone receptors, including estrogen receptor α, estrogen receptor β, and follicle-stimulating hormone receptor, are also regulated by B. licheniformis. Meanwhile, compared with the control, B. licheniformis significantly increase gonadotropin-releasing hormone level, but markedly reduce ghrelin and inhibin secretions. Overall, our data suggest that dietary inclusion of B. licheniformis can improve the intestinal barrier function and systemic immunity and regulate reproductive hormone secretions, which contribute to better laying performance and egg quality of hens.

  20. Link Between Increased Satiety Gut Hormones and Reduced Food Reward After Gastric Bypass Surgery for Obesity.

    PubMed

    Goldstone, Anthony P; Miras, Alexander D; Scholtz, Samantha; Jackson, Sabrina; Neff, Karl J; Pénicaud, Luc; Geoghegan, Justin; Chhina, Navpreet; Durighel, Giuliana; Bell, Jimmy D; Meillon, Sophie; le Roux, Carel W

    2016-02-01

    Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss maintenance, reducing appetite, and also food reward, via unclear mechanisms. To investigate the role of elevated satiety gut hormones after RYGB, we examined food hedonic-reward responses after their acute post-prandial suppression. These were randomized, placebo-controlled, double-blind, crossover experimental medicine studies. Two groups, more than 5 months after RYGB for obesity (n = 7-11), compared with nonobese controls (n = 10), or patients after gastric banding (BAND) surgery (n = 9) participated in the studies. Studies were performed after acute administration of the somatostatin analog octreotide or saline. In one study, patients after RYGB, and nonobese controls, performed a behavioral progressive ratio task for chocolate sweets. In another study, patients after RYGB, and controls after BAND surgery, performed a functional magnetic resonance imaging food picture evaluation task. Octreotide increased both appetitive food reward (breakpoint) in the progressive ratio task (n = 9), and food appeal (n = 9) and reward system blood oxygen level-dependent signal (n = 7) in the functional magnetic resonance imaging task, in the RYGB group, but not in the control groups. Octreotide suppressed postprandial plasma peptide YY, glucagon-like peptide-1, and fibroblast growth factor-19 after RYGB. The reduction in plasma peptide YY with octreotide positively correlated with the increase in brain reward system blood oxygen level-dependent signal in RYGB/BAND subjects, with a similar trend for glucagon-like peptide-1. Enhanced satiety gut hormone responses after RYGB may be a causative mechanism by which anatomical alterations of the gut in obesity surgery modify behavioral and brain reward responses to food.

  1. L-arginine promotes gut hormone release and reduces food intake in rodents.

    PubMed

    Alamshah, A; McGavigan, A K; Spreckley, E; Kinsey-Jones, J S; Amin, A; Tough, I R; O'Hara, H C; Moolla, A; Banks, K; France, R; Hyberg, G; Norton, M; Cheong, W; Lehmann, A; Bloom, S R; Cox, H M; Murphy, K G

    2016-05-01

    To investigate the anorectic effect of L-arginine (L-Arg) in rodents. We investigated the effects of L-Arg on food intake, and the role of the anorectic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), the G-protein-coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents. Oral gavage of L-Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet-induced obese mice. Lack of the GPRC6A in mice and subdiaphragmatic vagal deafferentation in rats did not influence these anorectic effects. L-Arg stimulated GLP-1 and PYY release in vitro and in vivo. Pharmacological blockade of GLP-1 and PYY receptors did not influence the anorectic effect of L-Arg. L-Arg-mediated PYY release modulated net ion transport across the gut mucosa. Intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of L-Arg suppressed food intake in rats. L-Arg reduced food intake and stimulated gut hormone release in rodents. The anorectic effect of L-Arg is unlikely to be mediated by GLP-1 and PYY, does not require GPRC6A signalling and is not mediated via the vagus. I.c.v. and i.p. administration of L-Arg suppressed food intake in rats, suggesting that L-Arg may act on the brain to influence food intake. Further work is required to determine the mechanisms by which L-Arg suppresses food intake and its utility in the treatment of obesity. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  2. Link Between Increased Satiety Gut Hormones and Reduced Food Reward After Gastric Bypass Surgery for Obesity

    PubMed Central

    Miras, Alexander D.; Scholtz, Samantha; Jackson, Sabrina; Neff, Karl J.; Pénicaud, Luc; Geoghegan, Justin; Chhina, Navpreet; Durighel, Giuliana; Bell, Jimmy D.; Meillon, Sophie; le Roux, Carel W.

    2016-01-01

    Context: Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss maintenance, reducing appetite, and also food reward, via unclear mechanisms. Objective: To investigate the role of elevated satiety gut hormones after RYGB, we examined food hedonic-reward responses after their acute post-prandial suppression. Design: These were randomized, placebo-controlled, double-blind, crossover experimental medicine studies. Patients: Two groups, more than 5 months after RYGB for obesity (n = 7–11), compared with nonobese controls (n = 10), or patients after gastric banding (BAND) surgery (n = 9) participated in the studies. Intervention: Studies were performed after acute administration of the somatostatin analog octreotide or saline. In one study, patients after RYGB, and nonobese controls, performed a behavioral progressive ratio task for chocolate sweets. In another study, patients after RYGB, and controls after BAND surgery, performed a functional magnetic resonance imaging food picture evaluation task. Main Outcome Measures: Octreotide increased both appetitive food reward (breakpoint) in the progressive ratio task (n = 9), and food appeal (n = 9) and reward system blood oxygen level-dependent signal (n = 7) in the functional magnetic resonance imaging task, in the RYGB group, but not in the control groups. Results: Octreotide suppressed postprandial plasma peptide YY, glucagon-like peptide-1, and fibroblast growth factor-19 after RYGB. The reduction in plasma peptide YY with octreotide positively correlated with the increase in brain reward system blood oxygen level-dependent signal in RYGB/BAND subjects, with a similar trend for glucagon-like peptide-1. Conclusions: Enhanced satiety gut hormone responses after RYGB may be a causative mechanism by which anatomical alterations of the gut in obesity surgery modify behavioral and brain reward responses to food. PMID:26580235

  3. L‐arginine promotes gut hormone release and reduces food intake in rodents

    PubMed Central

    Alamshah, A.; McGavigan, A. K.; Spreckley, E.; Kinsey‐Jones, J. S.; Amin, A.; Tough, I. R.; O'Hara, H. C.; Moolla, A.; Banks, K.; France, R.; Hyberg, G.; Norton, M.; Cheong, W.; Lehmann, A.; Bloom, S. R.; Cox, H. M.

    2016-01-01

    Aims To investigate the anorectic effect of L‐arginine (L‐Arg) in rodents. Methods We investigated the effects of L‐Arg on food intake, and the role of the anorectic gut hormones glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY), the G‐protein‐coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents. Results Oral gavage of L‐Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet‐induced obese mice. Lack of the GPRC6A in mice and subdiaphragmatic vagal deafferentation in rats did not influence these anorectic effects. L‐Arg stimulated GLP‐1 and PYY release in vitro and in vivo. Pharmacological blockade of GLP‐1 and PYY receptors did not influence the anorectic effect of L‐Arg. L‐Arg‐mediated PYY release modulated net ion transport across the gut mucosa. Intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of L‐Arg suppressed food intake in rats. Conclusions L‐Arg reduced food intake and stimulated gut hormone release in rodents. The anorectic effect of L‐Arg is unlikely to be mediated by GLP‐1 and PYY, does not require GPRC6A signalling and is not mediated via the vagus. I.c.v. and i.p. administration of L‐Arg suppressed food intake in rats, suggesting that L‐Arg may act on the brain to influence food intake. Further work is required to determine the mechanisms by which L‐Arg suppresses food intake and its utility in the treatment of obesity. PMID:26863991

  4. Pro-protein convertases in intermediary metabolism: islet hormones, brain/gut hormones and integrated physiology.

    PubMed

    Bataille, Dominique

    2007-07-01

    Many peptide hormones implicated in the regulation of intermediary metabolism arise from larger precursors called prohormones. These precursors are cut into pieces by proprotein convertases, more precisely those called prohormone convertases (PCs) that cleave at the C terminus of basic doublets. The remaining basic amino acids are eliminated by a specialized carboxypeptidase, leading to the active hormone. This processing may provide, from a single precursor, several peptides with different biological activities depending on the site(s) of cleavage on the precursor. When the processing is tissue-specific, this mechanism allows to produce, from a single protein, different sets of hormones depending on the tissue considered, leading to novel regulatory processes. The archetype of such a pluripotent prohormone in the field of intermediary metabolism is pro-glucagon that, when cut by PC1 in intestinal L cells, produces four different peptides with different specificities [glicentin, oxyntomodulin (OXM), glucagon-like peptide-1, and glucagon-like peptide-2], whereas, when cut by PC2 in the alpha cells of the endocrine pancreas, glucagon is produced and, through the supplementary action of NRD convertase, a fragment of glucagon (miniglucagon) with original properties.

  5. Antihyperglycemic potential of incretins orally delivered via nano and microsystems and subsequent glucoregulatory effects.

    PubMed

    Araujo, Francisca; Shrestha, Neha; Granja, Pedro L; Hirvonen, Jouni; Santos, Hélder A; Sarmento, Bruno

    2014-01-01

    Type 2 diabetes mellitus (T2DM) is mainly associated with impaired insulin secretion by the pancreatic β-cells, insulin resistance and elevated hepatic gluconeogenesis. Incretin based treatments for T2DM are now widely investigated and used. The incretin based therapies mainly include incretin hormones which are glucose-dependent insulinotropic peptides (GIP) and glucagon like peptide-1 (GLP-1) released from the endocrinal cells in the small intestine in response to food intake. The main function of GLP-1 is to induce insulin secretion and suppress glucagon secretion. This review describes the different formulation approaches for oral delivery of incretins and the limitations associated with this route of administration. We highlight the use of micro and nanosystems to efficiently deliver the incretins orally. Furthermore, we present several examples of the significant potential of these systems in pharmaceutical applications.

  6. Incretins and their role in the management of diabetes.

    PubMed

    Frias, Juan P; Edelman, Steven V

    2007-08-01

    To review data from clinical trials of incretin mimetics in patients with type 2 diabetes. Incretin mimetics are a new class of antidiabetic medication that mimic the actions of the hormone glucagon-like peptide-1. They exhibit several properties, including glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and induction of satiety, which result in improvements in glycemic control with weight loss in patients with type 2 diabetes. Recent 2-year data with exenatide, the only commercially available incretin mimetic, have demonstrated long-term sustained reductions in hemoglobin A1c with progressive weight loss. Glycemic and weight benefits were also recently reported in a 15-week study assessing once-weekly administration of long-acting release exenatide, a formulation currently in phase 3 of clinical development. Once-daily administration of liraglutide, also in phase 3 of development, has recently been shown to improve glycemic and weigh control as monotherapy, and in combination with metformin. The most common side effects of incretin mimetics are gastrointestinal in nature, particularly nausea. The ability of incretin mimetics to improve glycemic control and reduce body weight is a unique property that fills an important void in the treatment of patients with type 2 diabetes.

  7. Metabolic surgery: action via hormonal milieu changes, changes in bile acids or gut microbiota? A summary of the literature

    PubMed Central

    Sweeney, Timothy E.; Morton, John M.

    2015-01-01

    Obesity and type 2 diabetes remain epidemic problems. Different bariatric surgical techniques causes weight loss and diabetes remission to varying degrees. The underlying mechanisms of the beneficial effects of bariatric surgery are complex, and include changes in diet and behavior, as well as changes in hormones, bile acid flow, and gut bacteria. We summarized the effects of multiple different bariatric procedures, and their resulting effects on several hormones (leptin, ghrelin, adiponectin, glucagon-like peptide 1 (GLP-1), peptide YY, and glucagon), bile acid changes in the gut and the serum, and resulting changes to the gut microbiome. As much as possible, we have tried to incorporate multiple studies to try to explain underlying mechanistic changes. What emerges from the data is a picture of clear differences between restrictive and metabolic procedures. The latter, in particular the roux-en-Y gastric bypass, induces large and distinctive changes in most measured fat and gut hormones, including early and sustained increase in GLP-1, possible through intestinal bile acid signaling. The changes in bile flow and the gut microbiome are causally inseparable so far, but new studies show that each contributes to the effects of weight loss and diabetes resolution. PMID:25194186

  8. Obesity, Diabetes, and Gut Microbiota

    PubMed Central

    Musso, Giovanni; Gambino, Roberto; Cassader, Maurizio

    2010-01-01

    The connection between gut microbiota and energy homeostasis and inflammation and its role in the pathogenesis of obesity-related disorders are increasingly recognized. Animals models of obesity connect an altered microbiota composition to the development of obesity, insulin resistance, and diabetes in the host through several mechanisms: increased energy harvest from the diet, altered fatty acid metabolism and composition in adipose tissue and liver, modulation of gut peptide YY and glucagon-like peptide (GLP)-1 secretion, activation of the lipopolysaccharide toll-like receptor-4 axis, and modulation of intestinal barrier integrity by GLP-2. Instrumental for gut microbiota manipulation is the understanding of mechanisms regulating gut microbiota composition. Several factors shape the gut microflora during infancy: mode of delivery, type of infant feeding, hospitalization, and prematurity. Furthermore, the key importance of antibiotic use and dietary nutrient composition are increasingly recognized. The role of the Western diet in promoting an obesogenic gut microbiota is being confirmation in subjects. Following encouraging results in animals, several short-term randomized controlled trials showed the benefit of prebiotics and probiotics on insulin sensitivity, inflammatory markers, postprandial incretins, and glucose tolerance. Future research is needed to unravel the hormonal, immunomodulatory, and metabolic mechanisms underlying microbe-microbe and microbiota-host interactions and the specific genes that determine the health benefit derived from probiotics. While awaiting further randomized trials assessing long-term safety and benefits on clinical end points, a healthy lifestyle—including breast lactation, appropriate antibiotic use, and the avoidance of excessive dietary fat intake—may ensure a friendly gut microbiota and positively affect prevention and treatment of metabolic disorders. PMID:20876708

  9. Differences in Weight Loss and Gut Hormones: Rouen-Y Gastric Bypass and Sleeve Gastrectomy Surgery.

    PubMed

    Malin, Steven K; Kashyap, Sangeeta R

    2015-06-01

    Bariatric surgery is arguably the most effective therapy for weight loss, and Rouen-Y gastric bypass (RYGB) is considered the "gold-standard" procedure. However, sleeve gastrectomy (SG) surgery has become more prevalent in recent years and it is unclear if weight loss differences occur between these procedures. Herein, we discuss evidence from randomized clinical trials comparing the effectiveness of RYGB and SG on weight loss. Moreover, we highlight gut hormones (e.g., GLP-1, ghrelin, bile acids, etc.) as potentially important mechanisms that contribute to the durability of decreased appetite and opposed fat storage following RYGB and SG. Collectively, although a subtle (∼ 3-5 kg) weight loss difference may exist in favor of RYGB up to 3 years post-operation, it appears that RYGB and SG induce comparable weight loss and changes in gut physiology that parallel reduced disease risk. These findings are clinically relevant for optimizing treatment strategies that combat obesity-related diabetes and cardiovascular disease.

  10. Free fatty acids have more potent effects on gastric emptying, gut hormones, and appetite than triacylglycerides.

    PubMed

    Little, Tanya J; Russo, Antonietta; Meyer, James H; Horowitz, Michael; Smyth, Douglas R; Bellon, Max; Wishart, Judith M; Jones, Karen L; Feinle-Bisset, Christine

    2007-10-01

    The effects of fat on gastric emptying (GE), gut hormones, and energy intake are dependent on digestion to free fatty acids (FFAs). In animals, small intestinal oleic acid inhibits energy intake more potently than the triacylglyceride (TG) triolein, but there is limited information about the comparative effects of FFA and TG in human beings. We compared the effects of FFA and TG on GE, gut hormone secretion, appetite, and energy intake in healthy males. Nine men (age, 23 +/- 2 y; body mass index, 22 +/- 1 kg/m(2)) were studied on 3 occasions to evaluate the effects of (1) 40 g oleic acid (FFA, 1830 kJ), (2) 40 g macadamia oil (TG, 1856 kJ; both 600-mL oil-in-water emulsions stabilized with 4% milk protein and labeled with 15 MBq (123)I), or (3) 600 mL 4% milk protein (control, 352 kJ), administered intragastrically, on GE, plasma cholecystokinin (CCK) and peptide-YY (PYY) levels, appetite perceptions, and subsequent energy intake. GE of FFA was much slower than that of TG (P < .05), with greater retention of FFA, than TG, in the proximal stomach (P < .001). Hunger was less (P < .05), and fullness was greater (P < .05), after FFA when compared with control and TG. Increases in plasma CCK and PYY levels were greater after FFA than TG or control (P < .05). Energy intake tended to be less after FFA compared with TG (control, 4754 +/- 610 kJ; TG, 5463 +/- 662 kJ; FFA, 4199 +/- 410 kJ). FFAs empty from the stomach more slowly, but stimulate CCK and PYY and suppress appetite more potently than TG in healthy human beings.

  11. Sex differences and hormonal effects on gut microbiota composition in mice

    PubMed Central

    Org, Elin; Mehrabian, Margarete; Parks, Brian W.; Shipkova, Petia; Liu, Xiaoqin; Drake, Thomas A.; Lusis, Aldons J.

    2016-01-01

    ABSTRACT We previously reported quantitation of gut microbiota in a panel of 89 different inbred strains of mice, and we now examine the question of sex differences in microbiota composition. When the total population of 689 mice was examined together, several taxa exhibited significant differences in abundance between sexes but a larger number of differences were observed at the single strain level, suggesting that sex differences can be obscured by host genetics and environmental factors. We also examined a subset of mice on chow and high fat diets and observed sex-by-diet interactions. We further investigated the sex differences using gonadectomized and hormone treated mice from 3 different inbred strains. Principal coordinate analysis with unweighted UniFrac distances revealed very clear effects of gonadectomy and hormone replacement on microbiota composition in all 3 strains. Moreover, bile acid analyses showed gender-specific differences as well as effects of gonodectomy, providing one possible mechanism mediating sex differences in microbiota composition. PMID:27355107

  12. Fast pouch emptying, delayed small intestinal transit, and exaggerated gut hormone responses after Roux-en-Y gastric bypass.

    PubMed

    Dirksen, C; Damgaard, M; Bojsen-Møller, K N; Jørgensen, N B; Kielgast, U; Jacobsen, S H; Naver, L S; Worm, D; Holst, J J; Madsbad, S; Hansen, D L; Madsen, J L

    2013-04-01

    Roux-en-Y gastric bypass (RYGB) causes extensive changes in gastrointestinal anatomy and leads to reduced appetite and large weight loss, which partly is due to an exaggerated release of anorexigenic gut hormones. To examine whether the altered passage of foods through the gastrointestinal tract after RYGB could be responsible for the changes in gut hormone release, we studied gastrointestinal motility with a scintigraphic technique as well as the secretion of the gut hormones glucagon-like peptide (GLP)-1 and peptide YY3-36 (PYY3-36 ) in 17 patients>1 year after RYGB and in nine healthy control subjects. At meal completion, a smaller fraction of liquid and solid radiolabeled marker was retained in the pouch of RYGB patients than in the stomach of control subjects (P = 0.002 and P < 0.001, respectively). Accordingly, pouch emptying in patients was faster than gastric emptying in control subjects (P < 0.001 and P = 0.004, respectively liquid and solid markers). For the solid marker, small intestinal transit was slower in patients than control subjects (P = 0.034). Colonic transit rate did not differ between the groups. GLP-1 and PYY3-36 secretion was increased in patients compared to control subjects and fast pouch emptying of the liquid marker was associated with high gut hormone secretion. After RYGB, the bulk of foods pass without hindrance into the small intestine, while the small intestinal transit is prolonged. The rapid exposure of the gut epithelium contributes to the exaggerated release of GLP-1 and PYY3-36 after RYGB. © 2013 Blackwell Publishing Ltd.

  13. Medicinal Chemistry and Applications of Incretins and DPP-4 Inhibitors in the Treatment of Type 2 Diabetes Mellitus

    PubMed Central

    Lotfy, Mohamed; Singh, Jaipaul; Kalász, Huba; Tekes, Kornelia; Adeghate, Ernest

    2011-01-01

    Diabetes mellitus (DM) is a major metabolic disorder currently affecting over 200 million people worldwide. Approximately 90% of all diabetic patients suffer from Type 2 diabetes mellitus (T2DM). The world's economy coughs out billions of dollars annually to diagnose, treat and manage patients with diabetes. It has been shown that the naturally occurring gut hormones incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) can preserve the morphology and function of pancreatic beta cell. In addition, GIP and GLP-1 act on insulin receptors to facilitate insulin-receptor binding, resulting in optimal glucose metabolism. This review examines the medicinal chemistry and roles of incretins, specifically, GLP-1 and drugs which can mimic its actions and prevent its enzymatic degradation. The review discussed GLP-1 agonists such as exenatide, liraglutide, taspoglutide and albiglutide. The paper also identified and reviewed a number of inhibitors, which can block dipeptidyl peptidase 4 (DPP-4), the enzyme responsible for the rapid degradation of GLP-1. These DPP-4 inhibitors include sitagliptin, saxagliptin, vildagliptin and many others which are still in the experimental phase. PMID:21966329

  14. New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders

    PubMed Central

    Irwin, Nigel; Flatt, Peter R

    2015-01-01

    The applicability of stable gut hormones for the treatment of obesity-related diabetes is now undisputable. This is based predominantly on prominent and sustained glucose-lowering actions, plus evidence that these peptides can augment insulin secretion and pancreatic islet function over time. This review highlights the therapeutic potential of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), oxyntomodulin (OXM) and cholecystokinin (CCK) for obesity-related diabetes. Stable GLP-1 mimetics have already been successfully adopted into the diabetic clinic, whereas GIP, CCK and OXM molecules offer promise as potential new classes of antidiabetic drugs. Moreover, recent studies have shown improved therapeutic effects following simultaneous modulation of multiple receptor signalling pathways by combination therapy or use of dual/triple agonist peptides. However, timing and composition of injections may be important to permit interludes of beta-cell rest. The review also addresses the possible perils of incretin based drugs for treatment of prediabetes. Finally, the unanticipated utility of stable gut peptides as effective treatments for complications of diabetes, bone disorders, cognitive impairment and cardiovascular dysfunction is considered. PMID:26557956

  15. Effects of dipeptidyl peptidase IV inhibition on glycemic, gut hormone, triglyceride, energy expenditure, and energy intake responses to fat in healthy males.

    PubMed

    Heruc, Gabriella A; Horowitz, Michael; Deacon, Carolyn F; Feinle-Bisset, Christine; Rayner, Christopher K; Luscombe-Marsh, Natalie; Little, Tanya J

    2014-11-01

    Fat is the most potent stimulus for glucagon-like peptide-1 (GLP-1) secretion. The aims of this study were to determine whether dipeptidyl peptidase IV (DPP-IV) inhibition would enhance plasma active incretin [glucose-dependent insulinotropic polypeptide (GIP), GLP-1] concentrations and modulate the glycemic, gut hormone, triglyceride, energy expenditure, and energy intake responses to intraduodenal fat infusion. In a double-blind, randomized, placebo-controlled crossover design, 16 healthy lean males received 50 mg vildagliptin (V), or matched placebo (P), before intraduodenal fat infusion (2 kcal/min, 120 min). Blood glucose, plasma insulin, glucagon, active GLP-1, and GIP and peptide YY (PYY)-(3-36) concentrations; resting energy expenditure; and energy intake at a subsequent buffet meal (time = 120-150 min) were quantified. Data are presented as areas under the curve (0-120 min, means ± SE). Vildagliptin decreased glycemia (P: 598 ± 8 vs. V: 573 ± 9 mmol·l⁻¹·min⁻¹, P < 0.05) during intraduodenal lipid. This was associated with increased insulin (P: 15,964 ± 1,193 vs. V: 18,243 ± 1,257 pmol·l⁻¹·min⁻¹, P < 0.05), reduced glucagon (P: 1,008 ± 52 vs. V: 902 ± 46 pmol·l⁻¹·min⁻¹, P < 0.05), enhanced active GLP-1 (P: 294 ± 40 vs. V: 694 ± 78 pmol·l⁻¹·min⁻¹) and GIP (P: 2,748 ± 77 vs. V: 4,256 ± 157 pmol·l⁻¹·min⁻¹), and reduced PYY-(3-36) (P: 9,527 ± 754 vs. V: 4,469 ± 431 pM/min) concentrations compared with placebo (P < 0.05, for all). Vildagliptin increased resting energy expenditure (P: 1,821 ± 54 vs. V: 1,896 ± 65 kcal/day, P < 0.05) without effecting energy intake. Vildagliptin 1) modulates the effects of intraduodenal fat to enhance active GLP-1 and GIP, stimulate insulin, and suppress glucagon, thereby reducing glycemia and 2) increases energy expenditure. These observations suggest that the fat content of a meal, by enhancing GLP-1 and GIP secretion, may contribute to the response to DPP-IV inhibition

  16. Intestinal organoids for assessing nutrient transport, sensing and incretin secretion

    PubMed Central

    Zietek, Tamara; Rath, Eva; Haller, Dirk; Daniel, Hannelore

    2015-01-01

    Intestinal nutrient transport and sensing are of emerging interest in research on obesity and diabetes and as drug targets. Appropriate in vitro models are lacking that allow both, studies on transport processes as well as sensing and subsequent incretin hormone secretion including intracellular signaling. We here demonstrate that murine small-intestinal organoids are the first in vitro model system enabling concurrent investigations of nutrient and drug transport, sensing and incretin hormone secretion as well as fluorescent live-cell imaging of intracellular signaling processes. By generating organoid cultures from wild type mice and animals lacking different nutrient transporters, we show that organoids preserve the main phenotypic features and functional characteristics of the intestine. This turns them into the best in vitro model currently available and opens new avenues for basic as well as medical research. PMID:26582215

  17. Intestinal organoids for assessing nutrient transport, sensing and incretin secretion.

    PubMed

    Zietek, Tamara; Rath, Eva; Haller, Dirk; Daniel, Hannelore

    2015-11-19

    Intestinal nutrient transport and sensing are of emerging interest in research on obesity and diabetes and as drug targets. Appropriate in vitro models are lacking that allow both, studies on transport processes as well as sensing and subsequent incretin hormone secretion including intracellular signaling. We here demonstrate that murine small-intestinal organoids are the first in vitro model system enabling concurrent investigations of nutrient and drug transport, sensing and incretin hormone secretion as well as fluorescent live-cell imaging of intracellular signaling processes. By generating organoid cultures from wild type mice and animals lacking different nutrient transporters, we show that organoids preserve the main phenotypic features and functional characteristics of the intestine. This turns them into the best in vitro model currently available and opens new avenues for basic as well as medical research.

  18. Expression of sweet taste receptor and gut hormone secretion in modelled type 2 diabetes.

    PubMed

    Feng, Rilu; Qian, Cheng; Liu, Qianjing; Jin, Yunqiu; Liu, Lianyong; Li, Shengxian; Liao, Yu; Zhou, Huan; Liu, Wei; Rayner, Chris K; Ma, Jing

    2017-10-01

    Sweet taste receptors (STRs) are expressed in L cells which secret glucagon-like peptide-1 (GLP-1) in the gut. The STR blocker lactisole reduces GLP-1 secretion and increases blood glucose levels. Therefore, we investigated the expression of sweet taste molecules in the proximal and distal small intestine, and gut hormone secretion, in healthy control and type 2 diabetic rats. Two groups of rats (Sprague Dawley (SD), and Zucker diabetic fatty (ZDF)) were involved in the study. Each group (n=10) received an intragastric glucose infusion (50% glucose solution, 2g/kg body weight). Blood samples were taken for measurement of blood glucose, plasma insulin, and GLP-1 concentrations. One week later, we obtained small intestinal tissue and detected the expression of STRs and glucose transporters (GTs) by real time polymerase chain reaction (Real Time-PCR). Sweet taste molecules of T1R2, T1R3, α-gustducin and TRPM5 in ileum were dramatically higher than those in duodenum (P<0.01 for each). T1R3, α-gustducin and TRPM5 expression were less in the ileum of ZDF than those in SD (P<0.05 for each), while expression of glucose transporter 2 (GLUT-2) in ileum was significantly higher in ZDF rats. Plasma GLP-1 levels were higher in ZDF rats than SD rats at t=0, 15, 30, 60 and 120min (P<0.01). In conclusion, transcript levels of ileal T1R3 and GLUT-2 are disordered in ZDF rats suggesting that intestinal sweet taste receptor expression is associated with altered glucose metabolism. The mechanism needs further investigation, but might provide a potential therapy in the treatment of type 2 diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Independent and combined effects of eating rate and energy density on energy intake, appetite, and gut hormones.

    PubMed

    Karl, J Philip; Young, Andrew J; Rood, Jennifer C; Montain, Scott J

    2013-03-01

    Energy density (ED) and eating rate (ER) influence energy intake; their combined effects on intake and on postprandial pancreatic and gut hormone responses are undetermined. To determine the combined effects of ED and ER manipulation on voluntary food intake, subjective appetite, and postprandial pancreatic and gut hormone responses. Twenty nonobese volunteers each consumed high (1.6 kcal g(-1) ; HED) and low (1.2 kcal g(-1) ; LED) ED breakfasts slowly (20 g min(-1) ; SR) and quickly (80 g min(-1) ; FR) ad libitum to satiation. Appetite, and pancreatic and gut hormone concentrations were measured periodically over 3 h. Ad libitum energy intake during the subsequent lunch was then measured. Main effects of ED and ER on energy intake and a main effect of ER, but not ED, on mass of food consumed were observed, FR and HED being associated with increased intake (P < 0.05). Across all conditions, energy intake was highest during FR-HED (P ≤ 0.01). Area under the curve (AUC) of appetite ratings was not different between meals. Main effects of ED and ER on insulin, peptide-YY, and glucagon-like peptide-1 AUC (P < 0.05) were observed, FR and HED being associated with larger AUC. No effects on active or total ghrelin AUC were documented. Total energy intake over both meals was highest during the FR-HED trial with the greatest difference between FR-HED and SR-LED trials (P ≤ 0.01). Consuming an energy dense meal quickly compounds independent effects of ER and ED on energy intake. Energy compensation at the following meal may not occur despite altered gut hormone responses. Copyright © 2013 The Obesity Society.

  20. Effect of Alginate on Satiation, Appetite, Gastric Function and Selected Gut Satiety Hormones in Overweight and Obesity

    PubMed Central

    Odunsi, Suwebatu T.; Vázquez Roque, María I.; Camilleri, Michael; Papathanasopoulos, Athanasios; Clark, Matthew M.; Wodrich, Lynne; Lempke, Mary; McKinzie, Sanna; Ryks, Michael; Burton, Duane; Zinsmeister, Alan R.

    2010-01-01

    Lack of control of food intake, excess size and frequency of meals are critical in to the development of obesity. The stomach signals satiation postprandially and may play an important role in control of calorie intake. Sodium alginate (based on brown seaweed Laminaria Digitata) is currently marketed as a weight loss supplement, but its effects on gastric motor functions and satiation are unknown. We evaluated effects of 10 days treatment with alginate or placebo on gastric functions, satiation, appetite and gut hormones associated with satiety in overweight or obese adults. We conducted a randomized, 1:1, placebo-controlled, allocation-concealed study in 48 overweight or obese participants with excluded psychiatric co-morbidity and binge eating disorder. All underwent measurements of gastric emptying (GE), fasting and postprandial gastric volumes (GV), postprandial satiation, calorie intake at a free choice meal and selected gut hormones after 1 week of alginate (3 capsules vs. matching placebo per day, ingested 30 minutes before the main meal). Six capsules were ingested with water 30 minutes before the gastric emptying, gastric volume and satiation tests on days 8–10. There were no treatment group effects on gastric emptying or volumes, gut hormones (ghrelin, CCK, GLP-1, PYY), satiation, total and macronutrient calorie intake at a free choice meal. There was no difference detected in results between obese and overweight patients. Alginate treatment over 10 days has no effect on gastric motor functions, satiation, appetite or gut hormones. These results question the use of short-term alginate treatment for weight loss. PMID:19960001

  1. Effect of alginate on satiation, appetite, gastric function, and selected gut satiety hormones in overweight and obesity.

    PubMed

    Odunsi, Suwebatu T; Vázquez-Roque, María I; Camilleri, Michael; Papathanasopoulos, Athanasios; Clark, Matthew M; Wodrich, Lynne; Lempke, Mary; McKinzie, Sanna; Ryks, Michael; Burton, Duane; Zinsmeister, Alan R

    2010-08-01

    Lack of control of food intake, excess size, and frequency of meals are critical to the development of obesity. The stomach signals satiation postprandially and may play an important role in control of calorie intake. Sodium alginate (based on brown seaweed Laminaria digitata) is currently marketed as a weight loss supplement, but its effects on gastric motor functions and satiation are unknown. We evaluated effects of 10 days treatment with alginate or placebo on gastric functions, satiation, appetite, and gut hormones associated with satiety in overweight or obese adults. We conducted a randomized, 1:1, placebo-controlled, allocation-concealed study in 48 overweight or obese participants with excluded psychiatric comorbidity and binge eating disorder. All underwent measurements of gastric emptying (GE), fasting, and postprandial gastric volumes (GVs), postprandial satiation, calorie intake at a free choice meal and selected gut hormones after 1 week of alginate (three capsules vs. matching placebo per day, ingested 30 min before the main meal). Six capsules were ingested with water 30 min before the GE, GV, and satiation tests on days 8-10. There were no treatment group effects on GE or volumes, gut hormones (ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide YY (PYY)), satiation, total and macronutrient calorie intake at a free choice meal. There was no difference detected in results between obese and overweight patients. Alginate treatment for a period of 10 days showed no effect on gastric motor functions, satiation, appetite, or gut hormones. These results question the use of short-term alginate treatment for weight loss.

  2. The effect of α- or β-casein addition to waxy maize starch on postprandial levels of glucose, insulin, and incretin hormones in pigs as a model for humans

    PubMed Central

    Kett, Anthony P.; Bruen, Christine M.; O'Halloran, Fiona; Chaurin, Valérie; Lawlor, Peadar G.; O'Mahony, James A.; Giblin, Linda; Fenelon, Mark A.

    2012-01-01

    Background Starch is a main source of glucose and energy in the human diet. The extent to which it is digested in the gastrointestinal tract plays a major role in variations in postprandial blood glucose levels. Interactions with other biopolymers, such as dairy proteins, during processing can influence both the duration and extent of this postprandial surge. Objective To evaluate the effect of the addition of bovine α- or β-casein to waxy maize starch on changes in postprandial blood glucose, insulin, and incretin hormones [glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)] in 30 kg pigs used as an animal model for humans. Design Gelatinised starch, starch gelatinised with α-casein, and starch gelatinised with β-casein were orally administered to trained pigs (n = 8) at a level of 60 g of available carbohydrate. Pre- and postprandial glucose measurements were taken every 15 min for the first hour and every 30 min thereafter up to 180 min. Insulin, GIP, and GLP-1 levels were measured in plasma samples up to 90 min postprandial. Results Starch gelatinised with α-casein had a significantly (p < 0.05) lower peak viscosity on pasting and resulted in significantly lower glucose release at 15, 30, and 90 min postprandial compared to starch gelatinised with β-casein. During the first 45-min postprandial, the area under the glucose curve (AUC) for starch gelatinised with α-casein was significantly (p < 0.05) lower than that for starch gelatinised with β-casein. There was also a significant (p < 0.05) difference at T30 in GIP levels in response to the control compared to starch gelatinised with α- or β-casein. Significant (p < 0.05) increases in several free amino acid concentrations were observed on ingestion of either α- or β-casein gelatinised with starch at 30 and 90 min postprandial compared to starch alone. In addition, plasma levels of six individual amino acids were increased on ingestion of starch gelatinised with

  3. [Role of incretins in the regulation of bone metabolism].

    PubMed

    Yamada, Chizumi

    2011-05-01

    Diabetes is associated with increased risk of osteoporosis. Gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide(GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones released upon meal ingestion, and GIP and/or GLP-1 signaling is decreased in diabetic state. We have demonstrated that both GIP receptor knockout mice and GLP-1 receptor knockout mice have osteoporosis. GIP has anabolic effects on bone mainly by stimulating osteoblastic bone formation through intermittent elevation of intracellular cAMP levels. On the other hand, GLP-1 is suggested to regulate bone resorption indirectly through the thyroid C cell. Our studies show that incretins play important roles in bone metabolism by distinct mechanisms.

  4. The Effect of Normobaric Hypoxic Confinement on Metabolism, Gut Hormones, and Body Composition

    PubMed Central

    Mekjavic, Igor B.; Amon, Mojca; Kölegård, Roger; Kounalakis, Stylianos N.; Simpson, Liz; Eiken, Ola; Keramidas, Michail E.; Macdonald, Ian A.

    2016-01-01

    To assess the effect of normobaric hypoxia on metabolism, gut hormones, and body composition, 11 normal weight, aerobically trained (O2peak: 60.6 ± 9.5 ml·kg−1·min−1) men (73.0 ± 7.7 kg; 23.7 ± 4.0 years, BMI 22.2 ± 2.4 kg·m−2) were confined to a normobaric (altitude ≃ 940 m) normoxic (NORMOXIA; PIO2 ≃ 133.2 mmHg) or normobaric hypoxic (HYPOXIA; PIO was reduced from 105.6 to 97.7 mmHg over 10 days) environment for 10 days in a randomized cross-over design. The wash-out period between confinements was 3 weeks. During each 10-day period, subjects avoided strenuous physical activity and were under continuous nutritional control. Before, and at the end of each exposure, subjects completed a meal tolerance test (MTT), during which blood glucose, insulin, GLP-1, ghrelin, peptide-YY, adrenaline, noradrenaline, leptin, and gastro-intestinal blood flow and appetite sensations were measured. There was no significant change in body weight in either of the confinements (NORMOXIA: −0.7 ± 0.2 kg; HYPOXIA: −0.9 ± 0.2 kg), but a significant increase in fat mass in NORMOXIA (0.23 ± 0.45 kg), but not in HYPOXIA (0.08 ± 0.08 kg). HYPOXIA confinement increased fasting noradrenaline and decreased energy intake, the latter most likely associated with increased fasting leptin. The majority of all other measured variables/responses were similar in NORMOXIA and HYPOXIA. To conclude, normobaric hypoxic confinement without exercise training results in negative energy balance due to primarily reduced energy intake. PMID:27313541

  5. Effects of Gastrogastric Fistula Repair on Weight Loss and Gut Hormone Levels

    PubMed Central

    O’Brien, Ciaran; Wang, Gary; McGinty, James; Agenor, Keesandra; Dutia, Roxanne; Colarusso, Antonia; Park, Koji; Koshy, Ninan; Laferrère, Blandine

    2013-01-01

    Purpose Weight regain after gastric bypass (GBP) can be associated with a gastrogastric fistula (GGF), in which a channel forms between the gastric pouch and gastric remnant, allowing nutrients to pass through the ‘old route’ rather than bypassing the duodenum. To further understand the mechanisms by which GGF may lead to weight regain, we investigated gut hormone levels in GBP patients with a GGF, before and after repair. Materials and Methods Seven post-GBP subjects diagnosed with GGF were studied before and 4 months after GGF repair. Another cohort of 22 GBP control subjects without GGF complication were studied before and 1 year post-GBP. All subjects underwent a 50g oral glucose tolerance test and blood was collected from 0-120minutes for glucose, insulin, ghrelin, PYY3-36, GIP, and GLP-1 levels. Results Four months after GGF repair subjects lost 6.0 ±3.9kg and had significantly increased postprandial PYY3-36 levels. After GGF repair, fasting and postprandial ghrelin levels decreased and were strongly correlated with weight loss. The insulin response to glucose also tended to be increased after GGF repair, however no concomitant increase in GLP-1 was observed. Compared to the post-GBP group, GLP-1 and PYY3-36 levels were significantly lower before GGF repair; however, after GGF repair, PYY3-36 levels were no longer lower than the post-GBP group. Conclusions These data utilize the GGF model to highlight the possible role of duodenal shunting as a mechanism of sustained weight loss after GBP, and lend support to the potential link between blunted satiety peptide release and weight regain. PMID:23549962

  6. Neuroblastoma causes alterations of the intestinal microbiome, gut hormones, inflammatory cytokines, and bile acid composition.

    PubMed

    Castellani, Christoph; Singer, Georg; Kaiser, Margarita; Kaiser, Thomas; Huang, Jianfeng; Sperl, Daniela; Kashofer, Karl; Fauler, Guenter; Guertl-Lackner, Barbara; Höfler, Gerald; Till, Holger

    2017-08-01

    To assess the effect of neuroblastoma (NB) on the intestinal microbiome, metabolism, and inflammatory parameters in a murine model. Athymic Hsd:Fox1nu mice received subperitoneal implantation of human NB cells (MHH-NB11) (tumor group, TG) or culture medium (sham group). Following 10 weeks of tumor growth, all animals were sacrificed to collect total white adipose tissue (WAT). Luminex assays were performed for gut hormone and inflammation marker analysis. Bile acids were measured by high-performance liquid chromatography-mass spectrometry in feces and serum. The microbiome of the ileal content was determined by 16S rDNA next-generation sequencing. At 10 weeks, tumors masses in the TG reached a mean weight of 1.10 g (interquartile range 3.45 g) associated with a significant reduction in WAT. Furthermore, in the TG, there was a marked reduction in leptin and an increase in glucagon-like peptide 1 serum levels. Moreover, the TG mice displayed a pro-inflammatory profile, with significant increases in monocyte chemotactic protein 1, tumor necrosis factor alpha, and interleukin-10. Lithocholic acid, deoxycholic acid, and ursodeoxycholic acid were significantly decreased in the stool of TG mice. Significant alterations of the intestinal microbiome were found in the ileal contents of the TG. The present study provides a first glimpse that human NB in a murine model induces tumor cachexia associated with alterations in metabolic and inflammatory parameters, as well as changes in the intestinal microbiota. Since the intestinal microbiome is known to contribute to the host's ability to harvest energy, a favorable modulation of the intestinal microbiome in tumor patients could potentially represent a novel therapeutic target to prevent tumor-associated cachexia. © 2017 Wiley Periodicals, Inc.

  7. The gut hormone ghrelin partially reverses energy substrate metabolic alterations in the failing heart.

    PubMed

    Mitacchione, Gianfranco; Powers, Jeffrey C; Grifoni, Gino; Woitek, Felix; Lam, Amy; Ly, Lien; Settanni, Fabio; Makarewich, Catherine A; McCormick, Ryan; Trovato, Letizia; Houser, Steven R; Granata, Riccarda; Recchia, Fabio A

    2014-07-01

    The gut-derived hormone ghrelin, especially its acylated form, plays a major role in the regulation of systemic metabolism and exerts also relevant cardioprotective effects; hence, it has been proposed for the treatment of heart failure (HF). We tested the hypothesis that ghrelin can directly modulate cardiac energy substrate metabolism. We used chronically instrumented dogs, 8 with pacing-induced HF and 6 normal controls. Human des-acyl ghrelin [1.2 nmol/kg per hour] was infused intravenously for 15 minutes, followed by washout (rebaseline) and infusion of acyl ghrelin at the same dose. (3)H-oleate and (14)C-glucose were coinfused and arterial and coronary sinus blood sampled to measure cardiac free fatty acid and glucose oxidation and lactate uptake. As expected, cardiac substrate metabolism was profoundly altered in HF because baseline oxidation levels of free fatty acids and glucose were, respectively, >70% lower and >160% higher compared with control. Neither des-acyl ghrelin nor acyl ghrelin significantly affected function and metabolism in normal hearts. However, in HF, des-acyl and acyl ghrelin enhanced myocardial oxygen consumption by 10.2±3.5% and 9.9±3.7%, respectively (P<0.05), and cardiac mechanical efficiency was not significantly altered. This was associated, respectively, with a 41.3±6.7% and 32.5±10.9% increase in free fatty acid oxidation and a 31.3±9.2% and 41.4±8.9% decrease in glucose oxidation (all P<0.05). Acute increases in des-acyl or acyl ghrelin do not interfere with cardiac metabolism in normal dogs, whereas they enhance free fatty acid oxidation and reduce glucose oxidation in HF dogs, thus partially correcting metabolic alterations in HF. This novel mechanism might contribute to the cardioprotective effects of ghrelin in HF. © 2014 American Heart Association, Inc.

  8. The Gut Hormone Ghrelin Partially Reverses Energy Substrate Metabolic Alterations in the Failing Heart

    PubMed Central

    Mitacchione, Gianfranco; Powers, Jeffrey C.; Grifoni, Gino; Woitek, Felix; Ly, Amy Lam; Lien; Settanni, Fabio; Makarewich, Catherine A.; McCormick, Ryan; Trovato, Letizia; Houser, Steven R.; Granata, Riccarda; Recchia, Fabio A.

    2014-01-01

    Background The gut-derived hormone ghrelin, especially its acylated form, plays a major role in the regulation of systemic metabolism and exerts also relevant cardioprotective effects, hence it has been proposed for the treatment of heart failure (HF). We tested the hypothesis that ghrelin can directly modulate cardiac energy substrate metabolism. Methods and Results We used chronically instrumented dogs, 8 with pacing-induced HF and 6 normal controls. 1.2 nmol/kg/hour of human des-acyl ghrelin was infused intravenously for 15 min, followed by washout (re-baseline) and infusion of acyl ghrelin at the same dose. 3H-oleate and 14C-glucose were co-infused and arterial and coronary sinus blood sampled to measure cardiac free fatty acids (FFA) and glucose oxidation and lactate uptake. As expected, cardiac substrate metabolism was profoundly altered in HF, since baseline FFA and glucose oxidation were, respectively, >70% lower and >160% higher compared to control. Neither des-acyl ghrelin nor acyl ghrelin affected significantly function and metabolism in normal hearts. However, in HF, des-acyl and acyl ghrelin enhanced MVO2 by 10.2±3.5 and 9.9±3.7%, respectively, (P<0.05), while cardiac mechanical efficiency was not significantly altered. This was associated, respectively, with a 41.3±6.7 and 32.5±10.9% increase in FFA oxidation and a 31.3±9.2 and 41.4±8.9% decrease in glucose oxidation (all P<0.05). Conclusions Acute increases in des-acyl ghrelin or acyl ghrelin do not interfere with cardiac metabolism in normal, while they enhance FFA oxidation and reduce glucose oxidation in HF, thus partially correcting its metabolic alterations. This novel mechanism might contribute to the cardioprotective effects of ghrelin in HF. PMID:24855152

  9. Investigation of gene-diet interactions in the incretin system and risk of type 2 diabetes: the EPIC-InterAct study.

    PubMed

    2016-12-01

    The gut incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have a major role in the pathophysiology of type 2 diabetes. Specific genetic and dietary factors have been found to influence the release and action of incretins. We examined the effect of interactions between seven incretin-related genetic variants in GIPR, KCNQ1, TCF7L2 and WFS1 and dietary components (whey-containing dairy, cereal fibre, coffee and olive oil) on the risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study. The current case-cohort study included 8086 incident type 2 diabetes cases and a representative subcohort of 11,035 participants (median follow-up: 12.5 years). Prentice-weighted Cox proportional hazard regression models were used to investigate the associations and interactions between the dietary factors and genes in relation to the risk of type 2 diabetes. An interaction (p = 0.048) between TCF7L2 variants and coffee intake was apparent, with an inverse association between coffee and type 2 diabetes present among carriers of the diabetes risk allele (T) in rs12255372 (GG: HR 0.99 [95% CI 0.97, 1.02] per cup of coffee; GT: HR 0.96 [95% CI 0.93, 0.98]); and TT: HR 0.93 [95% CI 0.88, 0.98]). In addition, an interaction (p = 0.005) between an incretin-specific genetic risk score and coffee was observed, again with a stronger inverse association with coffee in carriers with more risk alleles (0-3 risk alleles: HR 0.99 [95% CI 0.94, 1.04]; 7-10 risk alleles: HR 0.95 [95% CI 0.90, 0.99]). None of these associations were statistically significant after correction for multiple testing. Our large-scale case-cohort study provides some evidence for a possible interaction of TCF7L2 variants and an incretin-specific genetic risk score with coffee consumption in relation to the risk of type 2 diabetes. Further large-scale studies and/or meta-analyses are needed to confirm these

  10. Gut hormone release and appetite regulation in healthy non-obese participants following oligofructose intake. A dose-escalation study.

    PubMed

    Pedersen, Camilla; Lefevre, Solenne; Peters, Véronique; Patterson, Michael; Ghatei, Mohammad A; Morgan, Linda M; Frost, Gary S

    2013-07-01

    Prevention of weight gain in adults is a major public health target. Animal experiments have consistently demonstrated a relationship between fermentable carbohydrate intake, such as oligofructose, anorectic gut hormones, and appetite suppression and body weight control. This study was designed to determine the dose of oligofructose which would augment the release of anorectic gut hormones and reduce appetite consistently in non-obese humans. Twelve non-obese participants were recruited for a 5-week dose-escalation study. Following a 9-14-day run-in, participants increased their daily oligofructose intake every week from 15, 25, 35, 45, to 55 g daily. Subjective appetite and side effects were monitored daily. Three-day food diaries were completed every week. Appetite study sessions explored the acute effects of 0, 15, 35, and 55 g oligofructose on appetite-related hormones, glycaemia, subjective appetite, and energy intake. In the home environment, oligofructose suppressed hunger, but did not affect energy intake. Oligofructose dose-dependently increased peptide YY, decreased pancreatic polypeptide and tended to decrease ghrelin, but did not significantly affect appetite profile, energy intake, glucose, insulin, or glucagon-like peptide 1 concentrations during appetite study sessions. In conclusion, oligofructose supplementation at ≥ 35 g/day increased peptide YY and suppressed pancreatic polypeptide and hunger; however, energy intake did not change significantly.

  11. Dose-Dependent Effects of a Soluble Dietary Fibre (Pectin) on Food Intake, Adiposity, Gut Hypertrophy and Gut Satiety Hormone Secretion in Rats

    PubMed Central

    Adam, Clare L.; Williams, Patricia A.; Garden, Karen E.; Thomson, Lynn M.; Ross, Alexander W.

    2015-01-01

    Soluble fermentable dietary fibre elicits gut adaptations, increases satiety and potentially offers a natural sustainable means of body weight regulation. Here we aimed to quantify physiological responses to graded intakes of a specific dietary fibre (pectin) in an animal model. Four isocaloric semi-purified diets containing 0, 3.3%, 6.7% or 10% w/w apple pectin were offered ad libitum for 8 or 28 days to young adult male rats (n = 8/group). Measurements were made of voluntary food intake, body weight, initial and final body composition by magnetic resonance imaging, final gut regional weights and histology, and final plasma satiety hormone concentrations. In both 8- and 28-day cohorts, dietary pectin inclusion rate was negatively correlated with food intake, body weight gain and the change in body fat mass, with no effect on lean mass gain. In both cohorts, pectin had no effect on stomach weight but pectin inclusion rate was positively correlated with weights and lengths of small intestine and caecum, jejunum villus height and crypt depth, ileum crypt depth, and plasma total glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) concentrations, and at 8 days was correlated with weight and length of colon and with caecal mucosal depth. Therefore, the gut’s morphological and endocrine adaptations were dose-dependent, occurred within 8 days and were largely sustained for 28 days during continued dietary intervention. Increasing amounts of the soluble fermentable fibre pectin in the diet proportionately decreased food intake, body weight gain and body fat content, associated with proportionately increased satiety hormones GLP-1 and PYY and intestinal hypertrophy, supporting a role for soluble dietary fibre-induced satiety in healthy body weight regulation. PMID:25602757

  12. Gut Hormones and Appetite Control: A Focus on PYY and GLP-1 as Therapeutic Targets in Obesity

    PubMed Central

    De Silva, Akila

    2012-01-01

    The global obesity epidemic has resulted in significant morbidity and mortality. However, the medical treatment of obesity is limited. Gastric bypass is an effective surgical treatment but carries significant perioperative risks. The gut hormones, peptide tyrosine tyrosine (PYY) and glucagon-like peptide 1 (GLP-1), are elevated following gastric bypass and have been shown to reduce food intake. They may provide new therapeutic targets. This review article provides an overview of the central control of food intake and the role of PYY and GLP-1 in appetite control. Key translational animal and human studies are reviewed. PMID:22375166

  13. [Exenatide--an incretin-mimetic agent for the treatment of type 2 diabetes mellitus].

    PubMed

    Reuter, H; Erdmann, E

    2007-03-16

    The incretin hormone glucagon-like peptide 1 (GLP-1) is being synthesized from L-cells in the gut and enhances glucose-induced insulin secretion. Metabolic control of type 2 diabetic patients can be markedly improved by additional administration of GLP-1, however, this peptide is almost immediately degraded and therefore has little clinical value. The synthetic GLP-1 agonist exenatide underlies a different metabolism and has recently been approved by the U.S. Food and Drug Administration for the adjunctive treatment of patients with type 2 diabetes who are suboptimally controlled with metformin and/or sulfonylurea. First controlled clinical trials provided evidence that glycaemic control under exenatide administered twice daily in a dose of 5-10 microg was not inferior to conventional insulin therapy. Novel aspects in the treatment of type 2 diabetes by GLP-1 receptor stimulation further include its influence on the insulin secretory pattern, insulin/glucagon ratio, body weight and possibly even pancreatic beta cell mass. However, a general application of exenatide in the treatment of type 2 diabetes will also largely depend on the therapy behavior of patients, a possible immunogenicity and the rate of adverse events. Furthermore, a possible indication for exenatide as first-line therapy of type 2 diabetes and the prognostic relevance of this novel therapeutic approach have yet to be defined.

  14. Extrapancreatic effects of incretin hormones: evidence for weight-independent changes in morphological aspects and oxidative status in insulin-sensitive organs of the obese nondiabetic Zucker rat (ZFR).

    PubMed

    Colin, Ides M; Colin, Henri; Dufour, Ines; Gielen, Charles-Edouard; Many, Marie-Christine; Saey, Jean; Knoops, Bernard; Gérard, Anne-Catherine

    2016-08-01

    Incretin-based therapies are widely used to treat type 2 diabetes. Although hypoglycemic actions of incretins are mostly due to their insulinotropic/glucagonostatic effects, they may also influence extrapancreatic metabolism. We administered exendin-4 (Ex-4), a long-acting glucagon-like peptide receptor agonist, at low dose (0.1 nmol/kg/day) for a short period (10 days), in obese nondiabetic fa/fa Zucker rats (ZFRs). Ex-4-treated ZFRs were compared to vehicle (saline)-treated ZFRs and vehicle- and Ex-4-treated lean rats (LRs). Blood glucose levels were measured at days 0, 9, and 10. Ingested food and animal weight were recorded daily. On the day of sacrifice (d10), blood was sampled along with liver, epididymal, subcutaneous, brown adipose, and skeletal muscle tissues from animals fasted for 24 h. Plasma insulin and blood glucose levels, food intake, and body and epididymal fat weight were unchanged, but gross morphological changes were observed in insulin-sensitive tissues. The average size of hepatocytes was significantly lower in Ex-4-treated ZFRs, associated with decreased number and size of lipid droplets and 4-hydroxy-2-nonenal (HNE) staining, a marker of oxidative stress (OS). Myocytes, which were smaller in ZFRs than in LRs, were significantly enlarged and depleted of lipid droplets in Ex-4-treated ZFRs. Weak HNE staining was increased by Ex-4. A similar observation was made in brown adipose tissue, whereas the elevated HNE staining observed in epididymal adipocytes of ZFRs, suggestive of strong OS, was decreased by Ex-4. These results suggest that incretins by acting on OS in insulin-sensitive tissues may contribute to weight-independent improvement in insulin sensitivity.

  15. Peptidyl hormones of endocrine cells origin in the gut--their discovery and physiological relevance.

    PubMed

    Ceranowicz, P; Warzecha, Z; Dembinski, A

    2015-02-01

    In 1902 William Bayliss and Ernest Starling discovered secretin and it was the beginning of general endocrinology as well as, endocrinology of gastrointestinal tract. Ernest Starling was also a first person who introduced a term hormone for the substances which serves to transfer the information between cells of organism. Subsequent years delivered discovery of successive hormones of the digestive tract. Gastrin was discovered in 1905; whereas cholecystokinin in 1928. Ghrelin and obestatin are last hormones determined in the gastrointestinal tract and they were found in 1999 and 2006, respectively. Both above hormones are originating from the common prohormone. In 60s of past century, the biochemical structure of the gastrointestinal tract hormones was determined for the first time. Substantial progress in endocrinology of the digestive tract took place when radioimmunoassay was employed to measure of hormones concentration. Subsequently, radiolabeled hormones were used to localize hormonal receptors. Next breakthrough in the gastrointestinal tract endocrinology happened after introduction to experimental methods the cloning of complementary DNA. This method has allowed, among the others, to establish the full structure of receptors as well as, a genes coding hormones and their receptors. Discovery of genes structure allowed subsequently introducing these genes into foreign cells, what gives a chance to obtain significant amount of recombined hormones possessing species specificity. This review is presenting a history of the gastrointestinal tract endocrinology, as well as a relevance of gastrointestinal tract hormones in the regulation of body physiological activity.

  16. Improving Effect of the Acute Administration of Dietary Fiber-Enriched Cereals on Blood Glucose Levels and Gut Hormone Secretion

    PubMed Central

    2016-01-01

    Dietary fiber improves hyperglycemia in patients with type 2 diabetes through its physicochemical properties and possible modulation of gut hormone secretion, such as glucagon-like peptide 1 (GLP-1). We assessed the effect of dietary fiber-enriched cereal flakes (DC) on postprandial hyperglycemia and gut hormone secretion in patients with type 2 diabetes. Thirteen participants ate isocaloric meals based on either DC or conventional cereal flakes (CC) in a crossover design. DC or CC was provided for dinner, night snack on day 1 and breakfast on day 2, followed by a high-fat lunch. On day 2, the levels of plasma glucose, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and insulin were measured. Compared to CC, DC intake exhibited a lower post-breakfast 2-hours glucose level (198.5±12.8 vs. 245.9±15.2 mg/dL, P<0.05) and a lower incremental peak of glucose from baseline (101.8±9.1 vs. 140.3±14.3 mg/dL, P<0.001). The incremental area under the curve (iAUC) of glucose after breakfast was lower with DC than with CC (P<0.001). However, there were no differences in the plasma insulin, glucagon, GLP-1, and GIP levels. In conclusion, acute administration of DC attenuates postprandial hyperglycemia without any significant change in the representative glucose-regulating hormones in patients with type 2 diabetes (ClinicalTrials.gov. NCT 01997281). PMID:26839476

  17. Improving Effect of the Acute Administration of Dietary Fiber-Enriched Cereals on Blood Glucose Levels and Gut Hormone Secretion.

    PubMed

    Kim, Eun Ky; Oh, Tae Jung; Kim, Lee-Kyung; Cho, Young Min

    2016-02-01

    Dietary fiber improves hyperglycemia in patients with type 2 diabetes through its physicochemical properties and possible modulation of gut hormone secretion, such as glucagon-like peptide 1 (GLP-1). We assessed the effect of dietary fiber-enriched cereal flakes (DC) on postprandial hyperglycemia and gut hormone secretion in patients with type 2 diabetes. Thirteen participants ate isocaloric meals based on either DC or conventional cereal flakes (CC) in a crossover design. DC or CC was provided for dinner, night snack on day 1 and breakfast on day 2, followed by a high-fat lunch. On day 2, the levels of plasma glucose, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and insulin were measured. Compared to CC, DC intake exhibited a lower post-breakfast 2-hours glucose level (198.5±12.8 vs. 245.9±15.2 mg/dL, P<0.05) and a lower incremental peak of glucose from baseline (101.8±9.1 vs. 140.3±14.3 mg/dL, P<0.001). The incremental area under the curve (iAUC) of glucose after breakfast was lower with DC than with CC (P<0.001). However, there were no differences in the plasma insulin, glucagon, GLP-1, and GIP levels. In conclusion, acute administration of DC attenuates postprandial hyperglycemia without any significant change in the representative glucose-regulating hormones in patients with type 2 diabetes (ClinicalTrials.gov. NCT 01997281).

  18. Comparable effects of moderate intensity exercise on changes in anorectic gut hormone levels and energy intake to high intensity exercise.

    PubMed

    Ueda, Shin-ya; Yoshikawa, Takahiro; Katsura, Yoshihiro; Usui, Tatsuya; Fujimoto, Shigeo

    2009-12-01

    There is growing interest in the effects of exercise on plasma gut hormone levels and subsequent energy intake (EI) but the effects of mode and exercise intensity on anorectic hormone profiles on subsequent EI remain to be elucidated. We aimed to investigate whether circulating peptide YY(3-36) (PYY(3-36)) and glucagon-like peptide-1 (GLP-1 or GCG as listed in the HUGO Database) levels depend on exercise intensity, which could affect subsequent EI. Ten young male subjects (mean+/-s.d., age: 23.4+/-4.3 years, body mass index: 22.5+/-1.0 kg/m(2), and maximum oxygen uptake (VO(2 max)): 45.9+/-8.5 ml/kg per min) received a standardized breakfast, which was followed by constant cycling exercise at 75% VO(2 max) (high intensity session), 50% VO(2 max) (moderate intensity session), or rest (resting session) for 30 min. At lunch, a test meal was presented, and EI was calculated. Blood samples were obtained during three sessions for measurements of glucose, insulin, PYY(3-36), and GLP-1, which includes GLP-1 (7-36) amide and GLP-1 (9-36) amide. Increases in blood PYY(3-36) levels were dependent on the exercise intensity (effect of session: P<0.001 by two-way ANOVA), whereas those in GLP-1 levels were similar between two different exercise sessions. Of note, increase in area under the curve values for GLP-1 levels was negatively correlated with decrease in the EI in each exercise session (high: P<0.001, moderate: P=0.002). The present findings raise the possibility that each gut hormone exhibits its specific blood kinetics in response to two different intensities of exercise stimuli and might play differential roles in regulation of EI after exercise.

  19. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms.

    PubMed

    Lin, Hua V; Frassetto, Andrea; Kowalik, Edward J; Nawrocki, Andrea R; Lu, Mofei M; Kosinski, Jennifer R; Hubert, James A; Szeto, Daphne; Yao, Xiaorui; Forrest, Gail; Marsh, Donald J

    2012-01-01

    Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.

  20. Weight loss and incretin responsiveness improve glucose control independently after gastric bypass surgery.

    PubMed

    Bose, Mousumi; Teixeira, Julio; Olivan, Blanca; Bawa, Baani; Arias, Sara; Machineni, Sriram; Pi-Sunyer, F Xavier; Scherer, Philipp E; Laferrère, Blandine

    2010-03-01

    The aim of the present study was to determine the mechanisms underlying Type 2 diabetes remission after gastric bypass (GBP) surgery by characterizing the short- and long-term changes in hormonal determinants of blood glucose. Eleven morbidly obese women with diabetes were studied before and 1, 6, and 12 months after GBP; eight non-diabetic morbidly obese women were used as controls. The incretin effect was measured as the difference in insulin levels in response to oral glucose and to an isoglycemic intravenous challenge. Outcome measures were glucose, insulin, C-peptide, proinsulin, amylin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) levels and the incretin effect on insulin secretion. The decrease in fasting glucose (r = 0.724) and insulin (r = 0.576) was associated with weight loss up to 12 months after GBP. In contrast, the blunted incretin effect (calculated at 22%) that improved at 1 month remained unchanged with further weight loss at 6 (52%) and 12 (52%) months. The blunted incretin (GLP-1 and GIP) levels, early phase insulin secretion, and other parameters of β-cell function (amylin, proinsulin/insulin) followed the same pattern, with rapid improvement at 1 month that remained unchanged at 1 year. The data suggest that weight loss and incretins may contribute independently to improved glucose levels in the first year after GBP surgery.

  1. Anti-incretin, Anti-proliferative Action of Dopamine on β-Cells

    PubMed Central

    Segal, Ann Marie; Alvarez-Perez, Juan Carlos; Garcia-Ocaña, Adolfo; Harris, Paul E.

    2015-01-01

    Human islet β-cells exploit an autocrine dopamine (DA)-mediated inhibitory circuit to regulate insulin secretion. β-Cells also express the DA active transporter and the large neutral amino acid transporter heterodimer enabling them to import circulating DA or its biosynthetic precursor, L-3,4-dihydroxyphenylalanine (L-DOPA). The capacity to import DA or L-DOPA from the extracellular space possibly indicates that DA may be an endocrine signal as well. In humans, a mixed meal stimulus is accompanied by contemporary serum excursions of incretins, DA and L-DOPA, suggesting that DA may act as an anti-incretin as postulated by the foregut hypothesis proposed to explain the early effects of bariatric surgery on type 2 diabetes. In this report, we take a translational step backwards and characterize the kinetics of plasma DA and incretin production after a mixed meal challenge in a rat model and study the integration of incretin and DA signaling at the biochemical level in a rodent β-cell line and islets. We found that there are similar excursions of incretins and DA in rats, as those reported in humans, after a mixed meal challenge and that DA counters incretin enhanced glucose-stimulated insulin secretion and intracellular signaling at multiple points from dampening calcium fluxes to inhibiting proliferation as well as apoptosis. Our data suggest that DA is an important regulator of insulin secretion and may represent 1 axis of a gut level circuit of glucose and β-cell mass homeostasis. PMID:25751312

  2. Preoperative assessment of gut hormones does not correlate to weight loss after Roux-en-Y gastric bypass surgery.

    PubMed

    Werling, Malin; Fändriks, Lars; Vincent, Royce P; Royce, Vincent P; Cross, Gemma F; le Roux, Carel W; Olbers, Torsten

    2014-01-01

    Roux-en-Y gastric bypass (RYGB) surgery is an effective and frequently used surgical treatment for severe obesity. Postoperative weight loss varies markedly, but biomarkers to predict weight loss outcomes remain elusive. Levels of the satiety gut hormones glucagon like peptide-1 (GLP-1) and peptide YY (PYY) are attenuated in obese patients but elevated after RYGB surgery. We aimed to evaluate the preoperative responses of GLP-1 and PYY to a standard meal as a predictor of weight loss after RYGB surgery. We hypothesized that weak satiety gut hormone responses preoperatively, would predict poor weight loss after RYGB surgery. Preoperatively 43 patients (F = 25/M = 18) had GLP-1 and PYY measured in the fasting state and at 30-minute intervals over 180 minutes after a standard 400 kcal mixed meal. Weight loss was assessed at weight stability after surgery (mean 16.2 mo [CI 15.516.9]). Body mass index decreased from 44.0 kg/m(2) (CI 42.2-45.7) before surgery to 30.3 kg/m(2) (CI 28.4-32.2) after surgery (P<.001). Preoperative GLP-1 and PYY responses to food intake; as delta value between fasting and maximum as well as total responses during 180 minutes did not correlate to total weight loss (GLP-1; rho = .060 and rho = -.089, PYY; rho = -.03 and rho = -.022, respectively) or to excess weight loss % (GLP-1; rho = .051 and rho = -.064, PYY; rho = -.1 and rho = -.088, respectively). Preoperative responses of GLP-1 and PYY to a 400 kcal mixed meal do not correlate to postoperative weight loss after RYGB surgery for morbid obesity. Copyright © 2014 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  3. Tumour necrosis factor-alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers.

    PubMed

    Nielsen, Signe Tellerup; Lehrskov-Schmidt, Louise; Krogh-Madsen, Rikke; Solomon, Thomas P J; Lehrskov-Schmidt, Lars; Holst, Jens Juul; Møller, Kirsten

    2013-11-01

    Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumour necrosis factor-alpha (TNF-α). Although TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce peripheral insulin resistance, the influence of this cytokine on the incretin effect is unknown. We investigated whether systemic inflammation induced by TNF-α infusion in healthy volunteers alters the incretin hormone response to oral and intravenous glucose loads in a crossover study design with ten healthy male volunteers (mean age 24 years, mean body mass index 23.7 kg/m(2) ). The study consisted of four study days: days 1 and 2, 6-h infusion of saline; days 3 and 4, 6-h infusion of TNF-α; days 1 and 3, 4-h oral glucose tolerance test; and days 2 and 4, 4-h corresponding intravenous isoglycaemic glucose tolerance test. Glucose tolerance tests were initiated after 2 h of saline/TNF-α infusion. Plasma concentrations of TNF-α, interleukin 6, glucose, incretin hormones, and cortisol, and serum concentrations of C-peptide and insulin were measured throughout the study days. Insulin sensitivity was estimated by the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Prehepatic insulin secretion rates were calculated. TNF-α infusion induced symptoms of systemic inflammation; increased plasma levels of cortisol, TNF-α, and interleukin 6; and increased the HOMA-IR. The secretion of incretin hormones as well as the incretin effect remained unchanged. In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect. Copyright © 2013 John Wiley & Sons, Ltd.

  4. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded?

    PubMed

    Musso, Giovanni; Gambino, Roberto; Cassader, Maurizio

    2010-10-01

    The connection between gut microbiota and energy homeostasis and inflammation and its role in the pathogenesis of obesity-related disorders are increasingly recognized. Animals models of obesity connect an altered microbiota composition to the development of obesity, insulin resistance, and diabetes in the host through several mechanisms: increased energy harvest from the diet, altered fatty acid metabolism and composition in adipose tissue and liver, modulation of gut peptide YY and glucagon-like peptide (GLP)-1 secretion, activation of the lipopolysaccharide toll-like receptor-4 axis, and modulation of intestinal barrier integrity by GLP-2. Instrumental for gut microbiota manipulation is the understanding of mechanisms regulating gut microbiota composition. Several factors shape the gut microflora during infancy: mode of delivery, type of infant feeding, hospitalization, and prematurity. Furthermore, the key importance of antibiotic use and dietary nutrient composition are increasingly recognized. The role of the Western diet in promoting an obesogenic gut microbiota is being confirmation in subjects. Following encouraging results in animals, several short-term randomized controlled trials showed the benefit of prebiotics and probiotics on insulin sensitivity, inflammatory markers, postprandial incretins, and glucose tolerance. Future research is needed to unravel the hormonal, immunomodulatory, and metabolic mechanisms underlying microbe-microbe and microbiota-host interactions and the specific genes that determine the health benefit derived from probiotics. While awaiting further randomized trials assessing long-term safety and benefits on clinical end points, a healthy lifestyle--including breast lactation, appropriate antibiotic use, and the avoidance of excessive dietary fat intake--may ensure a friendly gut microbiota and positively affect prevention and treatment of metabolic disorders.

  5. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors.

    PubMed

    Hansotia, Tanya; Baggio, Laurie L; Delmeire, Dominique; Hinke, Simon A; Yamada, Yuichiro; Tsukiyama, Katsushi; Seino, Yutaka; Holst, Jens J; Schuit, Frans; Drucker, D J

    2004-05-01

    Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived incretins that potentiate glucose clearance following nutrient ingestion. Elimination of incretin receptor action in GIPR(-/-) or GLP-1R(-/-) mice produces only modest impairment in glucose homeostasis, perhaps due to compensatory upregulation of the remaining incretin. We have now studied glucose homeostasis in double incretin receptor knockout (DIRKO) mice. DIRKO mice exhibit normal body weight and fail to exhibit an improved glycemic response after exogenous administration of GIP or the GLP-1R agonist exendin-4. Plasma glucagon and the hypoglycemic response to exogenous insulin were normal in DIRKO mice. Glycemic excursion was abnormally increased and levels of glucose-stimulated insulin secretion were decreased following oral but not intraperitoneal glucose challenge in DIRKO compared with GIPR(-/-) or GLP-1R(-/-) mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-IV (DPP-IV) inhibitors valine pyrrolidide (Val-Pyr) and SYR106124 lowered glucose and increased plasma insulin in wild-type and single incretin receptor knockout mice, the glucose-lowering actions of DPP-IV inhibitors were eliminated in DIRKO mice. These findings demonstrate that glucose-stimulated insulin secretion is maintained despite complete absence of both incretin receptors, and they delineate a critical role for incretin receptors as essential downstream targets for the acute glucoregulatory actions of DPP-IV inhibitors.

  6. Intestinal transit of a glucose bolus and incretin kinetics: a mathematical model with application to the oral glucose tolerance test.

    PubMed

    Salinari, Serenella; Bertuzzi, Alessandro; Mingrone, Geltrude

    2011-06-01

    The rate of appearance (R(a)) of exogenous glucose in plasma after glucose ingestion is presently measured by tracer techniques that cannot be used in standard clinical testing such as the oral glucose tolerance test (OGTT). We propose a mathematical model that represents in a simple way the gastric emptying, the transport of glucose along the intestinal tract, and its absorption from gut lumen into portal blood. The model gives the R(a) time course in terms of parameters with a physiological counterpart and provides an expression for the release of incretin hormones as related to glucose transit into gut lumen. Glucose absorption was represented by assuming two components related to a proximal and a distal transporter. Model performance was evaluated by numerical simulations. The model was then validated by fitting OGTT glucose and GLP-1 data in healthy controls and type 2 diabetic patients, and useful information was obtained for the rate of gastric emptying, the rate of glucose absorption, the R(a) profile, the insulin sensitivity, and the glucose effectiveness. Model-derived estimates of insulin sensitivity were well correlated (r = 0.929 in controls and 0.886 in diabetic patients) to data obtained from the euglycemic hyperinsulinemic clamp. Although the proposed OGTT analysis requires the measurement of an additional hormone concentration (GLP-1), it appears to be a reasonable choice since it avoids complex and expensive techniques, such as isotopes for glucose R(a) measurement and direct assessment of gastric emptying and intestinal transit, and gives additional correlated information, thus largely compensating for the extra expense.

  7. Gut feelings about diabetes

    PubMed Central

    Laferrère, Blandine

    2013-01-01

    Studies of patients going into diabetes remission after gastric bypass surgery have demonstrated the important role of the gut in glucose control. The improvement of type 2 diabetes after gastric bypass surgery occurs via weight dependent and weight independent mechanisms. The rapid improvement of glucose levels within days after the surgery, in relation to change of meal pattern, rapid nutrient transit, enhanced incretin release and improved incretin effect on insulin secretion, suggest mechanisms independent of weight loss. Alternatively, insulin sensitivity improves over time as a function of weight loss. The role of bile acids and microbiome in the metabolic improvement after bariatric surgery remains to be determined. While most patients after bariatric surgery experienced sustained weight loss and improved metabolism, small scale studies have shown weight regain and diabetes relapse, the mechanisms of which remain unknown. PMID:22386248

  8. Incretins, insulin secretion and Type 2 diabetes mellitus.

    PubMed

    Vilsbøll, T; Holst, J J

    2004-03-01

    When glucose is taken orally, insulin secretion is stimulated much more than it is when glucose is infused intravenously so as to result in similar glucose concentrations. This effect, which is called the incretin effect and is estimated to be responsible for 50 to 70% of the insulin response to glucose, is caused mainly by the two intestinal insulin-stimulating hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their contributions have been confirmed in mimicry experiments, in experiments with antagonists of their actions, and in experiments where the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism of the impaired incretin effect in Type 2 diabetic patients, it has been found that the secretion of GIP is generally normal, whereas the secretion of GLP-1 is reduced, presumably as a consequence of the diabetic state. It might be of even greater importance that the effect of GLP-1 is preserved whereas the effect of GIP is severely impaired. The impaired GIP effect seems to have a genetic background, but could be aggravated by the diabetic state. The preserved effect of GLP-1 has inspired attempts to treat Type 2 diabetes with GLP-1 or analogues thereof, and intravenous GLP-1 administration has been shown to be able to near-normalize both fasting and postprandial glycaemic concentrations in the patients, perhaps because the treatment compensates for both the impaired secretion of GLP-1 and the impaired action of GIP. Several GLP-1 analogues are currently in clinical development and the reported results are, so far, encouraging.

  9. A remarkable, precisely timed release of hyperglycemic hormone from endocrine cells in the gut is associated with ecdysis in the crab Carcinus maenas.

    PubMed

    Chung, J S; Dircksen, H; Webster, S G

    1999-11-09

    Molting or ecdysis is the most fundamentally important process in arthropod life history, because shedding of the exoskeleton is an absolute prerequisite for growth and metamorphosis. Although the hormonal mechanisms driving ecdysis in insects have been studied extensively, nothing is known about these processes in crustaceans. During late premolt and during ecdysis in the crab Carcinus maenas, we observed a precise and reproducible surge in hemolymph hyperglycemic hormone (CHH) levels, which was over 100-fold greater than levels seen in intermolt animals. The source of this hormone surge was not from the eyestalk neurosecretory tissues but from previously undescribed endocrine cells (paraneurons), in defined areas of the foregut and hindgut. During premolt (the only time when CHH is expressed by these tissues), the gut is the largest endocrine tissue in the crab. The CHH surge, which is a result of an unusual, almost complete discharge of the contents of the gut endocrine cell, regulates water and ion uptake during molting, thus allowing the swelling necessary for successful ecdysis and the subsequent increase in size during postmolt. This study defines an endocrine brain/gut axis in the arthropods. We propose that the ionoregulatory process controlled by CHH may be common to arthropods, in that, for insects, a similar mechanism seems to be involved in antidiuresis. It also seems likely that a cascade of very precisely coordinated release of (neuro) hormones controls ecdysis.

  10. An Update on the Effect of Incretin-Based Therapies on β-Cell Function and Mass

    PubMed Central

    Chon, Suk

    2016-01-01

    Type 2 diabetes mellitus (T2DM) is a multifactorial disease with a complex and progressive pathogenesis. The two primary mechanisms of T2DM pathogenesis are pancreatic β-cell dysfunction and insulin resistance. Pancreatic β-cell dysfunction is recognized to be a prerequisite for the development of T2DM. Therapeutic modalities that improve β-cell function are considered critical to T2DM management; however, blood glucose control remains a challenge for many patients due to suboptimal treatment efficacy and the progressive nature of T2DM. Incretin-based therapies are now the most frequently prescribed antidiabetic drugs in Korea. Incretin-based therapies are a favorable class of drugs due to their ability to reduce blood glucose by targeting the incretin hormone system and, most notably, their potential to improve pancreatic β-cell function. This review outlines the current understanding of the incretin hormone system in T2DM and summarizes recent updates on the effect of incretin-based therapies on β-cell function and β-cell mass in animals and humans. PMID:27126881

  11. Gut Hormones, Appetite Suppression and Cachexia in Patients with Pulmonary TB

    PubMed Central

    Chang, Suzanne W.; Pan, William S.; Lozano Beltran, Daniel; Oleyda Baldelomar, Lizet; Solano, Marco Antonio; Tuero, Iskra; Friedland, Jon S.; Torrico, Faustino; Gilman, Robert H.

    2013-01-01

    Background Cachexia is a hallmark of pulmonary tuberculosis and is associated with poor prognosis. A better understanding of the mechanisms behind such weight loss could reveal targets for therapeutic intervention. The role of appetite-regulatory hormones in tuberculosis is unknown. Methods and Findings 41 subjects with newly-diagnosed pulmonary TB (cases) were compared to 82 healthy controls. We measured appetite, body mass index (BMI), % body fat (BF), plasma peptide YY (PYY), leptin, ghrelin, and resistin for all subjects. Measurements were taken at baseline for controls and at treatment days 0, 30, and 60 for cases. Baseline appetite, BMI, and BF were lower in cases than in controls and improved during treatment. PYY, ghrelin, and resistin were significantly elevated in cases and fell during treatment. Leptin was lower in cases and rose with treatment. Appetite was inversely related to PYY in cases. High pre-treatment PYY predicted reduced gains in appetite and BF. PYY was the strongest independent predictor of appetite in cases across all time points. Conclusions Appetite-regulatory hormones are altered in TB patients. As hormones normalize during treatment, appetite is restored and nutritional status improves. High baseline PYY is an indicator of poor prognosis for improvement in appetite and nutrition during treatment. Wasting in TB patients may partly be mediated by upregulation of PYY with resulting appetite suppression. PMID:23358528

  12. Effects of exercise training on gut hormone levels after a single bout of exercise in middle-aged Japanese women.

    PubMed

    Ueda, Shin-Ya; Miyamoto, Tadayoshi; Nakahara, Hidehiro; Shishido, Toshiaki; Usui, Tatsuya; Katsura, Yoshihiro; Yoshikawa, Takahiro; Fujimoto, Shigeo

    2013-12-01

    The purpose of this study was to investigate the effects of 12 weeks of exercise training on gut hormone levels after a single bout of exercise in middle-aged Japanese women. Twenty healthy middle-aged women were recruited for this study. Several measurements were performed pre and post exercise training, including: body weight and composition, peak oxygen consumption (peak VO2), energy intake after the single bout of exercise, and the release of gut hormones with fasting and after the single bout of exercise. Exercise training resulted in significant increases in acylated ghrelin fasting levels (from 126.6 ± 5.6 to 135.9 ± 5.4 pmol/l, P < 0.01), with no significant changes in GLP-1 (from 0.54 ± 0.04 to 0.55 ± 0.03 pmol/ml) and PYY (from 1.20 ± 0.07 to 1.23 ± 0.06 pmol/ml) fasting levels. GLP-1 levels post exercise training after the single bout of exercise were significantly higher than those pre exercise training (areas under the curve (AUC); from 238.4 ± 65.2 to 286.5 ± 51.2 pmol/ml x 120 min, P < 0.001). There was a tendency for higher AUC for the time courses of PYY post exercise training than for those pre exercise training (AUC; from 519.5 ± 135.5 to 551.4 ± 128.7 pmol/ml x 120 min, P = 0.06). Changes in (delta) GLP-1 AUC were significantly correlated with decreases in body weight (r = -0.743, P < 0.001), body mass index (r = -0.732, P < 0.001), percent body fat (r = -0.731, P < 0.001), and energy intake after a single bout exercise (r = -0.649, P < 0.01) and increases in peak VO2 (r = 0.558, P < 0.05). These results suggest that the ability of exercise training to create a negative energy balance relies not only directly on its impact on energy expenditure, but also indirectly on its potential to modulate energy intake.

  13. Effects of sleeve gastrectomy and ileal transposition, alone and in combination, on food intake, body weight, gut hormones, and glucose metabolism in rats.

    PubMed

    Nausheen, S; Shah, I H; Pezeshki, A; Sigalet, D L; Chelikani, P K

    2013-08-15

    Bariatric surgeries are hypothesized to produce weight loss and improve diabetes control by multiple mechanisms including gastric restriction and lower gut stimulation; the relative importance of these mechanisms remains poorly understood. We compared the effects of a typical foregut procedure, sleeve gastrectomy, (SG) with a primarily hindgut surgery, ileal transposition (IT), alone and together (SGIT), or sham manipulations, on food intake, body weight, gut hormones, glucose tolerance, and key markers of glucose homeostasis in peripheral tissues of adult male Sprague-Dawley rats (450-550 g, n = 7-9/group). SG, IT, and SGIT surgeries produced transient reduction in food intake and weight gain; the effects of SG and IT on intake and body weight were nonadditive. SG, IT, and SGIT surgeries resulted in increased tissue expression and plasma concentrations of the lower gut hormones glucagon-like peptide-1 and peptide YY and decreased plasma glucose-dependent insulinotropic peptide, insulin, and leptin concentrations. Despite transient effects on intake and weight gain, the SG, IT, and SGIT surgeries produced a significant improvement in glucose tolerance. In support of glycemic improvements, the protein abundance of key markers of glucose metabolism (e.g., GLUT4, PKA, IRS-1) in muscle and adipose tissue were increased, whereas the expression of key gluconeogenic enzyme in liver (G-6-Pase) were decreased following the surgeries. Therefore, our data suggest that enhanced lower gut stimulation following SG, IT, and SGIT surgeries leads to transient reduction in food intake and weight gain together with enhanced secretion of lower gut hormones and improved glucose clearance by peripheral tissues.

  14. Increasing doses of fiber do not influence short-term satiety or food intake and are inconsistently linked to gut hormone levels

    PubMed Central

    Willis, Holly J.; Thomas, William; Eldridge, Alison L.; Harkness, Laura; Green, Hilary; Slavin, Joanne L.

    2010-01-01

    Background People who eat more fiber often have a lower body weight than people who eat less fiber. The mechanism for this relationship has been explained, in part, by increased satiety, which may occur as a result of changes in appetite-suppressing gut hormone levels, and decreases in food intake at subsequent meals. Objective We hypothesized that increasing doses of mixed fiber, consumed in muffins for breakfast, would proportionally influence satiety, gut hormone levels, and subsequent food intake. Design This was a randomized, double-blind, crossover study. Healthy men (n=10) and women (n=10) with a BMI of 24±2 (mean±SEM) participated in this study. Fasting subjects consumed a muffin with 0, 4, 8, or 12 g of mixed fibers and approximately 500 kcal. Visual analog scales rated hunger and satiety for 3 h; blood was drawn to measure ghrelin, glucagon-like peptide-1 (GLP-1), and peptide YY3–36 (PYY3–36) at various intervals; and food intake was measured at an ad libitum lunch. Results Responses to satiety-related questions did not differ among treatments. However, despite lack of differences in satiety, gut hormone levels differed among treatments. Ghrelin was higher after the 12 g fiber dose than after the 4 and 8 g fiber doses. GLP-1 was higher after the 0 g fiber dose than after the 12 and 4 g fiber doses, and PYY3–36 did not differ among fiber doses. Food intake was also indistinguishable among doses. Conclusion Satiety, gut hormone response, and food intake did not change in a dose-dependent manner after subjects consumed 0, 4, 8, and 12 g of mixed fiber in muffins for breakfast. PMID:20596303

  15. Increasing doses of fiber do not influence short-term satiety or food intake and are inconsistently linked to gut hormone levels.

    PubMed

    Willis, Holly J; Thomas, William; Eldridge, Alison L; Harkness, Laura; Green, Hilary; Slavin, Joanne L

    2010-06-29

    People who eat more fiber often have a lower body weight than people who eat less fiber. The mechanism for this relationship has been explained, in part, by increased satiety, which may occur as a result of changes in appetite-suppressing gut hormone levels, and decreases in food intake at subsequent meals. We hypothesized that increasing doses of mixed fiber, consumed in muffins for breakfast, would proportionally influence satiety, gut hormone levels, and subsequent food intake. This was a randomized, double-blind, crossover study. Healthy men (n=10) and women (n=10) with a BMI of 24+/-2 (mean+/-SEM) participated in this study. Fasting subjects consumed a muffin with 0, 4, 8, or 12 g of mixed fibers and approximately 500 kcal. Visual analog scales rated hunger and satiety for 3 h; blood was drawn to measure ghrelin, glucagon-like peptide-1 (GLP-1), and peptide YY(3-36) (PYY(3-36)) at various intervals; and food intake was measured at an ad libitum lunch. Responses to satiety-related questions did not differ among treatments. However, despite lack of differences in satiety, gut hormone levels differed among treatments. Ghrelin was higher after the 12 g fiber dose than after the 4 and 8 g fiber doses. GLP-1 was higher after the 0 g fiber dose than after the 12 and 4 g fiber doses, and PYY(3-36) did not differ among fiber doses. Food intake was also indistinguishable among doses. Satiety, gut hormone response, and food intake did not change in a dose-dependent manner after subjects consumed 0, 4, 8, and 12 g of mixed fiber in muffins for breakfast.

  16. mTOR links incretin signaling to HIF induction in pancreatic beta cells.

    PubMed

    Van de Velde, Sam; Hogan, Meghan F; Montminy, Marc

    2011-10-11

    Under feeding conditions, the incretin hormone GLP-1 promotes pancreatic islet viability by triggering the cAMP pathway in beta cells. Increases in PKA activity stimulate the phosphorylation of CREB, which in turn enhances beta cell survival by upregulating IRS2 expression. Although sustained GLP-1 action appears important for its salutary effects on islet function, the transient nature of CREB activation has pointed to the involvement of additional nuclear factors in this process. Following the acute induction of CREB-regulated genes, cAMP triggers a second delayed phase of gene expression that proceeds via the HIF transcription factor. Increases in cAMP promote the accumulation of HIF1α in beta cells by activating the mTOR pathway. As exposure to rapamycin disrupts GLP-1 effects on beta cell viability, these results demonstrate how a pathway associated with tumor growth also mediates salutary effects of an incretin hormone on pancreatic islet function.

  17. Effects of sitagliptin on glycemia, incretin hormones, and antropyloroduodenal motility in response to intraduodenal glucose infusion in healthy lean and obese humans and patients with type 2 diabetes treated with or without metformin.

    PubMed

    Wu, Tongzhi; Ma, Jing; Bound, Michelle J; Checklin, Helen; Deacon, Carolyn F; Jones, Karen L; Horowitz, Michael; Rayner, Christopher K

    2014-08-01

    The impact of variations in gastric emptying, which influence the magnitude of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) secretion, on glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60 g over 120 min [i.e., 2 kcal/min], a rate that predominantly stimulates GIP but not GLP-1) after sitagliptin versus control in 12 healthy lean, 12 obese, and 12 type 2 diabetic subjects taking metformin 850 mg b.i.d. versus placebo. As expected, sitagliptin augmented plasma-intact GIP substantially and intact GLP-1 modestly. Sitagliptin attenuated glycemic excursions in healthy lean and obese but not type 2 diabetic subjects, without affecting glucagon or energy intake. In contrast, metformin reduced fasting and glucose-stimulated glycemia, suppressed energy intake, and augmented total and intact GLP-1, total GIP, and glucagon in type 2 diabetic subjects, with no additional glucose lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes, 1) the capacity of endogenous GIP to lower blood glucose is impaired; 2) the effect of DPP-4 inhibition on glycemia is likely to depend on adequate endogenous GLP-1 release, requiring gastric emptying >2 kcal/min; and 3) the action of metformin to lower blood glucose is not predominantly by way of the incretin axis. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  18. The Acute Effects of Simple Sugar Ingestion on Appetite, Gut-Derived Hormone Response, and Metabolic Markers in Men

    PubMed Central

    Yau, Adora M. W.; McLaughlin, John; Gilmore, William; Maughan, Ronald J.; Evans, Gethin H.

    2017-01-01

    This pilot study aimed to investigate the effect of simple sugar ingestion, in amounts typical of common ingestion, on appetite and the gut-derived hormone response. Seven healthy men ingested water (W) and equicaloric solutions containing 39.6 g glucose monohydrate (G), 36 g fructose (F), 36 g sucrose (S), and 19.8 g glucose monohydrate + 18 g fructose (C), in a randomised order. Serum concentrations of ghrelin, glucose dependent insulinotropic polypeptide (GIP), glucagon like peptide-1 (GLP-1), insulin, lactate, triglycerides, non-esterified fatty acids (NEFA), and d-3 hydroxybutyrate, were measured for 60 min. Appetite was measured using visual analogue scales (VAS). The ingestion of F and S resulted in a lower GIP incremental area under the curve (iAUC) compared to the ingestion of G (p < 0.05). No differences in the iAUC for GLP-1 or ghrelin were present between the trials, nor for insulin between the sugars. No differences in appetite ratings or hepatic metabolism measures were found, except for lactate, which was greater following the ingestion of F, S, and C, when compared to W and G (p < 0.05). The acute ingestion of typical amounts of fructose, in a variety of forms, results in marked differences in circulating GIP and lactate concentration, but no differences in appetite ratings, triglyceride concentration, indicative lipolysis, or NEFA metabolism, when compared to glucose. PMID:28216550

  19. Supplementation of oligofructose, but not sucralose, decreases high-fat diet induced body weight gain in mice independent of gustducin-mediated gut hormone release.

    PubMed

    Steensels, Sandra; Cools, Leen; Avau, Bert; Vancleef, Laurien; Farré, Ricard; Verbeke, Kristin; Depoortere, Inge

    2017-03-01

    Enteroendocrine cells sense nutrients through taste receptors similar to those on the tongue. Sweet and fatty acid taste receptors (FFAR) coupled to the gustatory G-protein, gustducin, on enteroendocrine cells play a role in gut hormone release. We studied if supplementation of artificial (sucralose) or prebiotic (oligofructose; OFS) sweeteners target gustducin-mediated signaling pathways to alter gut hormone release and reduce obesity-associated disorders. Wild-type (WT) and α-gustducin knockout (α-gust(-/-) ) mice were fed a high-fat diet and gavaged once daily (8 wk) with water or equisweet concentrations of sweeteners. OFS but not sucralose decreased body weight gain (-19 ± 3%, p < 0.01), fat pad mass (-55 ± 6%, p < 0.001), and insulin resistance (-39 ± 5%, p < 0.001) independent of α-gustducin. Neither sweetener improved glucose intolerance, while solely OFS improved the disturbed colonic permeability. OFS decreased (-65 ± 8%, p < 0.001) plasma glucagon-like peptide 1 (GLP-1) but not ghrelin and peptide YY (PYY) levels in WT mice. Cecal acetate and butyrate levels were reduced by OFS in both genotypes suggesting enhanced uptake of SCFAs that may target FFAR2 (upregulated expression) in adipose tissue. OFS, but not sucralose, reduced body weight gain and decreased intestinal permeability, but not glucose intolerance. Effects were not mediated by altered gut hormone levels or gustducin-mediated signaling. Artificial sweeteners do not affect gut hormone levels and are metabolically inert in mice on a high-fat diet. In contrast, prebiotic oligosaccharides (OFS) prevent body weight gain but not glucose intolerance. Alterations in sweet and short-chain fatty acid receptors (FFAR) (studied in WT and α-gust(-/-) mice) that regulate gut hormone levels are not mandatory for the positive effects of OFS. Enhanced uptake of SCFAs may favor interaction with FFAR2/3 on adipose tissue to induce weight loss. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Crosstalk between advanced glycation end products (AGEs)-receptor RAGE axis and dipeptidyl peptidase-4-incretin system in diabetic vascular complications.

    PubMed

    Yamagishi, Sho-ichi; Fukami, Kei; Matsui, Takanori

    2015-01-13

    Advanced glycation end products (AGEs) consist of heterogenous group of macroprotein derivatives, which are formed by non-enzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids, and whose process has progressed at an accelerated rate under diabetes. Non-enzymatic glycation and cross-linking of protein alter its structural integrity and function, contributing to the aging of macromolecules. Furthermore, engagement of receptor for AGEs (RAGE) with AGEs elicits oxidative stress generation and subsequently evokes proliferative, inflammatory, and fibrotic reactions in a variety of cells. Indeed, accumulating evidence has suggested the active involvement of accumulation of AGEs in diabetes-associated disorders such as diabetic microangiopathy, atherosclerotic cardiovascular diseases, Alzheimer's disease and osteoporosis. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins, gut hormones secreted from the intestine in response to food intake, both of which augment glucose-induced insulin release, suppress glucagon secretion, and slow gastric emptying. Since GLP-1 and GIP are rapidly degraded and inactivated by dipeptidyl peptidase-4 (DPP-4), inhibition of DPP-4 and/or DPP-4-resistant GLP-1 analogues have been proposed as a potential target for the treatment of diabetes. Recently, DPP-4 has been shown to cleave multiple peptides, and blockade of DPP-4 could exert diverse biological actions in GLP-1- or GIP-independent manner. This article summarizes the crosstalk between AGEs-RAGE axis and DPP-4-incretin system in the development and progression of diabetes-associated disorders and its therapeutic intervention, especially focusing on diabetic vascular complications.

  1. Gut hormones such as amylin and GLP-1 in the control of eating and energy expenditure.

    PubMed

    Lutz, T A

    2016-12-01

    The control of meal size is the best studied aspect of the control of energy balance, and manipulation of this system constitutes a promising target to treat obesity. A major part of this control system is based on gastrointestinal hormones such as glucagon-like peptide-1 (GLP-1) or amylin, which are released in response to a meal and which limit the size of an ongoing meal. Both amylin and GLP-1 have also been shown to increase energy expenditure in experimental rodents, but mechanistically we know much less how this effect may be mediated, which brain sites may be involved, and what the physiological relevance of these findings may be. Most studies indicate that the effect of peripheral amylin is centrally mediated via the area postrema, but other brain areas, such as the ventral tegmental area, may also be involved. GLP-1's effect on eating seems to be mainly mediated by vagal afferents projecting to the caudal hindbrain. Chronic exposure to amylin, GLP-1 or their analogs decrease food intake and body weight gain. Next to the induction of satiation, amylin may also constitute an adiposity signal and in fact interact with the adiposity signal leptin. Amylin analogs are under clinical consideration for their effect to reduce food intake and body weight in humans, and similar to rodents, amylin analogs seem to be particularly active when combined with leptin analogs.

  2. Incretin therapy--present and future.

    PubMed

    Garber, Alan J

    2011-01-01

    Although newer treatments for type 2 diabetes (T2D) patients have produced continual improvements in outcome, a large and growing population with prediabetes remains under-treated. In the last few years, incretin-based therapies have become an important treatment option for patients with T2D. There are two classes of incretin agents: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon like peptide 1 (GLP-1) receptor agonists. The ultimate goal of agents within both of these classes is to increase GLP-1 signaling, which results in augmented glucose-induced insulin secretion, inhibition of glucagon secretion, and decreased appetite. This should result in improved regulation of glucose homeostasis. GLP-1 receptor agonists enable patients to achieve significant weight loss. In contrast, DPP-4 inhibitors result in a less dramatic increase in GLP-1 levels; therefore, they are weight neutral. Incretin therapies are currently recommended for use early in the treatment algorithm for T2D patients whose disease is not manageable by diet and exercise alone, but the potential for these agents may be farther reaching. Current studies are evaluating the potential benefits of combining incretin therapies with basal insulin to provide continuous glucose control before and after meals. In addition, these agents may be promising for patients with prediabetes since they effectively reduce glycosylated hemoglobin levels and fasting plasma glucose levels, enable weight control, and have the potential to preserve β-cell function. Clearly, all of these properties are desirable for patients with prediabetes.

  3. Can Targeting the Incretin Pathway Dampen RAGE-Mediated Events in Diabetic Nephropathy?

    PubMed

    Sourris, Karly C; Yao, Henry; Jerums, George; Cooper, Mark E; Ekinci, Elif I; Coughlan, Melinda T

    2016-01-01

    Diabetic nephropathy is the major cause of end-stage renal disease in Western societies. To date, interruption of the Renin-Angiotensin System is the most effective intervention for diabetic nephropathy, however these agents only slow progression of the disease. Thus, there is a major unmet need for new therapeutic targets. Aberrant activation of the receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of diabetic nephropathy via binding to a variety of ligands and inciting reactive oxygen species (ROS) production, inflammation and fibrosis. In recent years there have been considerable efforts in the development of effective RAGE antagonists, however, direct RAGE targeting may be problematic. Glucagon like peptide-1 (GLP-1) is an incretin hormone released by the L-cells of the small intestine to mediate glucose-dependent insulin release from pancreatic islets. The incretin-based therapies, GLP-1 receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors, are novel glucose-lowering agents used in type 2 diabetes. However, the extra pancreatic functions of GLP-1 have gained attention, including putative anti-apoptotic and anti-inflammatory properties. In rodent models of diabetes, incretin-based therapies are renoprotective. Interestingly, GLP-1 has been shown to interfere with the signalling and expression of RAGE. The current review aims to give an overview of the interactions between the RAGE and incretin pathways and to discuss the utility of targeting the GLP-1/incretin pathway in DN. It is possible that indirect targeting of RAGE through GLP-1 agonism will be of clinical benefit to patients with diabetic nephropathy.

  4. The role of the gut hormone GLP-1 in the metabolic improvements caused by Ileal Transposition

    PubMed Central

    Gaitonde, Shrawan; Kohli, Rohit; Seeley, Randy

    2011-01-01

    Bariatric surgery alters the gastrointestinal hormonal milieu leading to improved glucose homeostasis, though the mechanism leading to these changes is poorly understood. Ileal transposition (IT) is a procedure that is neither restrictive nor malabsorptive but nevertheless produces profound improvements in glucose regulation. Ileal transposition involves a short segment of distal ileum being transposed to the proximal jejunum in an isoperistaltic direction thereby avoiding any gastric resection or intenstinal bypass. Methods Diet-induced obese rats underwent either Ileal Transposition (IT), or Sham procedures. The Sham operated rats were pair fed to the IT surgical group to control for the effects of reduced food intake. Body composition data was recorded at specific time points, and glucose tolerance tests were performed at 5 and 6 weeks both in the presence and absence of Exendin 9–39, a known glucose-like peptide 1 (GLP-1) receptor antagonist. A subset of Naïve rats were also maintained for comparison. Results IT and Sham operated rats had no differences in food intake and body weight however, IT rats had a significant decrease in their body fat composition (P<0.05). No difference existed in glucose tolerance when exposed to an intrapertioneal glucose load, however, IT rats showed markedly improved glucose tolerance when submitted to an oral glucose tolerance test (p<0.001). Blocking GLP-1 receptors reversed these important improvements in rats with IT surgery. Conclusions The present work recapitulates what is seen in rodents and humans that IT improves glucose tolerance and body composition. The present data provide compelling evidence that these improvements are a product of increased GLP-1 secretion that results from placing the key GLP-1 secreting cells closer to chyme coming from the stomach. Such data support the notion that rather than restriction or malabsorption, the underling molecular mechanisms that mediate the potent improvements produced by

  5. Effects of randomized whey-protein loads on energy intake, appetite, gastric emptying, and plasma gut-hormone concentrations in older men and women.

    PubMed

    Giezenaar, Caroline; Trahair, Laurence G; Luscombe-Marsh, Natalie D; Hausken, Trygve; Standfield, Scott; Jones, Karen L; Lange, Kylie; Horowitz, Michael; Chapman, Ian; Soenen, Stijn

    2017-09-01

    Background: Protein- and energy-rich supplements are used widely for the management of malnutrition in the elderly. Information about the effects of protein on energy intake and related gastrointestinal mechanisms and whether these differ between men and women is limited.Objective: We determined the effects of whey protein on energy intake, appetite, gastric emptying, and gut hormones in healthy older men and women.Design: Eight older women and 8 older men [mean ± SEM age: 72 ± 1 y; body mass index (in kg/m(2)): 25 ± 1] were studied on 3 occasions in which they received protein loads of 30 g (120 kcal) or 70 g (280 kcal) or a flavored water control drink (0 kcal). At regular intervals over 180 min, appetite (visual analog scales), gastric emptying (3-dimensional ultrasonography), and blood glucose and plasma gut-hormone concentrations [insulin, glucagon, ghrelin, cholecystokinin, gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide tyrosine tyrosine (PYY)] were measured, and ad libitum energy intake was quantified from a buffet meal (180-210 min; energy intake, appetite, and gastric emptying in the men have been published previously).Results: Energy intake at the buffet meal was ∼80% higher in older men than in older women (P < 0.001). Energy intake was not suppressed by protein compared with the control in men or women (P > 0.05). There was no effect of sex on gastric emptying, appetite, gastrointestinal symptoms, glucose, or gut hormones (P > 0.05). There was a protein load-dependent slowing of gastric emptying, an increase in concentrations of insulin, glucagon, cholecystokinin, GIP, GLP-1, and PYY, and an increase in total energy intake (drink plus meal: 12% increase with 30 g and 32% increase with 70 g; P < 0.001). Energy intake at the buffet meal was inversely related to the stomach volume and area under the curve of hormone concentrations (P < 0.05).Conclusion: In older men and women, whey-protein drinks load

  6. Breaking up prolonged sitting time with walking does not affect appetite or gut hormone concentrations but does induce an energy deficit and suppresses postprandial glycaemia in sedentary adults.

    PubMed

    Bailey, Daniel P; Broom, David R; Chrismas, Bryna C R; Taylor, Lee; Flynn, Edward; Hough, John

    2016-03-01

    Breaking up periods of prolonged sitting can negate harmful metabolic effects but the influence on appetite and gut hormones is not understood and is investigated in this study. Thirteen sedentary (7 female) participants undertook three 5-h trials in random order: (i) uninterrupted sitting (SIT), (ii) seated with 2-min bouts of light-intensity walking every 20 min (SIT + LA), and (iii) seated with 2-min bouts of moderate-intensity walking every 20 min (SIT + MA). A standardised test drink was provided at the start of each trial and an ad libitum pasta test meal provided at the end of each trial. Subjective appetite ratings and plasma acylated ghrelin, peptide YY, insulin, and glucose were measured at regular intervals. Area under the curve (AUC) was calculated for each variable. AUC values for appetite and gut hormone concentrations were unaffected in the activity breaks conditions compared with uninterrupted sitting (linear mixed modelling: p > 0.05). Glucose AUC was lower in SIT + MA than in SIT + LA (p = 0.004) and SIT (p = 0.055). There was no difference in absolute ad libitum energy intake between conditions (p > 0.05); however, relative energy intake was lower in SIT + LA (39%; p = 0.011) and SIT + MA (120%; p < 0.001) than in SIT. In conclusion, breaking up prolonged sitting does not alter appetite and gut hormone responses to a meal over a 5-h period. Increased energy expenditure from activity breaks could promote an energy deficit that is not compensated for in a subsequent meal.

  7. Effect of lifestyle improvement program on the biomarkers of adiposity, inflammation and gut hormones in overweight/obese Asian Indians with prediabetes.

    PubMed

    Gokulakrishnan, Kuppan; Ranjani, Harish; Weber, Mary Beth; Pandey, Gautam Kumar; Anjana, Ranjit Mohan; Balasubramanyam, Muthuswamy; Prabhakaran, Dorairaj; Tandon, Nikhil; Narayan, K M; Mohan, Viswanathan

    2017-06-15

    While lifestyle modification is known to offer several metabolic benefits, there is paucity of comprehensive data on changes in biomarkers of adiposity, inflammation as well as gut hormones. We investigated these biomarkers in overweight/obese individuals with prediabetes randomized to either 4 months of a lifestyle improvement program or standard care and followed them up for a year. Participants [standard care and intervention arm (n = 75 each)] were randomly selected from the Diabetes Community Lifestyle Improvement Program trial. Glycemic and lipid control and anthropometric measurements were assessed by standard protocols. Adipokines, inflammatory markers and gut hormones were measured using multiplex and standard ELISA kits. Along with modest benefits in primary outcomes (glycemic and lipid control and weight reduction), participants in the intervention group showed significant reductions (p < 0.001) in plasma levels of leptin (17.6%), TNF-α (35%), IL-6 (33.3%), MCP-1 (22.3%) and PYY (28.3%) and increased levels of adiponectin (33.1%) and ghrelin (23.6%) at the end of 4 months of lifestyle intervention. The changes were independent of weight and persisted even at 1 year of follow-up. In contrast, participants from the standard care arm did not show any statistically significant improvements on the above parameters. Participants who underwent an intensive lifestyle improvement program showed metabolic benefits as well as favorable beneficial changes in systemic levels of adipokines, cytokines and gut hormones, not only during the intervention period, but also during 12-month follow-up period.

  8. Hormones

    MedlinePlus

    Hormones are your body's chemical messengers. They travel in your bloodstream to tissues or organs. They work ... glands, which are special groups of cells, make hormones. The major endocrine glands are the pituitary, pineal, ...

  9. The effect of moderate versus severe simulated altitude on appetite, gut hormones, energy intake and substrate oxidation in men.

    PubMed

    Matu, Jamie; Deighton, Kevin; Ispoglou, Theocharis; Duckworth, Lauren

    2017-06-01

    Acute exposure to high altitude (>3500 m) is associated with marked changes in appetite regulation and substrate oxidation but the effects of lower altitudes are unclear. This study examined appetite, gut hormone, energy intake and substrate oxidation responses to breakfast ingestion and exercise at simulated moderate and severe altitudes compared with sea-level. Twelve healthy males (mean ± SD; age 30 ± 9years, body mass index 24.4 ± 2.7 kg·m(-2)) completed in a randomised crossover order three, 305 min experimental trials at a simulated altitude of 0 m, 2150 m (∼15.8% O2) and 4300 m (∼11.7% O2) in a normobaric chamber. Participants entered the chamber at 8am following a 12 h fast. A standardised breakfast was consumed inside the chamber at 1 h. One hour after breakfast, participants performed a 60 min treadmill walk at 50% of relative V˙O2max. An ad-libitum buffet meal was consumed 1.5 h after exercise. Blood samples were collected prior to altitude exposure and at 60, 135, 195, 240 and 285 min. No trial based differences were observed in any appetite related measure before exercise. Post-exercise area under the curve values for acylated ghrelin, pancreatic polypeptide and composite appetite score were lower (all P < 0.05) at 4300 m compared with sea-level and 2150 m. There were no differences in glucagon-like peptide-1 between conditions (P = 0.895). Mean energy intake was lower at 4300 m (3728 ± 3179 kJ) compared with sea-level (7358 ± 1789 kJ; P = 0.007) and 2150 m (7390 ± 1226 kJ; P = 0.004). Proportional reliance on carbohydrate as a fuel was higher (P = 0.01) before breakfast but lower during (P = 0.02) and after exercise (P = 0.01) at 4300 m compared with sea-level. This study suggests that altitude-induced anorexia and a subsequent reduction in energy intake occurs after exercise during exposure to severe but not moderate simulated altitude. Acylated ghrelin concentrations may contribute to this

  10. Roles of the gut in the metabolic syndrome: an overview.

    PubMed

    Fändriks, L

    2017-04-01

    The metabolic syndrome is a cluster of risk factors (central obesity, hyperglycaemia, dyslipidaemia and arterial hypertension), indicating an increased risk of diabetes, cardiovascular disease and premature mortality. The gastrointestinal tract is seldom discussed as an organ system of principal importance for metabolic diseases. The present overview connects various metabolic research lines into an integrative physiological context in which the gastrointestinal tract is included. Strong evidence for the involvement of the gut in the metabolic syndrome derives from the powerful effects of weight-reducing (bariatric) gastrointestinal surgery. In fact, gastrointestinal surgery is now recommended as a standard treatment option for type 2 diabetes in obesity. Several gut-related mechanisms that potentially contribute to the metabolic syndrome will be presented. Obesity can be caused by hampered release of satiety-signalling gut hormones, reduced meal-associated energy expenditure and microbiota-assisted harvest of energy from nondigestible food ingredients. Adiposity per se is a well-established risk factor for hyperglycaemia. In addition, a leaky gut mucosa can trigger systemic inflammation mediating peripheral insulin resistance that together with a blunted incretin response aggravates the hyperglycaemic state. The intestinal microbiota is strongly associated with obesity and the related metabolic disease states, although the mechanisms involved remain unclear. Enterorenal signalling has been suggested to be involved in the pathophysiology of hypertension and postprandial triglyceride-rich chylomicrons; in addition, intestinal cholesterol metabolism probably contributes to atherosclerosis. It is likely that in the future, the metabolic syndrome will be treated according to novel pharmacological principles interfering with gastrointestinal functionality.

  11. Differential impacts of juvenile hormone, soldier head extract and alternate caste phenotypes on host and symbiont transcriptome composition in the gut of the termite Reticulitermes flavipes.

    PubMed

    Sen, Ruchira; Raychoudhury, Rhitoban; Cai, Yunpeng; Sun, Yijun; Lietze, Verena-Ulrike; Boucias, Drion G; Scharf, Michael E

    2013-07-19

    Termites are highly eusocial insects and show a division of labor whereby morphologically distinct individuals specialize in distinct tasks. In the lower termite Reticulitermes flavipes (Rhinotermitidae), non-reproducing individuals form the worker and soldier castes, which specialize in helping (e.g., brood care, cleaning, foraging) and defense behaviors, respectively. Workers are totipotent juveniles that can either undergo status quo molts or develop into soldiers or neotenic reproductives. This caste differentiation can be regulated by juvenile hormone (JH) and primer pheromones contained in soldier head extracts (SHE). Here we offered worker termites a cellulose diet treated with JH or SHE for 24-hr, or held them with live soldiers (LS) or live neotenic reproductives (LR). We then determined gene expression profiles of the host termite gut and protozoan symbionts concurrently using custom cDNA oligo-microarrays containing 10,990 individual ESTs. JH was the most influential treatment (501 total ESTs affected), followed by LS (24 ESTs), LR (12 ESTs) and SHE treatments (6 ESTs). The majority of JH up- and downregulated ESTs were of host and symbiont origin, respectively; in contrast, SHE, LR and LS treatments had more uniform impacts on host and symbiont gene expression. Repeat "follow-up" bioassays investigating combined JH + SHE impacts in relation to individual JH and SHE treatments on a subset of array-positive genes revealed (i) JH and SHE treatments had opposite impacts on gene expression and (ii) JH + SHE impacts on gene expression were generally intermediate between JH and SHE. Our results show that JH impacts hundreds of termite and symbiont genes within 24-hr, strongly suggesting a role for the termite gut in JH-dependent caste determination. Additionally, differential impacts of SHE and LS treatments were observed that are in strong agreement with previous studies that specifically investigated soldier caste regulation. However, it is likely

  12. Beyond Glycemic Control in Diabetes Mellitus: Effects of Incretin-Based Therapies on Bone Metabolism

    PubMed Central

    Ceccarelli, Elena; Guarino, Elisa G.; Merlotti, Daniela; Patti, Aurora; Gennari, Luigi; Nuti, Ranuccio; Dotta, Francesco

    2013-01-01

    Diabetes mellitus (DM) and osteoporosis (OP) are common disorders with a significant health burden, and an increase in fracture risk has been described both in type 1 (T1DM) and in type 2 (T2DM) diabetes. The pathogenic mechanisms of impaired skeletal strength in diabetes remain to be clarified in details and they are only in part reflected by a variation in bone mineral density. In T2DM, the occurrence of low bone turnover together with a decreased osteoblast activity and compromised bone quality has been shown. Of note, some antidiabetic drugs (e.g., thiazolidinediones, insulin) may deeply affect bone metabolism. In addition, the recently introduced class of incretin-based drugs (i.e., GLP-1 receptor agonists and DPP-4 inhibitors) is expected to exert potentially beneficial effects on bone health, possibly due to a bone anabolic activity of GLP-1, that can be either direct or indirect through the involvement of thyroid C cells. Here we will review the established as well as the putative effects of incretin hormones and of incretin-based drugs on bone metabolism, both in preclinical models and in man, taking into account that such therapeutic strategy may be effective not only to achieve a good glycemic control, but also to improve bone health in diabetic patients. PMID:23785355

  13. Beyond glycemic control in diabetes mellitus: effects of incretin-based therapies on bone metabolism.

    PubMed

    Ceccarelli, Elena; Guarino, Elisa G; Merlotti, Daniela; Patti, Aurora; Gennari, Luigi; Nuti, Ranuccio; Dotta, Francesco

    2013-01-01

    Diabetes mellitus (DM) and osteoporosis (OP) are common disorders with a significant health burden, and an increase in fracture risk has been described both in type 1 (T1DM) and in type 2 (T2DM) diabetes. The pathogenic mechanisms of impaired skeletal strength in diabetes remain to be clarified in details and they are only in part reflected by a variation in bone mineral density. In T2DM, the occurrence of low bone turnover together with a decreased osteoblast activity and compromised bone quality has been shown. Of note, some antidiabetic drugs (e.g., thiazolidinediones, insulin) may deeply affect bone metabolism. In addition, the recently introduced class of incretin-based drugs (i.e., GLP-1 receptor agonists and DPP-4 inhibitors) is expected to exert potentially beneficial effects on bone health, possibly due to a bone anabolic activity of GLP-1, that can be either direct or indirect through the involvement of thyroid C cells. Here we will review the established as well as the putative effects of incretin hormones and of incretin-based drugs on bone metabolism, both in preclinical models and in man, taking into account that such therapeutic strategy may be effective not only to achieve a good glycemic control, but also to improve bone health in diabetic patients.

  14. [New therapies for type 2 diabetes: what place for incretin-based agents and rimonabant compared to the previous ones?].

    PubMed

    Halimi, S; Debaty, I; Villaret, L; Muller, M

    2008-11-01

    Treatment of type 2 diabetes (T2DM) is based on lifestyle changes and oral antidiabetic agents or insulin. The UKPDS study has confirmed metformin (Met) as the initial monotherapy. Accordingly, Met is widely regarded as the first drug of choice for most patients with T2DM. Safety and efficacy of sulphonylureas (SU) have been confirmed by several clinical trials. Recently, thiazolidinediones (TZD) have addressed some aspects of insulin-resistance that characterized several T2DM patients. However, SU and TZD are associated with various side effects that limit their use in many patients. New agents have been recently developed which potentiate the activity of the incretin (GLP1). GLP1, a gut hormone secreted in response to meal ingestion, is rapidly degraded by dipeptidylpeptidase-4 (DPP-4). GLP1 enhances insulin secretion and inhibits glucagon secretion in a glucose-dependent manner, delays gastric emptying and, in animal studies, preserves beta-cell mass by reducing apoptosis and stimulates of beta-cell proliferation. GLP1 levels are abnormally low in T2DM patients. Two classes of agents based on GLP1 have been launched: DPP-4 inhibitors and DPP-4 resistant GLP1 analogues. Randomized studies confirmed their efficacy to improve glycemic control in T2DM patients. Orally administered DPP-4 inhibitors reduce HbA1c by 0.5-1.1%, without hypoglycaemic events and no weight gain. The sub-cutaneous injected GLP1 analogues (exenatide and liraglutide) show larger reductions in HbA1c by 0.8-1.7% and weight loss but are associated with gastrointestinal side effects contributing to a significant treatment interruption. Several studies support the use of DPP-4 inhibitors in combination with Met as a promising second line treatment.

  15. Increased gut hormones and insulin sensitivity index following a 3-d intervention with a barley kernel-based product: a randomised cross-over study in healthy middle-aged subjects.

    PubMed

    Nilsson, Anne C; Johansson-Boll, Elin V; Björck, Inger M E

    2015-09-28

    Certain purified indigestible carbohydrates such as inulin have been shown to stimulate gut-derived hormones involved in glycaemic regulation and appetite regulation, and to counteract systemic inflammation through a gut microbiota-mediated mechanism. Less is known about the properties of indigestible carbohydrates intrinsic to food. The aim of this study was to investigate the possibility to affect release of endogenous gut hormones and ameliorate appetite control and glycaemic control by ingestion of a whole-grain cereal food product rich in NSP and resistant starch in healthy humans. In all, twenty middle-aged subjects were provided with a barley kernel-based bread (BB) or a reference white wheat bread during 3 consecutive days, respectively, in a randomised cross-over design study. At a standardised breakfast the following day (day 4), blood was collected for the analysis of blood (b) glucose regulation, gastrointestinal hormones, markers of inflammation and markers of colonic fermentation; 3 d of intervention with BB increased gut hormones in plasma (p) the next morning at fasting (p-glucagon-like peptide-1; 56%) and postprandially (p-glucagon-like peptide-2; 13% and p-peptide YY; 18%). Breath H₂ excretion and fasting serum (s) SCFA concentrations were increased (363 and 18%, respectively), and b-glucose (22%) and s-insulin responses (17%) were decreased after BB intervention. Insulin sensitivity index (ISI(composite)) was also improved (25%) after BB. In conclusion, 3 d of intervention with BB increased systemic levels of gut hormones involved in appetite regulation, metabolic control and maintenance of gut barrier function, as well as improved markers of glucose homoeostasis in middle-aged subjects, altogether relevant for the prevention of obesity and the metabolic syndrome.

  16. Actions of incretin metabolites on locomotor activity, cognitive function and in vivo hippocampal synaptic plasticity in high fat fed mice.

    PubMed

    Porter, David; Faivre, Emilie; Flatt, Peter R; Hölscher, Christian; Gault, Victor A

    2012-05-01

    The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) improve markers of cognitive function in obesity-diabetes, however, both are rapidly degraded to their major metabolites, GLP-1(9-36)amide and GIP(3-42), respectively. Therefore, the present study investigated effects of GLP-1(9-36)amide and GIP(3-42) on locomotor activity, cognitive function and hippocampal synaptic plasticity in mice with diet-induced obesity and insulin resistance. High-fat fed Swiss TO mice treated with GLP-1(9-36)amide, GIP(3-42) or exendin(9-39)amide (twice-daily for 60 days) did not exhibit any changes in bodyweight, non-fasting plasma glucose and plasma insulin concentrations or glucose tolerance compared with high-fat saline controls. Similarly, locomotor and feeding activity, O(2) consumption, CO(2) production, respiratory exchange ratio and energy expenditure were not altered by chronic treatment with incretin metabolites. Administration of the truncated metabolites did not alter general behavior in an open field test or learning and memory ability as recorded during an object recognition test. High-fat mice exhibited a significant impairment in hippocampal long-term potentiation (LTP) which was not affected by treatment with incretin metabolites. These data indicate that incretin metabolites do not influence locomotor activity, cognitive function and hippocampal synaptic plasticity when administered at pharmacological doses to mice fed a high-fat diet.

  17. The gut microbiome of kittens is affected by dietary protein:carbohydrate ratio and associated with blood metabolite and hormone concentrations.

    PubMed

    Hooda, Seema; Vester Boler, Brittany M; Kerr, Katherine R; Dowd, Scot E; Swanson, Kelly S

    2013-05-01

    High-protein, low-carbohydrate (HPLC) diets are common in cats, but their effect on the gut microbiome has been ignored. The present study was conducted to test the effects of dietary protein:carbohydrate ratio on the gut microbiota of growing kittens. Male domestic shorthair kittens were raised by mothers fed moderate-protein, moderate-carbohydrate (MPMC; n 7) or HPLC (n 7) diets, and then weaned at 8 weeks onto the same diet. Fresh faeces were collected at 8, 12 and 16 weeks; DNA was extracted, followed by amplification of the V4–V6 region of the 16S rRNA gene using 454 pyrosequencing. A total of 384 588 sequences (average of 9374 per sample) were generated. Dual hierarchical clustering indicated distinct clustering based on the protein:carbohydrate ratio regardless of age. The protein:carbohydrate ratio affected faecal bacteria. Faecal Actinobacteria were greater (P< 0·05) and Fusobacteria were lower (P< 0·05) in MPMC-fed kittens. Faecal Clostridium, Faecalibacterium, Ruminococcus, Blautia and Eubacterium were greater (P< 0·05) in HPLC-fed kittens, while Dialister, Acidaminococcus, Bifidobacterium, Megasphaera and Mitsuokella were greater (P< 0·05) in MPMC-fed kittens. Principal component analysis of faecal bacteria and blood metabolites and hormones resulted in distinct clusters. Of particular interest was the clustering of blood TAG with faecal Clostridiaceae, Eubacteriaceae, Ruminococcaceae, Fusobacteriaceae and Lachnospiraceae; blood ghrelin with faecal Coriobacteriaceae, Bifidobacteriaceae and Veillonellaceae; and blood glucose, cholesterol and leptin with faecal Lactobacillaceae. The present results demonstrate that the protein:carbohydrate ratio affects the faecal microbiome, and highlight the associations between faecal microbes and circulating hormones and metabolites that may be important in terms of satiety and host metabolism.

  18. Responses in gut hormones and hunger to diets with either high protein or a mixture of protein plus free amino acids supplied under weight-loss conditions.

    PubMed

    Lobley, Gerald E; Holtrop, Grietje; Horgan, Graham W; Bremner, David M; Fyfe, Claire; Johnstone, Alexandra M

    2015-04-28

    High-protein diets are an effective means for weight loss (WL), but the mechanisms are unclear. One hypothesis relates to the release of gut hormones by either protein or amino acids (AA). The present study involved overweight and obese male volunteers (n 18, mean BMI 36·8 kg/m2) who consumed a maintenance diet for 7 d followed by fully randomised 10 d treatments with three iso-energetic WL diets, i.e. with either normal protein (NP, 15% of energy) or high protein (HP, 30%) or with a combination of protein and free AA, each 15% of energy (NPAA). Psychometric ratings of appetite were recorded hourly. On day 10, plasma samples were taken at 30 min intervals over two consecutive 5 h periods (covering post-breakfast and post-lunch) and analysed for AA, glucose and hormones (insulin, total glucose-dependent insulinotropic peptide, active ghrelin and total peptide YY (PYY)) plus leucine kinetics (first 5 h only). Composite hunger was 16% lower for the HP diet than for the NP diet (P<0·01) in the 5 h period after both meals. Plasma essential AA concentrations were greatest within 60 min of each meal for the NPAA diet, but remained elevated for 3-5 h after the HP diet. The three WL diets showed no difference for either fasting concentrations or the postprandial net incremental AUC (net AUCi) for insulin, ghrelin or PYY. No strong correlations were observed between composite hunger scores and net AUCi for either AA or gut peptides. Regulation of hunger may involve subtle interactions, and a range of signals may need to be integrated to produce the overall response.

  19. Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass.

    PubMed

    Dirksen, C; Jørgensen, N B; Bojsen-Møller, K N; Kielgast, U; Jacobsen, S H; Clausen, T R; Worm, D; Hartmann, B; Rehfeld, J F; Damgaard, M; Madsen, J L; Madsbad, S; Holst, J J; Hansen, D L

    2013-11-01

    To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB). Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor weight loss response (EBL <50%) >12 months after RYGB and a lean control group matched for age and gender. Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY3-36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite. Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test (P=0.006). In addition, the good responders had a larger release of GLP-1 (P=0.009) and a greater suppression of ghrelin (P=0.037) during the test, whereas the postprandial secretion of CCK was highest in the poor responders (P=0.005). PYY, neurotensin, PP and TBA release did not differ between the RYGB-operated groups. Compared with control subjects, patients had exaggerated release of GLP-1 (P<0.001), PYY (P=0.008), CCK (P=0.010) and neurotensin (P<0.001). Early dumping was comparable in the good and poor responders, but more pronounced than in controlled subjects. Differences in resting energy expenditure between the three groups were entirely explained by differences in body composition. Favorable meal-induced changes in hunger and gut hormone release in patients with good compared with poor weight loss response support the role of gut hormones in the weight loss after RYGB.

  20. Incretin effect and glucagon responses to oral and intravenous glucose in patients with maturity-onset diabetes of the young--type 2 and type 3.

    PubMed

    Østoft, Signe H; Bagger, Jonatan I; Hansen, Torben; Pedersen, Oluf; Holst, Jens J; Knop, Filip K; Vilsbøll, Tina

    2014-08-01

    Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous subgroup of nonautoimmune diabetes, constituting 1-2% of all diabetes. Because little is known about incretin function in patients with MODY, we studied the incretin effect and hormone responses to oral and intravenous glucose loads in patients with glucokinase (GCK)-diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A)-diabetes (MODY3), respectively, and in matched healthy control subjects. Both MODY groups exhibited glucose intolerance after oral glucose (most pronounced in patients with HNF1A-diabetes), but only patients with HNF1A-diabetes had impaired incretin effect and inappropriate glucagon responses to OGTT. Both groups of patients with diabetes showed normal suppression of glucagon in response to intravenous glucose. Thus, HNF1A-diabetes, similar to type 2 diabetes, is characterized by an impaired incretin effect and inappropriate glucagon responses, whereas incretin effect and glucagon response to oral glucose remain unaffected in GCK-diabetes, reflecting important pathogenetic differences between the two MODY forms. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  1. Deciphering metabolic messages from the gut drives therapeutic innovation: the 2014 Banting Lecture.

    PubMed

    Drucker, Daniel J

    2015-02-01

    -dependent subjects with short bowel syndrome. GLP-1 and GLP-2 are both cleaved by dipeptidyl peptidase-4 (DPP-4); hence, inhibition of DPP-4 activity enables yet another pathway for potentiation of incretin action and the therapy for type 2 diabetes. Here I review our 30-year experience with the elucidation of gut hormone action and, wherever possible, highlight therapeutic implications of our preclinical studies and future opportunities for incretin research.

  2. Gut chemosensing mechanisms

    PubMed Central

    Psichas, Arianna; Reimann, Frank; Gribble, Fiona M.

    2015-01-01

    The enteroendocrine system is the primary sensor of ingested nutrients and is responsible for secreting an array of gut hormones, which modulate multiple physiological responses including gastrointestinal motility and secretion, glucose homeostasis, and appetite. This Review provides an up-to-date synopsis of the molecular mechanisms underlying enteroendocrine nutrient sensing and highlights our current understanding of the neuro-hormonal regulation of gut hormone secretion, including the interaction between the enteroendocrine system and the enteric nervous system. It is hoped that a deeper understanding of how these systems collectively regulate postprandial physiology will further facilitate the development of novel therapeutic strategies. PMID:25664852

  3. Incretin physiology beyond glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: cholecystokinin and gastrin peptides.

    PubMed

    Rehfeld, J F

    2011-04-01

    Gastrin and cholecystokinin (CCK) are homologous hormone systems known to regulate gastric acid secretion, gallbladder emptying, and cell growth in the pancreas and stomach. They are, however, also involved in the development and secretory functions of pancreatic islet cells. For instance, foetal and neonatal islets express significant amounts of gastrin, and human as well as porcine islet cells express the gastrin/CCK-B receptor abundantly. Therefore, exogenous gastrin and CCK peptides stimulate insulin and glucagon secretion in man. Accordingly, endogenous hypergastrinaemia is accompanied by islet cell hyperplasia and increased insulin secretion. Conventionally, the effect of gastrointestinal hormones on insulin secretion (the incretin effect) has been defined and quantified in relation to oral versus intravenous glucose loadings. Under these unphysiological conditions, the release of gastrin and CCK and, hence, their effect on insulin secretion are modest in comparison with the effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1). Consequently, the interest of CCK and gastrin in incretin research has for decades been limited. A few years ago, however, it was suggested that gastrin together with epidermal growth factor or later GLP-1 might stimulate beta cell growth and secretion. Recent studies have shown that the combination of gastrin and GLP-1 actually restores normoglycaemia in diabetic mice. Therefore, a short review of the incretin system in a broader functional context that includes gastrin and CCK peptides may be timely.

  4. Plant-rich mixed meals based on Palaeolithic diet principles have a dramatic impact on incretin, peptide YY and satiety response, but show little effect on glucose and insulin homeostasis: an acute-effects randomised study.

    PubMed

    Bligh, H Frances J; Godsland, Ian F; Frost, Gary; Hunter, Karl J; Murray, Peter; MacAulay, Katrina; Hyliands, Della; Talbot, Duncan C S; Casey, John; Mulder, Theo P J; Berry, Mark J

    2015-02-28

    There is evidence for health benefits from 'Palaeolithic' diets; however, there are a few data on the acute effects of rationally designed Palaeolithic-type meals. In the present study, we used Palaeolithic diet principles to construct meals comprising readily available ingredients: fish and a variety of plants, selected to be rich in fibre and phyto-nutrients. We investigated the acute effects of two Palaeolithic-type meals (PAL 1 and PAL 2) and a reference meal based on WHO guidelines (REF), on blood glucose control, gut hormone responses and appetite regulation. Using a randomised cross-over trial design, healthy subjects were given three meals on separate occasions. PAL2 and REF were matched for energy, protein, fat and carbohydrates; PAL1 contained more protein and energy. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY) concentrations were measured over a period of 180 min. Satiation was assessed using electronic visual analogue scale (EVAS) scores. GLP-1 and PYY concentrations were significantly increased across 180 min for both PAL1 (P= 0·001 and P< 0·001) and PAL2 (P= 0·011 and P= 0·003) compared with the REF. Concomitant EVAS scores showed increased satiety. By contrast, GIP concentration was significantly suppressed. Positive incremental AUC over 120 min for glucose and insulin did not differ between the meals. Consumption of meals based on Palaeolithic diet principles resulted in significant increases in incretin and anorectic gut hormones and increased perceived satiety. Surprisingly, this was independent of the energy or protein content of the meal and therefore suggests potential benefits for reduced risk of obesity.

  5. Gluco-Incretins Regulate Beta-Cell Glucose Competence by Epigenetic Silencing of Fxyd3 Expression

    PubMed Central

    Vallois, David; Niederhäuser, Guy; Ibberson, Mark; Nagaray, Vini; Marselli, Lorella; Marchetti, Piero; Chatton, Jean-Yves; Thorens, Bernard

    2014-01-01

    Background/Aims Gluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms. Methods We searched for genes that were differentially expressed in islets from control and Glp1r−/−; Gipr−/− (dKO) mice, which show reduced glucose competence. Overexpression and knockdown studies; insulin secretion analysis; analysis of gene expression in islets from control and diabetic mice and humans as well as gene methylation and transcriptional analysis were performed. Results Fxyd3 was the most up-regulated gene in glucose incompetent islets from dKO mice. When overexpressed in beta-cells Fxyd3 reduced glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca++ influx. Fxyd3 expression was not acutely regulated by cAMP raising agents in either control or dKO adult islets. Instead, expression of Fxyd3 was controlled by methylation of CpGs present in its proximal promoter region. Increased promoter methylation reduced Fxyd3 transcription as assessed by lower abundance of H3K4me3 at the transcriptional start site and in transcription reporter assays. This epigenetic imprinting was initiated perinatally and fully established in adult islets. Glucose incompetent islets from diabetic mice and humans showed increased expression of Fxyd3 and reduced promoter methylation. Conclusions/Interpretation Because gluco-incretin secretion depends on feeding the epigenetic regulation of Fxyd3 expression may link nutrition in early life to establishment of adult beta-cell glucose competence; this epigenetic control is, however, lost in diabetes possibly as a result of gluco-incretin resistance and/or de-differentiation of beta-cells that are associated with the development of type 2 diabetes. PMID:25058609

  6. Effects of intraduodenal infusion of the branched-chain amino acid leucine on ad libitum eating, gut motor and hormone functions, and glycemia in healthy men.

    PubMed

    Steinert, Robert E; Landrock, Maria F; Ullrich, Sina S; Standfield, Scott; Otto, Bärbel; Horowitz, Michael; Feinle-Bisset, Christine

    2015-10-01

    Branched-chain amino acids (BCAAs), particularly leucine, act as nutrient signals regulating protein synthesis and degradation as well as glucose metabolism. In addition, leucine has been demonstrated in animal experiments to modulate eating and energy homeostasis. We aimed to characterize the effects of physiologic and supraphysiologic loads of intraduodenal leucine on eating, gut hormone and motor functions, and blood glucose in humans. Twelve lean men were studied on 3 occasions in a randomized, double-blind order. Antropyloroduodenal motility, plasma ghrelin, cholecystokinin, glucagon-like peptide 1, peptide YY, insulin, glucagon, blood glucose, appetite perceptions, and gastrointestinal symptoms were measured during 90-min intraduodenal infusions of leucine at 0.15 kcal/min (total 3.3 g, 13.5 kcal), 0.45 kcal/min (total 9.9 g, 40.5 kcal), or saline (control). Ad libitum eating from a buffet lunch was quantified immediately after the infusions. Leucine at 0.45 kcal/min inhibited eating (energy intake by ∼13%, P < 0.05), increased plasma cholecystokinin, slightly reduced blood glucose and increased plasma insulin, and decreased antral pressures (all P < 0.05). Leucine at 0.15 kcal/min had no effect on food intake, blood glucose, or antral pressures but also slightly increased plasma cholecystokinin (P < 0.05). Neither dose affected plasma ghrelin, glucagon, glucagon-like peptide 1 and peptide YY, or pyloric and duodenal pressures. Plasma leucine concentrations were related to the dose of intraduodenal leucine, with substantial increases during both 0.15 and 0.45 kcal/min. The effects of intraduodenal infusions of free leucine on eating are probably not primarily mediated by changes in gut motor and hormone functions, with perhaps the exception of cholecystokinin. Instead, increased plasma leucine concentrations may be a potential signal mediating the eating-inhibitory effect of leucine. The study was registered as a clinical trial with the Australia and New

  7. Prebiotic Fibre Supplementation In Combination With Metformin Modifies Appetite, Energy Metabolism, And Gut Satiety Hormones In Obese Rats

    NASA Astrophysics Data System (ADS)

    Pyra, Kim Alicia

    The prebiotic fibre, oligofructose (OFS), reduces energy intake and improves glycemic control in rodents and man. Metformin (MT) is a commonly used insulin-sensitizing agent that may limit weight gain in individuals with type 2 diabetes. Our objective was to determine if using OFS as an adjunct to MT therapy (AD) modifies satiety hormone production and metabolism in obese rats. Independently, OFS and MT decreased energy intake, body fat, hepatic triglyceride content, plasma leptin and glucose-dependent insulinotropic peptide (GIP) levels. OFS and AD but not MT rats showed superior glycemic control during an oral glucose tolerance test (OGTT) compared to C. Area under the curve for GIP was lowest in ADThe prebiotic fibre, oligofructose (OFS), reduces energy intake and improves glycemic control in rodents and man. Metformin (MT) is a commonly used insulin-sensitizing agent that may limit weight gain in individuals with type 2 diabetes. Our objective was to determine if using OFS as an adjunct to MT therapy (AD) modifies satiety hormone production and metabolism in obese rats. Independently, OFS and MT decreased energy intake, body fat, hepatic triglyceride content, plasma leptin and glucose-dependent insulinotropic peptide (GIP) levels. OFS and AD but not MT rats showed superior glycemic control during an oral glucose tolerance test (OGTT) compared to C. Area under the curve for GIP was lowest in AD

  8. Therapy for obesity based on gastrointestinal hormones.

    PubMed

    Bagger, Jonatan I; Christensen, Mikkel; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    It has long been known that peptide hormones from the gastrointestinal tract have significant impact on the regulation of nutrient metabolism. Among these hormones, incretins have been found to increase insulin secretion, and thus incretin-based therapies have emerged as new modalities for the treatment of type 2 diabetes. In contrast to other antidiabetic treatments, these agents have a positive outcome profile on body weight. Worldwide there are 500 million obese people, and 3 million are dying every year from obesity-related diseases. Recently, incretin-based therapy was proposed for the treatment of obesity. Currently two different incretin therapies are widely used in the treatment of type 2 diabetes: 1) the GLP-1 receptor agonists which cause significant and sustained weight loss in overweight patients, and 2) dipeptidyl peptidase 4 (DPP-4) inhibitors being weight neutral. These findings have led to a greater interest in the physiology of intestinal peptides with potential weight-reducing properties. This review discusses the effects of the incretin-based therapies in obesity, and provides an overview of intestinal peptides with promising effects as potential new treatments for obesity. Copyright © by Lab & Life Press/SBDR

  9. Cardiovascular actions of GLP-1 and incretin-based pharmacotherapy.

    PubMed

    Avogaro, Angelo; Vigili de Kreutzenberg, Saula; Fadini, Gian Paolo

    2014-01-01

    Incretin-based therapy became recently available as antihyperglycemic treatment for patients with type 2 diabetes (T2DM). Incretin therapy comprises glucagon-like peptide receptor agonists (GLP-1RA) and dipeptidyl-peptidase 4 inhibitors (DPP4-I): these classes of drugs not only have the ability to reduce blood glucose, but also can exert several cardioprotective effects. They have been shown to positively influence some risk factors for cardiovascular disease (CVD), to improve endothelial function, and to directly affect cardiac function. For these reasons incretins are considered not only antidiabetic drugs, but also cardiovascular effective. The first clinical trials aimed to demonstrate the safety of DPP4 inhibitors have been recently published: their clinical significance will be discussed in light of the prior experimental findings.

  10. Optical Control of Insulin Secretion Using an Incretin Switch.

    PubMed

    Broichhagen, Johannes; Podewin, Tom; Meyer-Berg, Helena; von Ohlen, Yorrick; Johnston, Natalie R; Jones, Ben J; Bloom, Stephen R; Rutter, Guy A; Hoffmann-Röder, Anja; Hodson, David J; Trauner, Dirk

    2015-12-14

    Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off-target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo, possesses an azobenzene photoresponsive element, affording isomer-biased GLP-1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival.

  11. Long-term changes in gut hormones, appetite and food intake 1 year after subtotal gastrectomy with normal body weight.

    PubMed

    Jeon, T Y; Lee, S; Kim, H H; Kim, Y J; Lee, J G; Jeong, D W; Kim, Y J

    2010-08-01

    No prospective study on the long-term effects of gastric resection on gastrointestinal hormonal changes in patients with normal body weight has been reported. The aim of this study was to evaluate the 1-year effect of subtotal gastrectomy on ghrelin and peptide YY (PYY)(3-36) levels. Eighteen patients with early gastric cancer underwent subtotal gastrectomy with Billroth I reconstruction. We assessed appetite, food intake, body composition, and ghrelin and PYY(3-36) levels preoperatively and 1 year after surgery. There were no significant difference in the preoperative daily food intake and 1 year after subtotal gastrectomy. Weight loss occurred in all study subjects; 11.7% (n=2), 55.5% (n=10) and 33.3% (n=6) of the patients lost <5%, 5-10% and >10% of their preoperative body weight, respectively. Body mass index, waist circumference and body fat significantly decreased 1 year after subtotal gastrectomy. There were no significant differences in the appetite visual analogue scale preoperatively and 1 year after subtotal gastrectomy. The plasma ghrelin concentration decreased significantly (P=0.006), whereas PYY(3-36) did not show a significant change 1 year after subtotal gastrectomy. Ghrelin levels and body fat decreased significantly, whereas PYY(3-36) levels as well as appetite and food intake did not change significantly 1 year after subtotal gastrectomy with normal body weight. These findings suggest that decreased ghrelin might contribute directly to reduced body fat.

  12. Anorexia induction by the trichothecene deoxynivalenol (vomitoxin) is mediated by the release of the gut satiety hormone peptide YY.

    PubMed

    Flannery, Brenna M; Clark, Erica S; Pestka, James J

    2012-12-01

    Consumption of deoxynivalenol (DON), a trichothecene mycotoxin known to commonly contaminate grain-based foods, suppresses growth of experimental animals, thus raising concerns over its potential to adversely affect young children. Although this growth impairment is believed to result from anorexia, the initiating mechanisms for appetite suppression remain unknown. Here, we tested the hypothesis that DON induces the release of satiety hormones and that this response corresponds to the toxin's anorectic action. Acute ip exposure to DON had no effect on plasma glucagon-like peptide-1, leptin, amylin, pancreatic polypeptide, gastric inhibitory peptide, or ghrelin; however, the toxin was found to robustly elevate peptide YY (PYY) and cholecystokinin (CCK). Specifically, ip exposure to DON at 1 and 5mg/kg bw induced PYY by up to 2.5-fold and CCK by up to 4.1-fold. These responses peaked within 15-120 min and lasted up to 120 min (CCK) and 240 min (PPY), corresponding with depressed rates of food intake. Direct administration of exogenous PYY or CCK similarly caused reduced food intake. Food intake experiments using the NPY2 receptor antagonist BIIE0246 and the CCK1A receptor antagonist devazepide, individually, suggested that PYY mediated DON-induced anorexia but CCK did not. Orolingual exposure to DON induced plasma PYY and CCK elevation and anorexia comparable with that observed for ip exposure. Taken together, these findings suggest that PYY might be one critical mediator of DON-induced anorexia and, ultimately, growth suppression.

  13. The effect of Korean pine nut oil on in vitro CCK release, on appetite sensations and on gut hormones in post-menopausal overweight women.

    PubMed

    Pasman, Wilrike J; Heimerikx, Jos; Rubingh, Carina M; van den Berg, Robin; O'Shea, Marianne; Gambelli, Luisa; Hendriks, Henk F J; Einerhand, Alexandra W C; Scott, Corey; Keizer, Hiskias G; Mennen, Louise I

    2008-03-20

    Appetite suppressants may be one strategy in the fight against obesity. This study evaluated whether Korean pine nut free fatty acids (FFA) and triglycerides (TG) work as an appetite suppressant. Korean pine nut FFA were evaluated in STC-1 cell culture for their ability to increase cholecystokinin (CCK-8) secretion vs. several other dietary fatty acids from Italian stone pine nut fatty acids, oleic acid, linoleic acid, alpha-linolenic acid, and capric acid used as a control. At 50 muM concentration, Korean pine nut FFA produced the greatest amount of CCK-8 release (493 pg/ml) relative to the other fatty acids and control (46 pg/ml). A randomized, placebo-controlled, double-blind cross-over trial including 18 overweight post-menopausal women was performed. Subjects received capsules with 3 g Korean pine (Pinus koraiensis) nut FFA, 3 g pine nut TG or 3 g placebo (olive oil) in combination with a light breakfast. At 0, 30, 60, 90, 120, 180 and 240 minutes the gut hormones cholecystokinin (CCK-8), glucagon like peptide-1 (GLP-1), peptide YY (PYY) and ghrelin, and appetite sensations were measured. A wash-out period of one week separated each intervention day.CCK-8 was higher 30 min after pine nut FFA and 60 min after pine nut TG when compared to placebo (p < 0.01). GLP-1 was higher 60 min after pine nut FFA compared to placebo (p < 0.01). Over a period of 4 hours the total amount of plasma CCK-8 was 60% higher after pine nut FFA and 22% higher after pine nut TG than after placebo (p < 0.01). For GLP-1 this difference was 25% after pine nut FFA (P < 0.05). Ghrelin and PYY levels were not different between groups. The appetite sensation "prospective food intake" was 36% lower after pine nut FFA relative to placebo (P < 0.05). This study suggests that Korean pine nut may work as an appetite suppressant through an increasing effect on satiety hormones and a reduced prospective food intake.

  14. The incretin effect in cats: comparison between oral glucose, lipids, and amino acids.

    PubMed

    Gilor, C; Graves, T K; Gilor, S; Ridge, T K; Weng, H-Y; Dossin, O

    2011-05-01

    Incretin hormones are secreted from the intestines in response to specific nutrients. They potentiate insulin secretion and have other beneficial effects in glucose homeostasis. We aimed to study the incretin effect in cats and to compare the effect of oral glucose, lipids, or amino acids on serum concentrations of insulin, total glucose-dependent insulinotropic peptide (GIP) and total glucagon-like peptide 1 (GLP-1). Ten healthy cats were used in a repeated measures design. Glucose, lipid, or amino acids were administered through nasoesophageal tubes on separate days. Blood glucose (BG) concentrations were matched between experiments by measuring BG every 5 min and infusing glucose intravenously at a changing rate. Intravenous glucose infusion with no prior treatment served as control. The incretin effect was estimated as the difference in insulin area under the curve (AUC) after oral compared with intravenous glucose. Temporal changes and total amount of hormone secretions were compared between treatment groups with the use of mixed models. Total glucose infused (TGI) at a mean dose of 0.49 g/kg resulted in slightly higher BG compared with 1 g/kg oral glucose (P = 0.038), but insulin concentrations were not significantly different (P = 0.367). BG and the TGI were not significantly different after the 3 oral challenges. Total GIP AUC was larger after lipids compared with amino acids (P = 0.0012) but GIP concentrations did not increase after oral glucose. Insulin and GIP concentrations were positively correlated after lipid (P < 0.001) and amino acids (P < 0.001) stimulations, respectively, but not after oral glucose stimulation. Total GLP-1 AUC was similar after all three oral stimulations. Insulin and GLP-1 concentrations were positively correlated after glucose (P = 0.001), amino acids (P < 0.001), or lipids (P = 0.001) stimulations. Our data indirectly support an insulinotropic effect of GIP and GLP-1. Potentiation of insulin secretion after oral glucose is

  15. The role of gut peptides in the gut-brain-axis of livestock

    USDA-ARS?s Scientific Manuscript database

    Gut peptides are small hormones produced within the gut that are involved in many biological processes including, but not limited to, appetite regulation, mucosal growth, and metabolism regulation. Some peptides, such as cholecystokinin (CCK) and xenin-25 may affect appetite by altering gut motilit...

  16. Dietary Whey and Casein Differentially Affect Energy Balance, Gut Hormones, Glucose Metabolism, and Taste Preference in Diet-Induced Obese Rats.

    PubMed

    Pezeshki, Adel; Fahim, Andrew; Chelikani, Prasanth K

    2015-10-01

    -like peptide 1 concentrations were greater in WH than in CA or WHCA rats. The improvements in glucose tolerance were greater in WH than in WHCA rats. The plasma membrane glucose transporter 4 (GLUT4)-to-total GLUT4 ratio in skeletal muscle was greater in CA and WHCA rats than in CO rats; other markers of glucose and energy metabolism in the adipose and cardiac tissues did not differ. In Expt. 2, during 4 conditioning trials, daily food intake was decreased in WH, CA, and WHCA rats by 26-37%, 30-43%, and 23-33%, respectively, compared with CO rats. Preferences for WH and CA rats were 45% and 31% lower, respectively, than those for CO rats, but that for WHCA rats did not differ. Together, these data demonstrate that in obese rats, whey, casein, and their combination improve energy balance through differential effects on food intake, taste preference, energy expenditure, glucose tolerance, and gut hormone secretion. © 2015 American Society for Nutrition.

  17. Short-term glucose metabolism and gut hormone modulations after Billroth II gastrojejunostomy in nonobese gastric cancer patients with type 2 diabetes mellitus, impaired glucose tolerance and normal glucose tolerance.

    PubMed

    Zhang, Xiao-juan; Xiao, Zhu; Yu, Hong-ling; Zhang, Xiang-xun; Cheng, Zhong; Tian, Hao-ming

    2013-08-01

    Roux-en-Y gastric bypass (RYGB) is effective in controlling blood glucose in obese patients with type 2 diabetes (T2DM). The alterations of gut hormones involving in glucose metabolism may play an important role. Our aim was to explore the short-term effects of Billroth II gastrojejunostomy (a similar type of RYGB) on glucose metabolism and gut hormone modulations in nonobese patients with different levels of blood glucose tolerance. Twenty one nonobese gastric cancer patients with different levels of blood glucose tolerance were submitted to Billroth II gastrojejunostomy. Among them, seven had T2DM, seven with impaired glucose tolerance (IGT) and the other seven had normal glucose tolerance (NGT). Body weight, glucose parameters, responses of plasma glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and gastric inhibitory polypeptide (GIP) to 75 g glucose were measured at baseline and 3 months after surgery. Similar weight losses were observed in all groups. Blood glucose was reduced in T2DM and IGT patients. Fasting and 30-min plasma glucose were increased significantly in NGT. GLP-1 showed insignificant alterations in all groups. PYY was evaluated in T2DM and IGT but remained unchanged in the NGT group. Decreased fasting and AUC GIP were observed in patients with T2DM; however, fasting and 30-min GIP were increased in NGT patients. Billroth II gastrojejunostomy is effective in reducing blood glucose in nonobese patients with T2DM and IGT but could deteriorate early blood glucose in nonobese NGT in a 3-month time period. Variations of glucose and gut hormone changes in the three groups suggest a role of proximal intestine in the pathophysiology of T2DM. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

  18. Obesity and the gut microbiota.

    PubMed

    Flint, Harry J

    2011-11-01

    Gut microorganisms have the potential to influence weight gain and fat deposition through a variety of mechanisms. One factor is the ability of microorganisms in the large intestine to release energy by fermenting otherwise indigestible components of the diet ("energy harvest"). This energy becomes available to the host indirectly through the absorption of microbially produced short-chain fatty acids. Energy recovery from fiber will be largely determined by dietary intake and gut transit, but can also depend on the makeup of the gut microbiota. The species composition of the gut microbiota changes with diet composition, as has been shown in studies with obese individuals after reduced carbohydrate weight loss diets, or diets containing different nondigestible carbohydrates. There is conflicting evidence, however, on the extent to which gut microbiota composition differs between obese and nonobese humans. In contrast, there is increasing evidence to suggest that gut microorganisms and their metabolic products can influence gut hormones, inflammation, and gut motility. Any changes in gut microbiota composition that influence energy expenditure, satiety, and food intake have the potential to alter weight gain and weight loss, but a better understanding of the impact of different members of the gut microbial community upon host physiology is needed to establish these relationships.

  19. Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus.

    PubMed

    Vilsbøll, T; Krarup, T; Sonne, J; Madsbad, S; Vølund, A; Juul, A G; Holst, J J

    2003-06-01

    Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones secreted in response to meal ingestion, thereby enhancing postprandial insulin secretion. Therefore, an attenuated incretin response could contribute to the impaired insulin responses in patients with diabetes mellitus. The aim of the present investigation was to investigate incretin secretion, in obesity and type 1 and type 2 diabetes mellitus, and its dependence on the magnitude of the meal stimulus. Plasma concentrations of incretin hormones (total, reflecting secretion and intact, reflecting potential action) were measured during two meal tests (260 kcal and 520 kcal) in eight type 1 diabetic patients, eight lean healthy subjects, eight obese type 2 diabetic patients, and eight obese healthy subjects. Both in diabetic patients and in healthy subjects, significant increases in GLP-1 and GIP concentrations were seen after ingestion of both meals. The incretin responses were significantly higher in all groups after the large meal, compared with the small meal, with correspondingly higher C-peptide responses. Both type 1 and type 2 diabetic patients had normal GIP responses, compared with healthy subjects, whereas decreased GLP-1 responses were seen in type 2 diabetic patients, compared with matched obese healthy subjects. Incremental GLP-1 responses were normal in type 1 diabetic patients. Increased fasting concentrations of GIP and an early enhanced postprandial GIP response were seen in obese, compared with lean healthy subjects, whereas GLP-1 responses were the same in the two groups. beta-cell sensitivity to glucose, evaluated as the slope of insulin secretion rates vs. plasma glucose concentration, tended to increase in both type 2 diabetic patients (29%, P = 0.19) and obese healthy subjects (22% P = 0.04) during the large meal, compared with the small meal, perhaps reflecting the increased incretin response. We conclude: 1) that a decreased GLP-1

  20. GUTs without guts

    NASA Astrophysics Data System (ADS)

    Gato-Rivera, B.; Schellekens, A. N.

    2014-06-01

    The structure of a Standard Model family is derived in a class of brane models with a U(M)×U(N) factor, from two mildly anthropic requirements: a massless photon and a universe that does not turn into a plasma of massless charged particles. If we choose M=3 and N=2, the only option is shown to be the Standard Model with an undetermined number of families. We do not assume the U(1) embedding, charge quantization, family repetition, nor the fermion representations; all of these features are derived, assuming a doublet Higgs. With a slightly stronger assumption even the Higgs representation is determined. We also consider a more general class, requiring an asymptotically free strong SU(M) (with M⩾3) interaction from the first factor and an electromagnetic U(1) embedded in both factors. We allow Higgs symmetry breaking of the U(N)×U(1) flavor group by at most one Higgs boson in any representation, combined with any allowed chiral symmetry breaking by SU(M). For M=3 there is a large number of solutions with an unbroken U(1). In all of these, “quarks” have third-integral charges and color singlets have integer charges in comparison to leptons. Hence Standard Model charge quantization holds for any N. Only for N=2 these models allow an SU(5) GUT extension, but this extension offers no advantages whatsoever for understanding the Standard Model; it only causes complications, such as the doublet-triplet splitting problem. Although all these models have a massless photon, all except the Standard Model are ruled out by the second anthropic requirement. In this class of brane models the Standard Model is realized as a GUT with its intestines removed, to keep only the good parts: a GUT without guts.

  1. Manipulation of starch bioaccessibility in wheat endosperm to regulate starch digestion, postprandial glycemia, insulinemia, and gut hormone responses: a randomized controlled trial in healthy ileostomy participants.

    PubMed

    Edwards, Cathrina H; Grundy, Myriam Ml; Grassby, Terri; Vasilopoulou, Dafni; Frost, Gary S; Butterworth, Peter J; Berry, Sarah Ee; Sanderson, Jeremy; Ellis, Peter R

    2015-10-01

    Cereal crops, particularly wheat, are a major dietary source of starch, and the bioaccessibility of starch has implications for postprandial glycemia. The structure and properties of plant foods have been identified as critical factors in influencing nutrient bioaccessibility; however, the physical and biochemical disassembly of cereal food during digestion has not been widely studied. The aims of this study were to compare the effects of 2 porridge meals prepared from wheat endosperm with different degrees of starch bioaccessibility on postprandial metabolism (e.g., glycemia) and to gain insight into the structural and biochemical breakdown of the test meals during gastroileal transit. A randomized crossover trial in 9 healthy ileostomy participants was designed to compare the effects of 55 g starch, provided as coarse (2-mm particles) or smooth (<0.2-mm particles) wheat porridge, on postprandial changes in blood glucose, insulin, C-peptide, lipids, and gut hormones and on the resistant starch (RS) content of ileal effluent. Undigested food in the ileal output was examined microscopically to identify cell walls and encapsulated starch. Blood glucose, insulin, C-peptide, and glucose-dependent insulinotropic polypeptide concentrations were significantly lower (i.e., 33%, 43%, 40%, and 50% lower 120-min incremental AUC, respectively) after consumption of the coarse porridge than after the smooth porridge (P < 0.01). In vitro, starch digestion was slower in the coarse porridge than in the smooth porridge (33% less starch digested at 90 min, P < 0.05, paired t test). In vivo, the structural integrity of coarse particles (∼2 mm) of wheat endosperm was retained during gastroileal transit. Microscopic examination revealed a progressive loss of starch from the periphery toward the particle core. The structure of the test meal had no effect on the amount or pattern of RS output. The structural integrity of wheat endosperm is largely retained during gastroileal digestion

  2. Manipulation of starch bioaccessibility in wheat endosperm to regulate starch digestion, postprandial glycemia, insulinemia, and gut hormone responses: a randomized controlled trial in healthy ileostomy participants12

    PubMed Central

    Edwards, Cathrina H; Grundy, Myriam ML; Grassby, Terri; Vasilopoulou, Dafni; Frost, Gary S; Butterworth, Peter J; Berry, Sarah EE; Sanderson, Jeremy; Ellis, Peter R

    2015-01-01

    Background: Cereal crops, particularly wheat, are a major dietary source of starch, and the bioaccessibility of starch has implications for postprandial glycemia. The structure and properties of plant foods have been identified as critical factors in influencing nutrient bioaccessibility; however, the physical and biochemical disassembly of cereal food during digestion has not been widely studied. Objectives: The aims of this study were to compare the effects of 2 porridge meals prepared from wheat endosperm with different degrees of starch bioaccessibility on postprandial metabolism (e.g., glycemia) and to gain insight into the structural and biochemical breakdown of the test meals during gastroileal transit. Design: A randomized crossover trial in 9 healthy ileostomy participants was designed to compare the effects of 55 g starch, provided as coarse (2-mm particles) or smooth (<0.2-mm particles) wheat porridge, on postprandial changes in blood glucose, insulin, C-peptide, lipids, and gut hormones and on the resistant starch (RS) content of ileal effluent. Undigested food in the ileal output was examined microscopically to identify cell walls and encapsulated starch. Results: Blood glucose, insulin, C-peptide, and glucose-dependent insulinotropic polypeptide concentrations were significantly lower (i.e., 33%, 43%, 40%, and 50% lower 120-min incremental AUC, respectively) after consumption of the coarse porridge than after the smooth porridge (P < 0.01). In vitro, starch digestion was slower in the coarse porridge than in the smooth porridge (33% less starch digested at 90 min, P < 0.05, paired t test). In vivo, the structural integrity of coarse particles (∼2 mm) of wheat endosperm was retained during gastroileal transit. Microscopic examination revealed a progressive loss of starch from the periphery toward the particle core. The structure of the test meal had no effect on the amount or pattern of RS output. Conclusion: The structural integrity of wheat

  3. Gut feeling is electric

    NASA Astrophysics Data System (ADS)

    Familoni, Jide

    2011-06-01

    Although "gut feeling" is a cliché in English parlance, there are neuro-physiological basis for registration of emotions in the gut. Control of the gastro-intestinal (GI) tract is by an integration of neuro-hormonal factors from the local myogenic to the central nervous system. Gastric contractile activity, which is responsible for the motor properties of the stomach, is regulated by this integrated complex. Signatures of the activity include gastric electrical activity (GEA) and bowel sounds. GEA has two distinct components: a high-frequency spike activity or post depolarization potential termed the electrical response activity superimposed on a lower frequency, rhythmic depolarization termed the control activity. These signatures are measured in the clinic with contact sensors and well understood for diagnosis of gut dysmotility. Can these signatures be measured at standoff and employed for purposes of biometrics, malintent and wellness assessment?

  4. The importance of Pharmacovigilance for the drug safety: Focus on cardiovascular profile of incretin-based therapy.

    PubMed

    Sportiello, Liberata; Rafaniello, Concetta; Scavone, Cristina; Vitale, Cristiana; Rossi, Francesco; Capuano, Annalisa

    2016-01-01

    With the recent introduction of the new European Pharmacovigilance legislation, all new drugs must be carefully monitored after admission on the European market, in order to assess the long safety profile. Currently, special attention is given to several hypoglycemic agents with recent market approval (agonists of glucagon-like peptide-1 [GLP-1] receptor and dipeptidyl peptidase 4 inhibitors [DPP-4i]), which act through the potentiation of incretin hormone signaling. Their inclusion in European additional monitoring is also due to safety problems, which seem to characterize their pharmacological class. In fact, these drugs initially showed a good tolerability profile with mainly gastrointestinal adverse events, low risk of hypoglycemia and minor effects on body weight. But, new concerns such as infections, pancreatitis, pancreatic cancer and above all cardiovascular events (especially risk of heart failure requiring hospitalization) are now arising. In this review, we highlighted aspects of the new Pharmacovigilance European dispositions, and then we investigated the tolerability profile of incretin-based therapies, in particular DPP-4 inhibitors. Notably, we focused our attention on new safety concerns, which are emerging mostly in the post-marketing period, as the cardiovascular risk profile. Evidence in literature and opinions of regulatory agencies (e.g., European Medicines Agency and Food and Drug Administration) about risks of incretin-based therapies are yet controversial, and there are many open questions in particular on cancer and cardiovascular effects. Thus, it is important to continue to monitor closely the use of these drugs in clinical practice to improve the knowledge on their long-term safety and their place in diabetes therapy.

  5. Preserved glucagon-like peptide-1 responses to oral glucose, but reduced incretin effect, insulin secretion and sensitivity in young Asians with type 2 diabetes mellitus

    PubMed Central

    Yeow, Toh Peng; Pacini, Giovanni; Tura, Andrea; Lim, Shueh Lin; Tan, Florence Hui Sieng; Tong, Chin Voon; Hong, Janet Yeow Hua; Md Zain, Fuziah; Holst, Jens Juul; Wan Mohamud, Wan Nazaimoon

    2017-01-01

    Objective Youth onset type 2 diabetes mellitus (YT2DM) is a globally rising phenomenon with substantial Asians representation. The understanding of its pathophysiology is derived largely from studies in the obese African-American and Caucasian populations, while studies on incretin effect are scarce. We examined the insulin resistance, β-cell function (BC), glucagon-like peptide (GLP)-1 hormone and incretin effect in Asian YT2DM. Research design and methods This case–control study recruited 25 Asian YT2DM and 15 healthy controls, matched for gender, ethnicity and body mass index. Serum glucose, insulin, C peptide and GLP-1 were sampled during 2-hour oral glucose tolerance tests (OGTTs) and 1-hour intravenous glucose tolerance tests (IVGTTs). Insulin sensitivity was derived from the Quantitative Insulin Sensitivity Check Index (QUICKI), Oral Glucose Insulin Sensitivity Index (OGIS) in OGTT and surrogate index of SI from the minimal model (calculated SI, CSI). Acute insulin response (AIR) was obtained from IVGTT. Total BC was computed as incremental area under the curve of insulin/incremental area under the curve of glucose, during OGTT (BCOG) and IVGTT (BCIV), respectively. Disposition index (DI) was calculated using the product of insulin sensitivity and insulin secretion. GLP-1 response to oral glucose was calculated as incremental area under the curve of GLP-1 (ΔAUCGLP-1). Per cent incretin effect was estimated as 100×(BCOG−BCIV)/BCOG). Results The YT2DM had marked impairment in BC (>80% reduction in AIR and BCOG, p<0.001) and lower QUICKI (p<0.001), OGIS (p<0.001) and CSI (p=0.015) compared with controls. There was no difference in GLP-1 at all time points and ΔAUCGLP-1 but the per cent incretin effect was reduced in the YT2DM compared with controls (12.1±8.93 vs 70.0±4.03, p<0.001). Conclusions Asian YT2DM showed similar GLP-1 response to oral glucose as controls but reduced incretin effect, BC and insulin sensitivity. The lack of compensatory

  6. Gastric bypass surgery restores meal stimulation of the anorexigenic gut hormones glucagon-like peptide-1 and peptide YY independently of caloric restriction.

    PubMed

    Evans, Sarah; Pamuklar, Zehra; Rosko, Jonathan; Mahaney, Patrick; Jiang, Ning; Park, Chan; Torquati, Alfonso

    2012-04-01

    The effects of gastric bypass surgery on the secretion of the anorexigenic gut-derived hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), independent of caloric restriction and due to different dietary macronutrients, is not well characterized. This study examines the effects of a mixed-nutrient or high-fat liquid meal on the postprandial stimulation of GLP-1 and PYY following gastric bypass or equivalent hypocaloric diet. Total PYY and active GLP-1 were measured fasting and at multiple points after standardized mixed-nutrient and high-fat liquid meals in two matched groups of obese subjects. The meal stimulation tests were performed before and 14.6 ± 3.3 days after gastric bypass (GBP, n = 10) and before and after a 7-day hypocaloric liquid diet matching the post-GBP diet (control, n = 10). Mixed-nutrient and high-fat postprandial GLP-1 levels increased following GBP (mixed-nutrient peak: 85.0 ± 28.6-323 ± 51 pg/ml, P < 0.01; high-fat peak: 81.8 ± 9.6-278 ± 49 pg/ml, P < 0.01), but not after diet (mixed-nutrient peak: 104.4 ± 9.4-114.9 ± 15.8 pg/ml, P = NS; high-fat peak: 118.1 ± 16.4-104.4 ± 10.8 pg/ml, P = NS). The postprandial PYY response also increased after GBP but not diet, though the increase in peak PYY did not reach statistical significance (GBP mixed-nutrient peak: 134.8 ± 26.0-220.7 ± 52.9 pg/ml, P = 0.09; GBP high-fat peak: 142.1 ± 34.6-197.9 ± 12.7 pg/ml, P = 0.07; diet mixed-nutrient peak: 99.8 ± 8.0-101.1 ± 13.3 pg/ml, P = NS; diet high-fat peak: 105.0 ± 8.8-103.1 ± 11.8 pg/ml, P = NS). The postprandial GLP-1 response was not affected by the macronutrient content of the meal. However, following GBP the mixed-nutrient PYY total area under the curve (AUC(0-120)) was significantly greater than the high-fat PYY AUC(0-120) (22,081 ± 5,662 pg/ml min vs. 18,711 ± 1,811 pg/ml min, P = 0.04). Following GBP there is an increase in the postprandial stimulation of PYY and GLP-1 that is independent of caloric restriction. The

  7. GASTRIC BYPASS SURGERY RESTORES MEAL STIMULATION OF THE ANOREXIGENIC GUT HORMONES GLUCAGON-LIKE PEPTIDE-1 AND PEPTIDE YY INDEPENDENTLY OF CALORIC RESTRICTION

    PubMed Central

    Evans, Sarah; Pamuklar, Zehra; Rosko, Jonathan; Mahaney, Patrick; Jiang, Ning; Park, Chan; Torquati, Alfonso

    2011-01-01

    Background The effects of gastric bypass surgery on the secretion of the anorexogenic gut-derived hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), independent of caloric restriction and due to different dietary macronutrients, is not well-characterized. This study examines the effects of a mixed-nutrient or high-fat liquid meal on the postprandial stimulation of GLP-1 and PYY following gastric bypass or equivalent hypocaloric diet. Methods Total PYY and active GLP-1 were measured fasting and at multiple points after standardized mixed-nutrient and high-fat liquid meals in two matched groups of obese subjects. The meal stimulation tests were performed before and 14.6±3.3 days after gastric bypass (GBP, n=10) and before and after a 7-day hypocaloric liquid diet matching the post-GBP diet (Control, n=10). Results Mixed-nutrient and high-fat postprandial GLP-1 levels increased following GBP (mixed-nutrient peak: 85.0±28.6 pg/ml to 323±51 pg/ml, p<0.01; high-fat peak: 81.8±9.6 pg/ml to 278±49 pg/ml, p<0.01), but not after diet (mixed-nutrient peak: 104.4±9.4 pg/ml to 114.9±15.8 pg/ml, p=NS; high-fat peak: 118.1±16.4 pg/ml to 104.4±10.8 pg/ml, p=NS). The postprandial PYY response also increased after GBP but not diet, though the increase in peak PYY did not reach statistical significance (GBP mixed-nutrient peak: 134.8±26.0 pg/ml to 220.7±52.9 pg/ml, p=0.09; GBP high-fat peak: 142.1±34.6 pg/ml to 197.9±12.7 pg/ml, p=0.07; diet mixed-nutrient peak: 99.8±8.0 pg/ml to 101.1±13.3 pg/ml, p=NS; diet high-fat peak: 105.0±8.8 pg/ml to 103.1±11.8 pg/ml, p=NS). The postprandial GLP-1 response was not affected by the macronutrient content of the meal. However, following GBP the mixed-nutrient PYY AUC0–120 was significantly greater than the high-fat PYY AUC0–120 (22081±5662 pg/ml•min versus 18711±1811 pg/ml•min, p=0.04). Conclusions Following GBP there is an increase in the postprandial stimulation of PYY and GLP-1 that is independent from

  8. Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome.

    PubMed

    Kaska, Lukasz; Sledzinski, Tomasz; Chomiczewska, Agnieszka; Dettlaff-Pokora, Agnieszka; Swierczynski, Julian

    2016-10-21

    Clinical studies have indicated that circulating bile acid (BA) concentrations increase following bariatric surgery, especially following malabsorptive procedures such as Roux-en-Y gastric bypasses (RYGB). Moreover, total circulating BA concentrations in patients following RYGB are positively correlated with serum glucagon-like peptide-1 concentrations and inversely correlated with postprandial glucose concentrations. Overall, these data suggest that the increased circulating BA concentrations following bariatric surgery - independently of calorie restriction and body-weight loss - could contribute, at least in part, to improvements in insulin sensitivity, incretin hormone secretion, and postprandial glycemia, leading to the remission of type-2 diabetes (T2DM). In humans, the primary and secondary BA pool size is dependent on the rate of biosynthesis and the enterohepatic circulation of BAs, as well as on the gut microbiota, which play a crucial role in BA biotransformation. Moreover, BAs and gut microbiota are closely integrated and affect each other. Thus, the alterations in bile flow that result from anatomical changes caused by bariatric surgery and changes in gut microbiome may influence circulating BA concentrations and could subsequently contribute to T2DM remission following RYGB. Research data coming largely from animal and cell culture models suggest that BAs can contribute, via nuclear farnezoid X receptor (FXR) and membrane G-protein-receptor (TGR-5), to beneficial effects on glucose metabolism. It is therefore likely that FXR, TGR-5, and BAs play a similar role in glucose metabolism following bariatric surgery in humans. The objective of this review is to discuss in detail the results of published studies that show how bariatric surgery affects glucose metabolism and subsequently T2DM remission.

  9. Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome

    PubMed Central

    Kaska, Lukasz; Sledzinski, Tomasz; Chomiczewska, Agnieszka; Dettlaff-Pokora, Agnieszka; Swierczynski, Julian

    2016-01-01

    Clinical studies have indicated that circulating bile acid (BA) concentrations increase following bariatric surgery, especially following malabsorptive procedures such as Roux-en-Y gastric bypasses (RYGB). Moreover, total circulating BA concentrations in patients following RYGB are positively correlated with serum glucagon-like peptide-1 concentrations and inversely correlated with postprandial glucose concentrations. Overall, these data suggest that the increased circulating BA concentrations following bariatric surgery - independently of calorie restriction and body-weight loss - could contribute, at least in part, to improvements in insulin sensitivity, incretin hormone secretion, and postprandial glycemia, leading to the remission of type-2 diabetes (T2DM). In humans, the primary and secondary BA pool size is dependent on the rate of biosynthesis and the enterohepatic circulation of BAs, as well as on the gut microbiota, which play a crucial role in BA biotransformation. Moreover, BAs and gut microbiota are closely integrated and affect each other. Thus, the alterations in bile flow that result from anatomical changes caused by bariatric surgery and changes in gut microbiome may influence circulating BA concentrations and could subsequently contribute to T2DM remission following RYGB. Research data coming largely from animal and cell culture models suggest that BAs can contribute, via nuclear farnezoid X receptor (FXR) and membrane G-protein-receptor (TGR-5), to beneficial effects on glucose metabolism. It is therefore likely that FXR, TGR-5, and BAs play a similar role in glucose metabolism following bariatric surgery in humans. The objective of this review is to discuss in detail the results of published studies that show how bariatric surgery affects glucose metabolism and subsequently T2DM remission. PMID:27818587

  10. Gastrointestinal hormones regulating appetite

    PubMed Central

    Chaudhri, Owais; Small, Caroline; Bloom, Steve

    2006-01-01

    The role of gastrointestinal hormones in the regulation of appetite is reviewed. The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones function to optimize the process of digestion and absorption of nutrients by the gut. In this capacity, their local effects on gastrointestinal motility and secretion have been well characterized. By altering the rate at which nutrients are delivered to compartments of the alimentary canal, the control of food intake arguably constitutes another point at which intervention may promote efficient digestion and nutrient uptake. In recent decades, gut hormones have come to occupy a central place in the complex neuroendocrine interactions that underlie the regulation of energy balance. Many gut peptides have been shown to influence energy intake. The most well studied in this regard are cholecystokinin (CCK), pancreatic polypeptide, peptide YY, glucagon-like peptide-1 (GLP-1), oxyntomodulin and ghrelin. With the exception of ghrelin, these hormones act to increase satiety and decrease food intake. The mechanisms by which gut hormones modify feeding are the subject of ongoing investigation. Local effects such as the inhibition of gastric emptying might contribute to the decrease in energy intake. Activation of mechanoreceptors as a result of gastric distension may inhibit further food intake via neural reflex arcs. Circulating gut hormones have also been shown to act directly on neurons in hypothalamic and brainstem centres of appetite control. The median eminence and area postrema are characterized by a deficiency of the blood–brain barrier. Some investigators argue that this renders neighbouring structures, such as the arcuate nucleus of the hypothalamus and the nucleus of the tractus solitarius in the brainstem, susceptible to influence by circulating factors. Extensive reciprocal connections exist between these areas and the hypothalamic paraventricular nucleus and other energy-regulating centres of the

  11. Uncertainties around incretin-based therapies: A literature review.

    PubMed

    Al Tulaihi, Bader; Alhabib, Samia

    2017-01-01

    Background: Diabetes mellitus is a chronic debilitating and non-communicable disease. It has several long-term outcomes that are associated with various end organ damage, mainly the heart, blood vessels, eyes, nerves, and kidneys. There are different modalities of treatment of diabetes. The recent incretin-based therapies provided an innovative class of drugs including GLP-1 receptor agonists and DPP-4 inhibitors. This review aims to summarize the available evidence of their effectiveness. Method: This is a narrative review. Several databases were searched. Search terms used were MeSH and keywords with different combinations of Boolean operators according to the database but were comparable. Studies included were: randomized controlled trials, cohort and case-controlled studies, health technology report, meta-analysis, and systematic reviews. Results were analysed and reported in a narrative style with emphasis on the effectiveness and adverse effects of various types of incretin based therapies. Results: 17 articles were retrieved as they fulfilled the inclusion criteria. They were heterogeneous in terms of interventions, participants, settings and outcomes. Studies varied in their quality and/or reporting of their findings conducted in several settings. There are two types of incretin: Glucose dependent Insulinotropic Peptide (GIP) and Glucagon-like Peptide 1 (GLP-1). There is no question that incretin-based glucose-lowering medications have demonstrated to be effective glucose-lowering drugs. They proved an evidence-based efficacy profile and appear to do so with significant effects to stimulate weight loss with minimal hypoglycaemia. However, there are few side effects that should not be overlooked when deciding to use such therapies. Conclusion: The findings of our review presented here, do not prove that these agents are unsafe, but it does suggest that the burden of evidence now rests with those who hope to persuade us of their safety. Continuous clinical

  12. The role of Gut Microbiota in the development of obesity and Diabetes.

    PubMed

    Baothman, Othman A; Zamzami, Mazin A; Taher, Ibrahim; Abubaker, Jehad; Abu-Farha, Mohamed

    2016-06-18

    Obesity and its associated complications like type 2 diabetes (T2D) are reaching epidemic stages. Increased food intake and lack of exercise are two main contributing factors. Recent work has been highlighting an increasingly more important role of gut microbiota in metabolic disorders. It's well known that gut microbiota plays a major role in the development of food absorption and low grade inflammation, two key processes in obesity and diabetes. This review summarizes key discoveries during the past decade that established the role of gut microbiota in the development of obesity and diabetes. It will look at the role of key metabolites mainly the short chain fatty acids (SCFA) that are produced by gut microbiota and how they impact key metabolic pathways such as insulin signalling, incretin production as well as inflammation. It will further look at the possible ways to harness the beneficial aspects of the gut microbiota to combat these metabolic disorders and reduce their impact.

  13. Incretin-Based Therapy for Prevention of Diabetic Vascular Complications

    PubMed Central

    Mima, Akira

    2016-01-01

    Diabetic vascular complications are the most common cause of mortality and morbidity worldwide, with numbers of affected individuals steadily increasing. Diabetic vascular complications can be divided into two categories: macrovascular andmicrovascular complications. Macrovascular complications include coronary artery diseaseand cerebrovascular disease, while microvascular complications include retinopathy and chronic kidney disease. These complications result from metabolic abnormalities, including hyperglycemia, elevated levels of free fatty acids, and insulin resistance. Multiple mechanisms have been proposed to mediate the adverse effects of these metabolic disorders on vascular tissues, including stimulation of protein kinase C signaling and activation of the polyol pathway by oxidative stress and inflammation. Additionally, the loss of tissue-specific insulin signaling induced by hyperglycemia and toxic metabolites can induce cellular dysfunction and both macro- and microvascular complications characteristic of diabetes. Despite these insights, few therapeutic methods are available for the management of diabetic complications. Recently, incretin-based therapeutic agents, such as glucagon-like peptide-1 and dipeptidyl peptidase-4 inhibitors, have been reported to elicit vasotropic actions, suggesting a potential for effecting an actual reduction in diabetic vascular complications. The present review will summarize the relationship between multiple adverse biological mechanisms in diabetes and putative incretin-based therapeutic interventions intended to prevent diabetic vascular complications. PMID:26881236

  14. Octreotide improves early dumping syndrome potentially through incretins: a case report.

    PubMed

    Sato, Daisuke; Morino, Katsutaro; Ohashi, Natsuko; Ueda, Emi; Ikeda, Kazuhiro; Yamamoto, Hideka; Ugi, Satoshi; Yamamoto, Hiroshi; Araki, Shinichi; Maegawa, Hiroshi

    2013-01-01

    Dumping syndrome, or rapid gastric emptying, is a frequent complication after gastric surgery. In this case, the patient was a 47-year-old woman who 10 years previously had undergone distal gastrectomy with Billroth I reconstruction for early-stage gastric cancer. She presented with symptoms of weakness, headache, palpitation, sweating, dizziness and significant fatigue between one and two hours after a meal. Because a 75 g oral glucose tolerance test (75 g-OGTT) induced both acute postprandial tachycardia (within 1 hour) and postprandial hypoglycemia, we diagnosed this patient with early and late dumping syndrome. Dietary measures and acarbose improved symptoms of late dumping syndrome but did not prevent the symptoms of early dumping syndrome such as postprandial tachycardia, weakness, headache, palpitation, and dizziness. We therefore used the somatostatin analogue octreotide, which has been reported as an effective therapy for early dumping syndrome. Octreotide prevented the symptoms of early dumping syndrome, especially postprandial tachycardia, but caused postprandial hyperglycemia. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were completely suppressed during the 75 g-OGTT following subcutaneous injection of octreotide. No change was observed in vasoactive intestinal polypeptide (VIP), which is the gastrointestinal peptide hormone generally responsible for early dumping syndrome, suggesting possible contribution of incretins in early dumping syndrome of this patient.

  15. Ghrelin: much more than a hunger hormone

    USDA-ARS?s Scientific Manuscript database

    Ghrelin is a multifaceted gut hormone that activates its receptor, growth hormone secretagogue receptor (GHS-R). Ghrelin's hallmark functions are its stimulatory effects on growth hormone release, food intake and fat deposition. Ghrelin is famously known as the 'hunger hormone'. However, ample recen...

  16. Evidence-based practice use of incretin-based therapy in the natural history of diabetes.

    PubMed

    Schwartz, Stanley

    2014-05-01

    The incretin class of anti-hyperglycemic agents, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-inhibitors, is an important addition to the therapeutic armamentarium for the management of appropriate patients with type 2 diabetes mellitus as an adjunct to diet and exercise and/or with the agents metformin, sulfonylureas, thiazolidinediones, or any combination thereof. More recently, US Food and Drug Administration (FDA)-approved indications for incretins were expanded to include use with basal insulin. This review article takes an evidence-based practice approach in discussing the importance of aggressive treatment for diabetes, the principles of incretin physiology and pathophysiology, use of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, and patient types and contexts where incretin therapy has been found beneficial, from metabolic syndrome to overt diabetes.

  17. Gut chemosensing: implications for disease pathogenesis

    PubMed Central

    Berg, Christopher J.; Kaunitz, Jonathan D.

    2016-01-01

    The ability of humans to sense chemical signals in ingested substances is implicit in the ability to detect the five basic tastes; sweet, sour, bitter, salty, and umami. Of these, sweet, bitter, and umami tastes are detected by lingual G-protein-coupled receptors (GPCRs). Recently, these receptors were also localized to the gut mucosa. In this review, we will emphasize recent advances in the understanding of the mechanisms and consequences of foregut luminal chemosensing, with special emphasis on cell surface GPCRs such as the sweet and proteinaceous taste receptors (TASRs), short- and long-chain fatty acid (FA) receptors, and bile acid receptors. The majority of these luminal chemosensors are expressed on enteroendocrine cells (EECs), which are specialized endocrine cells in the intestine and pancreas that release gut hormones with ligand activation. These gut hormones are responsible for a wide variety of physiologic and homeostatic mechanisms, including glycemic control, appetite stimulation and suppression, regulation of gastric emptying, and trophic effects on the intestinal epithelium. Released from the EECs, the gut peptides have paracrine, autocrine, and endocrine effects. Additionally, EECs have unique direct connections to the enteric nervous system enabling precise transmission of sensory data to and communication with the central nervous system. We will also describe how gut sensors are implicated in gut hormone release, followed by examples of how altered gut chemosensing has been implicated in pathological conditions such as metabolic diseases including diabetes and obesity, functional dyspepsia, helminthic infections, colitis, gastric bypass surgery, and gastric inflammation and cancer. PMID:27781093

  18. Obesity: genes, brain, gut, and environment.

    PubMed

    Das, Undurti N

    2010-05-01

    Obesity, which is assuming alarming proportions, has been attributed to genetic factors, hypothalamic dysfunction, and intestinal gut bacteria and an increase in the consumption of energy-dense food. Obesity predisposes to the development of type 2 diabetes mellitus, hypertension, coronary heart disease, and certain forms of cancer. Recent studies have shown that the intestinal bacteria in obese humans and mice differ from those in lean that could trigger a low-grade systemic inflammation. Consumption of a calorie-dense diet that initiates and perpetuates obesity could be due to failure of homeostatic mechanisms that regulate appetite, food consumption, and energy balance. Hypothalamic factors that regulate energy needs of the body, control appetite and satiety, and gut bacteria that participate in food digestion play a critical role in the onset of obesity. Incretins, cholecystokinin, brain-derived neurotrophic factor, leptin, long-chain fatty acid coenzyme A, endocannabinoids and vagal neurotransmitter acetylcholine play a role in the regulation of energy intake, glucose homeostasis, insulin secretion, and pathobiology of obesity and type 2 diabetes mellitus. Thus, there is a cross-talk among the gut, liver, pancreas, adipose tissue, and hypothalamus. Based on these evidences, it is clear that management of obesity needs a multifactorial approach. Copyright 2010 Elsevier Inc. All rights reserved.

  19. Effect of L-Tryptophan and L-Leucine on Gut Hormone Secretion, Appetite Feelings and Gastric Emptying Rates in Lean and Non-Diabetic Obese Participants: A Randomized, Double-Blind, Parallel-Group Trial

    PubMed Central

    Meyer-Gerspach, Anne Christin; Häfliger, Simon; Meili, Julian; Doody, Alison; Rehfeld, Jens F; Drewe, Jürgen; Beglinger, Christoph; Wölnerhanssen, Bettina

    2016-01-01

    Background/Objectives Gut hormones such as cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) play a role as satiation factors. Strategies to enhance satiation peptide secretion could provide a therapeutic approach for obesity. Carbohydrates and lipids have been extensively investigated in relation to peptide release. In contrast, the role of proteins or amino acids is less clear. Our aim was to compare the effects of the amino acids L-tryptophan (L-trp) and L-leucine (L-leu) separately on gastric emptying and gut peptide secretion. Participants/Methods The study was conducted as a randomized (balanced), double-blind, parallel-group trial. A total of 10 lean and 10 non-diabetic obese participants were included. Participants received intragastric loads of L-trp (0.52 g and 1.56 g) and L-leu (1.56 g), dissolved in 300 mL tap water; 75 g glucose and 300 mL tap water served as control treatments. Results Results of the study are: i) L-trp at the higher dose stimulates CCK release (p = 0.0018), and induces a significant retardation in gastric emptying (p = 0.0033); ii) L-trp at the higher dose induced a small increase in GLP-1 secretion (p = 0.0257); iii) neither of the amino acids modulated subjective appetite feelings; and iv) the two amino acids did not alter insulin or glucose concentrations. Conclusions L-trp is a luminal regulator of CCK release with effects on gastric emptying, an effect that could be mediated by CCK. L-trp’s effect on GLP-1 secretion is only minor. At the doses given, the two amino acids did not affect subjective appetite feelings. Trial Registration ClinicalTrials.gov NCT02563847 PMID:27875537

  20. Role of islet-, gut-, and adipocyte-derived hormones in the central control of food intake and body weight: implications for an integrated neurohormonal approach to obesity pharmacotherapy.

    PubMed

    Chen, Hubert C; Roth, Jonathan D; Schroeder, Brock E; Weyer, Christian

    2008-05-01

    Contrary to its historical epithet as a lifestyle disorder, obesity is now widely recognized as having a neurobiological basis. This progress is due to our knowledge not only about energy homoeostatic pathways within the central nervous system (CNS), but also about the role of peripheral peptide hormones acting upon the CNS. These hormones include long-term adiposity signals, such as leptin, that inform the CNS primarily of changes in the body's overall fat and energy reserves, and short-term signals such as amylin, peptide YY (PYY) and ghrelin, that primarily reflect changes in the immediate nutritive state (energy intake). The limited weight loss effects achieved with current monotherapy approaches to obesity have been attributed, at least in part, to the redundancies and potent counter-regulatory responses within the neurohormonal feedback loop governing energy balance. Recently, we reported that combinations of amylin, leptin and PYY(3-36) resulted in additive and/or synergistic interactions and caused marked weight loss in the diet-induced obese rat model, which to date has reasonably predicted the clinical effects of several hormones in obese humans. If confirmed in ongoing translational clinical research studies, these findings may provide a physiological rationale for a novel, integrated neurohormonal approach to pharmacotherapy for obesity.

  1. Differentiating incretin therapies based on structure, activity, and metabolism: focus on liraglutide.

    PubMed

    Grossman, Samuel

    2009-12-01

    The incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), plays an important role in the regulation of insulin secretion in response to oral glucose. The discovery of deficiencies in incretin pathways associated with development of type 2 diabetes mellitus has propelled the growth of incretin-based therapies in patients with this disease. The basic rationale for incretin-based therapies, including both GLP-1-receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors is reviewed, focusing on their roles in glucose regulation and potential therapeutic benefits. Increased awareness of the differences among incretin mimetics, GLP-1 analogs, and DPP-4 inhibitors, including their structures, half-lives, dosages, hemoglobin A(1c)-lowering capacities, effects on weight, and adverse events will help shape the future of these therapeutic agents. Improved understanding of the mechanism of action and clinical effects of incretin-based therapies will help advance their appropriate use within clinical practice.

  2. Effects of meal composition on postprandial incretin, glucose and insulin responses after surgical and medical weight loss

    PubMed Central

    Brown, T. T.; Cheskin, L. J.; Choi, P.; Moran, T. H.; Peterson, L.; Matuk, R.; Steele, K. E.

    2015-01-01

    Summary Background Meal tolerance tests are frequently used to study dynamic incretin and insulin responses in the postprandial state; however, the optimal meal that is best tolerated and suited for hormonal response following surgical and medical weight loss has yet to be determined. Objective To evaluate the tolerability and effectiveness of different test meals in inducing detectable changes in markers of glucose metabolism in individuals who have undergone a weight loss intervention. Methods Six individuals who underwent surgical or medical weight loss (two Roux‐en‐Y gastric bypass, two sleeve gastrectomy and two medical weight loss) each completed three meal tolerance tests using liquid‐mixed, solid‐mixed and high‐fat test meals. The tolerability of each test meal, as determined by the total amount consumed and palatability, as well as fasting and meal‐stimulated glucagon‐like peptide, glucose‐dependent insulinotropic polypeptide, insulin and glucose were measured. Results Among the six individuals, the liquid‐mixed meal was better and more uniformly tolerated with a median meal completion rate of 99%. Among the four bariatric surgical patients, liquid‐mixed meal stimulated on average a higher glucagon‐like peptide (percent difference: 83.7, 89), insulin secretion (percent difference: 155.1, 158.7) and glucose‐dependent insulinotropic polypeptide (percent difference: 113.5, 34.3) compared with solid‐mixed and high‐fat meals. Conclusions The liquid‐mixed meal was better tolerated with higher incretin and insulin response compared with the high‐fat and solid‐mixed meals and is best suited for the evaluation of stimulated glucose homeostasis. PMID:27774253

  3. Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide

    PubMed Central

    Candeias, Emanuel Monteiro; Sebastião, Inês Carolina; Cardoso, Susana Maria; Correia, Sónia Catarina; Carvalho, Cristina Isabel; Plácido, Ana Isabel; Santos, Maria Sancha; Oliveira, Catarina Resende; Moreira, Paula Isabel; Duarte, Ana Isabel

    2015-01-01

    Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for type 2 diabetes (T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors (GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions (e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation (thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2D, stroke and Alzheimer disease (AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss

  4. Neuroendocrine disorders of the gut.

    PubMed Central

    Yee, L F; Mulvihill, S J

    1995-01-01

    The regulation of gastrointestinal function is known to involve elements of the enteric nervous system. Processes such as secretion, motility, blood flow, and immune function are all influenced by a complex network of neurons whose cell bodies lie in the gut. These neurons use a wide spectrum of substances as neurotransmitters, although the majority use peptides once thought to function only as gut hormones. It has been increasingly recognized that abnormalities of this neuroendocrine regulatory system underlie many gastrointestinal disorders. The most obvious are states of peptide excess found in patients with gut endocrine tumors such as carcinoid, gastrinoma, and somatostatinoma. Conversely, other disorders appear to be related to deficiency states. Examples include both achalasia and Hirschsprung's disease (congenital megacolon), where the loss of inhibitory neural action leads to abnormalities of peristalsis and sphincter function. Evidence for abnormal neuroendocrine regulation leading to disease states is increasing for many other gastrointestinal disorders. PMID:8533409

  5. Effects of two dietary fibers as part of ready-to-eat cereal (RTEC) breakfasts on perceived appetite and gut hormones in overweight women.

    PubMed

    Lafond, David W; Greaves, Kathryn A; Maki, Kevin C; Leidy, Heather J; Romsos, Dale R

    2015-02-13

    The effects of an enzyme-hydrolyzed arabinoxylan from wheat (AXOS) versus an intact arabinoxylan from flax (FLAX) added to a ready-to-eat cereal (RTEC) on the postprandial appetitive, hormonal, and metabolic responses in overweight women (BMI 25.0-29.9 kg/m2) were evaluated. Subsequent meal energy intake was also assessed. Two randomized, double-blind, crossover design studies were completed. For trial 1, the participants consumed the following RTEC breakfast, matched for total weight and varied in energy content: low-fiber (LF, 4 g); high-fiber (HF, 15 g) as either AXOS or FLAX. For trial 2, the participants consumed LF, HF-AXOS, and HF-FLAX RTECs but also consumed another LF breakfast that was isocaloric (LF-iso) to that of the HF breakfasts. Perceived appetite and blood samples (trial 2 only) were assessed before and after breakfast. An ad libitum lunch was offered 4 h post-breakfast. No differences in postprandial appetite responses were observed among any breakfasts in either trial. The HF-AXOS and HF-FLAX led to increased postprandial GLP-1 and peptide YY (PYY) concentrations vs. LF-iso. No differences were observed in lunch meal energy intake among breakfast meals in either trial. Collectively, these data suggest that 15 g of low molecular weight fiber added to RTECs did not affect perceived appetite or subsequent energy intake despite differences in satiety hormone signaling in overweight females.

  6. The post-prandial pattern of gut hormones is related to magnitude of weight-loss following gastric bypass surgery: a case-control study.

    PubMed

    Gerner, Tom; Johansen, Odd-Erik; Olufsen, Mona; Torjesen, Peter A; Tveit, Arnljot

    2014-04-01

    The mechanisms of weight loss after gastric bypass, including the role of gastric hormones, are still not completely understood. While postprandial releases of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) increase post-surgery and ghrelin usually is reduced, their relationship to the magnitude of the weight loss is still obscure. We explored if differing weight loss after Roux Y gastric bypass (RYGB) in morbidly obese were associated with differing postprandial hormonal release. We compared patients with large (> 40%) or moderate (< 25%) weight loss three years following RYGP surgery, and an obese control group scheduled for RYGB (six in each group). A 300 kcal mixed meal test was given with blood sampling before and thereafter at 30-min intervals in 180 min. Peak and incremental area under the curve (iAUC) were calculated to characterize postprandial responses. Early postprandial GLP-1 response were significantly higher in the RYGB groups than in the controls, and highest in those with largest weight loss. Postprandial PYY response were also greater for the two RYGB groups vs. controls, but interestingly the controls had higher baseline values. Ghrelin, from similar baseline, was only suppressed in those with the largest weight loss, with close to no reduction in those with modest weight loss or controls. These results support the hypothesis that the magnitude of weight loss after RYGB surgery might be associated with differing patterns of postprandial responses in GLP-1 and ghrelin, but not PYY. Larger studies are warranted.

  7. Effects of Two Dietary Fibers as Part of Ready-to-Eat Cereal (RTEC) Breakfasts on Perceived Appetite and Gut Hormones in Overweight Women

    PubMed Central

    Lafond, David W.; Greaves, Kathryn A.; Maki, Kevin C.; Leidy, Heather J.; Romsos, Dale R.

    2015-01-01

    The effects of an enzyme-hydrolyzed arabinoxylan from wheat (AXOS) versus an intact arabinoxylan from flax (FLAX) added to a ready-to-eat cereal (RTEC) on the postprandial appetitive, hormonal, and metabolic responses in overweight women (BMI 25.0–29.9 kg/m2) were evaluated. Subsequent meal energy intake was also assessed. Two randomized, double-blind, crossover design studies were completed. For trial 1, the participants consumed the following RTEC breakfast, matched for total weight and varied in energy content: low-fiber (LF, 4 g); high-fiber (HF, 15 g) as either AXOS or FLAX. For trial 2, the participants consumed LF, HF-AXOS, and HF-FLAX RTECs but also consumed another LF breakfast that was isocaloric (LF-iso) to that of the HF breakfasts. Perceived appetite and blood samples (trial 2 only) were assessed before and after breakfast. An ad libitum lunch was offered 4 h post-breakfast. No differences in postprandial appetite responses were observed among any breakfasts in either trial. The HF-AXOS and HF-FLAX led to increased postprandial GLP-1 and peptide YY (PYY) concentrations vs. LF-iso. No differences were observed in lunch meal energy intake among breakfast meals in either trial. Collectively, these data suggest that 15 g of low molecular weight fiber added to RTECs did not affect perceived appetite or subsequent energy intake despite differences in satiety hormone signaling in overweight females. PMID:25689743

  8. Neuropeptides and the microbiota-gut-brain axis.

    PubMed

    Holzer, Peter; Farzi, Aitak

    2014-01-01

    Neuropeptides are important mediators both within the nervous system and between neurons and other cell types. Neuropeptides such as substance P, calcitonin gene-related peptide and neuropeptide Y (NPY), vasoactive intestinal polypeptide, somatostatin and corticotropin-releasing factor are also likely to play a role in the bidirectional gut-brain communication. In this capacity they may influence the activity of the gastrointestinal microbiota and its interaction with the gut-brain axis. Current efforts in elucidating the implication of neuropeptides in the microbiota-gut-brain axis address four information carriers from the gut to the brain (vagal and spinal afferent neurons; immune mediators such as cytokines; gut hormones; gut microbiota-derived signalling molecules) and four information carriers from the central nervous system to the gut (sympathetic efferent neurons; parasympathetic efferent neurons; neuroendocrine factors involving the adrenal medulla; neuroendocrine factors involving the adrenal cortex). Apart from operating as neurotransmitters, many biologically active peptides also function as gut hormones. Given that neuropeptides and gut hormones target the same cell membrane receptors (typically G protein-coupled receptors), the two messenger roles often converge in the same or similar biological implications. This is exemplified by NPY and peptide YY (PYY), two members of the PP-fold peptide family. While PYY is almost exclusively expressed by enteroendocrine cells, NPY is found at all levels of the gut-brain and brain-gut axis. The function of PYY-releasing enteroendocrine cells is directly influenced by short chain fatty acids generated by the intestinal microbiota from indigestible fibre, while NPY may control the impact of the gut microbiota on inflammatory processes, pain, brain function and behaviour. Although the impact of neuropeptides on the interaction between the gut microbiota and brain awaits to be analysed, biologically active peptides

  9. Neuropeptides and the Microbiota-Gut-Brain Axis

    PubMed Central

    Holzer, Peter; Farzi, Aitak

    2015-01-01

    Neuropeptides are important mediators both within the nervous system and between neurons and other cell types. Neuropeptides such as substance P, calcitonin gene-related peptide and neuropeptide Y (NPY), vasoactive intestinal polypeptide, somatostatin and corticotropin-releasing factor are also likely to play a role in the bidirectional gut-brain communication. In this capacity they may influence the activity of the gastrointestinal microbiota and its interaction with the gut-brain axis. Current efforts in elucidating the implication of neuropeptides in the microbiota-gut-brain axis address 4 information carriers from the gut to the brain (vagal and spinal afferent neurons; immune mediators such as cytokines; gut hormones; gut microbiota-derived signalling molecules) and 4 information carriers from the central nervous system to the gut (sympathetic efferent neurons; parasympathetic efferent neurons; neuroendocrine factors involving the adrenal medulla; neuroendocrine factors involving the adrenal cortex). Apart from operating as neurotransmitters, many biologically active peptides also function as gut hormones. Given that neuropeptides and gut hormones target the same cell membrane receptors (typically G protein-coupled receptors), the two messenger roles often converge in the same or similar biological implications. This is exemplified by NPY and peptide YY (PYY), two members of the PP-fold peptide family. While PYY is almost exclusively expressed by enteroendocrine cells, NPY is found at all levels of the gut-brain and brain-gut axis. The function of PYY-releasing enteroendocrine cells is directly influenced by short chain fatty acids generated by the intestinal microbiota from indigestible fibre, while NPY may control the impact of the gut microbiota on inflammatory processes, pain, brain function and behaviour. Although the impact of neuropeptides on the interaction between the gut microbiota and brain awaits to be analysed, biologically active peptides are

  10. Effects of solid-phase extraction of plasma in measuring gut metabolic hormones in fasted and fed blood of lean and diet-induced obese rats.

    PubMed

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

    2016-05-01

    Glucagon-like peptide-1 (GLP-1), peptide YY (3-36) [PYY(3-36)], amylin, ghrelin, insulin, and leptin are thought to act as hormonal signals from periphery to brain to control food intake. Here, we determined the effects of solid-phase extraction of plasma in measuring these hormones in blood of lean and diet-induced obese rats. Individual enzyme-linked immunoassays and a multiplex assay were used to measure active GLP-1, total PYY, active amylin, active ghrelin, insulin, leptin, and total GIP in response to (1) addition of known amounts of the peptides to lean and obese plasma, (2) a large meal in lean and obese rats, and (3) intravenous infusions of anorexigenic doses of GLP-1, PYY(3-36), amylin, and leptin in lean rats. Extraction of lean and obese plasma prior to assays produced consistent recoveries across assays for GLP-1, PYY, amylin, ghrelin, and insulin, reflecting losses inherent to the extraction procedure. Plasma extraction prior to assays generally revealed larger meal-induced changes in plasma GLP-1, PYY, amylin, ghrelin, and insulin in lean and obese rats. Plasma extraction and the multiplex assay were used to compare plasma levels of GLP-1, PYY, and amylin after a large meal with plasma levels produced by IV infusions of anorexigenic doses of GLP-1, PYY(3-36), and amylin. Infusions produced dose-dependent increases in plasma peptide levels, which were well above their postprandial levels. These results do not support the hypothesis that postprandial plasma levels of GLP-1, PYY(3-36), and amylin are sufficient to decrease food intake by an endocrine mechanism. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  11. Gastrointestinal hormone research - with a Scandinavian annotation.

    PubMed

    Rehfeld, Jens F

    2015-06-01

    Gastrointestinal hormones are peptides released from neuroendocrine cells in the digestive tract. More than 30 hormone genes are currently known to be expressed in the gut, which makes it the largest hormone-producing organ in the body. Modern biology makes it feasible to conceive the hormones under five headings: The structural homology groups a majority of the hormones into nine families, each of which is assumed to originate from one ancestral gene. The individual hormone gene often has multiple phenotypes due to alternative splicing, tandem organization or differentiated posttranslational maturation of the prohormone. By a combination of these mechanisms, more than 100 different hormonally active peptides are released from the gut. Gut hormone genes are also widely expressed outside the gut, some only in extraintestinal endocrine cells and cerebral or peripheral neurons but others also in other cell types. The extraintestinal cells may release different bioactive fragments of the same prohormone due to cell-specific processing pathways. Moreover, endocrine cells, neurons, cancer cells and, for instance, spermatozoa secrete gut peptides in different ways, so the same peptide may act as a blood-borne hormone, a neurotransmitter, a local growth factor or a fertility factor. The targets of gastrointestinal hormones are specific G-protein-coupled receptors that are expressed in the cell membranes also outside the digestive tract. Thus, gut hormones not only regulate digestive functions, but also constitute regulatory systems operating in the whole organism. This overview of gut hormone biology is supplemented with an annotation on some Scandinavian contributions to gastrointestinal hormone research.

  12. Calorie Restriction and Matched Weight Loss From Exercise: Independent and Additive Effects on Glucoregulation and the Incretin System in Overweight Women and Men.

    PubMed

    Weiss, Edward P; Albert, Stewart G; Reeds, Dominic N; Kress, Kathleen S; Ezekiel, Uthayashanker R; McDaniel, Jennifer L; Patterson, Bruce W; Klein, Samuel; Villareal, Dennis T

    2015-07-01

    It is not known whether calorie restriction (CR) has additive benefits to those from exercise (EX)-induced weight loss. We hypothesized that weight loss from CR and EX (CREX) improves insulin sensitivity more than matched weight loss induced by EX or CR alone and that the incretin system may be involved in adaptations to CR. Sedentary, overweight men and women (n = 52, 45-65 years of age) were randomized to undergo 6-8% weight loss by using CR, EX, or CREX. Glucose, insulin, C-peptide, insulin sensitivity, and incretin hormones (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) were measured during frequently sampled oral glucose tolerance tests (FSOGTTs). Incretin effects on insulin secretion were measured by comparing insulin secretion rates from the FSOGTTs to those from a glycemia-matched glucose infusion. Despite similar weight losses in all groups, insulin sensitivity index values increased twofold more in the CREX group (2.09 ± 0.35 μM/kg/pM × 100) than in the CR (0.89 ± 0.39 μM/kg/pM × 100) and EX (1.04 ± 0.39 μM/kg/pM × 100) groups. Postprandial GLP-1 concentrations decreased only in the CR group (P = 0.04); GIP concentrations decreased in all groups. Incretin effects on insulin secretion were unchanged. CR and EX have additive beneficial effects on glucoregulation. Furthermore, the adaptations to CR may involve reductions in postprandial GLP-1 concentrations. These findings underscore the importance of promoting both CR and EX for optimal health. However, because data from participants who withdrew from the study and from those who did not adhere to the intervention were excluded, the results may be limited to individuals who are capable of adhering to a healthy lifestyle intervention. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  13. Noopept normalizes parameters of the incretin system in rats with experimental diabetes.

    PubMed

    Ostrovskaya, R U; Zolotov, N N; Ozerova, I V; Ivanova, E A; Kapitsa, I G; Taraban, K V; Michunskaya, A M; Voronina, T A; Gudasheva, T A; Seredenin, S B

    2014-07-01

    Experiments on adult Wistar rats with streptozotocin-induced diabetes showed that antihyperglycemic activity of an original nootropic and neuroprotective drug Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) is more pronounced under conditions of oral application than after intraperitoneal injection. These data provided a basis for studying the effect of Noopept on major indexes of the incretin system. Streptozotocin was shown to decrease the concentrations of incretin GLP-1 and insulin in the blood. Noopept had a normalizing effect on these parameters. This influence of Noopept was not related to the inhibition of a major enzyme metabolizing incretins (dipeptidyl peptidase IV). A reference drug sitagliptin also increased the contents of incretins and insulin, which was associated with the inhibition of dipeptidyl peptidase IV. It is known that GLP-1 increases NGF expression in the insular system. Our results suggest that the increase in incretin activity contributes to the antiapoptotic effect of Noopept on pancreatic β cells. The mechanism for an increase in blood GLP-1 level after oral application of Noopept requires further investigations.

  14. [Research advances in association between childhood obesity and gut microbiota].

    PubMed

    Gao, Xiao-Lin; Wan, Chao-Min

    2017-03-01

    In recent years, more and more studies have noted the close association between gut microbiota and the development and progression of obesity. Gut microbiota may act on obesity by increasing energy intake, affecting the secretion of intestinal hormones, inducing chronic systemic inflammation, and producing insulin resistance. This article reviews the association between childhood obesity and gut microbiota, as well as possible mechanisms, in an attempt to provide a reference for the etiology, prevention and treatment of childhood obesity.

  15. Mosquito-specific microRNA-1890 targets the juvenile hormone-regulated serine protease JHA15 in the female mosquito gut

    PubMed Central

    Lucas, Keira J; Zhao, Bo; Roy, Sourav; Gervaise, Amanda L; Raikhel, Alexander S

    2015-01-01

    Females of the hematophagous mosquito species require a vertebrate blood meal to supply amino acids and other nutrients necessary for egg development, serving as the driving force for the spread of many vector-borne diseases in humans. Blood digestion utilizes both early and late phase serine proteases (SPs) that are differentially regulated at the transcriptional and post-transcriptional level. To uncover the regulatory complexity of SPs in the female mosquito midgut, we investigated involvement of miRNAs in regulating the juvenile hormone (JH)-controlled chymotrypsin-like SP, JHA15. We identified regulatory regions complementary to the mosquito-specific miRNA, miR-1890, within the 3′ UTR of JHA15 mRNA. The level of the JHA15 transcript is highest post eclosion and drastically declines post blood meal (PBM), exhibiting an opposite trend to miR-1890 that peaks at 24 h PBM. Depletion of miR-1890 results in defects in blood digestion, ovary development and egg deposition. JHA15 mRNA and protein levels are elevated in female mosquitoes with miR-1890 inhibition. JHA15 RNA interference in the miR-1890 depletion background alleviates miR-1890 depletion phenotypes. The miR-1890 gene is activated by the 20-hydroxyecdysone pathway that involves the ecdysone receptor and the early genes, E74B and Broad Z2. Our study suggests that miR-1890 controls JHA15 mRNA stability in a stage- and tissue- specific manner. PMID:26488481

  16. Contributions of upper gut hormones and motility to the energy intake-suppressant effects of intraduodenal nutrients in healthy, lean men - a pooled-data analysis.

    PubMed

    Schober, Gudrun; Lange, Kylie; Steinert, Robert E; Hutchison, Amy T; Luscombe-Marsh, Natalie D; Landrock, Maria F; Horowitz, Michael; Seimon, Radhika V; Feinle-Bisset, Christine

    2016-09-01

    We have previously identified pyloric pressures and plasma cholecystokinin (CCK) concentrations as independent determinants of energy intake following administration of intraduodenal lipid and intravenous CCK. We evaluated in healthy men whether these parameters also determine energy intake in response to intraduodenal protein, and whether, across the nutrients, any predominant gastrointestinal (GI) factors exist, or many factors make small contributions. Data from nine published studies, in which antropyloroduodenal pressures, GI hormones, and GI /appetite perceptions were measured during intraduodenal lipid or protein infusions, were pooled. In all studies energy intake was quantified immediately after the infusions. Specific variables for inclusion in a mixed-effects multivariable model for determination of independent predictors of energy intake were chosen following assessment for collinearity, and within-subject correlations between energy intake and these variables were determined using bivariate analyses adjusted for repeated measures. In models based on all studies, or lipid studies, there were significant effects for amplitude of antral pressure waves, premeal glucagon-like peptide-1 (GLP-1) and time-to-peak GLP-1 concentrations, GLP-1 AUC and bloating scores (P < 0.05), and trends for basal pyloric pressure (BPP), amplitude of duodenal pressure waves, peak CCK concentrations, and hunger and nausea scores (0.05 < P ≤ 0.094), to be independent determinants of subsequent energy intake. In the model including the protein studies, only BPP was identified as an independent determinant of energy intake (P < 0.05). No single parameter was identified across all models, and effects of the variables identified were relatively small. Taken together, while GI mechanisms contribute to the regulation of acute energy intake by lipid and protein, their contribution to the latter is much less. Moreover, the effects are likely to reflect small, cumulative

  17. 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.

  18. Glucose sensing by gut endocrine cells and activation of the vagal afferent pathway is impaired in a rodent model of type 2 diabetes mellitus.

    PubMed

    Lee, Jennifer; Cummings, Bethany P; Martin, Elizabeth; Sharp, James W; Graham, James L; Stanhope, Kimber L; Havel, Peter J; Raybould, Helen E

    2012-03-15

    Glucose in the gut lumen activates gut endocrine cells to release 5-HT, glucagon-like peptide 1/2 (GLP-1/2), and glucose-dependent insulinotropic polypeptide (GIP), which act to change gastrointestinal function and regulate postprandial plasma glucose. There is evidence that both release and action of incretin hormones is reduced in type 2 diabetes (T2D). We measured cellular activation of enteroendocrine and enterochromaffin cells, enteric neurons, and vagal afferent neurons in response to intestinal glucose in a model of type 2 diabetes mellitus, the UCD-T2DM rat. Prediabetic (PD), recent-diabetic (RD, 2 wk postonset), and 3-mo diabetic (3MD) fasted UCD-T2DM rats were given an orogastric gavage of vehicle (water, 0.5 ml /100 g body wt) or glucose (330 μmol/100 g body wt); after 6 min tissue was removed and cellular activation was determined by immunohistochemistry for phosphorylated calcium calmodulin-dependent kinase II (pCaMKII). In PD rats, pCaMKII immunoreactivity was increased in duodenal 5-HT (P < 0.001), K (P < 0.01) and L (P < 0.01) cells in response to glucose; glucose-induced activation of all three cell types was significantly reduced in RD and 3MD compared with PD rats. Immunoreactivity for GLP-1, but not GIP, was significantly reduced in RD and 3MD compared with PD rats (P < 0.01). Administration of glucose significantly increased pCaMKII in enteric and vagal afferent neurons in PD rats; glucose-induced pCaMKII immunoreactivity was attenuated in enteric and vagal afferent neurons (P < 0.01, P < 0.001, respectively) in RD and 3MD. These data suggest that glucose sensing in enteroendocrine and enterochromaffin cells and activation of neural pathways is markedly impaired in UCD-T2DM rats.

  19. [Potential of pharmacological modulation of level and activity incretins on diabetes mellitus type 2].

    PubMed

    Spasov, A A; Chepljaeva, N I

    2015-01-01

    This review summarizes data on the main approaches used for the search of biologically active compounds modulating the level and physiological activity of incretins. Currently two groups of drugs are used in clinical practice: they either replenish the deficit of incretins (glucagon-like peptide-1 receptor agonists) or inhibit the degradation processes (dipeptidyl peptidase 4 inhibitors). In addition, new groups of substances are actively searched. These include non-peptide agonists of glucagon-like peptide-1 receptors, agonists/antagonists of glucose-dependent insulinotropic peptide, the hybrid polypeptides based on glucagon-like peptide-1 and glucagon.

  20. Gut microbiota and probiotics: Focus on diabetes mellitus.

    PubMed

    Bordalo Tonucci, Livia; Dos Santos, Karina Maria Olbrich; De Luces Fortes Ferreira, Celia Lucia; Ribeiro, Sonia Machado Rocha; De Oliveira, Leandro Licursi; Martino, Hercia Stampini Duarte

    2017-07-24

    The characterization of gut microbiota has become an important area of research in several clinical conditions, including type 2 diabetes (T2DM). Changes in the composition and/or metabolic activity of the gut microbiota can contribute to human health. Thus, this review discusses the effects of probiotics and gut microbiota on metabolic control in these individuals. Relevant studies were obtained from electronic databases such as PubMed/Medline and ISI Web of Science. The main probiotics used in these studies belonged to the genera Lactobacillus and Bifidobacterium. The authors found seven randomized placebo-controlled clinical trials and 13 experimental studies directly related to the effect of probiotics on metabolic control in the context of T2DM. The hypothesis that gut microbiota plays a role in the development of diabetes indicates an important beginning, and the potential of probiotics to prevent and reduce the severity of T2DM is better observed in animal studies. In clinical trials, the use of probiotics in glycemic control presented conflicting results, and only few studies have attempted to evaluate factors that justify metabolic changes, such as markers of oxidative stress, inflammation, and incretins. Thus, further research is needed to assess the effects of probiotics in the metabolism of diabetic individuals, as well as the main mechanisms involved in this complex relationship.

  1. The incretin analogue D-Ala2GIP reduces plaque load, astrogliosis and oxidative stress in an APP/PS1 mouse model of Alzheimer's disease.

    PubMed

    Duffy, A M; Hölscher, C

    2013-01-03

    Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). Insulin is a neuroprotective growth factor, and an impairment of insulin signalling has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, normalises insulin signalling and also acts as a neuroprotective growth factor. GIP plays an important role in memory formation, synaptic plasticity and cell proliferation. We have shown previously that the long-lasting incretin hormone analogue D-Ala(2)GIP protects memory formation and synaptic plasticity, reduces plaques, normalises the proliferation of stem cells, reduces the activation of microglia, and prevents the loss of synapses in the cortex of the APPswe/PS1deltaE9 mouse model of Alzheimer's disease. D-Ala(2)GIP was injected for 35 days at 25 nmol/kg i.p. once daily in APP/PS1 male mice and wild-type (WT) littermates aged 6, 12 and 19 months. In a follow-up study, we analysed plaque load, the activation of astrocytes as a means of chronic inflammation in the brain, and oxidative stress in the brains of these mice (8-oxoguanine levels). D-Ala(2)GIP reduced the amyloid plaque load in 12- and 19-month-old mice, and the inflammation response as shown in the reduction of activated astrocytes in 12- and 19-month old APP/PS1 mice. Chronic oxidative stress in the brain was reduced in 12- and 19-month-old mice as shown in the reduction of 8-oxoguanine levels in the cortex of D-Ala(2)GIP-injected APP/PS1 mice. The results demonstrate that D-Ala(2)GIP has neuroprotective properties on key markers found in Alzheimer's disease. This finding shows that novel GIP analogues have the potential to be developed as novel therapeutics for Alzheimer's disease. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. The bioactive effects of casein proteins on enteroendocrine cell health, proliferation and incretin hormone secretion.

    PubMed

    Gillespie, Anna L; Green, Brian D

    2016-11-15

    Previous studies suggest that casein exerts various anti-diabetic effects. However, it is not known which casein proteins are bioactive, nor their effects on enteroendocrine cells. This study evaluated the effects of intact whole casein, intact individual proteins (alpha, beta and kappa casein) and hydrolysates on an enteroendocrine cell line. High content analysis accurately monitored changes in cell health and intracellular glucagon-like peptide-1 (GLP-1) content. Cheese ripening duration and GLP-1 secretory responses were also considered. Beta casein significantly stimulated enteroendocrine cell proliferation and all caseins were potent GLP-1 secretagogues (except kappa casein). Interestingly the GLP-1 secretory activity was almost always lost or significantly reduced upon hydrolysis with proteolytic enzymes. Only pepsin-derived beta casein hydrolysates had significantly increased potency compared with the intact protein, but this was diminished with prolonged hydrolysis. In conclusion casein proteins are not detrimental to enteroendocrine cells, and alpha and beta casein are particularly beneficial stimulating proliferation and GLP-1 secretion.

  3. The role of incretin-based therapies in prediabetes: a review.

    PubMed

    Ahmadieh, Hala; Azar, Sami T

    2014-12-01

    Prediabetes, a high-risk state for future development of diabetes, is prevalent globally. Abnormalities in the incretin axis are important in the progression of B-cell failure in type 2 diabetes. Incretin based therapy was found to improve B cell mass and glycaemic control in addition to having multiple beneficial effects on the systolic and diastolic blood pressure, weight loss in addition to their other beneficial effects on the liver and cardiovascular system. In prediabetes, several well-designed preventive trials have shown that lifestyle and pharmacologic interventions such as metformin, thiazolidinediones (TZD), acarbose and, nateglinide and orlistat, are effective in reducing diabetes development. In recent small studies, incretin based therapy (DPP IV inhibitors and GLP-1 agonists) have also been extended to patients with prediabetes since it was shown to better preserve B-cell function and mass in animal studies and in clinical trials and it was also shown to help maintain good long term metabolic control. Because of the limited studies and clinical experience, their side effects and costs currently guidelines do not recommend incretin-based therapies as an option for treatment in patients with prediabetes. With future clinical trials and studies they may be recommended for patients with impaired fasting glucose or impaired glucose tolerance. Copyright © 2014 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

  4. Incretin-Based Therapies for Diabetic Complications: Basic Mechanisms and Clinical Evidence

    PubMed Central

    Kawanami, Daiji; Matoba, Keiichiro; Sango, Kazunori; Utsunomiya, Kazunori

    2016-01-01

    An increase in the rates of morbidity and mortality associated with diabetic complications is a global concern. Glycemic control is important to prevent the development and progression of diabetic complications. Various classes of anti-diabetic agents are currently available, and their pleiotropic effects on diabetic complications have been investigated. Incretin-based therapies such as dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are now widely used in the treatment of patients with type 2 diabetes. A series of experimental studies showed that incretin-based therapies have beneficial effects on diabetic complications, independent of their glucose-lowering abilities, which are mediated by anti-inflammatory and anti-oxidative stress properties. Based on these findings, clinical studies to assess the effects of DPP-4 inhibitors and GLP-1RA on diabetic microvascular and macrovascular complications have been performed. Several but not all studies have provided evidence to support the beneficial effects of incretin-based therapies on diabetic complications in patients with type 2 diabetes. We herein discuss the experimental and clinical evidence of incretin-based therapy for diabetic complications. PMID:27483245

  5. Incretin-Based Therapies for Diabetic Complications: Basic Mechanisms and Clinical Evidence.

    PubMed

    Kawanami, Daiji; Matoba, Keiichiro; Sango, Kazunori; Utsunomiya, Kazunori

    2016-07-29

    An increase in the rates of morbidity and mortality associated with diabetic complications is a global concern. Glycemic control is important to prevent the development and progression of diabetic complications. Various classes of anti-diabetic agents are currently available, and their pleiotropic effects on diabetic complications have been investigated. Incretin-based therapies such as dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are now widely used in the treatment of patients with type 2 diabetes. A series of experimental studies showed that incretin-based therapies have beneficial effects on diabetic complications, independent of their glucose-lowering abilities, which are mediated by anti-inflammatory and anti-oxidative stress properties. Based on these findings, clinical studies to assess the effects of DPP-4 inhibitors and GLP-1RA on diabetic microvascular and macrovascular complications have been performed. Several but not all studies have provided evidence to support the beneficial effects of incretin-based therapies on diabetic complications in patients with type 2 diabetes. We herein discuss the experimental and clinical evidence of incretin-based therapy for diabetic complications.

  6. The Gut Microbiome and the Brain

    PubMed Central

    Galland, Leo

    2014-01-01

    Abstract The human gut microbiome impacts human brain health in numerous ways: (1) Structural bacterial components such as lipopolysaccharides provide low-grade tonic stimulation of the innate immune system. Excessive stimulation due to bacterial dysbiosis, small intestinal bacterial overgrowth, or increased intestinal permeability may produce systemic and/or central nervous system inflammation. (2) Bacterial proteins may cross-react with human antigens to stimulate dysfunctional responses of the adaptive immune system. (3) Bacterial enzymes may produce neurotoxic metabolites such as D-lactic acid and ammonia. Even beneficial metabolites such as short-chain fatty acids may exert neurotoxicity. (4) Gut microbes can produce hormones and neurotransmitters that are identical to those produced by humans. Bacterial receptors for these hormones influence microbial growth and virulence. (5) Gut bacteria directly stimulate afferent neurons of the enteric nervous system to send signals to the brain via the vagus nerve. Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome. Their role in multiple sclerosis and the neurologic manifestations of celiac disease is being studied. Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics. PMID:25402818

  7. Hormone levels

    MedlinePlus

    Blood or urine tests can determine the levels of various hormones in the body. This includes reproductive hormones, thyroid hormones, adrenal hormones, pituitary hormones, and many others. For more information, see: ...

  8. Association Between Incretin-Based Drugs and the Risk of Acute Pancreatitis.

    PubMed

    Azoulay, Laurent; Filion, Kristian B; Platt, Robert W; Dahl, Matthew; Dormuth, Colin R; Clemens, Kristin K; Durand, Madeleine; Hu, Nianping; Juurlink, David N; Paterson, J Michael; Targownik, Laura E; Turin, Tanvir C; Ernst, Pierre; Suissa, Samy; Dormuth, Colin R; Hemmelgarn, Brenda R; Teare, Gary F; Caetano, Patricia; Chateau, Dan; Henry, David A; Paterson, J Michael; LeLorier, Jacques; Levy, Adrian R; Ernst, Pierre; Platt, Robert W; Sketris, Ingrid S

    2016-10-01

    The association between incretin-based drugs, such as dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, and acute pancreatitis is controversial. To determine whether the use of incretin-based drugs, compared with the use of 2 or more other oral antidiabetic drugs, is associated with an increased risk of acute pancreatitis. A large, international, multicenter, population-based cohort study was conducted using combined health records from 7 participating sites in Canada, the United States, and the United Kingdom. An overall cohort of 1 532 513 patients with type 2 diabetes initiating the use of antidiabetic drugs between January 1, 2007, and June 30, 2013, was included, with follow-up until June 30, 2014. Current use of incretin-based drugs compared with current use of at least 2 oral antidiabetic drugs. Nested case-control analyses were conducted including hospitalized patients with acute pancreatitis matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and follow-up duration. Hazard ratios (HRs) and 95% CIs for hospitalized acute pancreatitis were estimated and compared current use of incretin-based drugs with current use of 2 or more oral antidiabetic drugs. Secondary analyses were performed to assess whether the risk varied by class of drug (DPP-4 inhibitors and GLP-1 agonists) or by duration of use. Site-specific HRs were pooled using random-effects models. Of 1 532 513 patients included in the analysis, 781 567 (51.0%) were male; mean age was 56.6 years. During 3 464 659 person-years of follow-up, 5165 patients were hospitalized for acute pancreatitis (incidence rate, 1.49 per 1000 person-years). Compared with current use of 2 or more oral antidiabetic drugs, current use of incretin-based drugs was not associated with an increased risk of acute pancreatitis (pooled adjusted HR, 1.03; 95% CI, 0.87-1.22). Similarly, the risk did not vary by drug class (DPP-4 inhibitors

  9. Role of Epac2A/Rap1 signaling in interplay between incretin and sulfonylurea in insulin secretion.

    PubMed

    Takahashi, Harumi; Shibasaki, Tadao; Park, Jae-Hyung; Hidaka, Shihomi; Takahashi, Toshimasa; Ono, Aika; Song, Dae-Kyu; Seino, Susumu

    2015-04-01

    Incretin-related drugs and sulfonylureas are currently used worldwide for the treatment of type 2 diabetes. We recently found that Epac2A, a cAMP binding protein having guanine nucleotide exchange activity toward Rap, is a target of both incretin and sulfonylurea. This suggests the possibility of interplay between incretin and sulfonylurea through Epac2A/Rap1 signaling in insulin secretion. In this study, we examined the combinatorial effects of incretin and various sulfonylureas on insulin secretion and activation of Epac2A/Rap1 signaling. A strong augmentation of insulin secretion by combination of GLP-1 and glibenclamide or glimepiride, which was found in Epac2A(+/+) mice, was markedly reduced in Epac2A(-/-) mice. In contrast, the combinatorial effect of GLP-1 and gliclazide was rather mild, and the effect was not altered by Epac2A ablation. Activation of Rap1 was enhanced by the combination of an Epac-selective cAMP analog with glibenclamide or glimepiride but not gliclazide. In diet-induced obese mice, ablation of Epac2A reduced the insulin secretory response to coadministration of the GLP-1 receptor agonist liraglutide and glimepiride. These findings clarify the critical role of Epac2A/Rap1 signaling in the augmenting effect of incretin and sulfonylurea on insulin secretion and provide the basis for the effects of combination therapies of incretin-related drugs and sulfonylureas.

  10. Expression of GLP-1 receptor and CD26 in human thyroid C-cells: The association of thyroid C-cell tumorigenesis with incretin-based medicine

    PubMed Central

    Song, Yuejia; Zhou, Min; Cao, Yang; Qi, Jiping; Geng, Jingshu; Liu, Xiaomin

    2017-01-01

    Recent reports have demonstrated that long-term and high dosage treatments with incretin-based medicine, such as hormone glucagon-like peptide-1 (GLP-1) may induce thyroid C-cell pathological changes in rodents, rather than in humans. Doubts regarding the tumorigenic potential of GLP-1 analogues in human thyroid C-cells remain. The present study aimed to determine the expression levels of GLP-1 receptor (GLP-1R) and cluster of differentiation 26 (CD26) in the C-cells of thyroid tissues from non-neoplastic, medullary carcinoma and hyperplasia subjects, and to explore the potential clinical significance. The following cases were analyzed: Medullary thyroid carcinoma (n=62, including 59 paraffin-embedded samples and 3 fresh frozen samples), C-cell hyperplasia (n=20, paraffin-embedded samples) and non-neoplastic thyroid tissue samples (n=7, paraffin-embedded samples). GLP-1R and CD26 expression was detected using immunohistochemical staining and western blotting. There were significant differences in the expression levels of the two markers between medullary thyroid carcinoma and C-cell hyperplasia, in addition to between medullary thyroid carcinoma and non-neoplastic thyroid tissue following immunohistochemical staining. Similar significant differences in the expression of GLP-1R and CD26 were detected using western blot analysis in the medullary thyroid carcinoma compared with non-neoplastic thyroid tissue sectioned from the aforementioned fresh frozen samples. There was a significant negative correlation between GLP-1R and CD26 expression. In addition, the present data indicated that GLP-1R expression was associated with the age of the patients with medullary thyroid carcinoma. These results suggested that GLP-1R and CD26 may be closely associated with the development of thyroid C-cell hyperplasia and medullary thyroid carcinoma, and indicated the importance of being aware of the side effects of incretin medicine. PMID:28454451

  11. SUSY GUT Model Building

    SciTech Connect

    Raby, Stuart

    2008-11-23

    In this talk I discuss the evolution of SUSY GUT model building as I see it. Starting with 4 dimensional model building, I then consider orbifold GUTs in 5 dimensions and finally orbifold GUTs embedded into the E{sub 8}xE{sub 8} heterotic string.

  12. [Incretin-based therapy for treating patients with type 2 diabetes].

    PubMed

    Jermendy, György

    2011-11-27

    In the last couple of years, a new class of antidiabetic drugs became available for the clinical practice. Due to the intensive research, several new drugs reached the market. Among the incretinmimetics both the GLP-1 (glucagon like peptide-1)-receptor agonist exenatide and the GLP-1-analogue liraglutide can be used for treatment. As for incretin enhancers (dipeptidyl-peptidase-4 [DPP-4]-inhibitors), sitagliptin, vildagliptin and saxagliptin are available in Hungary, linagliptin will be introduced to the market in the near future. In clinical practice, any incretin-based new drugs can be used for treating patients with type 2 diabetes, preferably in combination with metformin. The clinical experiences with these new drugs are reviewed focusing on both the benefits and the potential side-effects of the particular compounds.

  13. Incretin-based drugs for type 2 diabetes: Focus on East Asian perspectives.

    PubMed

    Seino, Yutaka; Kuwata, Hitoshi; Yabe, Daisuke

    2016-04-01

    Type 2 diabetes in East Asians is characterized primarily by β-cell dysfunction, and with less adiposity and less insulin resistance compared with that in Caucasians. Such pathophysiological differences can determine the appropriate therapeutics for the disease. Incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are secreted in response to meal ingestion, and enhance insulin secretion glucose-dependently. Incretin-based drugs, dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists, that ameliorate β-cell dysfunction with limited hypoglycemia risk are now widely used in type 2 diabetes management. Recent meta-analyses of clinical trials on DPP-4i and glucagon-like peptide-1 receptor agonists found that the drugs were more effective in Asians, most likely because of amelioration of β-cell dysfunction. In addition, we found increased glycated hemoglobin-lowering effects of DPP-4i to be associated with intake of fish in type 2 diabetes, which suggests that dietary customs of East Asians might also underlie the greater efficacy of DPP-4i. Despite the limited risk, cases of severe hypoglycemia were reported for DPP-4i/sulfonylureas combinations. Importantly, hypoglycemia was more frequent in patients also receiving glibenclamide or glimepiride, which activate exchange protein directly activated by cyclic adenosine monophosphate 2, a critical mediator of incretin signaling, and was less frequent in patients receiving gliclazide, which does not activate exchange protein directly activated by cyclic adenosine monophosphate 2. Prevention of insulin-associated hypoglycemia by DPP-4i has gained attention with regard to the enhancement of hypoglycemia-induced glucagon secretion by insulinotropic polypeptide, but remains to be investigated in East Asians. Despite the safety issues, which are paramount and must be carefully monitored, the incretin-based drugs could have potential as a first choice therapy in

  14. Incretin-based therapies in prediabetes: Current evidence and future perspectives

    PubMed Central

    Papaetis, Georgios S

    2014-01-01

    The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on β-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D. PMID:25512784

  15. Perspectives on cardiovascular effects of incretin-based drugs: From bedside to bench, return trip.

    PubMed

    Luconi, Michaela; Cantini, Giulia; Ceriello, Antonio; Mannucci, Edoardo

    2017-08-15

    Recently, cardiovascular outcome trials with glucose-lowering drugs used in type 2 diabetes mellitus, namely glucagon-like peptide-1 receptor agonists (GLP-1RA), liraglutide and semaglutide, showed a reduction in cardiovascular events, which had not been observed in trials with other incretin-based drugs, such as lixisenatide or with dipeptidyl peptidase-4 inhibitors (DPP4i). Mechanisms underlying the observed cardiovascular differences between DPP4i and GLP1-RA, and across individual GLP1-RA are poorly understood. This review is aimed at collecting and summarizing available evidence from experimental and mechanistic studies on the action of GLP1-RA and DPP4i on the cardiovascular system, both deriving from clinical and pre-clinical sources. The results of cardiovascular outcome trials are interpreted on the basis of the experimental preclinical data available, paying particular attention to the heart failure results, and suggesting some novel intriguing hypotheses to explain some of the unexpected findings of cardioprotection of incretin-based drugs. In particular, we discuss the possible contribution to the incretin cardiovascular effects of a direct cardiac action of GLP-1 metabolites through GLP-1 receptor-independent pathways, and of DPP4 substrates other than GLP-1. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  16. Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Health.

    PubMed

    Egger, Andrea; Kraenzlin, Marius E; Meier, Christian

    2016-12-01

    Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.

  17. Down-regulation of pancreatic transcription factors and incretin receptors in type 2 diabetes

    PubMed Central

    Kaneto, Hideaki; Matsuoka, Taka-aki

    2013-01-01

    Type 2 diabetes is one of the most prevalent and serious metabolic diseases. Under diabetic conditions, chronic hyperglycemia and subsequent induction of oxidative stress deteriorate pancreatic β-cell function, which leads to the aggravation of type 2 diabetes. Although such phenomena are well known as glucose toxicity, its molecular mechanism remains unclear. In this review article, we describe the possible molecular mechanism for β-cell dysfunction found in type 2 diabetes, focusing on (1) oxidative stress, (2) pancreatic transcription factors (PDX-1 and MafA) and (3) incretin receptors (GLP-1 and GIP receptors). Under such conditions, nuclear expression levels of PDX-1 and MafA are decreased, which leads to suppression of insulin biosynthesis and secretion. In addition, expression levels of GLP-1 and GIP receptors are decreased, which likely contributes to the impaired incretin effects found in diabetes. Taken together, it is likely that down-regulation of pancreatic transcription factors (PDX-1 and MafA) and down-regulation of incretin receptors (GLP-1 and GIP receptors) explain, at least in part, the molecular mechanism for β-cell dysfunction found in type 2 diabetes. PMID:24379916

  18. Incretin Kinetics Before and After Miglitol in Japanese Patients With Late Dumping Syndrome

    PubMed Central

    Amagai, Mari; Tsuchiya, Hirohisa; Chiba, Yukari; Suzuki, Jun; Nagakura, Jo; Shigematsu, Erina; Yamakawa, Tadashi; Terauchi, Yasuo

    2017-01-01

    Background In patients with late dumping syndrome following gastrectomy, it has been reported that hypoglycemia occurs due to inhibition of glucagon secretion as a result of excessive insulin production facilitated by an increase in glucagon-like peptide-1 (GLP-1). Methods To determine the kinetics of incretins in Japanese patients with late dumping syndrome, an oral glucose tolerance test was carried out before and after miglitol administration, and the kinetics of insulin and incretins were analyzed. Results After miglitol administration, there was improvement of hypoglycemia and early phase insulin secretion, with persistent excessive insulin secretion being minimized. These findings revealed that miglitol inhibited rapid excessive influx of carbohydrates into the blood and persistent elevation of GLP-1, resulting in improvement of early phase insulin secretion and minimizing persistent excessive insulin secretion. Conclusions Eating frequent small meals is generally effective for late dumping syndrome, but patients often find it difficult to continue such a regimen. Based on the present analysis of incretin kinetics, miglitol may be a useful treatment option for late dumping syndrome.

  19. Roux-en-Y gastric bypass versus calorie restriction: support for surgery per se as the direct contributor to altered responses of insulin and incretins to a mixed meal.

    PubMed

    Berggren, Johan; Lindqvist, Andreas; Hedenbro, Jan; Groop, Leif; Wierup, Nils

    2017-02-01

    To study the immediate effects of Roux-en-Y gastric bypass (RYGB) on glucose homeostasis, insulin, and incretin responses to mixed-meal tests compared with the effects of calorie restriction (CR). University-affiliated bariatric surgery clinic. RYGB induces remission of type 2 diabetes (T2D) long before significant weight loss occurs. The time course and underlying mechanisms of this remission remain enigmatic. A prevailing theory is that secretory patterns of incretin hormones are altered due to rearrangement of the gastrointestinal tract. To what extent reduced calorie intake contributes to the remission of T2D is unknown. Nine normoglycemic patients and 10 T2D patients were subjected to mixed-meal tests (MMT) 4 weeks before surgery before initiation of a very low calorie diet regimen (MMT-4 w), 1 day before surgery on a very low calorie diet regimen (MMT-1 d), on the morning of the first day after surgery (MMT+1 d; first postsurgical meal), and 6 weeks after surgery (MMT+6 w). Insulin, glucose, active glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured. CR lowered insulin in T2D patients, whereas glucose, GIP, and GLP-1 were unaffected. RYGB immediately increased plasma insulin and GIP. The GLP-1 response was delayed compared with the GIP response. T2D patients exhibited lower insulin responses after RYGB compared with normoglycemic patients. GIP responses were similar in both groups at all occasions, whereas T2D patients displayed markedly elevated GLP-1 responses 6 weeks after RYGB. Glucose was unaffected by CR and RYGB in both groups. Insulin sensitivity was unaffected by CR but improved with RYGB. RYGB exerts powerful and immediate effects on insulin and incretin responses to food, independently of changes caused by CR. Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  20. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus.

    PubMed

    Moreno-Indias, Isabel; Cardona, Fernando; Tinahones, Francisco J; Queipo-Ortuño, María Isabel

    2014-01-01

    Obesity and its associated disorders are a major public health concern. Although obesity has been mainly related with perturbations of the balance between food intake and energy expenditure, other factors must nevertheless be considered. Recent insight suggests that an altered composition and diversity of gut microbiota could play an important role in the development of metabolic disorders. This review discusses research aimed at understanding the role of gut microbiota in the pathogenesis of obesity and type 2 diabetes mellitus (TDM2). The establishment of gut microbiota is dependent on the type of birth. With effect from this point, gut microbiota remain quite stable, although changes take place between birth and adulthood due to external influences, such as diet, disease and environment. Understand these changes is important to predict diseases and develop therapies. A new theory suggests that gut microbiota contribute to the regulation of energy homeostasis, provoking the development of an impairment in energy homeostasis and causing metabolic diseases, such as insulin resistance or TDM2. The metabolic endotoxemia, modifications in the secretion of incretins and butyrate production might explain the influence of the microbiota in these diseases.

  1. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus

    PubMed Central

    Moreno-Indias, Isabel; Cardona, Fernando; Tinahones, Francisco J.; Queipo-Ortuño, María Isabel

    2014-01-01

    Obesity and its associated disorders are a major public health concern. Although obesity has been mainly related with perturbations of the balance between food intake and energy expenditure, other factors must nevertheless be considered. Recent insight suggests that an altered composition and diversity of gut microbiota could play an important role in the development of metabolic disorders. This review discusses research aimed at understanding the role of gut microbiota in the pathogenesis of obesity and type 2 diabetes mellitus (TDM2). The establishment of gut microbiota is dependent on the type of birth. With effect from this point, gut microbiota remain quite stable, although changes take place between birth and adulthood due to external influences, such as diet, disease and environment. Understand these changes is important to predict diseases and develop therapies. A new theory suggests that gut microbiota contribute to the regulation of energy homeostasis, provoking the development of an impairment in energy homeostasis and causing metabolic diseases, such as insulin resistance or TDM2. The metabolic endotoxemia, modifications in the secretion of incretins and butyrate production might explain the influence of the microbiota in these diseases. PMID:24808896

  2. Gut Microbiota and the Gut-Brain Axis: New Insights in the Pathophysiology of Metabolic Syndrome.

    PubMed

    de Clercq, Nicolien C; Frissen, Myrthe N; Groen, Albert K; Nieuwdorp, Max

    2017-10-01

    Emerging preclinical evidence has shown that the bidirectional signaling between the gastrointestinal (GI) tract and the brain, the so-called gut-brain axis, plays an important role in both host metabolism and behavior. In this review, we discuss the potential mechanisms of the brain-gut axis in relation to the pathophysiology of metabolic syndrome. A selective literature review was conducted to evaluate GI and brain interactions. Evidence suggests reduced microbial diversity in obesity and metabolic dysregulation. However, findings of microbiota composition in obese individuals are inconsistent, and the investigation of causality between gut microbiota and energy homeostasis is complex because multiple variables contribute to the gut microbiota composition. The microbial metabolites short chain fatty acids are found to exert numerous physiologic effects, including energy homeostasis through the regulation of GI hormones such as cholecystokinin, glucagon-like peptide 1, peptide tyrosine-tyrosine, and leptin. Preclinical studies show that modifying rodents' microbiota through fecal transplantation results in alterations of these GI hormones and subsequently an altered metabolism and behavior. However, whether and to what extent preclinical findings translate to human metabolism is unclear. One of the major limitations and challenges in this field of research is interindividual variability of the microbiome. Future research needs to combine recent insights gained into tracking the dynamics of the microbiome as well as the metabolic responses. Furthermore, advanced mapping of the human microbiome is required to investigate the metabolic implications of the gut-brain axis to develop targeted interventions for obesity and metabolic syndrome.

  3. Inflammation Meets Metabolic Disease: Gut Feeling Mediated by GLP-1

    PubMed Central

    Zietek, Tamara; Rath, Eva

    2016-01-01

    Chronic diseases, such as obesity and diabetes, cardiovascular, and inflammatory bowel diseases (IBD) share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways, such as the unfolded protein response (UPR), alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC) have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular, the L-cell-derived incretin hormone glucagon-like peptide 1 (GLP-1) has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D). Yet, accumulating data indicate a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment, including the microbiota via receptors and transporters. Subsequently, mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling. This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity, and disease. PMID:27148273

  4. Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study.

    PubMed

    Azoulay, Laurent; Filion, Kristian B; Platt, Robert W; Dahl, Matthew; Dormuth, Colin R; Clemens, Kristin K; Durand, Madeleine; Juurlink, David N; Targownik, Laura E; Turin, Tanvir C; Paterson, J Michael; Ernst, Pierre

    2016-02-17

    To determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes. Population based cohort. Large, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom. A cohort of 972,384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014. Within each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models. During 2,024,441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking. In this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas. Although this potential adverse drug reaction will need to be monitored long term owing to the

  5. Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study

    PubMed Central

    Filion, Kristian B; Platt, Robert W; Dahl, Matthew; Dormuth, Colin R; Clemens, Kristin K; Durand, Madeleine; Juurlink, David N; Targownik, Laura E; Turin, Tanvir C; Paterson, J Michael; Ernst, Pierre

    2016-01-01

    Objective To determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes. Design Population based cohort. Setting Large, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom. Participants A cohort of 972 384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014. Main outcome measures Within each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models. Results During 2 024 441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking. Conclusions In this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas

  6. Gut Melatonin in Vertebrates: Chronobiology and Physiology.

    PubMed

    Mukherjee, Sourav; Maitra, Saumen Kumar

    2015-01-01

    Melatonin, following discovery in the bovine pineal gland, has been detected in several extra-pineal sources including gastrointestinal tract or gut. Arylalkylamine N-acetyltransferase (AANAT) is the key regulator of its biosynthesis. Melatonin in pineal is rhythmically produced with a nocturnal peak in synchronization with environmental light-dark cycle. A recent study on carp reported first that melatonin levels and intensity of a ~23 kDa AANAT protein in each gut segment also exhibit significant daily variations but, unlike pineal, show a peak at midday in all seasons. Extensive experimental studies ruled out direct role of light-dark conditions in determining temporal pattern of gut melatoninergic system in carp, and opened up possible role of environmental non-photic cue(s) as its synchronizer. Based on mammalian findings, physiological significance of gut-derived melatonin also appears unique because its actions at local levels sharing paracrine and/or autocrine functions have been emphasized. The purpose of this mini review is to summarize the existing data on the chronobiology and physiology of gut melatonin and to emphasize their relation with the same hormone derived in the pineal in vertebrates including fish.

  7. Gut Melatonin in Vertebrates: Chronobiology and Physiology

    PubMed Central

    Mukherjee, Sourav; Maitra, Saumen Kumar

    2015-01-01

    Melatonin, following discovery in the bovine pineal gland, has been detected in several extra-pineal sources including gastrointestinal tract or gut. Arylalkylamine N-acetyltransferase (AANAT) is the key regulator of its biosynthesis. Melatonin in pineal is rhythmically produced with a nocturnal peak in synchronization with environmental light–dark cycle. A recent study on carp reported first that melatonin levels and intensity of a ~23 kDa AANAT protein in each gut segment also exhibit significant daily variations but, unlike pineal, show a peak at midday in all seasons. Extensive experimental studies ruled out direct role of light–dark conditions in determining temporal pattern of gut melatoninergic system in carp, and opened up possible role of environmental non-photic cue(s) as its synchronizer. Based on mammalian findings, physiological significance of gut-derived melatonin also appears unique because its actions at local levels sharing paracrine and/or autocrine functions have been emphasized. The purpose of this mini review is to summarize the existing data on the chronobiology and physiology of gut melatonin and to emphasize their relation with the same hormone derived in the pineal in vertebrates including fish. PMID:26257705

  8. Bile Acids and the Gut Microbiome

    PubMed Central

    Ridlon, Jason M.; Kang, Dae Joong; Hylemon, Phillip B.; Bajaj, Jasmohan S.

    2014-01-01

    Purpose of the review We examine the latest research on the emerging bile acid-gut microbiome axis and its role in health and disease. Our focus revolves around two key microbial pathways for degrading bile salts, and the impact of bile acid composition in the gut on the gut microbiome and host physiology. Recent findings Bile acid pool size has recently been shown to be a function of microbial metabolism of bile acids in the intestines. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. Bile acids are emerging as regulators of the gut microbiome at the highest taxomic levels. The role of bile acids as hormones and potentiators of liver cancer are also emerging. Summary The host and microbiome appear to regulate bile acid pool size. The host produces a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of FXR in intestine and liver. Members of the microbiome utilize bile acids and their conjugates resulting in agonism of FXR in intestine and liver resulting in a smaller, unconjugated hydrophobic bile acid pool. Hydrophilicity of the bile acid pool is associated with disease states. Reduced bile acid levels in the gut are associated with bacterial overgrowth and inflammation. Diet, antibiotic therapy, and disease states affect the balance of the microbiome-bile acid pool. PMID:24625896

  9. Cardiovascular Effect of Incretin-Based Therapy in Patients with Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis

    PubMed Central

    Kim, Je-Yon; Yang, Seungwon; Lee, Jangik I.; Chang, Min Jung

    2016-01-01

    Background To assess the cardiovascular (CV) risk associated with the use of incretin-based therapy in adult patients with type 2 diabetes mellitus (T2DM) primary prevention group with low CV risks. Methods The clinical studies on incretin-based therapy published in medical journals until August 2014 were comprehensively searched using MEDLINE, EMBASE and CENTRAL with no language restriction. The studies were systemically reviewed and evaluated for CV risks using a meta-analysis approach and where they meet the following criteria: clinical trial, incidence of predefined CV disease, T2DM with no comorbidities, age > 18 years old, duration of at least 12 weeks, incretin-based therapy compared with other antihyperglycaemic agents or placebo. Statistical analyses were performed using a Mantel-Haenszel (M-H) test. The odds ratios (OR) and their 95% confidence interval (CI) were estimated and displayed for comparison. Results A total of 75 studies comprising 45,648 patients with T2DM were selected. The pooled estimate demonstrated no significance in decreased CV risk with incretin-based therapy versus control (M-H OR, 0.90; 95% CI, 0.81–1.00). Conclusions This meta-analysis suggests that incretin-based therapy show no significant protective effect on CV events in T2DM primary prevention group with low CV risks. Prospective randomized controlled trials are required to confirm the results of this analysis. PMID:27078018

  10. Simulation of oral glucose tolerance tests and the corresponding isoglycemic intravenous glucose infusion studies for calculation of the incretin effect.

    PubMed

    Kim, Myeungseon; Oh, Tae Jung; Lee, Jung Chan; Choi, Karam; Kim, Min Young; Kim, Hee Chan; Cho, Young Min; Kim, Sungwan

    2014-03-01

    The incretin effect, which is a unique stimulus of insulin secretion in response to oral ingestion of nutrients, is calculated by the difference in insulin secretory responses from an oral glucose tolerance test (OGTT) and a corresponding isoglycemic intravenous glucose infusion (IIGI) study. The OGTT model of this study, which is individualized by fitting the glucose profiles during an OGTT, was developed to predict the glucose profile during an IIGI study in the same subject. Also, the model predicts the insulin and incretin profiles during both studies. The incretin effect, estimated by simulation, was compared with that measured by physiologic studies from eight human subjects with normal glucose tolerance, and the result exhibited a good correlation (r > 0.8); the incretin effect from the simulation was 56.5% ± 10.6% while the one from the measured data was 52.5% ± 19.6%. In conclusion, the parameters of the OGTT model have been successfully estimated to predict the profiles of both OGTTs and IIGI studies. Therefore, with glucose data from the OGTT alone, this model could control and predict the physiologic responses, including insulin secretion during OGTTs and IIGI studies, which could eventually eliminate the need for complex and cumbersome IIGI studies in incretin research.

  11. Gut microbiota and obesity.

    PubMed

    Gérard, Philippe

    2016-01-01

    The human intestine harbors a complex bacterial community called the gut microbiota. This microbiota is specific to each individual despite the existence of several bacterial species shared by the majority of adults. The influence of the gut microbiota in human health and disease has been revealed in the recent years. Particularly, the use of germ-free animals and microbiota transplant showed that the gut microbiota may play a causal role in the development of obesity and associated metabolic disorders, and lead to identification of several mechanisms. In humans, differences in microbiota composition, functional genes and metabolic activities are observed between obese and lean individuals suggesting a contribution of the gut microbiota to these phenotypes. Finally, the evidence linking gut bacteria to host metabolism could allow the development of new therapeutic strategies based on gut microbiota modulation to treat or prevent obesity.

  12. The role of gut endocrine cells in control of metabolism and appetite.

    PubMed

    Parker, Helen E; Gribble, Fiona M; Reimann, Frank

    2014-09-01

    After food is ingested, nutrients pass through the gastrointestinal tract, stimulating the release of a range of peptide hormones. Among their many local, central and peripheral actions, these hormones act to mediate glucose metabolism and satiety. Indeed, it is the modification of gut hormone secretion that is considered partly responsible for the normalization of glycaemic control and the reduction in appetite seen in many patients after certain forms of bariatric surgery. This review describes recent developments in our understanding of the secretion and action of anorexigenic gut hormones, primarily concentrating on glucagon-like peptide-1 (GLP-1). © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

  13. Gut microbiota and host metabolism in liver cirrhosis

    PubMed Central

    Usami, Makoto; Miyoshi, Makoto; Yamashita, Hayato

    2015-01-01

    The gut microbiota has the capacity to produce a diverse range of compounds that play a major role in regulating the activity of distal organs and the liver is strategically positioned downstream of the gut. Gut microbiota linked compounds such as short chain fatty acids, bile acids, choline metabolites, indole derivatives, vitamins, polyamines, lipids, neurotransmitters and neuroactive compounds, and hypothalamic-pituitary-adrenal axis hormones have many biological functions. This review focuses on the gut microbiota and host metabolism in liver cirrhosis. Dysbiosis in liver cirrhosis causes serious complications, such as bacteremia and hepatic encephalopathy, accompanied by small intestinal bacterial overgrowth and increased intestinal permeability. Gut dysbiosis in cirrhosis and intervention with probiotics and synbiotics in a clinical setting is reviewed and evaluated. Recent studies have revealed the relationship between gut microbiota and host metabolism in chronic metabolic liver disease, especially, non-alcoholic fatty liver disease, alcoholic liver disease, and with the gut microbiota metabolic interactions in dysbiosis related metabolic diseases such as diabetes and obesity. Recently, our understanding of the relationship between the gut and liver and how this regulates systemic metabolic changes in liver cirrhosis has increased. The serum lipid levels of phospholipids, free fatty acids, polyunsaturated fatty acids, especially, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid have significant correlations with specific fecal flora in liver cirrhosis. Many clinical and experimental reports support the relationship between fatty acid metabolism and gut-microbiota. Various blood metabolome such as cytokines, amino acids, and vitamins are correlated with gut microbiota in probiotics-treated liver cirrhosis patients. The future evaluation of the gut-microbiota-liver metabolic network and the intervention of these relationships using probiotics

  14. Gut microbiota and host metabolism in liver cirrhosis.

    PubMed

    Usami, Makoto; Miyoshi, Makoto; Yamashita, Hayato

    2015-11-07

    The gut microbiota has the capacity to produce a diverse range of compounds that play a major role in regulating the activity of distal organs and the liver is strategically positioned downstream of the gut. Gut microbiota linked compounds such as short chain fatty acids, bile acids, choline metabolites, indole derivatives, vitamins, polyamines, lipids, neurotransmitters and neuroactive compounds, and hypothalamic-pituitary-adrenal axis hormones have many biological functions. This review focuses on the gut microbiota and host metabolism in liver cirrhosis. Dysbiosis in liver cirrhosis causes serious complications, such as bacteremia and hepatic encephalopathy, accompanied by small intestinal bacterial overgrowth and increased intestinal permeability. Gut dysbiosis in cirrhosis and intervention with probiotics and synbiotics in a clinical setting is reviewed and evaluated. Recent studies have revealed the relationship between gut microbiota and host metabolism in chronic metabolic liver disease, especially, non-alcoholic fatty liver disease, alcoholic liver disease, and with the gut microbiota metabolic interactions in dysbiosis related metabolic diseases such as diabetes and obesity. Recently, our understanding of the relationship between the gut and liver and how this regulates systemic metabolic changes in liver cirrhosis has increased. The serum lipid levels of phospholipids, free fatty acids, polyunsaturated fatty acids, especially, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid have significant correlations with specific fecal flora in liver cirrhosis. Many clinical and experimental reports support the relationship between fatty acid metabolism and gut-microbiota. Various blood metabolome such as cytokines, amino acids, and vitamins are correlated with gut microbiota in probiotics-treated liver cirrhosis patients. The future evaluation of the gut-microbiota-liver metabolic network and the intervention of these relationships using probiotics

  15. Incretin-based therapy in combination with basal insulin: a promising tactic for the treatment of type 2 diabetes.

    PubMed

    Vora, J; Bain, S C; Damci, T; Dzida, G; Hollander, P; Meneghini, L F; Ross, S A

    2013-02-01

    Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose-lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed.

  16. Prior exercise does not alter the incretin response to a subsequent meal in obese women

    PubMed Central

    Nyhoff, Lauryn M; Heden, Timothy D; Leidy, Heather J; Winn, Nathan C; Park, Young-Min; Thyfault, John P; Kanaley, Jill A

    2015-01-01

    Prior research has shown an increase in GLP-1 concentrations during exercise but this exercise bout was conducted postprandially. The purpose of this study was to examine the incretin response to a meal following an exercise bout of different intensities in obese subjects. Eleven women (BMI>37.3±7.0 kg/m2; Age 24.3±4.6 y) participated in 3 counter-balanced study days where a standardized meal was preceded by: 1) No exercise (NoEx), 2) ModEx (55% VO2max), and 3) IntEx(4 min (80% VO2max)/3 min (50% VO2max). Frequent blood samples were analyzed for glucose, lactate, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and C-peptide concentrations throughout 280 min of testing. Glucose concentrations were not different between conditions during exercise or meals. There were no differences between conditions in insulin levels during exercise and recovery, but postprandial insulin incremental area under the curve was lower in ModEx vs. NoEx (p<0.01). GIP and GLP-1 levels were not different between conditions during exercise, but during exercise recovery, GLP-1 concentrations were higher in ModEx vs. NoEx (p=0.03). The meal increased the incretin responses (P<0.01) but this response was not affected by prior exercise. Glucagon concentrations increased with exercise (P<0.05) and continued to be elevated during recovery, with the greatest increase with IntEx compared with NoEx (P<0.05). No differences between conditions were detected for hepatic insulin extraction, insulin secretion, or insulin sensitivity. Exercise prior to an evening meal has no impact on the incretin response to the subsequent meal, yet insulin concentrations were lower during the meals that followed exercise. Exercise intensity had no impact on this response. PMID:26188172

  17. Prior exercise does not alter the incretin response to a subsequent meal in obese women.

    PubMed

    Nyhoff, Lauryn M; Heden, Timothy D; Leidy, Heather J; Winn, Nathan C; Park, Young-Min; Thyfault, John P; Kanaley, Jill A

    2015-09-01

    Prior research has shown an increase in GLP-1 concentrations during exercise but this exercise bout was conducted postprandially. The purpose of this study was to examine the incretin response to a meal following an exercise bout of different intensities in obese subjects. Eleven women (BMI>37.3±7.0kg/m(2); Age 24.3±4.6year) participated in 3 counter- balanced study days, where a standardized meal was preceded by: (1) No exercise (NoEx), (2) ModEx (55% VO2max), and (3) IntEx (4min (80% VO2max)/3min (50% VO2max). Frequent blood samples were analyzed for glucose, lactate, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and C-peptide concentrations throughout 280min of testing. Glucose concentrations were not different between conditions during exercise or meals. There were no differences between conditions in insulin levels during exercise and recovery, but postprandial insulin incremental area under the curve was lower in ModEx vs. NoEx (p<0.01). GIP and GLP-1 levels were not different between conditions during exercise, but during exercise recovery, GLP-1 concentrations were higher in ModEx vs. NoEx (p=0.03). The meal increased the incretin responses (p<0.01) but this response was not affected by prior exercise. Glucagon concentrations increased with exercise (p<0.05) and continued to be elevated during recovery, with the greatest increase with IntEx compared with NoEx (p<0.05). No differences between conditions were detected for hepatic insulin extraction, insulin secretion, or insulin sensitivity. Exercise prior to an evening meal has no impact on the incretin response to the subsequent meal, yet insulin concentrations were lower during the meals that followed exercise. Exercise intensity had no impact on this response.

  18. Effects of meal size and composition on incretin, alpha-cell, and beta-cell responses.

    PubMed

    Rijkelijkhuizen, Josina M; McQuarrie, Kelly; Girman, Cynthia J; Stein, Peter P; Mari, Andrea; Holst, Jens J; Nijpels, Giel; Dekker, Jacqueline M

    2010-04-01

    The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate postprandial insulin release from the beta-cells. We investigated the effects of 3 standardized meals with different caloric and nutritional content in terms of postprandial glucose, insulin, glucagon, and incretin responses. In a randomized crossover study, 18 subjects with type 2 diabetes mellitus and 6 healthy volunteers underwent three 4-hour meal tolerance tests (small carbohydrate [CH]-rich meal, large CH-rich meal, and fat-rich meal). Non-model-based and model-based estimates of beta-cell function and incremental areas under the curve of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP were calculated. Mixed models and Friedman tests were used to test for differences in meal responses. The large CH-rich meal and fat-rich meal resulted in a slightly larger insulin response as compared with the small CH-rich meal and led to a slightly shorter period of hyperglycemia, but only in healthy subjects. Model-based insulin secretion estimates did not show pronounced differences between meals. Both in healthy individuals and in those with diabetes, more CH resulted in higher GLP-1 release. In contrast with the other meals, GIP release was still rising 2 hours after the fat-rich meal. The initial glucagon response was stimulated by the large CH-rich meal, whereas the fat-rich meal induced a late glucagon response. Fat preferentially stimulates GIP secretion, whereas CH stimulates GLP-1 secretion. Differences in meal size and composition led to differences in insulin and incretin responses but not to differences in postprandial glucose levels of the well-controlled patients with diabetes.

  19. Mechanisms of incretin effects on plasma lipids and implications for the cardiovascular system.

    PubMed

    Xiao, Changting; Dash, Satya; Lewis, Gary F

    2012-12-01

    Dyslipidemia is a prominent feature of type 2 diabetes and insulin resistance that contributes to increased atherosclerosis and cardiovascular disease (CVD) risks under these conditions. Incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) have recently been developed and are approved for clinical use for treatment of type 2 diabetes. Besides improved glycemic control, other benefits are being increasingly appreciated, one of which is improved plasma lipid profile. This review aims to summarize the evidence and potential mechanism of such agents in humans in modulating fasting and postprandial lipoprotein metabolism.

  20. Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone in SH-SY5Y cells.

    PubMed

    Jalewa, Jaishree; Sharma, Mohit Kumar; Hölscher, Christian

    2016-10-01

    Currently, there is no viable treatment available for Parkinson's disease (PD) that stops or reverses disease progression. Interestingly, studies testing the glucagon-like-peptide-1 (GLP-1) mimetic Exendin-4 have shown neuroprotective/neurorestorative properties in pre-clinical tests and in a pilot clinical study of PD. Incretin analogues were originally developed to treat type 2 diabetes and several are currently on the market. In this study, we tested novel incretin analogues on the dopaminergic SH-SY5Y neuroblastoma cells against a toxic mitochondrial complex I inhibitor, Rotenone. Here, we investigate for the first time the effects of six different incretin receptor agonists - Liraglutide, D-Ser2-Oxyntomodulin, a GLP-1/GIP Dual receptor agonist, dAla(2)-GIP-GluPal, Val(8)GLP-1-GluPal and exendin-4. Post-treatment with doses of 1, 10 or 100 nM of incretin analogues for 12 h increased the survival of SH-SY5Y cells treated with 1 μM Rotenone for 12 h. Furthermore, we studied the post-treatment effect of 100 nM incretin analogues against 1 μM Rotenone stress on apoptosis, mitochondrial stress and autophagy markers. We found significant protective effects of the analogues against Rotenone stress on cell survival and on mitochondrial and autophagy-associated markers. The novel GLP-1/GIP Dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. Using the Phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, we further show that the neuroprotective effects are partially PI3K-independent. Our data suggest that the neuroprotective properties exhibited by incretin analogues against Rotenone stress involve enhanced autophagy, increased Akt-mediated cell survival and amelioration of mitochondrial dysfunction. These mechanisms can explain the neuroprotective effects of incretin analogues reported in clinical trials. GLP-1, GIP and dual incretin receptor agonists showed protective effects in SH-SY5Y cells

  1. The gut microbiome in autoimmunity: sex matters

    PubMed Central

    Gomez, Andres; Luckey, David; Taneja, Veena

    2015-01-01

    Autoimmune diseases like rheumatoid arthritis are multifactorial in nature, requiring both genetic and environmental factors for onset. Increased predisposition of females to a wide range of autoimmune diseases points to a gender bias in the multifactorial etiology of these disorders. However, the existing evidence tol date has not provided any conclusive mechanism of gender- bias beyond the role of hormones and sex chromosomes. The gut microbiome, which impacts the innate and adaptive branches of immunity, not only influences the development of autoimmune disorders but may interact with sex-hormones to modulate disease progression and sex-bias. Here, we review the current information on gender bias in autoimmunity and discuss the potential of microbiome-derived biomarkers to help unravel the complex interplay between genes, environment and hormones in rheumatoid arthritis. PMID:25956531

  2. Hormonal control of euryhalinity

    USGS Publications Warehouse

    Takei, Yoshio; McCormick, Stephen D.; McCormick, Stephen D.; Farrell, Anthony Peter; Brauner, Colin J.

    2013-01-01

    Hormones play a critical role in maintaining body fluid balance in euryhaline fishes during changes in environmental salinity. The neuroendocrine axis senses osmotic and ionic changes, then signals and coordinates tissue-specific responses to regulate water and ion fluxes. Rapid-acting hormones, e.g. angiotensins, cope with immediate challenges by controlling drinking rate and the activity of ion transporters in the gill, gut, and kidney. Slow-acting hormones, e.g. prolactin and growth hormone/insulin-like growth factor-1, reorganize the body for long-term acclimation by altering the abundance of ion transporters and through cell proliferation and differentiation of ionocytes and other osmoregulatory cells. Euryhaline species exist in all groups of fish, including cyclostomes, and cartilaginous and teleost fishes. The diverse strategies for responding to changes in salinity have led to differential regulation and tissue-specific effects of hormones. Combining traditional physiological approaches with genomic, transcriptomic, and proteomic analyses will elucidate the patterns and diversity of the endocrine control of euryhalinity.

  3. Protective and therapeutic effects of ghrelin in the gut.

    PubMed

    Warzecha, Z; Dembinski, A

    2012-01-01

    Ghrelin, a peptide predominantly produced in the stomach exhibits numerous physiological functions, including stimulation of growth hormone release, food intake and gastric empting, and regulation of energy expenditure. This peptide exhibits also some protective and healing-promoting effects. This review summarizes the recent findings concerning animal and human data showing protective and therapeutic effects of ghrelin in the gut.

  4. Gut Dysbiosis in Animals Due to Environmental Chemical Exposures

    PubMed Central

    Rosenfeld, Cheryl S.

    2017-01-01

    The gut microbiome consists of over 103–104 microorganism inhabitants that together possess 150 times more genes that the human genome and thus should be considered an “organ” in of itself. Such communities of bacteria are in dynamic flux and susceptible to changes in host environment and body condition. In turn, gut microbiome disturbances can affect health status of the host. Gut dysbiosis might result in obesity, diabetes, gastrointestinal, immunological, and neurobehavioral disorders. Such host diseases can originate due to shifts in microbiota favoring more pathogenic species that produce various virulence factors, such as lipopolysaccharide. Bacterial virulence factors and metabolites may be transmitted to distal target sites, including the brain. Other potential mechanisms by which gut dysbiosis can affect the host include bacterial-produced metabolites, production of hormones and factors that mimic those produced by the host, and epimutations. All animals, including humans, are exposed daily to various environmental chemicals that can influence the gut microbiome. Exposure to such chemicals might lead to downstream systemic effects that occur secondary to gut microbiome disturbances. Increasing reports have shown that environmental chemical exposures can target both host and the resident gut microbiome. In this review, we will first consider the current knowledge of how endocrine disrupting chemicals (EDCs), heavy metals, air pollution, and nanoparticles can influence the gut microbiome. The second part of the review will consider how potential environmental chemical-induced gut microbiome changes might subsequently induce pathophysiological responses in the host, although definitive evidence for such effects is still lacking. By understanding how these chemicals result in gut dysbiosis, it may open up new remediation strategies in animals, including humans, exposed to such chemicals. PMID:28936425

  5. Obesity Surgery and Gut-Brain Communication

    PubMed Central

    Berthoud, Hans-Rudolf; Shin, Andrew C.; Zheng, Huiyuan

    2011-01-01

    The prevalence of obesity, and the cluster of serious metabolic diseases it is associated with, continues to rise globally, and hopes for effective treatment with drugs have been considerably set back. Thus, success with bariatric surgeries to induce sustained body weight loss and effectively cure most of the associated co-morbidities appears almost “miraculous” and systematic investigation of the mechanisms at work has gained momentum. Here, we will discuss the basic organization of gut-brain communication and review clinical and pre-clinical investigations on the potential mechanisms by which gastric bypass surgery leads to its beneficial effects on energy balance and glucose homeostasis. Although a lot has been learned regarding changes in energy intake and expenditure, secretion of gut hormones, and improvement in glucose homeostasis, there has not yet been the “breakthrough observation” of identifying a key signaling component common to the beneficial effects of the surgery. However, given the complexity and redundancy of gut-brain signaling and gut signaling to other relevant organs, it is perhaps more realistic to expect a number of key signaling changes that act in concert to bring about the “miracle”. PMID:21315095

  6. Can a Bug in the Gut Act Like a Drug in the Brain?

    PubMed

    Howland, Robert H

    2015-10-01

    Microorganisms inhabiting the gut exist in a symbiotic relationship with our bodies, performing many essential metabolic tasks for human physiology. The gut-brain axis is a bidirectional communication system integrating neural, hormonal, and immunological signaling between the gut and brain. There is strong experimental evidence from animal studies that the intestinal microbiome has an important role in the control of brain development, function, and behavior. A small number of clinical studies, mainly in healthy individuals, using probiotic formulations as an experimental probe suggest that gut bugs may indeed act like a drug and affect the brain, but much more work is needed. Copyright 2015, SLACK Incorporated.

  7. Gastrointestinal hormones and their role in obesity.

    PubMed

    Choudhury, Sirazum M; Tan, Tricia M; Bloom, Stephen R

    2016-02-01

    Pandemic obesity is the most pressing health issue of this century. The most successful treatment so far is bariatric surgery, but for various reasons, surgery cannot be applied to all patients who require treatment. Gastrointestinal hormones are likely to play a key role in the success of bariatric surgery. This article examines in detail three of these gut hormones: peptide YY, oxyntomodulin and pancreatic polypeptide, and reviews how recent developments may offer new targets for therapy. Both the free fatty acid 2 and the melanocortin 4 receptors have been discovered to regulate peptide YY and glucagon-like peptide-1 secretion, and drugs targeting these may represent new antiobesity therapies. Dual agonism of glucagon-like peptide-1 and glucagon receptors, for example with oxyntomodulin, has synergistic effects in reducing appetite and increasing energy expenditure. Plasma pancreatic polypeptide concentration correlates with visceral adiposity, and may serve as a biomarker for metabolic syndrome. Gut hormones continue to show promise on an individual basis as anti-obesity treatments, but combination therapies are needed to achieve beneficial effects comparable to bariatric surgery. Innovative pathways for stimulating native gut hormone secretion may well provide an alternative method for weight loss without necessitating the administration of gut hormone analogues via injection.

  8. Mechanisms Linking the Gut Microbiome and Glucose Metabolism

    PubMed Central

    Kratz, Mario; Damman, Chris J.; Hullarg, Meredith

    2016-01-01

    Context: Type 2 diabetes mellitus is associated with gastrointestinal dysbiosis involving both compositional and functional changes in the gut microbiome. Changes in diet and supplementation with probiotics and prebiotics (ie, fermentable fibers) can induce favorable changes in gut bacterial species and improve glucose homeostasis. Objective: This paper will review the data supporting several potential mechanisms whereby gut dysbiosis contributes to metabolic dysfunction, including microbiota driven increases in systemic lipopolysaccharide concentrations, changes in bile acid metabolism, alterations in short chain fatty acid production, alterations in gut hormone secretion, and changes in circulating branched-chain amino acids. Methods: Data for this review were identified by searching English language references from PubMed and relevant articles. Conclusions: Understanding the mechanisms linking the gut microbiome to glucose metabolism, and the relevant compositional and functional characteristics of the gut microbiome, will help direct future research to develop more targeted approaches or novel compounds aimed at restoring a more healthy gut microbiome as a new approach to prevent and treat type 2 diabetes mellitus and related metabolic conditions. PMID:26938201

  9. The effects of incretins on energy homeostasis: physiology and implications for the treatment of type 2 diabetes mellitus and obesity.

    PubMed

    Karras, Spyridon; Goulis, Dimitrios G; Mintziori, Gesthimani; Katsiki, Niki; Tzotzas, Themistoklis

    2012-11-01

    Energy homeostasis in mammalians is a teleological process regulated by the interplay between caloric intake and energy expenditure. Incretins are a significant component of the complex homeostatic network regulating the metabolic state in humans. This narrative review will focus on the basic concepts regarding incretins physiology and their regulatory feedback mechanisms affecting energy homeostasis. In this context, glucagon-like peptide 1 (GLP-1) promotes satiety and weight loss through centrally and peripherally mediated pathways. On the other hand, gastric inhibitory peptide (GIP) is implicated in energy storage by its actions on adipose tissue. Understanding this biological model requires a holistic approach, since it is dually manifested by promoting weight reduction, in the case of GLP-1, or favoring lipid accumulation, in the case of GIP. The complete spectrum of incretin actions related to energy homeostasis is yet to be fully elucidated. Currently, new drugs based on incretin physiology are available for treatment of type 2 diabetes mellitus, whereas the implication of similar drugs in the treatment of obesity is under investigation. These agents exert several beneficial effects that minimize cardiovascular risk.

  10. Beta-glucans and cancer: The influence of inflammation and gut peptide.

    PubMed

    Baldassano, Sara; Accardi, Giulia; Vasto, Sonya

    2017-09-15

    Dietary β-glucans are soluble fibers with potentially health-promoting effects. Gut peptides are important signals in the regulation of energy and glucose homeostasis. This article reviews the effects of different enriched β-glucan food consumption on immune responses, inflammation, gut hormone and cancer. Gut hormones are influenced by enriched β-glucan food consumption and levels of such peptide as YY, ghrelin, glucagon-like peptide 1 and 2 in humans influence serum glucose concentration as well as innate and adaptive immunity. Cancer cell development is also regulated by obesity and glucose dishomeostasy that are influenced by β-glucan food consumption that in turn regulated gut hormones. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Schizophrenia and the gut-brain axis.

    PubMed

    Nemani, Katlyn; Hosseini Ghomi, Reza; McCormick, Beth; Fan, Xiaoduo

    2015-01-02

    Several risk factors for the development of schizophrenia can be linked through a common pathway in the intestinal tract. It is now increasingly recognized that bidirectional communication exists between the brain and the gut that uses neural, hormonal, and immunological routes. An increased incidence of gastrointestinal (GI) barrier dysfunction, food antigen sensitivity, inflammation, and the metabolic syndrome is seen in schizophrenia. These findings may be influenced by the composition of the gut microbiota. A significant subgroup of patients may benefit from the initiation of a gluten and casein-free diet. Antimicrobials and probiotics have therapeutic potential for reducing the metabolic dysfunction and immune dysregulation seen in patients with schizophrenia. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Interactions between the gut, the brain and brown adipose tissue function.

    PubMed

    van den Beukel, Johanna C; Grefhorst, Aldo

    2014-01-01

    Brown adipose tissue (BAT) has the unique ability to oxidize fatty acids to generate heat, a process termed thermogenesis. The mitochondrial uncoupling protein 1 is predominantly expressed in BAT and controls the thermogenetic properties of this tissue. Since activated BAT dissipates energy, it is considered beneficial in controlling metabolism, i.e. by combating obesity. Indeed, humans with a higher BMI have less active BAT. Many researchers attempt to uncover regulatory pathways in BAT activity in the pursuit for novel BAT modulators to control body weight. Endocrine factors such as thyroid hormone, sex steroid hormones and glucocorticoids can modulate BAT activity. Since the intestinal tract has emerged as an endocrine organ regulating energy balance and glucose homeostasis, this review will discuss how gut-derived hormones and other intestinal tract-related factors such as bile acids modulate BAT activity. Emphasis will be put on whether these hormones regulate BAT directly or via the central nervous system. In summary, it can be globally stated that anorexigenic gut hormones stimulate BAT while orexigenic gut hormones inhibit BAT activity. How these hormones modulate BAT and whether this is via a direct and/or central effect is largely unknown. Novel insights about gut-derived factors such as bile acids suggest that they also affect BAT activity. Altogether, effects of food intake per se on BAT activity are rather complex to interpret and depend on many (hormonal) factors. © 2014 S. Karger AG, Basel.

  13. Treating obesity: is it all in the gut?

    PubMed

    Davenport, Richard J; Wright, Susanne

    2014-07-01

    Obesity is a leading cause of preventable mortality worldwide, with current strategies for treatment including life-style changes, pharmacological intervention and bariatric surgery. With pharmacological intervention showing at best modest patient benefits, new treatments are required. Modulation of anorectic gut hormones could offer the potential to elicit the required life-changing level of efficacy only currently seen with bariatric surgery, and without the cardiovascular risk associated with a number of the current marketed therapies. This review will discuss the gut hormones glucagon-like peptide-1 (GLP-1), Ghrelin and cholecystokinin (CCK)--for which more advanced non-peptide chemical matter has been discovered acting through these hormone pathways and/or their receptors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Low calorie sweeteners: Evidence remains lacking for effects on human gut function.

    PubMed

    Bryant, Charlotte; Mclaughlin, John

    2016-10-01

    The importance of nutrient induced gut-brain signalling in the regulation of human food intake has become an increasing focus of research. Much of the caloric excess consumed comes from dietary sugars, but our knowledge about the mechanisms mediating the physiological and appetitive effects of sweet tastants in the human gut and gut-brain axis is far from complete. The comparative effects of natural sugars vs low calorie sweeteners are also poorly understood. Research in animal and cellular models has suggested a key functional role in gut endocrine cells for the sweet taste receptors previously well described in oral taste. However human studies to date have very consistently failed to show that activation of the sweet taste receptor by low calorie sweeteners placed in the human gut fails to replicate any of the effects on gastric motility, gut hormones or appetitive responses evoked by caloric sugars. Copyright © 2016. Published by Elsevier Inc.

  15. Alzheimer's disease and gut microbiota.

    PubMed

    Hu, Xu; Wang, Tao; Jin, Feng

    2016-10-01

    Alzheimer's disease (AD) is a most common neurodegenerative disorder, which associates with impaired cognition. Gut microbiota can modulate host brain function and behavior via microbiota-gut-brain axis, including cognitive behavior. Germ-free animals, antibiotics, probiotics intervention and diet can induce alterations of gut microbiota and gut physiology and also host cognitive behavior, increasing or decreasing risks of AD. The increased permeability of intestine and blood-brain barrier induced by gut microbiota disturbance will increase the incidence of neurodegeneration disorders. Gut microbial metabolites and their effects on host neurochemical changes may increase or decrease the risk of AD. Pathogenic microbes infection will also increase the risk of AD, and meanwhile, the onset of AD support the "hygiene hypothesis". All the results suggest that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention will probably become a new treatment for AD.

  16. Incretin-based medications for type 2 diabetes: an overview of reviews.

    PubMed

    Gamble, J-M; Clarke, A; Myers, K J; Agnew, M D; Hatch, K; Snow, M M; Davis, E M

    2015-07-01

    To summarize evidence from and assess the quality of published systematic reviews evaluating the safety, efficacy and effectiveness of incretin-based medications used in the treatment of type 2 diabetes. We identified systematic reviews of randomized controlled trials or observational studies published in any language that evaluated the safety and/or effectiveness of glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl-peptidase-4 (DPP-4) inhibitors. Data sources used include the Cochrane Library, PubMed, EMBASE, Web of Science, International Pharmaceutical Abstracts, table of contents of diabetes journals, and hand-searching of reference lists and clinical practice guidelines. The methodological quality of systematic reviews was independently assessed by two reviewers using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist. Our study protocol was registered with PROSPERO (2013:CRD42013005149). The primary outcomes were pooled treatment effect estimates for glycaemic control, macrovascular and microvascular complications, and hypoglycaemic events. We identified 467 unique citations of which 84 systematic reviews met our inclusion criteria. There were 51 reviews that evaluated GLP-1 receptor agonists and 64 reviews that evaluated DPP-4 inhibitors. The median (interquartile range) AMSTAR score was 6 (3) out of 11 for quantitative and 1 (1) for non-quantitative reviews. Among the 66 quantitative systematic reviews, there were a total of 718 pooled treatment effect estimates reported for our primary outcomes and 1012 reported pooled treatment effect estimates for secondary outcomes. Clinicians and policy makers, when using the results of systematic reviews to inform decision-making with regard to round clinical care or healthcare policies for incretin-based medications, should consider the variability in quality of reviews. © 2015 John Wiley & Sons Ltd.

  17. Investigating incretin-based therapies as a novel treatment for depression in type 2 diabetes: Findings from the South London Diabetes (SOUL-D) Study.

    PubMed

    Moulton, C D; Pickup, J C; Amiel, S A; Winkley, K; Ismail, K

    2016-04-01

    We aimed to investigate the association between incretin-based therapies and 1-year change in depressive symptoms in a cohort of 1735 patients with newly diagnosed type 2 diabetes. The incretin group experienced significant reduction in depressive symptoms compared to controls. This was independent of HbA1c and may be mediated by an anti-inflammatory mechanism. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

  18. The microbiota-gut-brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both?

    PubMed

    De Palma, Giada; Collins, Stephen M; Bercik, Premysl; Verdu, Elena F

    2014-07-15

    The gut-brain axis is the bidirectional communication between the gut and the brain, which occurs through multiple pathways that include hormonal, neural and immune mediators. The signals along this axis can originate in the gut, the brain or both, with the objective of maintaining normal gut function and appropriate behaviour. In recent years, the study of gut microbiota has become one of the most important areas in biomedical research. Attention has focused on the role of gut microbiota in determining normal gut physiology and immunity and, more recently, on its role as modulator of host behaviour ('microbiota-gut-brain axis'). We therefore review the literature on the role of gut microbiota in gut homeostasis and link it with mechanisms that could influence behaviour. We discuss the association of dysbiosis with disease, with particular focus on functional bowel disorders and their relationship to psychological stress. This is of particular interest because exposure to stressors has long been known to increase susceptibility to and severity of gastrointestinal diseases.

  19. Hormone Therapy

    MedlinePlus

    ... of estrogen , a hormone that helps control the menstrual cycle . Changing estrogen levels can bring on symptoms such ... of two hormones—estrogen and progesterone —control your menstrual cycle. These hormones are made by the ovaries . Estrogen ...

  20. Gut Microbiota-brain Axis

    PubMed Central

    Wang, Hong-Xing; Wang, Yu-Ping

    2016-01-01

    Objective: To systematically review the updated information about the gut microbiota-brain axis. Data Sources: All articles about gut microbiota-brain axis published up to July 18, 2016, were identified through a literature search on PubMed, ScienceDirect, and Web of Science, with the keywords of “gut microbiota”, “gut-brain axis”, and “neuroscience”. Study Selection: All relevant articles on gut microbiota and gut-brain axis were included and carefully reviewed, with no limitation of study design. Results: It is well-recognized that gut microbiota affects the brain's physiological, behavioral, and cognitive functions although its precise mechanism has not yet been fully understood. Gut microbiota-brain axis may include gut microbiota and their metabolic products, enteric nervous system, sympathetic and parasympathetic branches within the autonomic nervous system, neural-immune system, neuroendocrine system, and central nervous system. Moreover, there may be five communication routes between gut microbiota and brain, including the gut-brain's neural network, neuroendocrine-hypothalamic-pituitary-adrenal axis, gut immune system, some neurotransmitters and neural regulators synthesized by gut bacteria, and barrier paths including intestinal mucosal barrier and blood-brain barrier. The microbiome is used to define the composition and functional characteristics of gut microbiota, and metagenomics is an appropriate technique to characterize gut microbiota. Conclusions: Gut microbiota-brain axis refers to a bidirectional information network between the gut microbiota and the brain, which may provide a new way to protect the brain in the near future. PMID:27647198

  1. Healthy human gut phageome

    PubMed Central

    Manrique, Pilar; Bolduc, Benjamin; Walk, Seth T.; van der Oost, John; de Vos, Willem M.; Young, Mark J.

    2016-01-01

    The role of bacteriophages in influencing the structure and function of the healthy human gut microbiome is unknown. With few exceptions, previous studies have found a high level of heterogeneity in bacteriophages from healthy individuals. To better estimate and identify the shared phageome of humans, we analyzed a deep DNA sequence dataset of active bacteriophages and available metagenomic datasets of the gut bacteriophage community from healthy individuals. We found 23 shared bacteriophages in more than one-half of 64 healthy individuals from around the world. These shared bacteriophages were found in a significantly smaller percentage of individuals with gastrointestinal/irritable bowel disease. A network analysis identified 44 bacteriophage groups of which 9 (20%) were shared in more than one-half of all 64 individuals. These results provide strong evidence of a healthy gut phageome (HGP) in humans. The bacteriophage community in the human gut is a mixture of three classes: a set of core bacteriophages shared among more than one-half of all people, a common set of bacteriophages found in 20–50% of individuals, and a set of bacteriophages that are either rarely shared or unique to a person. We propose that the core and common bacteriophage communities are globally distributed and comprise the HGP, which plays an important role in maintaining gut microbiome structure/function and thereby contributes significantly to human health. PMID:27573828

  2. The Microbiota, the Gut and the Brain in Eating and Alcohol Use Disorders: A 'Ménage à Trois'?

    PubMed

    Temko, Jamie E; Bouhlal, Sofia; Farokhnia, Mehdi; Lee, Mary R; Cryan, John F; Leggio, Lorenzo

    2017-07-01

    Accumulating evidence for the influence of the gut microbiota on the bidirectional communication along the gut-brain axis suggests a role of the gut microbiota in eating disorders (EDs) and alcohol and substance use disorders. The potential influence of altered gut microbiota (dysbiosis) on behaviors associated with such disorders may have implications for developing therapeutic interventions. A systematic review of preclinical and clinical studies evaluating the gut microbiota, EDs and alcohol and substance use disorders was conducted using MEDLINE, Embase and Web of Science databases with the objective being to examine the role of the gut microbiota in behavioral correlates of these disorders. Original papers focused on the gut microbiota and potential behavioral implications were deemed eligible for consideration. The resulting 12 publications were limited to gut microbiota studies related to EDs and alcohol and substance use disorders. Some studies suggest that dysbiosis and gut microbial byproducts may influence the pathophysiology of EDs via direct and indirect interference with peptide hormone signaling. Additionally, dysbiosis was shown to be correlated with alcohol use disorder-related symptoms, i.e. craving, depression and anxiety. Finally, a mouse study suggests that manipulations in the gut microbiota may affect cocaine-related behaviors. Promising, albeit preliminary, findings suggest a potential role of the gut microbiota in behavioral correlates of EDs and alcohol and substance use disorders. Preliminary evidence exists supporting the role of the gut microbiota in eating disorders and alcohol and substance use disorders, although additional investigation is needed to determine what is causative versus epiphenomenological.

  3. Villification of the gut

    NASA Astrophysics Data System (ADS)

    Tallinen, Tuomas; Shyer, Amy E.; Tabin, Clifford J.; Mahadevan, L.

    2014-03-01

    The villi of the human and chick gut are formed in similar stepwise progressions, wherein the mesenchyme and attached epithelium first fold into longitudinal ridges, then a zigzag pattern, and lastly individual villi. We combine biological manipulations and quantitative modeling to show that these steps of villification depend on the sequential differentiation of the distinct smooth muscle layers of the gut, which restrict the expansion of the growing endoderm and mesenchyme, generating compressive stresses that lead to their buckling and folding. Our computational model incorporates measured elastic properties and growth rates in the developing gut, recapitulating the morphological patterns seen during villification in a variety of species. Our study provides a mechanical basis for the genesis of these epithelial protrusions that are essential for providing sufficient surface area for nutrient absorption.

  4. Evidence for a gut-brain axis used by glucagon-like peptide-1 to elicit hyperglycaemia in fish.

    PubMed

    Polakof, S; Míguez, J M; Soengas, J L

    2011-06-01

    In mammals, glucagon-like peptide-1 (GLP-1) produces changes in glucose and energy homeostasis through a gut-pancreas-brain axis. In fish, the effects of GLP-1 are opposed to those described in other vertebrates, such as stimulation of hyperglycaemia and the lack of an effect of incretin. In the present study conducted in a teleost fish such as the rainbow trout, we present evidence of a gut-brain axis used by GLP-1 to exert its actions on glucose and energy homeostasis. We have assessed the effects of GLP-1 on glucose metabolism in the liver as well as the glucose-sensing potential in the hypothalamus and hindbrain. We confirm that peripheral GLP-1 administration elicits sustained hyperglycaemia, whereas, for the first time in a vertebrate species, we report that central GLP-1 treatment increases plasma glucose levels. We have observed (using capsaicin) that at least part of the action of GLP-1 on glucose homeostasis was mediated by vagal and splanchnic afferents. GLP-1 has a direct effect in parameters involved in glucose sensing in the hindbrain, whereas, in the hypothalamus, changes occurred indirectly through hyperglycaemia. Moreover, in the hindbrain, GLP-1 altered the expression of peptides involved in the control of food intake. We have elaborated a model for the actions of GLP-1 in fish in which this peptide uses a mammalian-like ancestral gut-brain axis to elicit the regulation of glucose homeostasis in different manner than the model described in mammals. Finally, it is worth noting that the hyperglycaemia induced by this peptide and the lack of incretin function could be related to the glucose intolerance observed in carnivorous teleost fish species such as the rainbow trout.

  5. Gut microbiome, surgical complications and probiotics

    PubMed Central

    Stavrou, George; Kotzampassi, Katerina

    2017-01-01

    The trigger for infectious complications in patients following major abdominal operations is classically attributed to endogenous enteral bacterial translocation, due to the critical condition of the gut. Today, extensive gut microbiome analysis has enabled us to understand that almost all “evidence-based” surgical or medical intervention (antibiotics, bowel preparation, opioids, deprivation of nutrition), in addition to stress-released hormones, could affect the relative abundance and diversity of the enteral microbiome, allowing harmful bacteria to proliferate in the place of depressed beneficial species. Furthermore, these bacteria, after tight sensing of host stress and its consequent humoral alterations, can and do switch their virulence accordingly, towards invasion of the host. Probiotics are the exogenously given, beneficial clusters of live bacteria that, upon digestion, seem to succeed in partially restoring the distorted microbial diversity, thus reducing the infectious complications occurring in surgical and critically ill patients. This review presents the latest data on the interrelationship between the gut microbiome and the occurrence of complications after colon surgery, and the efficacy of probiotics as therapeutic instruments for changing the bacterial imbalance. PMID:28042237

  6. Diet, gut microbiota and cognition.

    PubMed

    Proctor, Cicely; Thiennimitr, Parameth; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2017-02-01

    The consumption of a diet high in fat and sugar can lead to the development of obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease and cognitive decline. In the human gut, the trillions of harmless microorganisms harboured in the host's gastrointestinal tract are called the 'gut microbiota'. Consumption of a diet high in fat and sugar changes the healthy microbiota composition which leads to an imbalanced microbial population in the gut, a phenomenon known as "gut dysbiosis". It has been shown that certain types of gut microbiota are linked to the pathogenesis of obesity. In addition, long-term consumption of a high fat diet is associated with cognitive decline. It has recently been proposed that the gut microbiota is part of a mechanistic link between the consumption of a high fat diet and the impaired cognition of an individual, termed "microbiota-gut-brain axis". In this complex relationship between the gut, the brain and the gut microbiota, there are several types of gut microbiota and host mechanisms involved. Most of these mechanisms are still poorly understood. Therefore, this review comprehensively summarizes the current evidence from mainly in vivo (rodent and human) studies of the relationship between diet, gut microbiota and cognition. The possible mechanisms that the diet and the gut microbiota have on cognition are also presented and discussed.

  7. Incretin-based therapies in the treatment of type 2 diabetes--more than meets the eye?

    PubMed

    Labuzek, Krzysztof; Kozłowski, Michał; Szkudłapski, Dawid; Sikorska, Patrycja; Kozłowska, Monika; Okopień, Bogusław

    2013-04-01

    A lot of contradictory data regarding the serious side effects of incretin-based therapies are currently available, with more being prepared or published every month. Considering the widespread use of these drugs it should be considered a priority to establish both short- and long-term risks connected with incretin treatment. We performed an extensive literature search of the PubMed database looking for articles dealing with connections between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Data obtained indicate that GLP-1 agonists and DPPIV inhibitors could increase the risk of pancreatitis and pancreatic cancer, possibly due to their capacity to increase ductal cell turnover, which has previously been found to be up-regulated in patients with obesity and T2DM. GLP-1 analogues exenatide and liraglutide seem to be connected with medullary thyroid carcinoma in rat models and, surprisingly, GLP-1 receptors have been found in papillary thyroid carcinoma, currently the most common neoplasm of the thyroid gland in humans. Changes in expression of DPPIV have been described in ovarian carcinoma, melanoma, endometrial adenocarcinoma, prostate cancer, non-small cell lung cancer and in certain haematological malignancies. In most cases loss of DPPIV activity is connected with a higher grading scale, more aggressive tumour behaviour and higher metastatic potential. In conclusion animal and human studies indicate that there could be a connection between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Therefore whenever such therapy is started it would be wise to proceed with caution, especially if personal history of neoplasms is present. Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  8. Neuroimaging, Gut Peptides and Obesity: Novel Studies of the Neurobiology of Appetite

    PubMed Central

    Gibson, C. D.; Carnell, S.; Ochner, C. N.; Geliebter, A.

    2011-01-01

    Two major biological players in the regulation of body weight are the gut and the brain. Peptides released from the gut convey information about energy needs to areas of the brain involved in homeostatic control of food intake. There is emerging evidence that human food intake is also under the control of cortical and subcortical areas related to reward and cognition. The extent to which gut hormones influence these brain areas is not fully understood. Novel methods combining the study of neural activity and hormonal signalling promise to advance our understanding of gut–brain interactions. Here, we review a growing number of animal and human studies using neuroimaging methods (functional magnetic resonance imaging, positron emission tomography) to measure brain activation in relation to nutrient loads and infusion of gut peptides. Implications for current and future pharmacological treatments for obesity are discussed. PMID:20553371

  9. Gut Microbiota and Atherosclerosis.

    PubMed

    Li, Daniel Y; Tang, W H Wilson

    2017-08-25

    Studies in microbiota-mediated health risks have gained traction in recent years since the compilation of the Human Microbiome Project. No longer do we believe that our gut microbiota is an inert set of microorganisms that reside in the body without consequence. In this review, we discuss the recent findings which further our understanding of the connection between the gut microbiota and the atherosclerosis. We evaluate studies which illustrate the current understanding of the relationship between infection, immunity, altered metabolism, and bacterial products such as immune activators or dietary metabolites and their contributions to the development of atherosclerosis. In particular, we critically examine rec ent clinical and mechanistic findings for the novel microbiota-dependent dietary metabolite, trimethylamine N-oxide (TMAO), which has been implicated in atherosclerosis. These discoveries are now becoming integrated with advances in microbiota profiling which enhance our ability to interrogate the functional role of the gut microbiome and develop strategies for targeted therapeutics. The gut microbiota is a multi-faceted system that is unraveling novel contributors to the development and progression of atherosclerosis. In this review, we discuss historic and novel contributors while highlighting the TMAO story mainly as an example of the various paths taken beyond deciphering microbial composition to elucidate downstream mechanisms that promote (or protect from) atherogenesis in the hopes of translating these findings from bench to bedside.

  10. Gut health in poultry

    USDA-ARS?s Scientific Manuscript database

    Although the gastrointestinal tract is frequently described simply as "the gut," it is actually made up of (1) an epithelium; (2) a diverse and robust immune arm, which contains most of the immune cells in the body; and (3) the commensal bacteria, which contain more cells than are present in the ent...

  11. Philosophy with Guts

    ERIC Educational Resources Information Center

    Sherman, Robert R.

    2014-01-01

    Western philosophy, from Plato on, has had the tendency to separate feeling and thought, affect and cognition. This article argues that a strong philosophy (metaphorically, with "guts") utilizes both in its work. In fact, a "complete act of thought" also will include action. Feeling motivates thought, which formulates ideas,…

  12. Starch with high amylose and low in vitro digestibility increases short-chain fatty acid absorption, reduces peak insulin secretion, and modulates incretin secretion in pigs.

    PubMed

    Regmi, Prajwal R; van Kempen, Theo A T G; Matte, J Jacques; Zijlstra, Ruurd T

    2011-03-01

    Diets containing different starch types affect peripheral glucose and insulin responses. However, the role of starch chemistry in kinetics of nutrient absorption and insulin and incretin secretion is poorly understood. Four portal vein-catheterized pigs (35.0 ± 0.2 kg body weight) consumed 4 diets containing 70% purified starch [0-63.2% amylose content and 0.22 (slowly) to 1.06%/min (rapidly) maximum rate of in vitro digestion] for 7-d periods in a 4 × 4 Latin square. On d 7, blood was collected for 12 h postprandial with simultaneous blood flow measurement for determining the net portal appearance (NPA) of nutrients and hormones. The NPA of glucose, insulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) during 0-4 h postprandial were lower (P < 0.05) and those of butyrate and total SCFA were higher (P < 0.05) when pigs consumed the diet containing slowly digestible compared with rapidly digestible starch. The peak NPA of insulin occurred prior to that of glucose when pigs consumed diets containing rapidly digestible starch. The kinetics of insulin secretion had a linear positive relation with kinetics of NPA of glucose (R(2) = 0.50; P < 0.01). In conclusion, starch with high amylose and low in vitro digestibility decreases the kinetics of glucose absorption and insulin and GIP secretion and increases SCFA absorption and glucagon-like peptide-1 secretion. In conclusion, starch with high amylose content and a lower rate and extent of in vitro digestion decreased glucose absorption and insulin secretion and increased SCFA absorption.

  13. The Realization of the Brain-Gut Interactions with Corticotropin-Releasing Factor and Glucocorticoids

    PubMed Central

    Filaretova, Ludmila; Bagaeva, Tatiana

    2016-01-01

    Background The brain and the gut interact bi-directionally through the brain-gut axis. The interaction is mediated by the autonomic nervous system and the hypothalamic-pituitary-adrenocortical (HPA) system. The first brilliant demonstration of the brain-gut interactions was the cephalic phase of gastric and pancreatic secretion discovered by Ivan Pavlov, the first physiologist who was awarded the Nobel Prize for Physiology or Medicine in 1904. This review aims to identify the HPA system as a key hormonal branch of the brain-gut axis in stress. Methods We first outlined main components of the brain-gut axis and then focused on the HPA system as a key hormonal branch of the brain-gut axis in stress. We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question. Results Seventy-one articles were included in the review, the eleventh of them were articles of Filaretova L. and co-authors. We will discuss in our articles how an endocrinological approach to gastroenterological field can advance our understanding of the HPA axis role in regulation of gastric mucosal integrity and uncover new findings. According to these findings activation of the HPA system is gastroprotective component of the brain-gut axis in stress but not ulcerogenic one as it was generally accepted. Corticotropin-releasing factor (CRF) and glucocorticoids are important natural players provided gastroprotection. The results suggest that an initial action of endogenous glucocorticoids, including stress- and CRF-produced ones, as well as exogenous glucocorticoids, even used at pharmacological doses, is physiological gastroprotective. Prolongation of the hormonal action may lead to the transformation of gastroprotective hormonal effect to proulcerogenic one. Conclusion The findings of this review demonstrate that corticotropin-releasing factor and glucocorticoids contribute to the realization of the brain-gut interactions and that

  14. Assessment of incretins in oral glucose and lipid tolerance tests may be indicative in the diagnosis of metabolic syndrome aggravation.

    PubMed

    Kiec-Klimczak, M; Malczewska-Malec, M; Razny, U; Zdzienicka, A; Gruca, A; Goralska, J; Pach, D; Gilis-Januszewska, A; Dembinska-Kiec, A; Hubalewska-Dydejczyk, A

    2016-04-01

    Incretins stimulated by oral meals are claimed to be protective for the pancreatic beta cells, to increase insulin secretion, to inhibit glucagon release, slow gastric emptying (glucagon-like peptide-1) and suppress appetite. Recently it has however been suggested that glucagon-like peptide-1 (GLP-1) is putative early biomarker of metabolic consequences of the obesity associated proinflammatory state. The study was aimed to compare the release of incretins and some of early markers of inflammation at the fasting and postprandial period induced by functional oral glucose as well as lipid load in healthy controls and patients with metabolic syndrome (MS) to see if functional tests may be helpful in searching for the inflammatory status of patients. Fifty patients with MS and 20 healthy volunteers (C) participated in this study. The 3-hour oral glucose (OGTT) and the 8-hour oral lipid (OLTT) tolerance tests were performed. At fasting leptin and adiponectin, as well as every 30 minutes of OGTT and every 2 hours of OLTT blood concentration of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucose, insulin, triglycerides, free fatty acids, glutathione peroxidase, interleukin-6, sE-selectin, monocyte chemoattractant protein-1 (MCP1) and visfatin were measured. At fasting and during both OGTT and OLTT the level of incretins did not differ between the MS and the C group. Both glucose and lipids reach food activated incretins secretion. Glucose was the main GLP-1 release activator, while the lipid load activated evidently GIP secretion. A significantly larger AUC-GIP after the lipid-rich meal over the carbohydrate meal was observed, while statistically bigger value of AUC-GLP-1 was noticed in OGTT than in OLTT (P < 0.001) within each of the investigated groups. In patients with the highest fasting plasma GIP concentration (3(rd) tertile), IL-6, MCP-1, sE-selectin and visfatin blood levels were increased and correlated with glutathione peroxydase, leptin

  15. Bioidentical Hormones and Menopause

    MedlinePlus

    ... Center Pacientes y Cuidadores Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ... Learn About Clinical Trials Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ...

  16. Hormones and Obesity

    MedlinePlus

    ... Chemicals (EDCs) Endocrine Glands and Types of Hormones Brainy Hormones What Do Hormones Do? Infographics Myth vs ... Chemicals (EDCs) Endocrine Glands and Types of Hormones Brainy Hormones What Do Hormones Do? Infographics Myth vs ...

  17. Neonatal Androgen Exposure Causes Persistent Gut Microbiota Dysbiosis Related to Metabolic Disease in Adult Female Rats.

    PubMed

    Moreno-Indias, Isabel; Sánchez-Alcoholado, Lidia; Sánchez-Garrido, Miguel Ángel; Martín-Núñez, Gracia María; Pérez-Jiménez, Francisco; Tena-Sempere, Manuel; Tinahones, Francisco J; Queipo-Ortuño, María Isabel

    2016-12-01

    Alterations of gut microbiome have been proposed to play a role in metabolic disease, but the major determinants of microbiota composition remain ill defined. Nutritional and sex hormone challenges, especially during early development, have been shown to permanently alter adult female phenotype and contribute to metabolic disturbances. In this study, we implemented large-scale microbiome analyses to fecal samples from groups of female rats sequentially subjected to various obesogenic manipulations, including sex hormone perturbations by means of neonatal androgenization or adult ovariectomy (OVX), as a model of menopause, to establish whether these phenomena are related to changes in gut microbiota. Basic metabolic profiles concerning glucose/insulin homeostasis were also explored. The effects of the sex hormonal perturbations, either developmentally (androgenization) or in adulthood (OVX), clearly outshone the impact of nutritional interventions, especially concerning the gut microbiota profile. Notably, we observed a lower diversity in the androgenized group, with the highest Firmicutes to Bacteroidetes ratio, supporting the occurrence of durable alterations in gut microbiota composition, even in adulthood. Moreover, the elimination of adult ovarian secretions by OVX affected the richness of gut microbiota. Our data are the first to document the durable impact of sex steroid manipulations, and particularly early androgenization, on gut microbiota composition. Such dysbiosis is likely to contribute to the metabolic perturbations of conditions of obesity linked to gonadal dysfunction in the female.

  18. Gut-brain nutrient sensing in food reward.

    PubMed

    Shechter, Ari; Schwartz, Gary J

    2016-12-20

    For the past several decades, vagal and hormonal gut-brain negative feedback signaling mechanisms that promote satiety and subsequent suppression of food intake have been explored. In addition, a separate positive feedback process termed "appetition," involving postoral signaling from the gut to the brain, has been shown to promote food intake and produce flavor-nutrient preference conditioning. Afferent fibers emerging from the vagus nerve form the main pathway by which information is relayed from the abdominal viscera to the hindbrain and eventually other higher brain regions involved in food intake. Using a specialized subdiaphragmatic vagal deafferentation technique, it was observed that gut vagal and splanchnic afferents play a role in the negative feedback control of satiety after nutrient intake; however, these afferents are not required for nutrient reinforcement or flavor-nutrient preference conditioning, thereby highlighting the distinction between the processes of satiation and appetition. By linking these physiological and behavioral processes to a neurochemical mechanism, it was found that striatal dopamine release induced by intragastric glucose infusion is involved in sweet appetite conditioning. The mechanisms underlying appetition are still being investigated but may involve other nondopaminergic neurochemical systems and/or presently undiscovered hormonal mediators. Future work to delineate the biological mechanisms whereby appetition drives increased intake and conditioned food preference in response to ingestion should take a multifaceted approach by integrating hormonal, neurophysiological, and behavioral techniques. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Association between Polycystic Ovary Syndrome and Gut Microbiota

    PubMed Central

    Guo, Yanjie; Qi, Yane; Yang, Xuefei; Zhao, Lihui; Wen, Shu; Liu, Yinhui; Tang, Li

    2016-01-01

    Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy in women of reproductive age. It is difficult to treat PCOS because of its complex etiology and pathogenesis. Here, we characterized the roles of gut microbiota on the pathogenesis and treatments in letrozole (a nonsteroidal aromatase inhibitor) induced PCOS rat model. Changes in estrous cycles, hormonal levels, ovarian morphology and gut microbiota by PCR-DGGE and real-time PCR were determined. The results showed that PCOS rats displayed abnormal estrous cycles with increasing androgen biosynthesis and exhibited multiple large cysts with diminished granulosa layers in ovarian tissues. Meanwhile, the composition of gut microbiota in letrozole-treated rats was different from that in the controls. Lactobacillus, Ruminococcus and Clostridium were lower while Prevotella was higher in PCOS rats when compared with control rats. After treating PCOS rats with Lactobacillus and fecal microbiota transplantation (FMT) from healthy rats, it was found that the estrous cycles were improved in all 8 rats in FMT group, and in 6 of the 8 rats in Lactobacillus transplantation group with decreasing androgen biosynthesis. Their ovarian morphologies normalized. The composition of gut microbiota restored in both FMT and Lactobacillus treated groups with increasing of Lactobacillus and Clostridium, and decreasing of Prevotella. These results indicated that dysbiosis of gut microbiota was associated with the pathogenesis of PCOS. Microbiota interventions through FMT and Lactobacillus transplantation were beneficial for the treatments of PCOS rats. PMID:27093642

  20. Erythromycin and the gut.

    PubMed Central

    Catnach, S M; Fairclough, P D

    1992-01-01

    The commonly reported gastrointestinal side effects that occur with erythromycin are related to its prokinetic action on the gut, mediated, at least in part, by its motilin receptor stimulating activity. This action may be of clinical use in conditions associated with gastrointestinal hypomotility such as diabetic gastroparesis and intestinal pseudo-obstruction, although further work needs to be done to establish the long term therapeutic uses of erythromycin in these disorders. Macrolide compounds with no antibacterial properties but which have a pronounced prokinetic action on the gut have already been synthesised and are currently being developed for future use in man. These 'motilides' should provide a useful addition to our rather limited armamentarium of effective gastrointestinal prokinetic agents. PMID:1568663

  1. The gut microbiome.

    PubMed

    Sidhu, Mayenaaz; van der Poorten, David

    2017-01-01

    More than a trillion, mostly good, microbes live within our gastrointestinal tract and are responsible for vital metabolic, immune and nutritional functions. Dysbiosis, meaning a maladaptive imbalance of the microbiome, is associated with many common diseases and is a target for therapy. This article provides an overview of the gut microbiome in health and disease, highlighting conditions such as Clostridium difficile infection, inflammatory bowel disease, irritable bowel syndrome, obesity and non-alcoholic fatty liver disease, with which dysbiosis is associated. Information about treatments that affect the gut microbiome, including probiotics and faecal microbiota transplant, are discussed. As our knowledge of the microbiome increases, we are likely to better understand the complex interactions that cause disease, and develop new and more effective treatments for many common conditions.

  2. Gut microbiota and aging.

    PubMed

    O'Toole, Paul W; Jeffery, Ian B

    2015-12-04

    The potential for the gut microbiota to affect health has a particular relevance for older individuals. This is because the microbiota may modulate aging-related changes in innate immunity, sarcopaenia, and cognitive function, all of which are elements of frailty. Both cell culture-dependent and -independent studies show that the gut microbiota of older people differs from that of younger adults. There is no chronological threshold or age at which the composition of the microbiota suddenly alters; rather, changes occur gradually with time. Our detailed analyses have separated the microbiota into groups associated with age, long-term residential care, habitual diet, and degree of retention of a core microbiome. We are beginning to understand how these groups change with aging and how they relate to clinical phenotypes. These data provide a framework for analyzing microbiota-health associations, distinguishing correlation from causation, identifying microbiota interaction with physiological aging processes, and developing microbiota-based health surveillance for older adults.

  3. [Brain-gut interactions].

    PubMed

    Bonaz, B

    2010-08-01

    Our digestive tract has an autonomous functioning but also has a bidirectional relation with our brain known as brain-gut interactions. This communication is mediated by the autonomous nervous system, i.e., the sympathetic and parasympathetic nervous systems, with a mixed afferent and efferent component, and the circumventricular organs located outside the blood-brain barrier. The vagus nerve, known as the principal component of the parasympathetic nervous system, is a mixed nerve composed of 90% afferent fibers, which has physiological roles due to its putative vegetative functions. The vagus nerve has also anti-inflammatory properties both through the hypothalamic pituitary adrenal axis (through its afferents) and the cholinergic anti-inflammatory pathway (through its efferents). The sympathetic nervous system has a classical antagonist effect on the parasympathetic nervous system at the origin of an equilibrated sympathovagal balance in normal conditions. The brain is able to integrate inputs coming from the digestive tract inside a central autonomic network organized around the hypothalamus, limbic system and cerebral cortex (insula, prefrontal, cingulate) and in return to modify the autonomic nervous system and the hypothalamic pituitary adrenal axis in the frame of physiological loops. A dysfunction of these brain-gut interactions, favoured by stress, is most likely involved in the pathophysiology of digestive diseases such as irritable bowel syndrome or even inflammatory bowel diseases. A better knowledge of these brain-gut interactions has therapeutic implications in the domain of pharmacology, neurophysiology, behavioural and cognitive management.

  4. Endocannabinoids in the Gut

    PubMed Central

    DiPatrizio, Nicholas V.

    2016-01-01

    Cannabis has been used medicinally for centuries to treat a variety of disorders, including those associated with the gastrointestinal tract. The discovery of our bodies’ own “cannabis-like molecules” and associated receptors and metabolic machinery – collectively called the endocannabinoid system – enabled investigations into the physiological relevance for the system, and provided the field with evidence of a critical function for this endogenous signaling pathway in health and disease. Recent investigations yield insight into a significant participation for the endocannabinoid system in the normal physiology of gastrointestinal function, and its possible dysfunction in gastrointestinal pathology. Many gaps, however, remain in our understanding of the precise neural and molecular mechanisms across tissue departments that are under the regulatory control of the endocannabinoid system. This review highlights research that reveals an important – and at times surprising – role for the endocannabinoid system in the control of a variety of gastrointestinal functions, including motility, gut-brain mediated fat intake and hunger signaling, inflammation and gut permeability, and dynamic interactions with gut microbiota. PMID:27413788

  5. Gut microbiota and liver diseases

    PubMed Central

    Minemura, Masami; Shimizu, Yukihiro

    2015-01-01

    Several studies revealed that gut microbiota are associated with various human diseases, e.g., metabolic diseases, allergies, gastroenterological diseases, and liver diseases. The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein, and the liver-gut axis is important to understand the pathophysiology of several liver diseases, especially non-alcoholic fatty liver disease and hepatic encephalopathy. Moreover, gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis. Based on these previous findings, trials using probiotics have been performed for the prevention or treatment of liver diseases. In this review, we summarize the current understanding of the changes in gut microbiota associated with various liver diseases, and we describe the therapeutic trials of probiotics for those diseases. PMID:25684933

  6. Diabetes, obesity and gut microbiota.

    PubMed

    Everard, Amandine; Cani, Patrice D

    2013-02-01

    The gut microbiota composition has been associated with several hallmarks of metabolic syndrome (e.g., obesity, type 2 diabetes, cardiovascular diseases, and non-alcoholic steatohepatitis). Growing evidence suggests that gut microbes contribute to the onset of the low-grade inflammation characterising these metabolic disorders via mechanisms associated with gut barrier dysfunctions. Recently, enteroendocrine cells and the endocannabinoid system have been shown to control gut permeability and metabolic endotoxaemia. Moreover, targeted nutritional interventions using non-digestible carbohydrates with prebiotic properties have shown promising results in pre-clinical studies in this context, although human intervention studies warrant further investigations. Thus, in this review, we discuss putative mechanisms linking gut microbiota and type 2 diabetes. These data underline the advantage of investigating and changing the gut microbiota as a therapeutic target in the context of obesity and type 2 diabetes. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Clinical uses of gut peptides.

    PubMed Central

    Geoghegan, J; Pappas, T N

    1997-01-01

    OBJECTIVE: The authors review clinical applications of gut-derived peptides as diagnostic and therapeutic agents. SUMMARY BACKGROUND DATA: An increasing number of gut peptides have been evaluated for clinical use. Earlier uses as diagnostic agents have been complemented more recently by increasing application of gut peptides as therapeutic agents. METHOD: The authors conducted a literature review. RESULTS: Current experience with clinical use of gut peptides is described. Initial clinical applications focused on using secretomotor effects of gut peptides in diagnostic tests, many of which have now fallen into disuse. More recently, attention has been directed toward harnessing these secretomotor effects for therapeutic use in a variety of disorders, and also using the trophic effects of gut peptides to modulate gut mucosal growth in benign and malignant disease. Gut peptides have been evaluated in a variety of other clinical situations including use as adjuncts to imaging techniques, and modification of behaviors such as feeding and panic disorder. CONCLUSIONS: Gut peptides have been used successfully in an increasing variety of clinical conditions. Further refinements in analogue and antagonist design are likely to lead to even more selective agents that may have important clinical applications. Further studies are needed to identity and evaluate these new agents. PMID:9065291

  8. Gut microbiome and metabolic diseases.

    PubMed

    Fukuda, Shinji; Ohno, Hiroshi

    2014-01-01

    The prevalence of obesity and obesity-related disorders is increasing worldwide. In the last decade, the gut microbiota has emerged as an important factor in the development of obesity and metabolic syndrome, through its interactions with dietary, environmental, and host genetic factors. Various studies have shown that alteration of the gut microbiota, shifting it toward increased energy harvest, is associated with an obese phenotype. However, the molecular mechanisms by which the gut microbiota affects host metabolism are still obscure. In this review, we discuss the complexity of the gut microbiota and its relationship to obesity and obesity-related diseases. Furthermore, we discuss the anti-obesity potential of probiotics and prebiotics.

  9. Gut microbiota signatures of longevity.

    PubMed

    Kong, Fanli; Hua, Yutong; Zeng, Bo; Ning, Ruihong; Li, Ying; Zhao, Jiangchao

    2016-09-26

    An aging global population poses substantial challenges to society [1]. Centenarians are a model for healthy aging because they have reached the extreme limit of life by escaping, surviving, or delaying chronic diseases [2]. The genetics of centenarians have been extensively examined [3], but less is known about their gut microbiotas. Recently, Biagi et al.[4] characterized the gut microbiota in Italian centenarians and semi-supercentenarians. Here, we compare the gut microbiota of Chinese long-living people with younger age groups, and with the results from the Italian population [4], to identify gut-microbial signatures of healthy aging.

  10. Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat.

    PubMed

    Hoban, A E; Moloney, R D; Golubeva, A V; McVey Neufeld, K A; O'Sullivan, O; Patterson, E; Stanton, C; Dinan, T G; Clarke, G; Cryan, J F

    2016-12-17

    Gut microbiota colonization is a key event for host physiology that occurs early in life. Disruption of this process leads to altered brain development which ultimately manifests as changes in brain function and behaviour in adulthood. Studies using germ-free (GF) mice highlight the extreme impact on brain health that results from life without commensal microbes. However, the impact of microbiota disturbances occurring in adulthood is less studied. To this end, we depleted the gut microbiota of 10-week-old male SpragueDawley rats via chronic antibiotic treatment. Following this marked, sustained depletion of the gut bacteria, we investigated behavioural and molecular hallmarks of gut-brain communication. Our results reveal that depletion of the gut microbiota during adulthood results in deficits in spatial memory as tested by Morris water maze, increased visceral sensitivity and a greater display of depressive-like behaviours in the forced swim test. In tandem with these clear behavioural alterations we found changes in altered CNS serotonin concentration along with changes in the mRNA levels of corticotrophin releasing hormone receptor 1 and glucocorticoid receptor. Additionally, we found changes in the expression of brain derived neurotrophic factor (BDNF), a hallmark of altered microbiota-gut-brain axis signalling. In summary, this model of antibiotic-induced depletion of the gut microbiota can be used for future studies interested in the impact of the gut microbiota on host health without the confounding developmental influence of early-life microbial alterations.

  11. Insight into role of microbiota-gut-brain peptides as a target for biotechnology innovations.

    PubMed

    Elisei, Carina; de Castro, Alinne Pereira

    2017-01-01

    It has long been understood that some microorganisms may modify their hosts behavior in various systems. Nevertheless, it has only been in recent years that gut microbiota have opened new perspectives to appreciate their potential for affect complex neurological function in mammals. Efforts have demonstrated the ability of these gut-microbiota to impact neurological outcomes, suggested a prominent role for the gut microbiota in the gut-brain interactions, indicating that alterations in bidirectional microbiota-brain-gut may be involved in a number of brain disorders. Further, the identification of bioactive microbial signals, including their immune mediators, gut hormones and/or peptides, during health and disease situations, can serve as a tool for discovering novel activities that influence behavior and neurological function in hosts. Current review aims to provide an overview and shed some light on fundamental characteristics of the gut microbiota in modulating neurological disorders and consequently to draw up alternative strategies for using the gut microbiota or their active molecules as a therapeutic target for future diagnoses.

  12. Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes.

    PubMed

    Laferrère, Blandine; Teixeira, Julio; McGinty, James; Tran, Hao; Egger, Joseph R; Colarusso, Antonia; Kovack, Betty; Bawa, Baani; Koshy, Ninan; Lee, Hongchan; Yapp, Kimberly; Olivan, Blanca

    2008-07-01

    Gastric bypass surgery (GBP) results in rapid weight loss, improvement of type 2 diabetes (T2DM), and increase in incretins levels. Diet-induced weight loss also improves T2DM and may increase incretin levels. Our objective was to determine whether the magnitude of the change of the incretin levels and effect is greater after GBP compared with a low caloric diet, after equivalent weight loss. Obese women with T2DM studied before and 1 month after GBP (n = 9), or after a diet-induced equivalent weight loss (n = 10), were included in the study. Patients from both groups were matched for age, body weight, body mass index, diabetes duration and control, and amount of weight loss. This outpatient study was conducted at the General Clinical Research Center. Glucose, insulin, proinsulin, glucagon, gastric inhibitory peptide (GIP), and glucagon-like peptide (GLP)-1 levels were measured after 50-g oral glucose. The incretin effect was measured as the difference in insulin levels in response to oral and to an isoglycemic iv glucose load. At baseline, none of the outcome variables (fasting and stimulated values) were different between the GBP and diet groups. Total GLP-1 levels after oral glucose markedly increased six times (peak:17 +/- 6 to 112 +/- 54 pmol/liter; P < 0.001), and the incretin effect increased five times (9.4 +/- 27.5 to 44.8 +/- 12.7%; P < 0.001) after GBP, but not after diet. Postprandial glucose levels (P = 0.001) decreased more after GBP. These data suggest that early after GBP, the greater GLP-1 and GIP release and improvement of incretin effect are related not to weight loss but rather to the surgical procedure. This could be responsible for better diabetes outcome after GBP.

  13. Effect of Weight Loss by Gastric Bypass Surgery Versus Hypocaloric Diet on Glucose and Incretin Levels in Patients with Type 2 Diabetes

    PubMed Central

    Laferrère, Blandine; Teixeira, Julio; McGinty, James; Tran, Hao; Egger, Joseph R.; Colarusso, Antonia; Kovack, Betty; Bawa, Baani; Koshy, Ninan; Lee, Hongchan; Yapp, Kimberly; Olivan, Blanca

    2008-01-01

    Context: Gastric bypass surgery (GBP) results in rapid weight loss, improvement of type 2 diabetes (T2DM), and increase in incretins levels. Diet-induced weight loss also improves T2DM and may increase incretin levels. Objective: Our objective was to determine whether the magnitude of the change of the incretin levels and effect is greater after GBP compared with a low caloric diet, after equivalent weight loss. Design and Methods: Obese women with T2DM studied before and 1 month after GBP (n = 9), or after a diet-induced equivalent weight loss (n = 10), were included in the study. Patients from both groups were matched for age, body weight, body mass index, diabetes duration and control, and amount of weight loss. Setting: This outpatient study was conducted at the General Clinical Research Center. Main Outcome Measures: Glucose, insulin, proinsulin, glucagon, gastric inhibitory peptide (GIP), and glucagon-like peptide (GLP)-1 levels were measured after 50-g oral glucose. The incretin effect was measured as the difference in insulin levels in response to oral and to an isoglycemic iv glucose load. Results: At baseline, none of the outcome variables (fasting and stimulated values) were different between the GBP and diet groups. Total GLP-1 levels after oral glucose markedly increased six times (peak:17 ± 6 to 112 ± 54 pmol/liter; P < 0.001), and the incretin effect increased five times (9.4 ± 27.5 to 44.8 ± 12.7%; P < 0.001) after GBP, but not after diet. Postprandial glucose levels (P = 0.001) decreased more after GBP. Conclusions: These data suggest that early after GBP, the greater GLP-1 and GIP release and improvement of incretin effect are related not to weight loss but rather to the surgical procedure. This could be responsible for better diabetes outcome after GBP. PMID:18430778

  14. Comparative gut physiology symposium: The microbe-gut-brain axis

    USDA-ARS?s Scientific Manuscript database

    The Comparative Gut Physiology Symposium titled “The Microbe-Gut-Brain Axis” was held at the Joint Annual Meeting of the American Society of Animal Science and the American Dairy Science Association on Thursday, July 21, 2016, in Salt Lake City Utah. The goal of the symposium was to present basic r...

  15. Blood pressure-lowering effects of incretin-based diabetes therapies.

    PubMed

    Lovshin, Julie A; Zinman, Bernard

    2014-10-01

    Glucagon-like peptide-1 receptor (GLP-1) agonists and dipeptidyl-peptidase-4 (DPP-4) inhibitors are therapies that are used to treat hyperglycemia in patients with type 2 diabetes mellitus. Although both of these medication types primarily lower prandial and fasting blood glucose levels by enhanced GLP-1 receptor signalling, they have distinct mechanisms of action. Whereas DPP-4 inhibitors boost patient levels of endogenously produced GLP-1 (and glucose-dependent insulinotropic peptide) by preventing its metabolism by DPP-4 enzymatic activity, GLP-1 receptor agonists are either synthetic analogues of human GLP-1 or exendin-4 based molecules. They are tailored to resist hydrolysis by DPP-4 activity and to provide longer durability in the circulation compared with native GLP-1. Several roles for incretin-based diabetes therapies beyond the endocrine pancreas and their glycemic-lowering properties have now been described, including attenuation of cardiac myocyte injury and reduction in post-ischemic infarction size after cardiovascular insult. Favourable outcomes have also been observed on systolic blood pressure reduction, postprandial intestinal lipoprotein metabolism, endothelial cell function, modulation of innate immune-mediated inflammation and surrogate markers of renal function. As hypertension is an independent risk factor for premature death in patients with type 2 diabetes, potential favourable extrapancreatic actions, particularly within the heart, blood vessels and kidney, for this drug class are of considerable clinical interest. Herein, we highlight and provide critical appraisal of the clinical data supporting the antihypertensive effects of GLP-1 receptor agonists and DPP-4 inhibitors and link possible mechanisms of action to clinical outcomes reported for this drug class.

  16. Incretin action maintains insulin secretion, but not hepatic insulin action, in people with impaired fasting glucose.

    PubMed

    Perreault, Leigh; Man, Chiara Dalla; Hunerdosse, Devon M; Cobelli, Claudio; Bergman, Bryan C

    2010-10-01

    To determine whether altered GLP-1 activity contributes to the abnormal endogenous glucose production (EGP) and insulin secretion characteristic of people with impaired fasting glucose (IFG). People with IFG (n=10) and normal glucose tolerance (NGT; n=13) underwent assessment of EGP (via [6,6-(2)H(2)]-glucose infusion). Parameters of whole body insulin action and secretion were estimated by IVGTT and OGTT. Measures of EGP and insulin secretion were made before and after sitagliptin administration. EGP was not different at baseline (glucose R(a); 1.47+/-0.08 vs. 1.46+/-0.05mg/kg/min, IFG vs. NGT, p=0.93). However, when differences in circulating insulin were accounted for (EGPXSSPI; 20.2+/-2.1 vs. 14.4+/-1.0AU, vs. NGT, p=0.03) the hepatic insulin resistance index was significantly higher in IFG. Baseline insulin action (S(i); 2.3+/-0.1x10(-4)/microU/ml vs. 3.5+/-0.4x10(-4)/microU/ml, p=0.01, IFG vs. NGT) and secretion (DI; 587+/-81x10(-4)/min vs. 1171+/-226x10(-4)/min, p=0.04, IFG vs. NGT) were impaired in IFG when evaluated by the IVGTT, but not by OGTT (insulin sensitivity 4.52+/-1.08x10(-4)dl/kg/min vs. 6.73+/-1.16x10(-4)dl/kg/min, IFG vs. NGT, p=0.16; indices of basal (Phi(b)), static (Phi(s)), dynamic (Phi(d)), and total (Phi(t)) insulin secretion, p>0.07). Sitagliptin did not change EGP or insulin secretion in either group. Incretin action maintained insulin secretion, but not hepatic insulin action, in people with IFG.

  17. Bioidentical Hormones and Menopause

    MedlinePlus

    ... Balance › Bioidentical Hormones and Menopause Fact Sheet Bioidentical Hormones and Menopause January, 2012 Download PDFs English Espanol ... take HT for symptom relief.) What are bioidentical hormones? Bioidentical hormones are identical to the hormones that ...

  18. Growth Hormone

    MedlinePlus

    ... to help diagnose and monitor the treatment of acromegaly and gigantism . Growth hormone is essential for normal ... signs and symptoms of GH excess ( gigantism and acromegaly ). Suppression testing may be done when a pituitary ...

  19. Minireview: Gut Microbiota: The Neglected Endocrine Organ

    PubMed Central

    Clarke, Gerard; Stilling, Roman M.; Kennedy, Paul J.; Stanton, Catherine; Cryan, John F.

    2014-01-01

    The concept that the gut microbiota serves as a virtual endocrine organ arises from a number of important observations. Evidence for a direct role arises from its metabolic capacity to produce and regulate multiple compounds that reach the circulation and act to influence the function of distal organs and systems. For example, metabolism of carbohydrates results in the production of short-chain fatty acids, such as butyrate and propionate, which provide an important source of nutrients as well as regulatory control of the host digestive system. This influence over host metabolism is also seen in the ability of the prebiotic inulin to influence production of relevant hormones such as glucagon-like peptide-1, peptide YY, ghrelin, and leptin. Moreover, the probiotic Lactobacillus rhamnosus PL60, which produces conjugated linoleic acid, has been shown to reduce body-weight gain and white adipose tissue without effects on food intake. Manipulating the microbial composition of the gastrointestinal tract modulates plasma concentrations of tryptophan, an essential amino acid and precursor to serotonin, a key neurotransmitter within both the enteric and central nervous systems. Indirectly and through as yet unknown mechanisms, the gut microbiota exerts control over the hypothalamic-pituitary-adrenal axis. This is clear from studies on animals raised in a germ-free environment, who show exaggerated responses to psychological stress, which normalizes after monocolonization by certain bacterial species including Bifidobacterium infantis. It is tempting to speculate that therapeutic targeting of the gut microbiota may be useful in treating stress-related disorders and metabolic diseases. PMID:24892638

  20. GUTs and TOEs

    SciTech Connect

    Lincoln, Don

    2015-01-20

    Albert Einstein said that what he wanted to know was “God’s thoughts,” which is a metaphor for the ultimate and most basic rules of the universe. Once known, all other phenomena would then be a consequence of these simple rules. While modern science is far from that goal, we have some thoughts on how this inquiry might unfold. In this video, Fermilab’s Dr. Don Lincoln tells what we know about GUTs (grand unified theories) and TOEs (theories of everything).

  1. GUTs and TOEs

    ScienceCinema

    Lincoln, Don

    2016-07-12

    Albert Einstein said that what he wanted to know was “God’s thoughts,” which is a metaphor for the ultimate and most basic rules of the universe. Once known, all other phenomena would then be a consequence of these simple rules. While modern science is far from that goal, we have some thoughts on how this inquiry might unfold. In this video, Fermilab’s Dr. Don Lincoln tells what we know about GUTs (grand unified theories) and TOEs (theories of everything).

  2. The giant panda gut microbiome.

    PubMed

    Wei, Fuwen; Wang, Xiao; Wu, Qi

    2015-08-01

    Giant pandas (Ailuropoda melanoleuca) are bamboo specialists that evolved from carnivores. Their gut microbiota probably aids in the digestion of cellulose and this is considered an example of gut microbiota adaptation to a bamboo diet. However, this issue remains unresolved and further functional and compositional studies are needed.

  3. Metagenomic Surveys of Gut Microbiota

    PubMed Central

    Mandal, Rahul Shubhra; Saha, Sudipto; Das, Santasabuj

    2015-01-01

    Gut microbiota of higher vertebrates is host-specific. The number and diversity of the organisms residing within the gut ecosystem are defined by physiological and environmental factors, such as host genotype, habitat, and diet. Recently, culture-independent sequencing techniques have added a new dimension to the study of gut microbiota and the challenge to analyze the large volume of sequencing data is increasingly addressed by the development of novel computational tools and methods. Interestingly, gut microbiota maintains a constant relative abundance at operational taxonomic unit (OTU) levels and altered bacterial abundance has been associated with complex diseases such as symptomatic atherosclerosis, type 2 diabetes, obesity, and colorectal cancer. Therefore, the study of gut microbial population has emerged as an important field of research in order to ultimately achieve better health. In addition, there is a spontaneous, non-linear, and dynamic interaction among different bacterial species residing in the gut. Thus, predicting the influence of perturbed microbe–microbe interaction network on health can aid in developing novel therapeutics. Here, we summarize the population abundance of gut microbiota and its variation in different clinical states, computational tools available to analyze the pyrosequencing data, and gut microbe–microbe interaction networks. PMID:26184859

  4. Gut Microbiota: The Brain Peacekeeper.

    PubMed

    Mu, Chunlong; Yang, Yuxiang; Zhu, Weiyun

    2016-01-01

    Gut microbiota regulates intestinal and extraintestinal homeostasis. Accumulating evidence suggests that the gut microbiota may also regulate brain function and behavior. Results from animal models indicate that disturbances in the composition and functionality of some microbiota members are associated with neurophysiological disorders, strengthening the idea of a microbiota-gut-brain axis and the role of microbiota as a "peacekeeper" in the brain health. Here, we review recent discoveries on the role of the gut microbiota in central nervous system-related diseases. We also discuss the emerging concept of the bidirectional regulation by the circadian rhythm and gut microbiota, and the potential role of the epigenetic regulation in neuronal cell function. Microbiome studies are also highlighted as crucial in the development of targeted therapies for neurodevelopmental disorders.

  5. Gut: a key player in the pathogenesis of type 2 diabetes?

    PubMed

    Muscogiuri, Giovanna; Balercia, Giancarlo; Barrea, Luigi; Cignarelli, Angelo; Giorgino, Francesco; Holst, Jens J; Laudisio, Daniela; Orio, Francesco; Tirabassi, Giacomo; Colao, Annamaria

    2016-11-28

    The gut regulates glucose and energy homeostasis; thus, the presence of ingested nutrients into the gut activates sensing mechanisms that affect both glucose homeostasis and regulate food intake. Increasing evidence suggest that gut may also play a key role in the pathogenesis of type 2 diabetes which may be related to both the intestinal microbiological profile and patterns of gut hormones secretion. Intestinal microbiota includes trillions of microorganisms but its composition and function may be adversely affected in type 2 diabetes. The intestinal microbiota may be responsible of the secretion of molecules that may impair insulin secretion/action. At the same time intestinal milieu regulates the secretion of hormones such as GLP-1, GIP, ghrelin, gastrin, somatostatin, CCK, serotonin, peptide YY, GLP-2, all of which importantly influence metabolism in general and in particular glucose metabolism. Thus, the aim of this manuscript is to review the current evidence on the role of the gut in the pathogenesis of type 2 diabetes, taking into account both hormonal and microbiological aspects.

  6. Yogurt and gut function.

    PubMed

    Adolfsson, Oskar; Meydani, Simin Nikbin; Russell, Robert M

    2004-08-01

    In recent years, numerous studies have been published on the health effects of yogurt and the bacterial cultures used in the production of yogurt. In the United States, these lactic acid-producing bacteria (LAB) include Lactobacillus and Streptococcus species. The benefits of yogurt and LAB on gastrointestinal health have been investigated in animal models and, occasionally, in human subjects. Some studies using yogurt, individual LAB species, or both showed promising health benefits for certain gastrointestinal conditions, including lactose intolerance, constipation, diarrheal diseases, colon cancer, inflammatory bowel disease, Helicobacter pylori infection, and allergies. Patients with any of these conditions could possibly benefit from the consumption of yogurt. The benefits of yogurt consumption to gastrointestinal function are most likely due to effects mediated through the gut microflora, bowel transit, and enhancement of gastrointestinal innate and adaptive immune responses. Although substantial evidence currently exists to support a beneficial effect of yogurt consumption on gastrointestinal health, there is inconsistency in reported results, which may be due to differences in the strains of LAB used, in routes of administration, or in investigational procedures or to the lack of objective definition of "gut health." Further well-designed, controlled human studies of adequate duration are needed to confirm or extend these findings.

  7. The role of gut microbiota in the gut-brain axis: current challenges and perspectives.

    PubMed

    Chen, Xiao; D'Souza, Roshan; Hong, Seong-Tshool

    2013-06-01

    Brain and the gastrointestinal (GI) tract are intimately connected to form a bidirectional neurohumoral communication system. The communication between gut and brain, knows as the gut-brain axis, is so well established that the functional status of gut is always related to the condition of brain. The researches on the gut-brain axis were traditionally focused on the psychological status affecting the function of the GI tract. However, recent evidences showed that gut microbiota communicates with the brain via the gut-brain axis to modulate brain development and behavioral phenotypes. These recent findings on the new role of gut microbiota in the gut-brain axis implicate that gut microbiota could associate with brain functions as well as neurological diseases via the gut-brain axis. To elucidate the role of gut microbiota in the gut-brain axis, precise identification of the composition of microbes constituting gut microbiota is an essential step. However, identification of microbes constituting gut microbiota has been the main technological challenge currently due to massive amount of intestinal microbes and the difficulties in culture of gut microbes. Current methods for identification of microbes constituting gut microbiota are dependent on omics analysis methods by using advanced high tech equipment. Here, we review the association of gut microbiota with the gut-brain axis, including the pros and cons of the current high throughput methods for identification of microbes constituting gut microbiota to elucidate the role of gut microbiota in the gut-brain axis.

  8. The intersection of safety and adherence: new incretin-based therapies in patients with type 2 diabetes mellitus.

    PubMed

    Zarowitz, Barbara J; Conner, Christopher

    2009-12-01

    One of the challenges facing health care providers in the treatment of patients with type 2 diabetes mellitus is maintaining the balance between achieving hemoglobin A(1c) targets while simultaneously minimizing adverse events-most notably hypoglycemia and weight gain-that may negatively affect adherence to therapy and thus treatment outcomes. Incretin-based treatments, such as glucagon-like peptide-1 (GLP-1)-receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are the newest class of therapies for the management of patients with type 2 diabetes. Data from clinical trials in which liraglutide, exenatide, saxagliptin, or sitagliptin were employed as monotherapy or added to ongoing antidiabetic treatment indicate that the incretin-based therapies have very low risk for the development of hypoglycemia and either decrease body weight (GLP-1-receptor agonists) or are weight neutral (DPP-4 inhibitors). Decreased risk for hypoglycemia and weight gain may improve adherence. Avoiding weight gain, which is commonly associated with older oral antidiabetic agents and some insulins, also has the potential to decrease the risk for cardiovascular disease. Future pharmacoeconomic studies may demonstrate translation of these benefits into good cost-effectiveness for these therapies.

  9. The impact of low and no-caloric sweeteners on glucose absorption, incretin secretion and glucose tolerance.

    PubMed

    Chan, Catherine B; Hashemi, Zohre; Subhan, Fatheema Begum

    2017-04-13

    The consumption of non-nutritive, low or no-calorie sweeteners (LCS) is increasing globally. Previously thought to be physiologically inert, there is a growing body of evidence that LCS not only provide a sweet taste but may also elicit metabolic effects in the gastrointestinal tract. This review provides a brief overview of the chemical and receptor-binding properties and effects on chemosensation of different LCS but focuses on the extent to which LCS stimulates glucose transport, incretin and insulin secretion, and effects on glucose tolerance. Aspartame and sucralose both bind to a similar region of the sweet receptor. For sucralose, the data are contradictory regarding effects on glucose tolerance in humans and may depend on the food or beverage matrix and the duration of administration, as suggested by longer-term rodent studies. For aspartame, there are fewer data. On the other hand, acesulfame-potassium (Ace-K) and saccharin have similar binding characteristics to each other but, while Ace-K may increase incretin secretion and glucose responses in humans, there are no data on saccharin except in rats, which show impaired glucose tolerance after chronic administration. Additional research, particularly of the effects of chronic consumption, is needed to provide concrete evidence for beneficial or detrimental effects of LCS on blood glucose regulation in humans.

  10. Altered crosstalk in the dipeptidyl peptidase-4-incretin-immune system in type 1 diabetes: A hypothesis generating pilot study.

    PubMed

    Zóka, András; Barna, Gábor; Hadarits, Orsolya; Al-Aissa, Zahra; Wichmann, Barna; Műzes, Györgyi; Somogyi, Anikó; Firneisz, Gábor

    2015-09-01

    Both GLP1(7)(-)(36) (via GLP1 receptor) and the dipeptidyl peptidase-4 (DPP4) cleaved form of GLP1 (GLP1(9)(-)(36), independently of GLP1R) may modulate the response of lymphocytes to cytokine stimuli. The incretin axis, CXCR3 (receptor of DPP4 ligand cytokines CXCL9-11) expression on T(reg)s and hematologic parameters were assessed in 34 patients with long standing type 1 diabetes (T1DM) and in 35 healthy controls. Serum DPP4 (sDPP4) activity, plasma total GLP1 and GLP1(7)(-)(36) concentrations were determined. GLP1(9)(-)(36) concentrations were calculated. CXCR3 expression (flow cytometry) was higher on the CD25(-/)(low)Foxp3(+) than on the CD25(+)Foxp3(+) T(reg)s independently from T1DM, suggesting that CD25(-/)(low)Foxp3(+) T(reg)s are possibly waiting for orientational chemotactic stimuli in a "standby mode". The higher sDPP4 activities in T1DM were inversely correlated with GLP1(7)(-)(36) levels and GLP1(9)(-)(36) levels directly with lymphocyte counts in controls. Our results might indicate an altered DPP4-incretin system and altered immunoregulation including a potentially dysfunctional GLP1(9)(-)(36) signaling in T1DM.

  11. Incretin-based therapies: a new potential treatment approach to overcome clinical inertia in type 2 diabetes.

    PubMed

    Nicolucci, Antonio; Rossi, Maria Chiara

    2008-12-01

    Maintaining an adequate metabolic control is still a challenge in many patients with type 2 diabetes. Among the many factors advocated to explain the failure to achieve recommended goals, clinical inertia is increasingly recognised as a primary cause of poor glycaemic control. The existence of a "metabolic memory" strongly supports the adoption of a more aggressive treat-to-target approach, instead of waiting for treatment failure. This approach may be particularly important in the initial phases of the disease, to slow the progressive decline of beta-cell function and improve overall outcomes. The fear of hypoglycaemia and weight gain associated with most of the available treatments are among the main causes of clinical inertia, and strongly affect the attitudes of providers and patients toward therapy intensification. The incretin-based therapies represent a new potential goal-oriented treatment approach. Two classes of incretin-based drugs have been developed: GLP-1 mimetics (exenatide and liraglutide) and DPP-IV inhibitors (sitagliptin and vildagliptin). Incretino-mimetics have a peculiar mechanism of action that is associated with lack of hypoglycaemia and weight loss or neutrality; these characteristics may facilitate therapy intensification and help to attain established goals. Furthermore, they can induce benefits in terms of post-prandial hyperglicemia control and beta-cell function preservation. An early use of this class of drugs may show a positive impact on the disease progression and a delay in the need of insulin injections.

  12. 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...

  13. The gut endocrine system as a coordinator of postprandial nutrient homoeostasis.

    PubMed

    Gribble, Fiona M

    2012-11-01

    Hormones from the gastrointestinal (GI) tract are released following food ingestion and trigger a range of physiological responses including the coordination of appetite and glucose homoeostasis. The aim of this review is to discuss the pathways by which food ingestion triggers secretion of cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and the altered patterns of gut hormone release observed following gastric bypass surgery. Our understanding of how ingested nutrients trigger secretion of these gut hormones has increased dramatically, as a result of physiological studies in human subjects and animal models and in vitro studies on cell lines and primary intestinal cultures. Specialised enteroendocrine cells located within the gut epithelium are capable of directly detecting a range of nutrient stimuli through a range of receptors and transporters. It is concluded that the arrival of nutrients at the apical surface of enteroendocrine cells is a major stimulus for gut hormone release, thereby coupling these endocrine signals to the arrival of absorbed nutrients in the bloodstream.

  14. Characterization of the serum and liver proteomes in gut-microbiota-lacking mice.

    PubMed

    Tung, Yu-Tang; Chen, Ying-Ju; Chuang, Hsiao-Li; Huang, Wen-Ching; Lo, Chun-Tsung; Liao, Chen-Chung; Huang, Chi-Chang

    2017-01-01

    Current nutrition research is focusing on health promotion, disease prevention, and performance improvement for individuals and communities around the world. The humans with required nutritional ingredients depend on both how well the individual is provided with balanced foods and what state of gut microbiota the host has. Studying the mutually beneficial relationships between gut microbiome and host is an increasing attention in biomedical science. The purpose of this study is to understand the role of gut microbiota and to study interactions between gut microbiota and host. In this study, we used a shotgun proteomic approach to reveal the serum and liver proteomes in gut-microbiota-lacking mice. For serum, 15 and 8 proteins were uniquely detected in specific-pathogen-free (SPF) and germ-free (GF) mice, respectively, as well as the 3 and 20 proteins were significantly increased and decreased, respectively, in GF mice compared to SPF mice. Among the proteins of the serum, major urinary protein 1 (MUP-1) of GF mice was significantly decreased compared to SPF mice. In addition, MUP-1 expression is primarily regulated by testosterone. Lacking in gut flora has been implicated in many adverse effects, and now we have found its pathogenic root maybe gut bacteria can regulate the sex-hormone testosterone levels. In the liver, 8 and 22 proteins were uniquely detected in GF mice and SPF mice, respectively, as well as the 14 and 30 proteins were significantly increased and decreased, respectively, in GF mice compared to SPF mice. Furthermore, ingenuity pathway analysis (IPA) indicated that gut microbiota influence the host in cancer, organismal injury and abnormalities, respiratory disease; cell cycle, cellular movement and tissue development; cardiovascular disease, reproductive system disease; and lipid metabolism, molecular transport and small molecule biochemistry. Our findings provide more detailed information of the role of gut microbiota and will be useful to help

  15. Characterization of the serum and liver proteomes in gut-microbiota-lacking mice

    PubMed Central

    Tung, Yu-Tang; Chen, Ying-Ju; Chuang, Hsiao-Li; Huang, Wen-Ching; Lo, Chun-Tsung; Liao, Chen-Chung; Huang, Chi-Chang

    2017-01-01

    Current nutrition research is focusing on health promotion, disease prevention, and performance improvement for individuals and communities around the world. The humans with required nutritional ingredients depend on both how well the individual is provided with balanced foods and what state of gut microbiota the host has. Studying the mutually beneficial relationships between gut microbiome and host is an increasing attention in biomedical science. The purpose of this study is to understand the role of gut microbiota and to study interactions between gut microbiota and host. In this study, we used a shotgun proteomic approach to reveal the serum and liver proteomes in gut-microbiota-lacking mice. For serum, 15 and 8 proteins were uniquely detected in specific-pathogen-free (SPF) and germ-free (GF) mice, respectively, as well as the 3 and 20 proteins were significantly increased and decreased, respectively, in GF mice compared to SPF mice. Among the proteins of the serum, major urinary protein 1 (MUP-1) of GF mice was significantly decreased compared to SPF mice. In addition, MUP-1 expression is primarily regulated by testosterone. Lacking in gut flora has been implicated in many adverse effects, and now we have found its pathogenic root maybe gut bacteria can regulate the sex-hormone testosterone levels. In the liver, 8 and 22 proteins were uniquely detected in GF mice and SPF mice, respectively, as well as the 14 and 30 proteins were significantly increased and decreased, respectively, in GF mice compared to SPF mice. Furthermore, ingenuity pathway analysis (IPA) indicated that gut microbiota influence the host in cancer, organismal injury and abnormalities, respiratory disease; cell cycle, cellular movement and tissue development; cardiovascular disease, reproductive system disease; and lipid metabolism, molecular transport and small molecule biochemistry. Our findings provide more detailed information of the role of gut microbiota and will be useful to help

  16. Influence of Gut Microbiota on Subclinical Inflammation and Insulin Resistance

    PubMed Central

    Carvalho, Bruno Melo; Abdalla Saad, Mario Jose

    2013-01-01

    Obesity is the main condition that is correlated with the appearance of insulin resistance, which is the major link among its comorbidities, such as type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. Obesity affects a large number of individuals worldwide; it degrades human health and quality of life. Here, we review the role of the gut microbiota in the pathophysiology of obesity and type 2 diabetes, which is promoted by a bacterial diversity shift mediated by overnutrition. Whole bacteria, their products, and metabolites undergo increased translocation through the gut epithelium to the circulation due to degraded tight junctions and the consequent increase in intestinal permeability that culminates in inflammation and insulin resistance. Several strategies focusing on modulation of the gut microbiota (antibiotics, probiotics, and prebiotics) are being experimentally employed in metabolic derangement in order to reduce intestinal permeability, increase the production of short chain fatty acids and anorectic gut hormones, and promote insulin sensitivity to counteract the inflammatory status and insulin resistance found in obese individuals. PMID:23840101

  17. The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases.

    PubMed

    Brown, J Mark; Hazen, Stanley L

    2015-01-01

    The human gastrointestinal tract is home to trillions of bacteria, which vastly outnumber host cells in the body. Although generally overlooked in the field of endocrinology, gut microbial symbionts organize to form a key endocrine organ that converts nutritional cues from the environment into hormone-like signals that impact both normal physiology and chronic disease in the human host. Recent evidence suggests that several gut microbial-derived products are sensed by dedicated host receptor systems to alter cardiovascular disease (CVD) progression. In fact, gut microbial metabolism of dietary components results in the production of proatherogenic circulating factors that act through a meta-organismal endocrine axis to impact CVD risk. Whether pharmacological interventions at the level of the gut microbial endocrine organ will reduce CVD risk is a key new question in the field of cardiovascular medicine. Here we discuss the opportunities and challenges that lie ahead in targeting meta-organismal endocrinology for CVD prevention.

  18. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases

    PubMed Central

    Brown, J. Mark; Hazen, Stanley L.

    2015-01-01

    The human gastrointestinal tract is home to trillions of bacteria, which vastly outnumber host cells in the body. Although generally overlooked in the field of endocrinology, gut microbial symbionts organize to form a key endocrine organ that convert nutritional cues from the environment into hormone-like signals that impact both normal physiology and chronic disease in the human host. Recent evidence suggests that several gut microbial-derived products are sensed by dedicated host receptor systems to alter cardiovascular disease (CVD) progression. In fact, gut microbial metabolism of dietary components results in the production of proatherogenic circulating factors that act through a meta-organismal endocrine axis to impact CVD risk. Whether pharmacological interventions at the level of the gut microbial endocrine organ will reduce CVD risk is a key new question in the field of cardiovascular medicine. Here we discuss the opportunities and challenges that lie ahead in targeting meta-organismal endocrinology for CVD prevention. PMID:25587655

  19. Gut microbiota and metabolic syndrome

    PubMed Central

    Festi, Davide; Schiumerini, Ramona; Eusebi, Leonardo Henry; Marasco, Giovanni; Taddia, Martina; Colecchia, Antonio

    2014-01-01

    Gut microbiota exerts a significant role in the pathogenesis of the metabolic syndrome, as confirmed by studies conducted both on humans and animal models. Gut microbial composition and functions are strongly influenced by diet. This complex intestinal “superorganism” seems to affect host metabolic balance modulating energy absorption, gut motility, appetite, glucose and lipid metabolism, as well as hepatic fatty storage. An impairment of the fine balance between gut microbes and host’s immune system could culminate in the intestinal translocation of bacterial fragments and the development of “metabolic endotoxemia”, leading to systemic inflammation and insulin resistance. Diet induced weight-loss and bariatric surgery promote significant changes of gut microbial composition, that seem to affect the success, or the inefficacy, of treatment strategies. Manipulation of gut microbiota through the administration of prebiotics or probiotics could reduce intestinal low grade inflammation and improve gut barrier integrity, thus, ameliorating metabolic balance and promoting weight loss. However, further evidence is needed to better understand their clinical impact and therapeutic use. PMID:25473159

  20. Promising Diabetes Therapy Based on the Molecular Mechanism for Glucose Toxicity: Usefulness of SGLT2 Inhibitors as well as Incretin-Related Drugs.

    PubMed

    Kaneto, Hideaki; Obata, Atsushi; Shimoda, Masashi; Kimura, Tomohiko; Hirukawa, Hidenori; Okauchi, Seizo; Matsuoka, Taka-Aki; Kaku, Kohei

    2016-01-01

    Pancreatic β-cell dysfunction and insulin resistance are the main characteristics of type 2 diabetes. Chronic exposure of β-cells to hyperglycemia leads to the deterioration of β-cell function. Such phenomena are well known as pancreatic β-cell glucose toxicity. MafA, a strong transactivator of insulin gene, is particularly important for the maintenance of mature β-cell function, but its expression level is significantly reduced under diabetic conditions which is likely associated with β-cell failure. Reduction of incretin receptor expression level in β-cells in diabetes is also likely associated with β-cell failure. On the other hand, incretin-related drugs and sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising diabetes therapy based on the mechanism for pancreatic β-cell glucose toxicity. Indeed, it was shown that incretin-related drugs exerted protective effects on β-cells through the augmentation of IRS-2 expression especially in the presence of pioglitazone. It was also shown that incretin-related drug and/or pioglitazone exerted more protective effects on β-cells at the early stage of diabetes compared to the advanced stage. SGLT2 inhibitors, new hypoglycemic agents, also exert beneficial effects for the protection of pancreatic β-cells as well as for the reduction of insulin resistance in various insulin target tissues. Taken together, it is important to select appropriate therapy based on the molecular mechanism for glucose toxicity.

  1. Response of incretins (GIP and GLP-1) to an oral glucose load in female and male subjects with normal glucose tolerance.

    PubMed

    Matsuo, Toshihiro; Kusunoki, Yoshiki; Katsuno, Tomoyuki; Ikawa, Takashi; Akagami, Takafumi; Murai, Kazuki; Miuchi, Masayuki; Miyagawa, Jun-ichiro; Namba, Mitsuyoshi

    2014-11-01

    The aim of this study was to analyze the blood glucose profile and the response of incretins in healthy young subjects by the 75 g oral glucose tolerance test (OGTT). We first reported that plasma glucose and GIP levels were higher in males during the early phase of the OGTT.

  2. The human gut mobile metagenome

    PubMed Central

    2010-01-01

    Using the culture independent TRACA system in conjunction with a comparative metagenomic approach, we have recently explored the pool of plasmids associated with the human gut mobile metagenome. This revealed that some plasmids or plasmid families are present in the gut microbiomes of geographically isolated human hosts with a broad global distribution (America, Japan and Europe), and are potentially unique to the human gut microbiome. Functions encoded by the most widely distributed plasmid (pTRACA22) were found to be enriched in the human gut microbiome when compared to microbial communities from other environments, and of particular interest was the increased prevalence of a putative RelBE toxin-antitoxin (TA) addiction module. Subsequent analysis revealed that this was most closely related to putative TA modules from gut associated bacteria belonging to the Firmicutes, but homologues of the RelE toxin were associated with all major bacterial divisions comprising the human gut microbiota. In this addendum, functions of the gut mobile metagenome are considered from the perspective of the human host, and within the context of the hologenome theory of human evolution. In doing so, our original analysis is also extended to include the gut metagenomes of a further 124 individuals comprising the METAHIT dataset. Differences in the incidence and relative abundance of pTRACA22 and associated TA modules between healthy individuals and those with inflammatory bowel diseases are explored, and potential functions of pTRACA22 type RelBE modules in the human gut microbiome are discussed. PMID:21468227

  3. A fatty gut feeling.

    PubMed

    Piomelli, Daniele

    2013-07-01

    The absorptive epithelium of the proximal small intestine converts oleic acid released during fat digestion into oleoylethanolamide (OEA), an endogenous high-affinity agonist of peroxisome proliferator-activated receptor-α (PPAR-α). OEA interacts with this receptor to cause a state of satiety characterized by prolonged inter-meal intervals and reduced feeding frequency. The two main branches of the autonomic nervous system, sympathetic and parasympathetic, contribute to this effect: the former by enabling OEA mobilization in the gut and the latter by relaying the OEA signal to brain structures, such as the hypothalamus, that are involved in feeding regulation. OEA signaling may be a key component of the physiological system devoted to the monitoring of dietary fat intake, and its dysfunction might contribute to overweight and obesity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Gut pain & visceral hypersensitivity

    PubMed Central

    Aziz, Qasim

    2013-01-01

    Visceral pain is a highly complex entity whose experience is variable in health and disease. It can occur in patients with organic disease and also in those without any readily identifiable structural or biochemical abnormality such as in the functional gastrointestinal disorders (FGID). Despite considerable progress in our understanding of the culpable underlying mechanisms significant knowledge gaps remain, representing a significant unmet need in gastroenterology. A key, but not universal, pathological feature is that patients with FGID often display heightened sensitivity to experimental gut stimulation, termed visceral hypersensitivity. A plethora of factors have been proposed to account for this epiphenomenon including peripheral sensitization, central sensitization, aberrant central processing, genetic, psychological and abnormalities within the stress responsive systems. Further research is needed, bringing together complementary research themes from a diverse array of academic disciplines ranging from gastroenterology to nociceptive physiology to functional neuro-imaging, to address this unmet need. PMID:26516496

  5. Flipped GUT inflation

    SciTech Connect

    Ellis, John; Gonzalo, Tomás E.; Harz, Julia; Huang, Wei-Chih

    2015-03-23

    We analyse the prospects for constructing hybrid models of inflation that provide a dynamical realisation of the apparent closeness between the supersymmetric GUT scale and the possible scale of cosmological inflation. In the first place, we consider models based on the flipped SU(5)×U(1) gauge group, which has no magnetic monopoles. In one model, the inflaton is identified with a sneutrino field, and in the other model it is a gauge singlet. In both cases we find regions of the model parameter spaces that are compatible with the experimental magnitudes of the scalar perturbations, A{sub s}, and the tilt in the scalar perturbation spectrum, n{sub s}, as well as with an indicative upper limit on the tensor-to-scalar perturbation ratio, r. We also discuss embeddings of these models into SO(10), which is broken at a higher scale so that its monopoles are inflated away.

  6. A fatty gut feeling

    PubMed Central

    Piomelli, Daniele

    2013-01-01

    The absorptive epithelium of the proximal small intestine converts oleic acid released during fat digestion into oleoylethanolamide (OEA), an endogenous high-affinity agonist of peroxisome proliferator-activated receptor-α (PPAR-α). OEA interacts with this receptor to cause a state of satiety characterized by prolonged inter-meal intervals and reduced feeding frequency. The two main branches of the autonomic nervous system, sympathetic and parasympathetic, contribute to this effect: the former by enabling OEA mobilization in the gut and the latter by relaying the OEA signal to brain structures, such as the hypothalamus, that are involved in feeding regulation. OEA signaling may be a key component of the physiological system devoted to the monitoring of dietary fat intake, and its dysfunction might contribute to overweight and obesity. PMID:23567058

  7. The gut microbiome.

    PubMed

    Actis, Giovanni C

    2014-01-01

    Since the discovery and use of the microscope in the 17(th) century, we know that we host trillions of micro-organisms mostly in the form of bacteria indwelling the "barrier organs" skin, gut, and airways. They exert regulatory functions, are in a continuous dialogue with the intestinal epithelia, influence energy handling, produce nutrients, and may cause diabetes and obesity. The human microbiome has developed by modulating or avoiding inflammatory responses; the host senses bacterial presence through cell surface sensors (the Toll-like receptors) as well as by refining mucous barriers as passive defense mechanisms. The cell density and composition of the microbiome are variable and multifactored. The way of delivery establishes the type of initial flora; use of antibiotics is another factor; diet composition after weaning will shape the adult's microbiome composition, depending on the subject's life-style. Short-chain fatty acids participate in the favoring action exerted by microbiome in the pathogenesis of type-2 diabetes and obesity. Clinical observation has pinpointed a sharp rise of various dysimmune conditions in the last decades, including IBD and rheumatoid arthritis, changes that outweigh the input of simple heritability. It is nowadays proposed that the microbiome, incapable to keep up with the changes of our life-style and feeding sources in the past few decades might have contributed to these immune imbalances, finding itself inadequate to handle the changed gut environment. Another pathway to pathology is the rise of directly pathogenic phyla within a given microbiome: growth of adherent E. coli, of C. concisus, and of C. jejuni, might be examples of causes of local enteropathy, whereas the genus Prevotella copri is now suspected to be linked to rise of arthritic disorders. Inflammasomes are required to shape a non colitogenic flora. Treatment of IBD and infectious enteritides by the use of fecal transplant is warranted by this knowledge.

  8. Gut Protozoa: Friends or Foes of the Human Gut Microbiota?

    PubMed

    Chabé, Magali; Lokmer, Ana; Ségurel, Laure

    2017-09-01

    The importance of the gut microbiota for human health has sparked a strong interest in the study of the factors that shape its composition and diversity. Despite the growing evidence suggesting that helminths and protozoa significantly interact with gut bacteria, gut microbiome studies remain mostly focused on prokaryotes and on populations living in industrialized countries that typically have a low parasite burden. We argue that protozoa, like helminths, represent an important factor to take into account when studying the gut microbiome, and that their presence - especially considering their long coevolutionary history with humans - may be beneficial. From this perspective, we examine the relationship between the protozoa and their hosts, as well as their relevance for public health. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Gut microbiota disturbance during helminth infection: can it affect cognition and behaviour of children?

    PubMed

    Guernier, Vanina; Brennan, Bradley; Yakob, Laith; Milinovich, Gabriel; Clements, Archie C A; Soares Magalhaes, Ricardo J

    2017-01-10

    Bidirectional signalling between the brain and the gastrointestinal tract is regulated at neural, hormonal, and immunological levels. Recent studies have shown that helminth infections can alter the normal gut microbiota. Studies have also shown that the gut microbiota is instrumental in the normal development, maturation and function of the brain. The pathophysiological pathways by which helminth infections contribute to altered cognitive function remain poorly understood. We put forward the hypothesis that gastrointestinal infections with parasitic worms, such as helminths, induce an imbalance of the gut-brain axis, which, in turn, can detrimentally manifest in brain development. Factors supporting this hypothesis are: 1) research focusing on intelligence and school performance in school-aged children has shown helminth infections to be associated with cognitive impairment, 2) disturbances in gut microbiota have been shown to be associated with important cognitive developmental effects, and 3) helminth infections have been shown to alter the gut microbiota structure. Evidence on the complex interactions between extrinsic (parasite) and intrinsic (host-derived) factors has been synthesised and discussed. While evidence in favour of the helminth-gut microbiota-central nervous system hypothesis is circumstantial, it would be unwise to rule it out as a possible mechanism by which gastrointestinal helminth infections induce childhood cognitive morbidity. Further empirical studies are necessary to test an indirect effect of helminth infections on the modulation of mood and behaviour through its effects on the gut microbiota.

  10. Development and physiology of the rumen and the lower gut: Targets for improving gut health.

    PubMed

    Steele, Michael A; Penner, Greg B; Chaucheyras-Durand, Frédérique; Guan, Le Luo

    2016-06-01

    The gastrointestinal epithelium of the dairy cow and calf faces the challenge of protecting the host from the contents of the luminal milieu while controlling the absorption and metabolism of nutrients. Adaptations of the gastrointestinal tract play an important role in animal energetics as the portal-drained viscera accounts for 20% of the total oxygen consumption of the ruminant. The mechanisms that govern growth and barrier function of the gastrointestinal epithelium have received particular attention over the past decade, especially with advancements in molecular-based techniques, such as microarrays and next-generation DNA sequencing. The rumen has been the focal point of dairy cow and calf nutritional physiology research, whereas the lower gut has received less attention. Three key areas that require discovery-based and applied research include (1) early-life intestinal gut barrier function and growth; (2) how the weaning transition affects function of the rumen and intestine; and (3) gastrointestinal adaptations during the transition to high-energy diets in early lactation. In dairy nutrition, nutrients are seen not only as metabolic substrates, but also as signals that can alter gastrointestinal growth and barrier function. Nutrients have been shown to affect epithelial cell gene expression directly and, in concert with insulin-like growth factor, growth hormone, and glucagon-like peptide 2, play a pivotal role in gut tissue growth. The latest research suggests that ruminal and intestinal barrier function is compromised during the preweaning phase, at weaning, and in early lactation. Gastrointestinal barrier function is influenced by the presence of metabolites, such as butyrate, the resident microbiota, and the microbes provided in feed. In the first studies that investigated barrier function in cows and calves, it was determined that the expression of genes encoding tight junction proteins, such as claudins, occludins, and desmosomal cadherins, are

  11. Hormone impostors

    SciTech Connect

    Colborn, T.; Dumanoski, D.; Myers, J.P.

    1997-01-01

    This article discusses the accumulating evidence that some synthetic chemicals disrupt hormones in one way or another. Some mimic estrogen and others interfere with other parts of the body`s control or endocrine system such as testosterone and thyroid metabolism. Included are PCBs, dioxins, furans, atrazine, DDT. Several short sidebars highlight areas where there are or have been particular problems.

  12. Beyond gut feelings: how the gut microbiota regulates blood pressure.

    PubMed

    Marques, Francine Z; Mackay, Charles R; Kaye, David M

    2017-08-24

    Hypertension is the leading risk factor for heart disease and stroke, and is estimated to cause 9.4 million deaths globally every year. The pathogenesis of hypertension is complex, but lifestyle factors such as diet are important contributors to the disease. High dietary intake of fruit and vegetables is associated with reduced blood pressure and lower cardiovascular mortality. A critical relationship between dietary intake and the composition of the gut microbiota has been described in the literature, and a growing body of evidence supports the role of the gut microbiota in the regulation of blood pressure. In this Review, we describe the mechanisms by which the gut microbiota and its metabolites, including short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides, act on downstream cellular targets to prevent or contribute to the pathogenesis of hypertension. These effects have a direct influence on tissues such as the kidney, the endothelium, and the heart. Finally, we consider the role of the gut microbiota in resistant hypertension, the possible intergenerational effect of the gut microbiota on blood pressure regulation, and the promising therapeutic potential of gut microbiota modification to improve health and prevent disease.

  13. GUTs and supersymmetric GUTs in the very early universe

    SciTech Connect

    Ellis, J.

    1982-10-01

    This talk is intended as background material for many of the other talks treating the possible applications of GUTs to the very early universe. I start with a review of the present theoretical and phenomenological status of GUTs before going on to raise some new issues for their prospective cosmological applications which arise in supersymmetric (susy) GUTs. The first section is an update on conventional GUTs, which is followed by a reminder of some of the motivations for going supersymmetric. There then follows a simple primer on susy and a discussion of the structure and phenomenology of simple sysy GUTs. Finally we come to the cosmological issues, including problems arising from the degeneracy of susy minima, baryosynthesis and supersymmetric inflation, the possibility that gravity is an essential complication in constructing susy GUTs and discussing their cosmology, and the related question of what mass range is allowed for the gravitino. Several parts of this write-up contain new material which has emerged either during the Workshop or subsequently. They are included here for completeness and the convenience of the prospective reader. Wherever possible, these anachronisms will be flagged so as to keep straight the historical record.

  14. Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus.

    PubMed

    Scheen, André J

    2014-09-01

    Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

  15. Bench-to-bedside review: the gut as an endocrine organ in the critically ill.

    PubMed

    Deane, Adam; Chapman, Marianne J; Fraser, Robert J L; Horowitz, Michael

    2010-01-01

    In health, hormones secreted from the gastrointestinal tract have an important role in regulating gastrointestinal motility, glucose metabolism and immune function. Recent studies in the critically ill have established that the secretion of a number of these hormones is abnormal, which probably contributes to disordered gastrointestinal and metabolic function. Furthermore, manipulation of endogenous secretion, physiological replacement and supra-physiological treatment (pharmacological dosing) of these hormones are likely to be novel therapeutic targets in this group. Fasting ghrelin concentrations are reduced in the early phase of critical illness, and exogenous ghrelin is a potential therapy that could be used to accelerate gastric emptying and/or stimulate appetite. Motilin agonists, such as erythromycin, are effective gastrokinetic drugs in the critically ill. Cholecystokinin and peptide YY concentrations are elevated in both the fasting and postprandial states, and are likely to contribute to slow gastric emptying. Accordingly, there is a rationale for the therapeutic use of their antagonists. So-called incretin therapies (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) warrant evaluation in the management of hyperglycaemia in the critically ill. Exogenous glucagon-like peptide-2 (or its analogues) may be a potential therapy because of its intestinotropic properties.

  16. Gut Microbiota: The Brain Peacekeeper

    PubMed Central

    Mu, Chunlong; Yang, Yuxiang; Zhu, Weiyun

    2016-01-01

    Gut microbiota regulates intestinal and extraintestinal homeostasis. Accumulating evidence suggests that the gut microbiota may also regulate brain function and behavior. Results from animal models indicate that disturbances in the composition and functionality of some microbiota members are associated with neurophysiological disorders, strengthening the idea of a microbiota–gut–brain axis and the role of microbiota as a “peacekeeper” in the brain health. Here, we review recent discoveries on the role of the gut microbiota in central nervous system-related diseases. We also discuss the emerging concept of the bidirectional regulation by the circadian rhythm and gut microbiota, and the potential role of the epigenetic regulation in neuronal cell function. Microbiome studies are also highlighted as crucial in the development of targeted therapies for neurodevelopmental disorders. PMID:27014255

  17. Types of hormone therapy

    MedlinePlus

    ... types of hormone therapy; Hormone replacement therapy - types; Menopause - types of hormone therapy; HT - types; Menopausal hormone ... Menopause symptoms include: Hot flashes Night sweats Sleep problems Vaginal dryness Anxiety Moodiness Less interest in sex ...

  18. Incretins and selective renal sodium-glucose co-transporter 2 inhibitors in hypertension and coronary heart disease

    PubMed Central

    Sanchez, Ramiro A; Sanabria, Hugo; de los Santos, Cecilia; Ramirez, Agustin J

    2015-01-01

    Hyperglycemia is associated with an increased risk of cardiovascular disease, and the consequences of intensive therapy may depend on the mechanism of the anti-diabetic agent(s) used to achieve a tight control. In animal models, stable analogues of glucagon-like peptide-1 (GLP-1) were able to reduce body weight and blood pressure and also had favorable effects on ischemia following coronary reperfusion. In a similar way, dipeptidyl peptidase IV (DPP-IV) showed to have favorable effects in animal models of ischemia/reperfusion. This could be due to the fact that DPP-IV inhibitors were able to prevent the breakdown of GLP-1 and glucose-dependent insulinotropic polypeptide, but they also decreased the degradation of several vasoactive peptides. Preclinical data for GLP-1, its derivatives and inhibitors of the DPP-IV enzyme degradation suggests that these agents may be able to, besides controlling glycaemia, induce cardio-protective and vasodilator effects. Notwithstanding the many favorable cardiovascular effects of GLP-1/incretins reported in different studies, many questions remain unanswered due the limited number of studies in human beings that aim to examine the effects of GLP-1 on cardiovascular endpoints. For this reason, long-term trials searching for positive cardiovascular effects are now in process, such as the CAROLINA and CARMELINA trials, which are supported by small pilot studies performed in humans (and many more animal studies) with incretin-based therapies. On the other hand, selective renal sodium-glucose co-transporter 2 inhibitors were also evaluated in the prevention of cardiovascular outcomes in type 2 diabetes. However, it is quite early to draw conclusions, since data on cardiovascular outcomes and cardiovascular death are limited and long-term studies are still ongoing. In this review, we will analyze the mechanisms underlying the cardiovascular effects of incretins and, at the same time, we will present a critical position about the real

  19. Gut microbiome and metabolic syndrome.

    PubMed

    Mazidi, Mohsen; Rezaie, Peyman; Kengne, Andre Pascal; Mobarhan, Majid Ghayour; Ferns, Gordon A

    2016-01-01

    The gut microbiome contributes approximately 2kg of the whole body weight, and recent studies suggest that gut microbiota has a profound effect on human metabolism, potentially contributing to several features of the metabolic syndrome. Metabolic syndrome is defined by a clustering of metabolic disorders that include central adiposity with visceral fat accumulation, dyslipidemia, insulin resistance, dysglycemia and non-optimal blood pressure levels. Metabolic syndrome is associated with an increased risk of cardiovascular diseases and type 2 diabetes. It is estimated that around 20-25 percent of the world's adult population has metabolic syndrome. In this manuscript, we have reviewed the existing data linking gut microbiome with metabolic syndrome. Existing evidence from studies both in animals and humans support a link between gut microbiome and various components of metabolic syndrome. Possible pathways include involvement with energy homeostasis and metabolic processes, modulation of inflammatory signaling pathways, interferences with the immune system, and interference with the renin-angiotensin system. Modification of gut microbiota via prebiotics, probiotics or other dietary interventions has provided evidence to support a possible beneficial effect of interventions targeting gut microbiota modulation to treat components or complications of metabolic syndrome.

  20. Gut dysfunction in Parkinson's disease

    PubMed Central

    Mukherjee, Adreesh; Biswas, Atanu; Das, Shyamal Kumar

    2016-01-01

    Early involvement of gut is observed in Parkinson’s disease (PD) and symptoms such as constipation may precede motor symptoms. α-Synuclein pathology is extensively evident in the gut and appears to follow a rostrocaudal gradient. The gut may act as the starting point of PD pathology with spread toward the central nervous system. This spread of the synuclein pathology raises the possibility of prion-like propagation in PD pathogenesis. Recently, the role of gut microbiota in PD pathogenesis has received attention and some phenotypic correlation has also been shown. The extensive involvement of the gut in PD even in its early stages has led to the evaluation of enteric α-synuclein as a possible biomarker of early PD. The clinical manifestations of gastrointestinal dysfunction in PD include malnutrition, oral and dental disorders, sialorrhea, dysphagia, gastroparesis, constipation, and defecatory dysfunction. These conditions are quite distressing for the patients and require relevant investigations and adequate management. Treatment usually involves both pharmacological and non-pharmacological measures. One important aspect of gut dysfunction is its contribution to the clinical fluctuations in PD. Dysphagia and gastroparesis lead to inadequate absorption of oral anti-PD medications. These lead to response fluctuations, particularly delayed-on and no-on, and there is significant relationship between levodopa pharmacokinetics and gastric emptying in patients with PD. Therefore, in such cases, alternative routes of administration or drug delivery systems may be required. PMID:27433087

  1. Gut Microbes, Diet, and Cancer

    PubMed Central

    Hullar, Meredith A. J.; Burnett-Hartman, Andrea N.

    2014-01-01

    An expanding body of evidence supports a role for gut microbes in the etiology of cancer. Previously, the focus was on identifying individual bacterial species that directly initiate or promote gastrointestinal malignancies; however, the capacity of gut microbes to influence systemic inflammation and other downstream pathways suggests that the gut microbial community may also affect risk of cancer in tissues outside of the gastrointestinal tract. Functional contributions of the gut microbiota that may influence cancer susceptibility in the broad sense include (1) harvesting otherwise inaccessible nutrients and/or sources of energy from the diet (i.e., fermentation of dietary fibers and resistant starch); (2) metabolism of xenobiotics, both potentially beneficial or detrimental (i.e., dietary constituents, drugs, carcinogens, etc.); (3) renewal of gut epithelial cells and maintenance of mucosal integrity; and (4) affecting immune system development and activity. Understanding the complex and dynamic interplay between the gut microbiome, host immune system, and dietary exposures may help elucidate mechanisms for carcinogenesis and guide future cancer prevention and treatment strategies. PMID:24114492

  2. Probiotics, gut microbiota and health.

    PubMed

    Butel, M-J

    2014-01-01

    The human gut is a huge complex ecosystem where microbiota, nutrients, and host cells interact extensively, a process crucial for the gut homeostasis and host development with a real partnership. The various bacterial communities that make up the gut microbiota have many functions including metabolic, barrier effect, and trophic functions. Hence, any dysbiosis could have negative consequences in terms of health and many diseases have been associated to impairment of the gut microbiota. These close relationships between gut microbiota, health, and disease, have led to great interest in using probiotics (i.e. live micro-organisms), or prebiotics (i.e. non-digestible substrates) to positively modulate the gut microbiota to prevent or treat some diseases. This review focuses on probiotics, their mechanisms of action, safety, and major health benefits. Health benefits remain to be proven in some indications, and further studies on the best strain(s), dose, and algorithm of administration to be used are needed. Nevertheless, probiotic administration seems to have a great potential in terms of health that justifies more research. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  3. The gut sensor as regulator of body weight.

    PubMed

    Reinehr, Thomas; Roth, Christian L

    2015-05-01

    The gastrointestinal (GI) tract comprises a large endocrine organ that regulates not only nutrient sensing and metabolising but also satiety and energy homeostasis. More than 20 hormones secreted from the stomach, intestine, and pancreas as well as signaling mediators of the gut microbiome are involved in this process. A better understanding of how related pathways affect body weight and food intake will help us to find new strategies and drugs to treat obesity. For example, weight loss secondary to lifestyle intervention is often accompanied by unfavorable changes in multiple GI hormones, which may cause difficulties in maintaining a lower body weight status. Conversely, bariatric surgery favorably changes the hormone profile to support improved satiety and metabolic function. This partially explains stronger sustained body weight reduction resulting in better long-term results of improved metabolic functions. This review focuses on GI hormones and signaling mediators of the microbiome involved in satiety regulation and energy homeostasis and summarizes their changes following weight loss. Furthermore, the potential role of GI hormones as anti-obesity drugs is discussed.

  4. Gut-Brain Glucose Signaling in Energy Homeostasis.

    PubMed

    Soty, Maud; Gautier-Stein, Amandine; Rajas, Fabienne; Mithieux, Gilles

    2017-06-06

    Intestinal gluconeogenesis is a recently identified function influencing energy homeostasis. Intestinal gluconeogenesis induced by specific nutrients releases glucose, which is sensed by the nervous system surrounding the portal vein. This initiates a signal positively influencing parameters involved in glucose control and energy management controlled by the brain. This knowledge has extended our vision of the gut-brain axis, classically ascribed to gastrointestinal hormones. Our work raises several questions relating to the conditions under which intestinal gluconeogenesis proceeds and may provide its metabolic benefits. It also leads to questions on the advantage conferred by its conservation through a process of natural selection. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes.

    PubMed

    Fulcher, G; Matthews, D R; Perkovic, V; de Zeeuw, D; Mahaffey, K W; Mathieu, C; Woo, V; Wysham, C; Capuano, G; Desai, M; Shaw, W; Vercruysse, F; Meininger, G; Neal, B

    2016-01-01

    To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist]. CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18. Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues. In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition. © 2015 John Wiley & Sons Ltd.

  6. The Glucagon-Like Peptide-1 Receptor Regulates Endogenous Glucose Production and Muscle Glucose Uptake Independent of Its Incretin Action

    PubMed Central

    Ayala, Julio E.; Bracy, Deanna P.; James, Freyja D.; Julien, Brianna M.; Wasserman, David H.; Drucker, Daniel J.

    2009-01-01

    Glucagon-like peptide-1 (GLP-1) diminishes postmeal glucose excursions by enhancing insulin secretion via activation of the β-cell GLP-1 receptor (Glp1r). GLP-1 may also control glucose levels through mechanisms that are independent of this incretin effect. The hyperinsulinemic-euglycemic clamp (insulin clamp) and exercise were used to examine the incretin-independent glucoregulatory properties of the Glp1r because both perturbations stimulate glucose flux independent of insulin secretion. Chow-fed mice with a functional disruption of the Glp1r (Glp1r−/−) were compared with wild-type littermates (Glp1r+/+). Studies were performed on 5-h-fasted mice implanted with arterial and venous catheters for sampling and infusions, respectively. During insulin clamps, [3-3H]glucose and 2[14C]deoxyglucose were used to determine whole-body glucose turnover and glucose metabolic index (Rg), an indicator of glucose uptake. Rg in sedentary and treadmill exercised mice was determined using 2[3H]deoxyglucose. Glp1r−/− mice exhibited increased glucose disappearance, muscle Rg, and muscle glycogen levels during insulin clamps. This was not associated with enhanced muscle insulin signaling. Glp1r−/− mice exhibited impaired suppression of endogenous glucose production and hepatic glycogen accumulation during insulin clamps. This was associated with impaired liver insulin signaling. Glp1r−/− mice became significantly hyperglycemic during exercise. Muscle Rg was normal in exercised Glp1r−/− mice, suggesting that hyperglycemia resulted from an added drive to stimulate glucose production. Muscle AMP-activated protein kinase phosphorylation was higher in exercised Glp1r−/− mice. This was associated with increased relative exercise intensity and decreased exercise endurance. In conclusion, these results show that the endogenous Glp1r regulates hepatic and muscle glucose flux independent of its ability to enhance insulin secretion. PMID:19008308

  7. First Foods and Gut Microbes

    PubMed Central

    Laursen, Martin F.; Bahl, Martin I.; Michaelsen, Kim F.; Licht, Tine R.

    2017-01-01

    The establishment of the human gut microbiota in early life has been associated with later health and disease. During the 1st months after birth, the microbial composition in the gut is known to be affected by the mode of delivery, use of antibiotics, geographical location and type of feeding (breast/formula). Consequently, the neonatal period and early infancy has attracted much attention. However, after this first period the gut microbial composition continues to develop until the age of 3 years, and these 1st years have been designated “a window of opportunity” for microbial modulation. The beginning and end of this window is currently debated, but it likely coincides with the complementary feeding period, marking the gradual transition from milk-based infant feeding to family diet usually occurring between 6 and 24 months. Furthermore, the ‘first 1000 days,’ i.e., the period from conception until age 2 years, are generally recognized to be of particular importance for the healthy development of children. While dietary changes are known to affect the adult gut microbiota, there is a gap in our knowledge on how the introduction of new dietary components into the diet of infants/young children affects the gut microbiota development. This perspective paper summarizes the currently very few studies addressing the effects of complementary diet on gut microbiota, and highlights the recent finding that transition to family foods greatly impacts the development of gut microbial diversity. Further, we discuss potential impacts on child health and the need for further studies on this important topic. PMID:28321211

  8. Metabolomic insights into the intricate gut microbial–host interaction in the development of obesity and type 2 diabetes

    PubMed Central

    Palau-Rodriguez, Magali; Isabel Queipo-Ortuño, Maria; Urpi-Sarda, Mireia; Tinahones, Francisco J.; Andres-Lacueva, Cristina

    2015-01-01

    Gut microbiota has recently been proposed as a crucial environmental factor in the development of metabolic diseases such as obesity and type 2 diabetes, mainly due to its contribution in the modulation of several processes including host energy metabolism, gut epithelial permeability, gut peptide hormone secretion, and host inflammatory state. Since the symbiotic interaction between the gut microbiota and the host is essentially reflected in specific metabolic signatures, much expectation is placed on the application of metabolomic approaches to unveil the key mechanisms linking the gut microbiota composition and activity with disease development. The present review aims to summarize the gut microbial–host co-metabolites identified so far by targeted and untargeted metabolomic studies in humans, in association with impaired glucose homeostasis and/or obesity. An alteration of the co-metabolism of bile acids, branched fatty acids, choline, vitamins (i.e., niacin), purines, and phenolic compounds has been associated so far with the obese or diabese phenotype, in respect to healthy controls. Furthermore, anti-diabetic treatments such as metformin and sulfonylurea have been observed to modulate the gut microbiota or at least their metabolic profiles, thereby potentially affecting insulin resistance through indirect mechanisms still unknown. Despite the scarcity of the metabolomic studies currently available on the microbial–host crosstalk, the data-driven results largely confirmed findings independently obtained from in vitro and animal model studies, putting forward the mechanisms underlying the implication of a dysfunctional gut microbiota in the development of metabolic disorders. PMID:26579078

  9. Metabolomic insights into the intricate gut microbial-host interaction in the development of obesity and type 2 diabetes.

    PubMed

    Palau-Rodriguez, Magali; Tulipani, Sara; Isabel Queipo-Ortuño, Maria; Urpi-Sarda, Mireia; Tinahones, Francisco J; Andres-Lacueva, Cristina

    2015-01-01

    Gut microbiota has recently been proposed as a crucial environmental factor in the development of metabolic diseases such as obesity and type 2 diabetes, mainly due to its contribution in the modulation of several processes including host energy metabolism, gut epithelial permeability, gut peptide hormone secretion, and host inflammatory state. Since the symbiotic interaction between the gut microbiota and the host is essentially reflected in specific metabolic signatures, much expectation is placed on the application of metabolomic approaches to unveil the key mechanisms linking the gut microbiota composition and activity with disease development. The present review aims to summarize the gut microbial-host co-metabolites identified so far by targeted and untargeted metabolomic studies in humans, in association with impaired glucose homeostasis and/or obesity. An alteration of the co-metabolism of bile acids, branched fatty acids, choline, vitamins (i.e., niacin), purines, and phenolic compounds has been associated so far with the obese or diabese phenotype, in respect to healthy controls. Furthermore, anti-diabetic treatments such as metformin and sulfonylurea have been observed to modulate the gut microbiota or at least their metabolic profiles, thereby potentially affecting insulin resistance through indirect mechanisms still unknown. Despite the scarcity of the metabolomic studies currently available on the microbial-host crosstalk, the data-driven results largely confirmed findings independently obtained from in vitro and animal model studies, putting forward the mechanisms underlying the implication of a dysfunctional gut microbiota in the development of metabolic disorders.

  10. Do nutrient-gut-microbiota interactions play a role in human obesity, insulin resistance and type 2 diabetes?

    PubMed

    Diamant, M; Blaak, E E; de Vos, W M

    2011-04-01

    The current obesity and type 2 diabetes pandemics have causes beyond changes in eating and exercise habits against a susceptible genetic background. Gut bacteria seem to additionally contribute to the differences in body weight, fat distribution, insulin sensitivity and glucose- and lipid-metabolism. Data, mostly derived from preclinical studies, suggest that gut microbiota play an important role in conditions such as obesity, diabetes, metabolic syndrome and non-alcoholic fatty liver disease. Regulation of energy uptake from the gut, by digesting otherwise indigestible common polysaccharides in our diet, production or activation of signalling molecules involved in host metabolism, modification of gut permeability, the release of gut hormones and inflammation, are among the mechanisms by which gut microbiota may influence the host cardiometabolic phenotype. Recent evidence suggests that quantitative and qualitative differences in gut microbiota exist between lean and obese, and between diabetic and non-diabetic individuals. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may favourably affect host metabolism. Large-scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high-risk populations, are eagerly awaited. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.

  11. Gut Microbiota and Celiac Disease.

    PubMed

    Marasco, Giovanni; Di Biase, Anna Rita; Schiumerini, Ramona; Eusebi, Leonardo Henry; Iughetti, Lorenzo; Ravaioli, Federico; Scaioli, Eleonora; Colecchia, Antonio; Festi, Davide

    2016-06-01

    Recent evidence regarding celiac disease has increasingly shown the role of innate immunity in triggering the immune response by stimulating the adaptive immune response and by mucosal damage. The interaction between the gut microbiota and the mucosal wall is mediated by the same receptors which can activate innate immunity. Thus, changes in gut microbiota may lead to activation of this inflammatory pathway. This paper is a review of the current knowledge regarding the relationship between celiac disease and gut microbiota. In fact, patients with celiac disease have a reduction in beneficial species and an increase in those potentially pathogenic as compared to healthy subjects. This dysbiosis is reduced, but might still remain, after a gluten-free diet. Thus, gut microbiota could play a significant role in the pathogenesis of celiac disease, as described by studies which link dysbiosis with the inflammatory milieu in celiac patients. The use of probiotics seems to reduce the inflammatory response and restore a normal proportion of beneficial bacteria in the gastrointestinal tract. Additional evidence is needed in order to better understand the role of gut microbiota in the pathogenesis of celiac disease, and the clinical impact and therapeutic use of probiotics in this setting.

  12. The heart and the gut.

    PubMed

    Rogler, Gerhard; Rosano, Giuseppe

    2014-02-01

    The heart and the gut seem to be two organs that do not have much in common. However, there is an obvious and clinically relevant impact of gut functions on the absorption of drugs and oral therapies on the one hand. On the other hand, the gut determines the quantity of nutrient uptake and plays a central role in metabolic diseases. Patients with inflammatory bowel diseases appear to have a higher risk for coronary heart disease despite a lower prevalence of 'classical' risk factors, indicating additional links between the gut and the heart. However, they certainly have a 'leaky' intestinal barrier associated with increased permeability for bacterial wall products. An impaired intestinal barrier function will be followed by bacterial translocation and presence of bacterial products in the circulation, which can contribute to atherosclerosis and chronic heart failure (CHF) as recent data indicate. Impaired cardiac function in CHF vice versa impacts intestinal microcirculation leading to a barrier defect of the intestinal mucosa and increased bacterial translocation. These pathways and the most recent insights into the impact of the gut on acute and chronic heart disease will be discussed in this review.

  13. Distribution, function and physiological role of melatonin in the lower gut

    PubMed Central

    Chen, Chun-Qiu; Fichna, Jakub; Bashashati, Mohammad; Li, Yong-Yu; Storr, Martin

    2011-01-01

    Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. Melatonin exerts its physiological effects through specific membrane receptors, named melatonin-1 receptor (MT1), MT2 and MT3. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies. Stable levels of melatonin in the lower gut that are unchanged following a pinealectomy suggest local synthesis and, furthermore, implicate physiological importance of endogenous melatonin in the GI tract. Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. These human studies include patients with lower GI diseases, especially patients with irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. In this review, we summarize the presently available information on melatonin effects in the lower gut and discuss available in vitro and in vivo data. We furthermore aim to evaluate whether melatonin may be useful in future treatment of symptoms or diseases involving the lower gut. PMID:22025877

  14. Prebiotic fiber modulation of the gut microbiota improves risk factors for obesity and the metabolic syndrome

    PubMed Central

    Parnell, Jill A.; Reimer, Raylene A.

    2013-01-01

    Prebiotic fibers are non-digestible carbohydrates that promote the growth of beneficial bacteria in the gut. Prebiotic consumption may benefit obesity and associated co-morbidities by improving or normalizing the dysbiosis of the gut microbiota. We evaluated the dose response to a prebiotic diet on the gut microbiota, body composition and obesity associated risk factors in lean and genetically obese rats. Prebiotic fibers increased Firmicutes and decreased Bacteroidetes, a profile often associated with a leaner phenotype. Bifidobacteria and Lactobacillus numbers also increased. Changes in the gut microbiota correlated with energy intake, glucose, insulin, satiety hormones, and hepatic cholesterol and triglyceride accumulation. Here we provide a comprehensive analysis evaluating the results through the lens of the gut microbiota. Salient, new developments impacting the interpretation and significance of our data are discussed. We propose that prebiotic fibers have promise as a safe and cost-effective means of modulating the gut microbiota to promote improved host:bacterial interactions in obesity and insulin resistance. Human clinical trials should be undertaken to confirm these effects. PMID:22555633

  15. Distribution, function and physiological role of melatonin in the lower gut.

    PubMed

    Chen, Chun-Qiu; Fichna, Jakub; Bashashati, Mohammad; Li, Yong-Yu; Storr, Martin

    2011-09-14

    Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. Melatonin exerts its physiological effects through specific membrane receptors, named melatonin-1 receptor (MT1), MT2 and MT3. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies. Stable levels of melatonin in the lower gut that are unchanged following a pinealectomy suggest local synthesis and, furthermore, implicate physiological importance of endogenous melatonin in the GI tract. Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. These human studies include patients with lower GI diseases, especially patients with irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. In this review, we summarize the presently available information on melatonin effects in the lower gut and discuss available in vitro and in vivo data. We furthermore aim to evaluate whether melatonin may be useful in future treatment of symptoms or diseases involving the lower gut.

  16. Growth Hormone Deficiency in Adults

    MedlinePlus

    ... Center Pacientes y Cuidadores Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ... Learn About Clinical Trials Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ...

  17. Confusing or Ambiguous Upper Gut Symptoms

    MedlinePlus

    ... Diarrhea Relaxation to Treat Digestive Disorders Medications SAFER Medicine Managing Medications Avoiding Drug Adverse Effects Medications that can Affect Colonic Function Gut Microbiota and Brain-Gut Interactions in Functional GI Disorders Tips & Daily Living Personal Relationships Holiday ...

  18. Carbohydrates and the human gut microbiota.

    PubMed

    Chassard, Christophe; Lacroix, Christophe

    2013-07-01

    Due to its scale and its important role in maintaining health, the gut microbiota can be considered as a 'new organ' inside the human body. Many complex carbohydrates are degraded and fermented by the human gut microbiota in the large intestine to both yield basic energy salvage and impact gut health through produced metabolites. This review will focus on the gut microbes and microbial mechanisms responsible for polysaccharides degradation and fermentation in the large intestine. Gut microbes and bacterial metabolites impact the host at many levels, including modulation of inflammation, and glucose and lipid metabolisms. A complex relationship occurs in the intestine between the human gut microbiota, diet and the host. Research on carbohydrates and gut microbiota composition and functionality is fast developing and will open opportunities for prevention and treatment of obesity, diabetes and other related metabolic disorders through manipulation of the gut ecosystem.

  19. Maternal high-fat diet-induced programing of gut taste receptor and inflammatory gene expression in rat offspring is ameliorated by CLA supplementation.

    PubMed

    Reynolds, Clare M; Segovia, Stephanie A; Zhang, Xiaoyuan D; Gray, Clint; Vickers, Mark H

    2015-10-01

    Consumption of a high-fat (HF) diet during pregnancy and lactation influences later life predisposition to obesity and cardiometabolic disease in offspring. The mechanisms underlying this phenomenon remain poorly defined, but one potential target that has received scant attention and is likely pivotal to disease progression is that of the gut. The present study examined the effects of maternal supplementation with the anti-inflammatory lipid, conjugated linoleic acid (CLA), on offspring metabolic profile and gut expression of taste receptors and inflammatory markers. We speculate that preventing high-fat diet-induced metainflammation improved maternal metabolic parameters conferring beneficial effects on adult offspring. Sprague Dawley rats were randomly assigned to a purified control diet (CD; 10% kcal from fat), CD with CLA (CLA; 10% kcal from fat, 1% CLA), HF (45% kcal from fat) or HF with CLA (HFCLA; 45% kcal from fat, 1% CLA) throughout gestation and lactation. Plasma/tissues were taken at day 24 and RT-PCR was carried out on gut sections. Offspring from HF mothers were significantly heavier at weaning with impaired insulin sensitivity compared to controls. This was associated with increased plasma IL-1β and TNFα concentrations. Gut Tas1R1, IL-1β, TNFα, and NLRP3 expression was increased and Tas1R3 expression was decreased in male offspring from HF mothers and was normalized by maternal CLA supplementation. Tas1R1 expression was increased while PYY and IL-10 decreased in female offspring of HF mothers. These results suggest that maternal consumption of a HF diet during critical developmental windows influences offspring predisposition to obesity and metabolic dysregulation. This may be associated with dysregulation of taste receptor, incretin, and inflammatory gene expression in the gut. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  20. Maternal high-fat diet-induced programing of gut taste receptor and inflammatory gene expression in rat offspring is ameliorated by CLA supplementation

    PubMed Central

    Reynolds, Clare M; Segovia, Stephanie A; Zhang, Xiaoyuan D; Gray, Clint; Vickers, Mark H

    2015-01-01

    Consumption of a high-fat (HF) diet during pregnancy and lactation influences later life predisposition to obesity and cardiometabolic disease in offspring. The mechanisms underlying this phenomenon remain poorly defined, but one potential target that has received scant attention and is likely pivotal to disease progression is that of the gut. The present study examined the effects of maternal supplementation with the anti-inflammatory lipid, conjugated linoleic acid (CLA), on offspring metabolic profile and gut expression of taste receptors and inflammatory markers. We speculate that preventing high-fat diet-induced metainflammation improved maternal metabolic parameters conferring beneficial effects on adult offspring. Sprague Dawley rats were randomly assigned to a purified control diet (CD; 10% kcal from fat), CD with CLA (CLA; 10% kcal from fat, 1% CLA), HF (45% kcal from fat) or HF with CLA (HFCLA; 45% kcal from fat, 1% CLA) throughout gestation and lactation. Plasma/tissues were taken at day 24 and RT-PCR was carried out on gut sections. Offspring from HF mothers were significantly heavier at weaning with impaired insulin sensitivity compared to controls. This was associated with increased plasma IL-1β and TNFα concentrations. Gut Tas1R1, IL-1β, TNFα, and NLRP3 expression was increased and Tas1R3 expression was decreased in male offspring from HF mothers and was normalized by maternal CLA supplementation. Tas1R1 expression was increased while PYY and IL-10 decreased in female offspring of HF mothers. These results suggest that maternal consumption of a HF diet during critical developmental windows influences offspring predisposition to obesity and metabolic dysregulation. This may be associated with dysregulation of taste receptor, incretin, and inflammatory gene expression in the gut. PMID:26493953

  1. Global F-theory GUTs

    SciTech Connect

    Blumenhagen, Ralph; Grimm, Thomas W.; Jurke, Benjamin; Weigand, Timo; /SLAC

    2010-08-26

    We construct global F-theory GUT models on del Pezzo surfaces in compact Calabi-Yau fourfolds realized as complete intersections of two hypersurface constraints. The intersections of the GUT brane and the flavour branes as well as the gauge flux are described by the spectral cover construction. We consider a split S[U(4) x U(1){sub X}] spectral cover, which allows for the phenomenologically relevant Yukawa couplings and GUT breaking to the MSSM via hypercharge flux while preventing dimension-4 proton decay. General expressions for the massless spectrum, consistency conditions and a new method for the computation of curvature-induced tadpoles are presented. We also provide a geometric toolkit for further model searches in the framework of toric geometry. Finally, an explicit global model with three chiral generations and all required Yukawa couplings is defined on a Calabi-Yau fourfold which is fibered over the del Pezzo transition of the Fano threefold P{sup 4}.

  2. The Gut Microbiome and Obesity.

    PubMed

    John, George Kunnackal; Mullin, Gerard E

    2016-07-01

    The gut microbiome consists of trillions of bacteria which play an important role in human metabolism. Animal and human studies have implicated distortion of the normal microbial balance in obesity and metabolic syndrome. Bacteria causing weight gain are thought to induce the expression of genes related to lipid and carbohydrate metabolism thereby leading to greater energy harvest from the diet. There is a large body of evidence demonstrating that alteration in the proportion of Bacteroidetes and Firmicutes leads to the development of obesity, but this has been recently challenged. It is likely that the influence of gut microbiome on obesity is much more complex than simply an imbalance in the proportion of these phyla of bacteria. Modulation of the gut microbiome through diet, pre- and probiotics, antibiotics, surgery, and fecal transplantation has the potential to majorly impact the obesity epidemic.

  3. Developmental origins of a novel gut morphology in frogs.

    PubMed

    Bloom, Stephanie; Ledon-Rettig, Cris; Infante, Carlos; Everly, Anne; Hanken, James; Nascone-Yoder, Nanette

    2013-05-01

    Phenotypic variation is a prerequisite for evolution by natural selection, yet the processes that give rise to the novel morphologies upon which selection acts are poorly understood. We employed a chemical genetic screen to identify developmental changes capable of generating ecologically relevant morphological variation as observed among extant species. Specifically, we assayed for exogenously applied small molecules capable of transforming the ancestral larval foregut of the herbivorous Xenopus laevis to resemble the derived larval foregut of the carnivorous Lepidobatrachus laevis. Appropriately, the small molecules that demonstrate this capacity modulate conserved morphogenetic pathways involved in gut development, including downregulation of retinoic acid (RA) signaling. Identical manipulation of RA signaling in a species that is more closely related to Lepidobatrachus, Ceratophrys cranwelli, yielded even more similar transformations, corroborating the relevance of RA signaling variation in interspecific morphological change. Finally, we were able to recover the ancestral gut phenotype in Lepidobatrachus by performing a reverse chemical manipulation to upregulate RA signaling, providing strong evidence that modifications to this specific pathway promoted the emergence of a lineage-specific phenotypic novelty. Interestingly, our screen also revealed pathways that have not yet been implicated in early gut morphogenesis, such as thyroid hormone signaling. In general, the chemical genetic screen may be a valuable tool for identifying developmental mechanisms that underlie ecologically and evolutionarily relevant phenotypic variation. © 2013 Wiley Periodicals, Inc.

  4. Developmental origins of novel gut morphology in frogs

    PubMed Central

    Bloom, Stephanie; Ledon-Rettig, Cris; Infante, Carlos; Everly, Anne; Hanken, James; Nascone-Yoder, Nanette

    2013-01-01

    SUMMARY Phenotypic variation is a prerequisite for evolution by natural selection, yet the processes that give rise to the novel morphologies upon which selection acts are poorly understood. We employed a chemical genetic screen to identify developmental changes capable of generating ecologically relevant morphological variation as observed among extant species. Specifically, we assayed for exogenously applied small molecules capable of transforming the ancestral larval foregut of the herbivorous Xenopus laevis to resemble the derived larval foregut of the carnivorous Lepidobatrachus laevis. Appropriately, the small molecules that demonstrate this capacity modulate conserved morphogenetic pathways involved in gut development, including downregulation of retinoic acid (RA) signaling. Identical manipulation of RA signaling in a species that is more closely related to Lepidobatrachus, Ceratophrys cranwelli, yielded even more similar transformations, corroborating the relevance of RA signaling variation in interspecific morphological change. Finally, we were able to recover the ancestral gut phenotype in Lepidobatrachus by performing a reverse chemical manipulation to upregulate RA signaling, providing strong evidence that modifications to this specific pathway promoted the emergence of a lineage-specific phenotypic novelty. Interestingly, our screen also revealed pathways that have not yet been implicated in early gut morphogenesis, such as thyroid hormone signaling. In general, the chemical genetic screen may be a valuable tool for identifying developmental mechanisms that underlie ecologically and evolutionarily relevant phenotypic variation. PMID:23607305

  5. Incretins amplify TNF-α-stimulated IL-6 synthesis in osteoblasts: Suppression of the IκB/NF-κB pathway.

    PubMed

    Fujita, Kazuhiko; Tokuda, Haruhiko; Yamamoto, Naohiro; Kainuma, Shingo; Kawabata, Tetsu; Sakai, Go; Kuroyanagi, Gen; Matsushima-Nishiwaki, Rie; Harada, Atsushi; Kozawa, Osamu; Otsuka, Takanobu

    2017-02-15

    Incretins including glucagon-like peptide-1 (GLP-1) and glucose‑dependent insulinotropic polypeptide (GIP) secreted from the small intestine after oral food ingestion are currently recognized to stimulate insulin secretion from pancreatic β cells. We previously reported that p70 S6 kinase limits the tumor necrosis factor‑α (TNF‑α)‑stimulated interleukin-6 (IL‑6) synthesis in osteoblast‑like MC3T3‑E1 cells. In the present study, we investigated the effects of incretins on the TNF‑α‑induced IL‑6 synthesis and the underlying mechanism in MC3T3‑E1 cells. GLP‑1 and GIP significantly upregulated both TNF‑α‑stimulated IL‑6 release and mRNA levels. Wedelolactone, an inhibitor of IκB kinase, amplified the TNF-α-induced IL‑6 release. GLP‑1 significantly attenuated the TNF‑α‑induced phosphorylation of IκB without affecting the phosphorylation of p70 S6 kinase. On the other hand, GLP‑1 markedly induced the phosphorylation of cAMP response element-binding protein (CREB). H‑89, an inhibitor of protein kinase A, significantly suppressed the enhancement by GLP-1 of TNF-α-stimulated IL‑6 release. Dibutyryl cAMP, a permeable analogue of cAMP, which suppressed the TNF-α-induced IκB phosphorylation, amplified the IL‑6 release. These results strongly suggest that incretins upregulate the TNF-α-stimulated IL‑6 synthesis in osteoblasts, and that the amplifying effect of incretin is exerted via reducing the IκB/NF‑κB pathway through the adenylyl cyclase-cAMP system.

  6. Mast Cell and M1 Macrophage Infiltration and Local Pro-Inflammatory Factors Were Attenuated with Incretin-Based Therapies in Obesity-Related Glomerulopathy.

    PubMed

    He, Jiao; Yuan, Geheng; Cheng, Fangxiao; Zhang, Junqing; Guo, Xiaohui

    2017-09-01

    The global increase of obesity parallels the obesity-related glomerulopathy (ORG) epidemic. Dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 receptor agonists were well recognized to attenuate renal injury independent of glucose control in diabetic nephropathy. There are limited studies focusing on their effects on ORG. We explored the effects of incretin-based therapies on early ORG and the inflammatory responses involved mainly concentrated on mast cell (MC) and macrophage (M) infiltration and local pro-inflammatory factors. ORG rat models were induced by high-fat diet and then divided into ORG vehicle, vildagliptin (3 mg/kg/day, qd) and liraglutide (200 μg/kg, bid) treated groups. After 8 weeks of treatments, albuminuria, glomerular histology, renal inflammatory cell infiltration, and pro-inflammatory factors were analyzed. Early ORG model was demonstrated by albuminuria, glomerulomegaly, foot process fusion, and mesangial and endothelial mild proliferation. Incretin-based therapies limited body weight gain and improved insulin sensitivity. ORG was alleviated, manifested by decreased average glomerular area, attenuated mesangial and endothelial cell proliferation, and revived cell-to-cell propagation of podocytes, which contributed to reduced albuminuria. Compared with ORG vehicle, MC and M1 macrophage (pro-inflammatory) infiltration and M1/M2 ratio were significantly decreased; M2 macrophage (anti-inflammatory) was not significantly increased after incretin-based treatments. Tumor necrosis factor-α (TNF-α) and IL-6 in renal cortex were significantly downregulated, while transforming growth factor-β1 (TGF-β1) remained unchanged. Incretin-based treatments could alleviate high-fat diet-induced ORG partly through the systemic insulin sensitivity improvement and the attenuated local inflammation, mainly by the decrease of MC and M1 macrophage infiltration and reduction of TNF-α and IL-6.

  7. Sitagliptin (MK0431) Inhibition of Dipeptidyl Peptidase IV Decreases Nonobese Diabetic Mouse CD4+ T-Cell Migration Through Incretin-Dependent and -Independent Pathways

    PubMed Central

    Kim, Su-Jin; Nian, Cuilan; McIntosh, Christopher H.S.

    2010-01-01

    OBJECTIVE Treatment of NOD mice with the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin preserved islet transplants through a pathway involving modulation of splenic CD4+ T-cell migration. In the current study, effects of sitagliptin on migration of additional subsets of CD4+ T-cells were examined and underlying molecular mechanisms were further defined. RESEARCH DESIGN AND METHODS Effects of sitagliptin on migration of NOD mouse splenic, thymic, and lymph node CD4+ T-cells were determined. Signaling modules involved in DPP-IV-, Sitagliptin- and incretin-mediated modulation of CD4+ T-cell migration were studied using Western blot and Rac1 and nuclear factor-κB (NF-κB) activity assays. RESULTS Migration of splenic and lymph node CD4+ T-cells of diabetic NOD mice was reduced by sitagliptin treatment. In vitro treatment of splenic, but not thymic or lymph node CD4+ T-cells, from nondiabetic NOD mice with soluble (s) DPP-IV increased migration. Sitagliptin abolished sDPP-IV effects on splenic CD4+ T-cell migration, whereas incretins decreased migration of lymph node, but not splenic, CD4+ T-cells. Splenic CD4+ T-cells demonstrating increased in vitro migration in response to sDPP-IV and lymph node CD4+ T-cells that were nonresponsive to incretins selectively infiltrated islets of NOD mice, after injection. Sitagliptin decreases migration of splenic CD4+ T-cells through a pathway involving Rac1/vasodilator-stimulated phosphoprotein, whereas its inhibitory effects on the migration of lymph node CD4+ T-cells involve incretin-activation of the NF-κB pathway. CONCLUSIONS Benefits of sitagliptin treatment in diabetic NOD mice may be mediated through selective effects on subpopulations of T-cells that are related to autoimmunity. PMID:20368408

  8. Gut microbiota in 2015: Prevotella in the gut: choose carefully.

    PubMed

    Ley, Ruth E

    2016-02-01

    Gut microbial communities often contain many Bacteroides or their close relatives, Prevotella, but not both. Prevotella strains are associated with plant-rich diets but are also linked with chronic inflammatory conditions. In 2015, papers probed the genomic diversity of Prevotella strains and interactions of Prevotella copri with its host and other bacteria.

  9. Role of the Gut on Glucose Homeostasis: Lesson Learned from Metabolic Surgery.

    PubMed

    Kamvissi-Lorenz, V; Raffaelli, M; Bornstein, S; Mingrone, G

    2017-02-01

    Bariatric surgery was initially intended to reduce weight, and only subsequently was the remission of type two diabetes (T2D) observed as a collateral event. At the moment, the term "metabolic surgery" is used to underline the fact that this type of surgery is performed specifically to treat diabetes and its metabolic complications, such as hyperlipidemia. Randomized, controlled studies have recently supported the use of bariatric surgery, and in particular of Roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion (BPD) as an effective treatment for decompensated T2D. The lesson learned from these randomized and many other non-randomized clinical studies is that the stomach and the small intestine play a central role in glucose homeostasis. Bypassing the duodenum and parts of the jejunum exerts a substantial effect on insulin sensitivity and secretion. In fact, with BPD, nutrient transit bypasses duodenum, the entire jejunum and a small portion of the ileum, resulting in reversal of insulin sensitivity back to normal and reduction of insulin secretion, whereas RYGB has little effect on insulin resistance but increases insulin secretion. Hypotheses concerning the mechanism of action of metabolic surgery for diabetes remission vary from theories focusing on jejunal nutrient sensing, to incretin action, to the blunted secretion of putative insulin resistance hormone(s), to changes in the microbiota. Whatever the mechanism, metabolic surgery has the undoubted merit of exposing the central role of the small intestine in insulin sensitivity and glucose homeostasis.

  10. Sex, Body Mass Index, and Dietary Fiber Intake Influence the Human Gut Microbiome

    PubMed Central

    Dominianni, Christine; Sinha, Rashmi; Goedert, James J.; Pei, Zhiheng; Yang, Liying; Hayes, Richard B.; Ahn, Jiyoung

    2015-01-01

    Increasing evidence suggests that the composition of the human gut microbiome is important in the etiology of human diseases; however, the personal factors that influence the gut microbiome composition are poorly characterized. Animal models point to sex hormone-related differentials in microbiome composition. In this study, we investigated the relationship of sex, body mass index (BMI) and dietary fiber intake with the gut microbiome in 82 humans. We sequenced fecal 16S rRNA genes by 454 FLX technology, then clustered and classified the reads to microbial genomes using the QIIME pipeline. Relationships of sex, BMI, and fiber intake with overall gut microbiome composition and specific taxon abundances were assessed by permutational MANOVA and multivariate logistic regression, respectively. We found that sex was associated with the gut microbiome composition overall (p=0.001). The gut microbiome in women was characterized by a lower abundance of Bacteroidetes (p=0.03). BMI (>25 kg/m2 vs. <25 kg/m2) was associated with the gut microbiome composition overall (p=0.05), and this relationship was strong in women (p=0.03) but not in men (p=0.29). Fiber from beans and from fruits and vegetables were associated, respectively, with greater abundance of Actinobacteria (p=0.006 and false discovery rate adjusted q=0.05) and Clostridia (p=0.009 and false discovery rate adjusted q=0.09). Our findings suggest that sex, BMI, and dietary fiber contribute to shaping the gut microbiome in humans. Better understanding of these relationships may have significant implications for gastrointestinal health and disease prevention. PMID:25874569

  11. The Gut Microbiome Feelings of the Brain: A Perspective for Non-Microbiologists.

    PubMed

    Lerner, Aaron; Neidhöfer, Sandra; Matthias, Torsten

    2017-10-12

    Objectives: To comprehensively review the scientific knowledge on the gut-brain axis. Methods: Various publications on the gut-brain axis, until 31 July 2017, were screened using the Medline, Google, and Cochrane Library databases. The search was performed using the following keywords: "gut-brain axis", "gut-microbiota-brain axis", "nutrition microbiome/microbiota", "enteric nervous system", "enteric glial cells/network", "gut-brain pathways", "microbiome immune system", "microbiome neuroendocrine system" and "intestinal/gut/enteric neuropeptides". Relevant articles were selected and reviewed. Results: Tremendous progress has been made in exploring the interactions between nutrients, the microbiome, and the intestinal, epithelium-enteric nervous, endocrine and immune systems and the brain. The basis of the gut-brain axis comprises of an array of multichannel sensing and trafficking pathways that are suggested to convey the enteric signals to the brain. These are mediated by neuroanatomy (represented by the vagal and spinal afferent neurons), the neuroendocrine-hypothalamic-pituitary-adrenal (HPA) axis (represented by the gut hormones), immune routes (represented by multiple cytokines), microbially-derived neurotransmitters, and finally the gate keepers of the intestinal and brain barriers. Their mutual and harmonious but intricate interaction is essential for human life and brain performance. However, a failure in the interaction leads to a number of inflammatory-, autoimmune-, neurodegenerative-, metabolic-, mood-, behavioral-, cognitive-, autism-spectrum-, stress- and pain-related disorders. The limited availability of information on the mechanisms, pathways and cause-and-effect relationships hinders us from translating and implementing the knowledge from the bench to the clinic. Implications: Further understanding of this intricate field might potentially shed light on novel preventive and therapeutic strategies to combat these disorders. Nutritional approaches

  12. Sex, body mass index, and dietary fiber intake influence the human gut microbiome.

    PubMed

    Dominianni, Christine; Sinha, Rashmi; Goedert, James J; Pei, Zhiheng; Yang, Liying; Hayes, Richard B; Ahn, Jiyoung

    2015-01-01

    Increasing evidence suggests that the composition of the human gut microbiome is important in the etiology of human diseases; however, the personal factors that influence the gut microbiome composition are poorly characterized. Animal models point to sex hormone-related differentials in microbiome composition. In this study, we investigated the relationship of sex, body mass index (BMI) and dietary fiber intake with the gut microbiome in 82 humans. We sequenced fecal 16S rRNA genes by 454 FLX technology, then clustered and classified the reads to microbial genomes using the QIIME pipeline. Relationships of sex, BMI, and fiber intake with overall gut microbiome composition and specific taxon abundances were assessed by permutational MANOVA and multivariate logistic regression, respectively. We found that sex was associated with the gut microbiome composition overall (p=0.001). The gut microbiome in women was characterized by a lower abundance of Bacteroidetes (p=0.03). BMI (>25 kg/m2 vs. <25 kg/m2) was associated with the gut microbiome composition overall (p=0.05), and this relationship was strong in women (p=0.03) but not in men (p=0.29). Fiber from beans and from fruits and vegetables were associated, respectively, with greater abundance of Actinobacteria (p=0.006 and false discovery rate adjusted q=0.05) and Clostridia (p=0.009 and false discovery rate adjusted q=0.09). Our findings suggest that sex, BMI, and dietary fiber contribute to shaping the gut microbiome in humans. Better understanding of these relationships may have significant implications for gastrointestinal health and disease prevention.

  13. Incretin effect potentiates beta-cell responsivity to glucose as well as to its rate of change: OGTT and matched intravenous study.

    PubMed

    Campioni, Marco; Toffolo, Gianna; Shuster, Lynne T; Service, F John; Rizza, Robert A; Cobelli, Claudio

    2007-01-01

    The aim of this study is to gain greater insight into the mechanism whereby "incretins" (greater insulinemia after oral than intravenous glucose) enhance insulin secretion. To do so, we use a model of C-peptide secretion to reanalyze data from a previously published study in which glycemic profiles observed following glucose ingestion were matched in the same 10 subjects by means of an intravenous glucose infusion. We report that incretins increase insulin secretion by enhancing both the dynamic (to the rate of increase of glucose) and static (to given glucose concentration) response with an increase of 58% for the static (Phi(s) = 16.4 +/- 1.8 vs. 24.6 +/- 2.0 10(-9) min(-1), P = 0.01) and 63% for the dynamic (Phi(d) = 278 +/- 32 vs. 463 +/- 86 10(-9), P = 0.02) indexes. Since increases in the dynamic response to glucose are believed to be due to an increase in the rate of docking, and exocytosis of insulin containing granules and increases in the static response to glucose are believed to be caused by a shift in the sensitivity of the beta-cell to glucose, these results suggest that incretins may modulate more than one step in the beta-cell insulin secretory cascade.

  14. Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

    PubMed

    Lamont, Benjamin J; Andrikopoulos, Sofianos

    2014-04-01

    Incretin-based therapies appear to offer many advantages over other approaches for treating type 2 diabetes. Some preclinical studies have suggested that chronic activation of glucagon-like peptide 1 receptor (GLP1R) signalling in the pancreas may result in the proliferation of islet β-cells and an increase in β-cell mass. This provided hope that enhancing GLP1 action could potentially alter the natural progression of type 2 diabetes. However, to date, there has been no evidence from clinical trials suggesting that GLP1R agonists or dipeptidyl peptidase-4 (DPP4) inhibitors can increase β-cell mass. Nevertheless, while the proliferative capacity of these agents remains controversial, some studies have raised concerns that they could potentially contribute to the development of pancreatitis and hence increase the risk of pancreatic cancer. Currently, there are very limited clinical data to directly assess these potential benefits and risks of incretin-based therapies. However, a review of the preclinical studies indicates that incretin-based therapies probably have only a limited capacity to regenerate pancreatic β-cells, but may be useful for preserving any remaining β-cells in type 2 diabetes. In addition, the majority of preclinical evidence does not support the notion that GLP1R agonists or DPP4 inhibitors cause pancreatitis.

  15. Patients With Long-QT Syndrome Caused by Impaired hERG-Encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated With Reactive Hypoglycemia.

    PubMed

    Hyltén-Cavallius, Louise; Iepsen, Eva W; Wewer Albrechtsen, Nicolai J; Svendstrup, Mathilde; Lubberding, Anniek F; Hartmann, Bolette; Jespersen, Thomas; Linneberg, Allan; Christiansen, Michael; Vestergaard, Henrik; Pedersen, Oluf; Holst, Jens J; Kanters, Jørgen K; Hansen, Torben; Torekov, Signe S

    2017-05-02

    Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long-QT syndrome type 2 (LQT2) because of prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic α and β cells and intestinal L and K cells, secreting glucagon, insulin, and the incretins glucagon-like peptide-1 (GLP-1) and GIP (glucose-dependent insulinotropic polypeptide), respectively. These hormones are crucial for glucose regulation, and long-QT syndrome may cause disturbed glucose regulation. We measured secretion of these hormones and cardiac repolarization in response to glucose ingestion in LQT2 patients with functional mutations in hERG and matched healthy participants, testing the hypothesis that LQT2 patients have increased incretin and β-cell function and decreased α-cell function, and thus lower glucose levels. Eleven patients with LQT2 and 22 sex-, age-, and body mass index-matched control participants underwent a 6-hour 75-g oral glucose tolerance test with ECG recording and blood sampling for measurements of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP. In comparison with matched control participants, LQT2 patients had 56% to 78% increased serum insulin, serum C-peptide, plasma GLP-1, and plasma GIP responses (P=0.03-0.001) and decreased plasma glucose levels after glucose ingestion (P=0.02) with more symptoms of hypoglycemia (P=0.04). Sixty-three percent of LQT2 patients developed hypoglycemic plasma glucose levels (<70 mg/dL) versus 36% control participants (P=0.16), and 18% patients developed serious hypoglycemia (<50 mg/dL) versus none of the controls. LQT2 patients had defective glucagon responses to low glucose, P=0.008. β-Cell function (Insulin Secretion Sensitivity Index-2) was 2-fold higher in LQT2 patients than in controls (4398 [95% confidence interval, 2259-8562] versus 2156 [1961-3201], P=0.03). Pharmacological Kv11.1 blockade (dofetilide) in rats had similar effect, and small interfering RNA inhibition

  16. Growth hormone deficiency - children

    MedlinePlus

    Growth hormone deficiency means the pituitary gland does not make enough growth hormone. ... The pituitary gland is located at the base of the brain. This gland controls the body's balance of hormones. It ...

  17. Hormone Replacement Therapy

    MedlinePlus

    ... before and during menopause, the levels of female hormones can go up and down. This can cause ... hot flashes and vaginal dryness. Some women take hormone replacement therapy (HRT), also called menopausal hormone therapy, ...

  18. Menopause and Hormones

    MedlinePlus

    ... use hormone therapy to prevent memory loss or Alzheimer’s disease? No, do not use hormone therapy to prevent memory loss or Alzheimer’s disease. Do hormones protect against aging and wrinkles ...

  19. 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...

  20. [Current view on gut microbiota].

    PubMed

    Bourlioux, P

    2014-01-01

    Gut microbiota is more and more important since metagenomic research have brought new knowledge on this topic especially for human health. Firstly, gut microbiota is a key element for our organism he lives in symbiosis with. Secondly, it interacts favorably with many physiological functions of our organism. Thirdly, at the opposite, it can be an active participant in intestinal pathologies linked to a dysbiosis mainly in chronic inflammatory bowel diseases like Crohn disease or ulcerative colitis but also in obesity, metabolic syndrome, and more prudently in autism and behavioral disorders. In order to keep a good health, it is essential to protect our gut microbiota as soon as our young age and maintain it healthy. Face to a more and more important number of publications for treating certain digestive diseases with fecal microbial transplantation, it needs to be very careful and recommend further studies in order to assess risks and define standardized protocols. Gut microbiota metabolic capacities towards xenobiotics need to be developed, and we must take an interest in the modifications they induce on medicinal molecules. On the other hand, it is essential to study the potent effects of pesticides and other pollutants on microbiota functions. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  1. Xenobiotic Metabolism and Gut Microbiomes

    PubMed Central

    Das, Anubhav; Srinivasan, Meenakshi; Ghosh, Tarini Shankar; Mande, Sharmila S.

    2016-01-01

    Humans are exposed to numerous xenobiotics, a majority of which are in the form of pharmaceuticals. Apart from human enzymes, recent studies have indicated the role of the gut bacterial community (microbiome) in metabolizing xenobiotics. However, little is known about the contribution of the plethora of gut microbiome in xenobiotic metabolism. The present study reports the results of analyses on xenobiotic metabolizing enzymes in various human gut microbiomes. A total of 397 available gut metagenomes from individuals of varying age groups from 8 nationalities were analyzed. Based on the diversities and abundances of the xenobiotic metabolizing enzymes, various bacterial taxa were classified into three groups, namely, least versatile, intermediately versatile and highly versatile xenobiotic metabolizers. Most interestingly, specific relationships were observed between the overall drug consumption profile and the abundance and diversity of the xenobiotic metabolizing repertoire in various geographies. The obtained differential abundance patterns of xenobiotic metabolizing enzymes and bacterial genera harboring them, suggest their links to pharmacokinetic variations among individuals. Additional analyses of a few well studied classes of drug modifying enzymes (DMEs) also indicate geographic as well as age specific trends. PMID:27695034

  2. Neuroimmune modulation of gut function

    USDA-ARS?s Scientific Manuscript database

    There is considerable interest in the mechanisms and pathways involved in the neuro-immune regulation of gut function. The number of cell types and possible interactions is staggering and there are a number of recent reviews detailing various aspects of these interactions, many of which focus on ...

  3. Effects of environmental pollutants on gut microbiota.

    PubMed

    Jin, Yuanxiang; Wu, Sisheng; Zeng, Zhaoyang; Fu, Zhengwei

    2017-03-01

    Environmental pollutants have become an increasingly common health hazard in the last several decades. Recently, a number of studies have demonstrated the profound relationship between gut microbiota and our health. Gut microbiota are very sensitive to drugs, diet, and even environmental pollutants. In this review, we discuss the possible effects of environmental pollutants including antibiotics, heavy metals, persistent organic pollutants, pesticides, nanomaterials, and food additives on gut microbiota and their subsequent effects on health. We emphasize that gut microbiota are also essential for the toxicity evaluation of environmental pollution. In the future, more studies should focus on the relationship between environmental pollution, gut microbiota, and human health.

  4. Gut Microbiota in Inflammatory Bowel Disease

    PubMed Central

    2013-01-01

    The gut mucosal barrier plays an important role in maintaining a delicate immune homeostasis. The pathogenesis of inflammatory bowel disease (IBD) is considered to involve a defective mucosal immunity along with a genetic predisposition. Recent views have suggested an excessive response to components of the gut microbiota in IBD. A condition of "dysbiosis", with alterations of the gut microbial composition, has been observed in patients with IBD. In this article, the author review recent studies of gut microbiota in IBD, particularly the importance of the gut microbiota in the pathogenesis of pediatric IBD. PMID:24010101

  5. Gut-Brain Axis in Gastric Mucosal Damage and Protection

    PubMed Central

    Sgambato, Dolores; Capuano, Annalisa; Sullo, Maria Giuseppa; Miranda, Agnese; Federico, Alessandro; Romano, Marco

    2016-01-01

    Abstract: Background The gut-brain axis plays a potential role in numerous physiological and pathological conditions. Several substances link stomach with central nervous system. In particular, hypothalamo-pituitary-adrenocortical axis, thyrotropin-releasing factor-containing nerve fibers and capsaicin-sensitive nerves are principal mediators of the harmful and protective central nervous system-mediated effects on gastric mucosa. Also, existing evidence indicates that nitric oxide, prostaglandins and calcitonin gene-related peptide play a role as final effectors of gastric protection. Methods We undertook a structured search of bibliographic databases for peer-reviewed research literature with the aim of focusing on the role of gut-brain axis in gastric damage and protection. In particular, we examined manuscripts dealing with the role of steroids, thyrotropin-releasing hormone, prostaglandins, melatonin, hydrogen sulfide and peptides influencing food intake (i.e. leptin, cholecystokinin, peptide YY, central glucagon–like peptide-1, and ghrelin). Also, the role of GABAergic and glutamatergic pathways in gastric mucosal protection have been examined. Results We found and reviewed 61 peer-reviewed papers dealing with the major aspects related to the role of gut brain axis in gastric mucosal damage and protection. Conclusions A dense neuronal network links stomach with central nervous system and a number of neurotransmitters and peptides functionally and anatomically related to central nervous system play a major role in contributing to gastric mucosal integrity. Exploiting the mechanisms underlying the connection between brain and gut may lead to a better understanding of the pathophysiology of gastric mucosal injury and to an improvement in the prevention and, eventually, management of gastric damage. PMID:26903151

  6. The brain-gut axis in regulation of appetite and obesity.

    PubMed

    Dham, Shefali; Banerji, Mary A

    2006-12-01

    Obesity is the most common metabolic disease globally. It is increasingly a problem of children and individuals in poor countries characterized by food insecurity. This is of great concern as childhood obesity predicts increased future adult obesity. To curb the epidemic of obesity, it is essential to understand the regulation of appetite. Energy stores and nutrient homeostasis are maintained by hypothalamic regulation of energy balance. The hypothalamus receives neural and endocrine signals from the gut, adipose tissue and pancreas in response to food intake. These are integrated, interpreted and directed to other centers in the brain and peripheral organs to orchestrate energy homeostasis. This brain-gut axis is disrupted in obesity. This review discusses the various hormones involved in the regulation of energy balance both at the level of the gut and in the central nervous system.

  7. Gender-related differences in irritable bowel syndrome: potential mechanisms of sex hormones.

    PubMed

    Meleine, Mathieu; Matricon, Julien

    2014-06-14

    According to epidemiological studies, twice as many women as men are affected by irritable bowel syndrome (IBS) in western countries, suggesting a role for sex hormones in IBS pathophysiology. Despite growing evidence about the implications of sex hormones in IBS symptom modulation, data on mechanisms by which they influence disease development are sparse. This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS. The scientific bibliography was searched using the following keywords: irritable bowel syndrome, sex, gender, ovarian hormone, estradiol, progesterone, testosterone, symptoms, pain, sensitivity, motility, permeability, stress, immune system, brain activity, spinal, supraspinal, imaging. Ovarian hormones variations along the menstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations. They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception. These hormones can also modulate the susceptibility to stress, which is a pivotal factor in IBS occurrence and symptom severity. For instance, estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function. In conclusion, whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS, they arguably modulate IBS onset and symptomatology. However, our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender. Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS. Finally, investigation of brain-gut interactions is critical

  8. Gender-related differences in irritable bowel syndrome: Potential mechanisms of sex hormones

    PubMed Central

    Meleine, Mathieu; Matricon, Julien

    2014-01-01

    According to epidemiological studies, twice as many women as men are affected by irritable bowel syndrome (IBS) in western countries, suggesting a role for sex hormones in IBS pathophysiology. Despite growing evidence about the implications of sex hormones in IBS symptom modulation, data on mechanisms by which they influence disease development are sparse. This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS. The scientific bibliography was searched using the following keywords: irritable bowel syndrome, sex, gender, ovarian hormone, estradiol, progesterone, testosterone, symptoms, pain, sensitivity, motility, permeability, stress, immune system, brain activity, spinal, supraspinal, imaging. Ovarian hormones variations along the menstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations. They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception. These hormones can also modulate the susceptibility to stress, which is a pivotal factor in IBS occurrence and symptom severity. For instance, estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function. In conclusion, whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS, they arguably modulate IBS onset and symptomatology. However, our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender. Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS. Finally, investigation of brain-gut interactions is critical

  9. Recent and emerging therapeutic medications in type 2 diabetes mellitus: incretin-based, Pramlintide, Colesevelam, SGLT2 Inhibitors, Tagatose, Succinobucol.

    PubMed

    Lo, Margaret C; Lansang, M Cecilia

    2013-01-01

    Nearly 285 million people worldwide, with 10% being Americans, suffer from diabetes mellitus and its associated comorbidities. This is projected to increase by 6.5% per year, with 439 million inflicted by year 2030. Both morbidity and mortality from diabetes stem from the consequences of microvascular and macrovascular complications. Of the 285 million with diabetes, over a quarter of a million die per year from related complications, making diabetes the fifth leading cause of death in high-income countries. These startling statistics illustrate the therapeutic failure of current diabetes drugs to retard the progression of diabetes. These statistics further illustrate the continual need for further research and development of alternative drugs with novel mechanisms to slow disease progression and disease complications. The treatment algorithm updated in 2008 by American Diabetes Association and the European Association for the Study of Diabetes currently recommends the traditional medications of metformin, either as monotherapy or in combination with sulfonylurea or insulin, as the preferred choice in the tier 1 option. The algorithm only suggests addition of alternative medications such as pioglitazone and incretin-based drugs as second-line agents in the tier 2 "less well-validated" option. However, these traditional medications have not proven to delay the progressive course of diabetes as evidence of increasing need over time for multiple drug therapy to maintain sufficient glycemic control. Because current diabetes medications have limited efficacy and untoward side effects, the development of diabetes mellitus drugs with newer mechanisms of action continues. This article will review the clinical data on the newly available incretin-based drugs on the market, including glucagon-like peptide agonists and of dipeptidyl peptidase type-4 inhibitors. It will also discuss 2 unique medications: pramlintide, which is indicated for both type and type-2 diabetes, and

  10. Deciding about hormone therapy

    MedlinePlus

    HRT - deciding; Estrogen replacement therapy - deciding; ERT- deciding; Hormone replacement therapy - deciding; Menopause - deciding; HT - deciding; Menopausal hormone therapy - deciding; MHT - deciding

  11. Interaction between gut immunity and polysaccharides.

    PubMed

    Huang, Xiaojun; Nie, Shaoping; Xie, Mingyong

    2017-09-22

    The human gut is colonized with a vast and diverse microbial ecosystem, and these bacteria play fundamental roles in the well being of our bodies. Gut-associated lymphoid tissues, the largest mucosal immune system, should never be overlooked for their profound effect in maintaining the host immunity. Therefore, we discussed the relationship between gut immunity and host health, primarily from two aspects: the homeostasis of gut microbiota, and the function of gut-associated lymphoid tissues. Polysaccharides, widely concerned as bioactive macromolecules in recent centuries, have been proved to benefit the intestinal health. Dietary polysaccharides can improve the ratio of probiotics, regulate the intestinal microenvironment like decreasing the gut pH, and stimulate the macrophages or lymphocytes in gut tissues to fight against diseases like cancer. Based on various experimental and clinical evidence, the impacts of dietary polysaccharides on intestinal health are summarized, in order to reveal the possible immunomodulatory mechanisms of polysaccharides.

  12. [Hormonal dysnatremia].

    PubMed

    Karaca, P; Desailloud, R

    2013-10-01

    Because of antidiuretic hormone (ADH) disorder on production or function we can observe dysnatremia. In the absence of production by posterior pituitary, central diabetes insipidus (DI) occurs with hypernatremia. There are hereditary autosomal dominant, autosomal recessive or X- linked forms. When ADH is secreted but there is an alteration on his receptor AVPR2, it is a nephrogenic diabetes insipidus in acquired or hereditary form. We can make difference on AVP levels and/or on desmopressine response which is negative in nephrogenic forms. Hyponatremia occurs when there is an excess of ADH production: it is a euvolemic hypoosmolar hyponatremia. The most frequent etiology is SIADH (syndrome of inappropriate secretion of ADH), a diagnostic of exclusion which is made after eliminating corticotropin deficiency and hypothyroidism. In case of brain injury the differential diagnosis of cerebral salt wasting (CSW) syndrome has to be discussed, because its treatment is perfusion of isotonic saline whereas in SIADH, the treatment consists in administration of hypertonic saline if hyponatremia is acute and/or severe. If not, fluid restriction demeclocycline or vaptans (antagonists of V2 receptors) can be used in some European countries. Four types of SIADH exist; 10 % of cases represent not SIADH but SIAD (syndrome of inappropriate antidiuresis) due to a constitutive activation of vasopressin receptor that produces water excess. c 2013 Published by Elsevier Masson SAS.

  13. The molecular basis for the prolonged blood circulation of lipidated incretin peptides: Peptide oligomerization or binding to serum albumin?

    PubMed

    Wang, Ying; Lomakin, Aleksey; Kanai, Sonoko; Alex, Rainer; Belli, Sara; Donzelli, Massimiliano; Benedek, George B

    2016-11-10

    Hybrid incretin peptides are a new generation of drugs for the treatment of diabetes and obesity. Despite their biological potency, the effectiveness of these peptides as drugs is limited by their short circulation time in blood (typically within minutes). In this work, we show that lipid conjugated forms of a GLP-1/GIP/glucagon hybrid peptides stay in circulation for hours. We studied the oligomerization and albumin-binding of the unconjugated hybrid peptide as well as its lipidated variants. These lipidated peptides differ in the N-terminal mutation, the position of lipidation and the linkage to lipid. We found that these lipidated peptides form stable oligomers at concentrations above 1mg/mL. This concentration range is relevant to formulation and storage of the peptides. We observed no binding between the peptide oligomers and human serum albumin. However, at the expected therapeutic concentration range (~10-100ng/mL), the oligomers dissociate into monomers. The monomers of lipidated peptides bind to albumin. We have determined the dissociation constants of binding between the lipidated peptides and serum albumin. The dissociation constants of albumin-binding of our lipidated peptides are all very close and similar to that of the fatty acid binding of albumin. Our findings suggest that the monomeric lipidated peptides bind to HSA mainly by the fatty acid chain. Therefore, albumin binding is likely to be a universal mechanism of the prolonged circulating duration of lipidated pharmaceutical peptides.

  14. An update in incretin-based therapy: a focus on glucagon-like peptide-1 receptor agonists.

    PubMed

    Edwards, Krystal L; Stapleton, Megan; Weis, Jessica; Irons, Brian K

    2012-10-01

    The glucagon-like peptide-1 receptor agonists, exenatide and liraglutide, offer a unique mechanism in the treatment of type 2 diabetes mellitus (T2DM) as part of the incretin system. Their mechanism of action is to increase insulin secretion, decrease glucagon release, reduce food intake, and slow gastric emptying. They target postprandial blood glucose values and have some effect on fasting levels as well. In addition, they promote weight loss and may help to preserve β-cell function, both major problems in T2DM patients. Changes in hemoglobin A1c are similar to those produced by other T2DM agents, including thiazolidinediones, low-dose metformin, and sulfonylureas, and better than those caused by α-reductase inhibitors and dipeptidyl peptidase-4 inhibitors. These agents have been safely studied in combination with metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin therapy. Overall, data are limited for head-to-head comparisons, but it appears that liraglutide may have better efficacy and tolerability compared with exenatide; however, more studies are needed. They are overall well tolerated, with the main adverse events being similar to those with metformin (gastrointestinal intolerances that are transient and dose dependent). However, patients must be monitored for pancreatitis as a rare but possible side effect. For T2DM patients willing to use an injectable agent, exenatide and liraglutide offer another therapeutic option to control hyperglycemia with the potential for weight loss and may be combined with other agents safely.

  15. Effects of sitagliptin on plasma incretin concentrations after glucose administration through an esophagostomy tube or feeding in healthy cats.

    PubMed

    Nishii, N; Takashima, S; Iguchi, A; Murahata, Y; Matsuu, A; Hikasa, Y; Kitagawa, H

    2014-10-01

    We investigated the effect of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on plasma incretin concentrations after glucose administration through an esophagostomy tube or feeding in healthy cats. Six cats were used for the glucose administration experiment and 5 cats were used for the feeding experiment. Glucose administration through an esophagostomy tube increased plasma glucagon-like peptide 1 (GLP-1) concentrations by 6-fold, whereas plasma glucose-dependent insulinotropic polypeptide (GIP) concentrations did not change. Feeding increased both plasma GLP-1 concentrations by 1.5-fold and GIP concentrations by 4.6-fold. Sitagliptin was administered through an esophagostomy tube (25 and 50 mg per cat) in the glucose administration experiment and orally (25 mg per cat) in the feeding experiment. Sitagliptin treatment potentiated the GLP-1 response to glucose by 1.5-fold (P < 0.05). In addition, postprandial plasma GLP-1 concentration was higher by 2-fold when sitagliptin was administered (P < 0.05). In contrast, administration of sitagliptin did not affect plasma GIP concentrations after glucose administration or feeding. Sitagliptin enhanced insulin secretion following glucose administration by 1.5-fold (P < 0.05); however, it did not influence the plasma glucose concentration. Furthermore, sitagliptin had no effect on the postprandial plasma glucose and insulin concentrations. In conclusion, this study provides no evidence that sitagliptin is beneficial for management of feline diabetes mellitus. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Effects of miglitol, sitagliptin or their combination on plasma glucose, insulin and incretin levels in non-diabetic men.

    PubMed

    Aoki, Kazutaka; Masuda, Kiyomi; Miyazaki, Takashi; Togashi, Yu; Terauchi, Yasuo

    2010-01-01

    alpha-glucosidase inhibitors (alphaGIs) increase active glucagon-like peptide-1 (GLP-1) and reduce the total glucosedependent insulinotropic polypeptide (GIP) levels, but their ability to prevent diabetes remains uncertain. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, increase active GLP-1 and GIP levels and improve hyperglycemia in a glucose-dependent fashion. However, the effectiveness of their combination in subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) is uncertain. The present study evaluated the effect of miglitol, sitagliptin, and their combination on glucose, insulin and incretin levels in non-diabetic men. Miglitol and sitagliptin were administered according to four different intake schedules (C: no drug, M: miglitol; S: sitagliptin, M+S: miglitol and sitagliptin). The plasma glucose levels were significantly lower for M, S and M+S than for the control. The areas under the curve (AUCs) of the plasma active GLP-1 level in the M, S, and M+S groups were significantly greater than that in the control group. The AUC of the plasma active GLP-1 level was significantly greater for M+S group than for the M and S groups. The AUC of the plasma total GIP level was significantly smaller for M+S group than for the control and M and S groups. The results of our study suggest that miglitol, sitagliptin, or their combination contributes to the prevention of type 2 diabetes.

  17. Gut microbiome, gut function, and probiotics: Implications for health.

    PubMed

    Hajela, Neerja; Ramakrishna, B S; Nair, G Balakrish; Abraham, Philip; Gopalan, Sarath; Ganguly, Nirmal K

    2015-03-01

    New insights from a rapidly developing field of research have ushered in a new era of understanding of the complexity of host-microbe interactions within the human body. The paradigm shift from culturing to metagenomics has provided an insight into the complex diversity of the microbial species that we harbor, revealing the fact that we are in fact more microbes than human cells. The largest consortium of these microbes resides in the gut and is called the gut microbiota. This new science has expanded the ability to document shifts in microbial populations to an unparalleled degree. It is now understood that signals from the microbiota provide trophic, nutritional, metabolic, and protective effects for the development and maintenance of the host digestive, immune, and neuroendocrine system. Evidence linking changes in the gut microbiota to gastrointestinal and extraintestinal disorders like irritable bowel syndrome, inflammatory bowel disease, obesity, diabetes, and celiac disease have begun to emerge recently. Probiotics act through diverse mechanisms positively affecting the composition and/or function of the commensal microbiota and alter host immunological responses. Well-controlled intervention trials, systematic reviews, and meta-analysis provide convincing evidence for the benefit of probiotics in prevention and treatment of gastrointestinal as well as extraintestinal disorders.

  18. Role of gastrointestinal hormones in feeding behavior and obesity treatment.

    PubMed

    Kairupan, Timothy Sean; Amitani, Haruka; Cheng, Kai-Chun; Runtuwene, Joshua; Asakawa, Akihiro; Inui, Akio

    2016-02-01

    Food intake regulation is generally evaluated by many aspects consisting of complex mechanisms, including homeostatic regulatory mechanism, which is based on negative feedback, and hedonic regulatory mechanism, which is driven by a reward system. One important aspect of food intake regulation is the peripheral hormones that are secreted from the gastrointestinal tract. These hormones are secreted from enteroendocrine cells as feedback to nutrient and energy intake, and will communicate with the brain directly or via the vagus nerve. Gastrointestinal hormones are very crucial in maintaining a steady body weight, despite variations in nutrient intake and energy expenditure. In this review, we provide an overview of the regulation of feeding behavior by gut hormones, and its role in obesity treatments.

  19. The regulation of food intake by the gut-brain axis: implications for obesity.

    PubMed

    Hussain, S S; Bloom, S R

    2013-05-01

    Our understanding of the regulation of appetite has improved considerably over the last few decades. Recent work, stimulated by efforts aimed at curbing the current obesity epidemic, has unravelled some of the complex pathways regulating energy homeostasis. Key factors to this progress have been the discovery of leptin and the neuronal circuitry involved in mediating its effects, as well as the identification of gut hormones that have important physiological roles relating to energy homeostasis. Despite these advances in research, there are currently no effective treatments for the growing problem of obesity. In this article, we summarise the regulatory pathways controlling appetite with a special focus on gut hormones. We detail how recent findings have contributed to our knowledge regarding the pathogenesis and treatment of common obesity. A number of barriers still need to be overcome to develop safe and effective anti-obesity treatments. We outline problems highlighted by historical failures and discuss the potential of augmenting natural satiety signals, such as gut hormones, to treat obesity.

  20. Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration.

    PubMed

    Dinan, Timothy G; Cryan, John F

    2017-01-15

    There is a growing realisation that the gut-brain axis and its regulation by the microbiota may play a key role in the biological and physiological basis of neurodevelopmental, age-related and neurodegenerative disorders. The routes of communication between the microbiota and brain are being unravelled and include the vagus nerve, gut hormone signalling, the immune system, tryptophan metabolism or by way of microbial metabolites such as short chain fatty acids. The importance of early life gut microbiota in shaping future health outcomes is also emerging. Disturbances of this composition by way of antibiotic exposure, lack of breastfeeding, infection, stress and the environmental influences coupled with the influence of host genetics can result in long-term effects on physiology and behaviour, at least in animal models. It is also worth noting that mode of delivery at birth influences microbiota composition with those born by Caesarean section having a distinctly different microbiota in early life to those born per vaginum. At the other extreme of life, ageing is associated with a narrowing in microbial diversity and healthy ageing correlates with a diverse microbiome. Recently, the gut microbiota has been implicated in a variety of conditions including depression, autism, schizophrenia and Parkinson's disease. There is still considerable debate as to whether or not the gut microbiota changes are core to the pathophysiology of such conditions or are merely epiphenomenal. It is plausible that such neuropsychiatric disorders might be treated in the future by targeting the microbiota either by microbiota transplantation, antibiotics or psychobiotics.

  1. Prebiotic inulin: Useful dietary adjuncts to manipulate the livestock gut microflora.

    PubMed

    Samanta, A K; Jayapal, Natasha; Senani, S; Kolte, A P; Sridhar, Manpal

    2013-05-07

    In recent years, there has been a growing appreciation on the relevance of gastrointestinal microflora in both ruminants and non-ruminants owing to revelation of their role in several physiological functions including digestion, nutrient utilization, pathogen exclusion, gastrointestinal development, immunity system, gut gene expression and quality of animal products. The ban imposed on the use of antibiotics and hormones in feed has compelled animal researchers in finding an alternative which could overcome the issues of conventional feed additives. Though the concept of prebiotic was evolved keeping in mind the gastrointestinal flora of human beings, presently animal researchers are exploring the efficiency of prebiotic (inulin) for modulating the gut ecosystem of both ruminants and non-ruminants. It was revealed that prebiotic inulin is found to exhibit desirable changes in the gut of non-ruminants like poultry, swine, rabbit etc for augmenting gut health and improvement of product quality. Similarly, in ruminants the prebiotic reduces rumen ammonia nitrogen, methane production, increase microbial protein synthesis and live weight gains in calves. Unlike other feed additives, prebiotic exhibits its effect in multipronged ways for overall increase in the performances of the animals. In coming days, it is expected that prebiotics could be the part of diets in both ruminants and non-ruminants for enabling modulation of gut microflora vis a vis animals productivity in ecological ways.

  2. Prebiotic inulin: Useful dietary adjuncts to manipulate the livestock gut microflora

    PubMed Central

    Samanta, A.K.; Jayapal, Natasha; Senani, S.; Kolte, A.P.; Sridhar, Manpal

    2013-01-01

    In recent years, there has been a growing appreciation on the relevance of gastrointestinal microflora in both ruminants and non-ruminants owing to revelation of their role in several physiological functions including digestion, nutrient utilization, pathogen exclusion, gastrointestinal development, immunity system, gut gene expression and quality of animal products. The ban imposed on the use of antibiotics and hormones in feed has compelled animal researchers in finding an alternative which could overcome the issues of conventional feed additives. Though the concept of prebiotic was evolved keeping in mind the gastrointestinal flora of human beings, presently animal researchers are exploring the efficiency of prebiotic (inulin) for modulating the gut ecosystem of both ruminants and non-ruminants. It was revealed that prebiotic inulin is found to exhibit desirable changes in the gut of non-ruminants like poultry, swine, rabbit etc for augmenting gut health and improvement of product quality. Similarly, in ruminants the prebiotic reduces rumen ammonia nitrogen, methane production, increase microbial protein synthesis and live weight gains in calves. Unlike other feed additives, prebiotic exhibits its effect in multipronged ways for overall increase in the performances of the animals. In coming days, it is expected that prebiotics could be the part of diets in both ruminants and non-ruminants for enabling modulation of gut microflora vis a vis animals productivity in ecological ways. PMID:24159277

  3. Role of Gut Microbiota in the Aetiology of Obesity: Proposed Mechanisms and Review of the Literature

    PubMed Central

    Gerasimidis, Konstantinos; Edwards, Christine Ann; Shaikh, M. Guftar

    2016-01-01

    The aetiology of obesity has been attributed to several factors (environmental, dietary, lifestyle, host, and genetic factors); however none of these fully explain the increase in the prevalence of obesity worldwide. Gut microbiota located at the interface of host and environment in the gut are a new area of research being explored to explain the excess accumulation of energy in obese individuals and may be a potential target for therapeutic manipulation to reduce host energy storage. Several mechanisms have been suggested to explain the role of gut microbiota in the aetiology of obesity such as short chain fatty acid production, stimulation of hormones, chronic low-grade inflammation, lipoprotein and bile acid metabolism, and increased endocannabinoid receptor system tone. However, evidence from animal and human studies clearly indicates controversies in determining the cause or effect relationship between the gut microbiota and obesity. Metagenomics based studies indicate that functionality rather than the composition of gut microbiota may be important. Further mechanistic studies controlling for environmental and epigenetic factors are therefore required to help unravel obesity pathogenesis. PMID:27703805

  4. Role of gut nutrient sensing in stimulating appetite and conditioning food preferences

    PubMed Central

    Ackroff, Karen

    2012-01-01

    The discovery of taste and nutrient receptors (chemosensors) in the gut has led to intensive research on their functions. Whereas oral sugar, fat, and umami taste receptors stimulate nutrient appetite, these and other chemosensors in the gut have been linked to digestive, metabolic, and satiating effects that influence nutrient utilization and inhibit appetite. Gut chemosensors may have an additional function as well: to provide positive feedback signals that condition food preferences and stimulate appetite. The postoral stimulatory actions of nutrients are documented by flavor preference conditioning and appetite stimulation produced by gastric and intestinal infusions of carbohydrate, fat, and protein. Recent findings suggest an upper intestinal site of action, although postabsorptive nutrient actions may contribute to flavor preference learning. The gut chemosensors that generate nutrient conditioning signals remain to be identified; some have been excluded, including sweet (T1R3) and fatty acid (CD36) sensors. The gut-brain signaling pathways (neural, hormonal) are incompletely understood, although vagal afferents are implicated in glutamate conditioning but not carbohydrate or fat conditioning. Brain dopamine reward systems are involved in postoral carbohydrate and fat conditioning but less is known about the reward systems mediating protein/glutamate conditioning. Continued research on the postoral stimulatory actions of nutrients may enhance our understanding of human food preference learning. PMID:22442194

  5. Gut decontamination with norfloxacin and ampicillin enhances insulin sensitivity in mice.

    PubMed

    Chou, Chieh Jason; Membrez, Mathieu; Blancher, Florence

    2008-01-01

    Recent data suggest that gut microbiota plays a significant role in fat accumulation. However, it is not clear whether gut microbiota is involved in the pathophysiology of type-2 diabetes. To address this issue, we modulated gut microbiota with two combinations of antibiotics in two different mouse models with insulin resistance. Treatment with norfloxacin and ampicillin for 2 weeks reduced the cecal bacterial DNA below the level of detection in ob/ob, diet-induced obese and insulin resistance (DIO) mice, and significantly improved fasting glycemia and oral glucose tolerance of the treated animals. The enhanced insulin sensitivity was independent of food intake or adiposity because pair-fed ob/ob mice were as glucose intolerant as the untreated ob/ob mice. The reduced liver triglycerides, increased liver glycogen and improved glucose tolerance in the treated mice indicate broad impacts on metabolism by gut decontamination. The treatment with non-absorbable antibiotics polymyxin B and neomycin significantly modified cecal microbiota profile in the DIO mice, and the modified intestinal microbiota was associated with a gradual reduction in glycemia during a washout period. In summary, modulation of gut microbiota ameliorated glucose intolerance in mice and altered the hormonal, inflammatory and metabolic status of the host.

  6. The Microbiota-Gut-Brain Axis in Neuropsychiatric Disorders: Pathophysiological Mechanisms and Novel Treatments.

    PubMed

    Kim, Yong-Ku; Shin, Cheolmin

    2017-09-15

    The human gut microbiome comprise a huge number of microorganisms with co-evolutionary associations with humans. It has been repeatedly revealed that bidirectional communication exists between the brain and the gut and involves neural, hormonal, and immunological pathways. Evidences from neuroscience researches over the past few years suggest that microbiota is essential for the development and maturation of brain systems that are associated to stress responses. This review provides that the summarization of the communication among microbiota, gut and brain and the results of preclinical and clinical studies on gut microbiota used in treatments for neuropsychiatric disorders. Recent studies have reported that diverse forms of neuropsychiatric disorders (such as autism, depression, anxiety, and schizophrenia) are associated with or modulated by variations in the microbiome, by microbial substrates, and by exogenous prebiotics, antibiotics, and probiotics. The microbiota-gut-brain axis might provide novel targets for prevention and treatment of neuropsychiatric disorders. However, further studies are required to substantiate the clinical use of probiotics, prebiotics and FMT. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Role of gut nutrient sensing in stimulating appetite and conditioning food preferences.

    PubMed

    Sclafani, Anthony; Ackroff, Karen

    2012-05-15

    The discovery of taste and nutrient receptors (chemosensors) in the gut has led to intensive research on their functions. Whereas oral sugar, fat, and umami taste receptors stimulate nutrient appetite, these and other chemosensors in the gut have been linked to digestive, metabolic, and satiating effects that influence nutrient utilization and inhibit appetite. Gut chemosensors may have an additional function as well: to provide positive feedback signals that condition food preferences and stimulate appetite. The postoral stimulatory actions of nutrients are documented by flavor preference conditioning and appetite stimulation produced by gastric and intestinal infusions of carbohydrate, fat, and protein. Recent findings suggest an upper intestinal site of action, although postabsorptive nutrient actions may contribute to flavor preference learning. The gut chemosensors that generate nutrient conditioning signals remain to be identified; some have been excluded, including sweet (T1R3) and fatty acid (CD36) sensors. The gut-brain signaling pathways (neural, hormonal) are incompletely understood, although vagal afferents are implicated in glutamate conditioning but not carbohydrate or fat conditioning. Brain dopamine reward systems are involved in postoral carbohydrate and fat conditioning but less is known about the reward systems mediating protein/glutamate conditioning. Continued research on the postoral stimulatory actions of nutrients may enhance our understanding of human food preference learning.

  8. Edible Plants and Their Influence on the Gut Microbiome and Acne

    PubMed Central

    Clark, Ashley K.; Haas, Kelly N.; Sivamani, Raja K.

    2017-01-01

    Acne vulgaris affects most people at some point in their lives. Due to unclear etiology, likely with multiple factors, targeted and low-risk treatments have yet to be developed. In this review, we explore the multiple causes of acne and how plant-based foods and supplements can control these. The proposed causative factors include insulin resistance, sex hormone imbalances, inflammation and microbial dysbiosis. There is an emerging body of work on the human gut microbiome and how it mediates feedback between the foods we eat and our bodies. The gut microbiome is also an important mediator of inflammation in the gut and systemically. A low-glycemic load diet, one rich in plant fibers and low in processed foods, has been linked to an improvement in acne, possibly through gut changes or attenuation of insulin levels. Though there is much interest in the human microbiome, there is much more unknown, especially along the gut-skin axis. Collectively, the evidence suggests that approaches such as plant-based foods and supplements may be a viable alternative to the current first line standard of care for moderate acne, which typically includes antibiotics. Though patient compliance with major dietary changes is likely much lower than with medications, it is a treatment avenue that warrants further study and development. PMID:28513546

  9. Arabinoxylans, gut microbiota and immunity.

    PubMed

    Mendis, Mihiri; Leclerc, Estelle; Simsek, Senay

    2016-03-30

    Arabinoxylan (AX) is a non-starch polysaccharide found in many cereal grains and is considered as a dietary fiber. Despite their general structure, there is structural heterogeneity among AX originating from different botanical sources. Furthermore, the extraction procedure and hydrolysis by xylolytic enzymes can further render differences to theses AX. The aim of this review was to address the effects of AX on the gut bacteria and their immunomodulatory properties. Given the complex structure of AX, we also aimed to discuss how the structural heterogeneity of AX affects its role in bacterial growth and immunomodulation. The existing literature indicates the role of fine structural details of AX on its potential as polysaccharides that can impact the gut associated microbial growth and immune system.

  10. Training the gut for competition.

    PubMed

    Murray, Robert

    2006-05-01

    The gut is an important athletic organ because it mediates water and nutrient uptake during exercise. But upper- and lower-gastrointestinal complaints, common to many athletes during exercise, can negatively impact performance, and in severe cases put health at risk. The gut is sensitive to water and nutrient intake during exercise and to hypovolemia, hyperthermia, hypoglycemia, hypoxia, and ischemia. Most gastrointestinal complaints during exercise are mild and of no risk to health, but hemorrhagic gastritis, hematochezia, and ischemic bowel can present medical challenges. Proper training and nutrition minimize the risk of gastrointestinal discomfort during exercise by assuring rapid gastric emptying and absorption of water and nutrients and by maintaining adequate perfusion of the splanchnic vasculature.

  11. Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome

    PubMed Central

    Liu, Rui; Zhang, Chenhong; Shi, Yu; Zhang, Feng; Li, Linxia; Wang, Xuejiao; Ling, Yunxia; Fu, Huaqing; Dong, Weiping; Shen, Jian; Reeves, Andrew; Greenberg, Andrew S.; Zhao, Liping; Peng, Yongde; Ding, Xiaoying

    2017-01-01

    Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. Gut microbiota has been implicated to play a critical role in metabolic diseases and may modulate the secretion of mediators of the brain–gut axis. Interaction between gut microbiota and the endocrine and biochemical disturbances in PCOS still remains elusive. Here, we showed an altered gut microbiota significantly correlated with PCOS phenotype. There were 33 patients with PCOS (non-obese PCOS individuals, PN, n = 12; obese PCOS individuals, PO, n = 21) as well as 15 control subjects (non-obese control individuals, CN, n = 9; obese control individuals, CO, n = 6) enrolled in our study. The plasma levels of serotonin, ghrelin, and peptide YY (PYY) were significantly decreased in patients with PCOS compared with controls, and have a significantly negative correlation with waist circumference and testosterone. Sequencing of the V3–V4 region of the 16S rRNA gene in fecal samples revealed the substantial differences of gut microbial species between the PCOS and non-obese controls. Bacterial species were clustered into 23 co-abundance groups (CAGs) based on the SparCC correlation coefficients of their relative abundance. The CAGs increased in PCOS, including the bacteria belonging to Bacteroides, Escherichia/Shigella and Streptococcus, were negatively correlated with ghrelin, and positively correlated with testosterone and BMI. Furthermore, the CAGs that were decreased in PCOS, including the bacteria from Akkermansia and Ruminococcaceae, showed opposite relationship with body-weight, sex-hormone, and brain–gut peptides. In conclusion, gut microbial dysbiosis in women with PCOS is associated with the disease phenotypes. PMID:28293234

  12. Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome.

    PubMed

    Liu, Rui; Zhang, Chenhong; Shi, Yu; Zhang, Feng; Li, Linxia; Wang, Xuejiao; Ling, Yunxia; Fu, Huaqing; Dong, Weiping; Shen, Jian; Reeves, Andrew; Greenberg, Andrew S; Zhao, Liping; Peng, Yongde; Ding, Xiaoying

    2017-01-01

    Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. Gut microbiota has been implicated to play a critical role in metabolic diseases and may modulate the secretion of mediators of the brain-gut axis. Interaction between gut microbiota and the endocrine and biochemical disturbances in PCOS still remains elusive. Here, we showed an altered gut microbiota significantly correlated with PCOS phenotype. There were 33 patients with PCOS (non-obese PCOS individuals, PN, n = 12; obese PCOS individuals, PO, n = 21) as well as 15 control subjects (non-obese control individuals, CN, n = 9; obese control individuals, CO, n = 6) enrolled in our study. The plasma levels of serotonin, ghrelin, and peptide YY (PYY) were significantly decreased in patients with PCOS compared with controls, and have a significantly negative correlation with waist circumference and testosterone. Sequencing of the V3-V4 region of the 16S rRNA gene in fecal samples revealed the substantial differences of gut microbial species between the PCOS and non-obese controls. Bacterial species were clustered into 23 co-abundance groups (CAGs) based on the SparCC correlation coefficients of their relative abundance. The CAGs increased in PCOS, including the bacteria belonging to Bacteroides, Escherichia/Shigella and Streptococcus, were negatively correlated with ghrelin, and positively correlated with testosterone and BMI. Furthermore, the CAGs that were decreased in PCOS, including the bacteria from Akkermansia and Ruminococcaceae, showed opposite relationship with body-weight, sex-hormone, and brain-gut peptides. In conclusion, gut microbial dysbiosis in women with PCOS is associated with the disease phenotypes.

  13. BURNS: WHERE ARE WE STANDING WITH PROPRANOLOL, OXANDROLONE, rhGH, AND THE NEW INCRETIN ANALOGUES?

    PubMed Central

    Gauglitz, Gerd G; Williams, Felicia N; Herndon, David N.; Jeschke, Marc G

    2012-01-01

    Purpose of review The hypermetabolic response in critically ill patients is characterized by hyperdynamic circulatory, physiologic, catabolic and immune system responses. Failure to satisfy overwhelming energy and protein requirements after, and during critical illness, results in multiorgan dysfunction, increased susceptibility to infection, and death. Attenuation of the hypermetabolic response by various pharmacologic modalities is emerging as an essential component of the management of severe burn patients. This review focuses on the more recent advances in therapeutic strategies to attenuate the hypermetabolic response and its associated insulin resistance post-burn. Recent findings At present, beta-adrenergic blockade with propranolol represents probably the most efficacious anti-catabolic therapy in the treatment of burns. Other pharmacological strategies include growth hormone, insulin-like growth factor, oxandrolone and intensive insulin therapy. Summary Novel approaches to the management of critical illness by judicious glucose control and the use of pharmacologic modulators to the hypercatabolic response to critical illness have emerged. Investigation of alternative strategies, including the use of metformin, glucagon-like-peptide-1 and the PPAR-γ agonists are under current investigation. PMID:21157309

  14. Sex hormones in the modulation of irritable bowel syndrome.

    PubMed

    Mulak, Agata; Taché, Yvette; Larauche, Muriel

    2014-03-14

    Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of "microgenderome" related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.

  15. Sex hormones in the modulation of irritable bowel syndrome

    PubMed Central

    Mulak, Agata; Taché, Yvette; Larauche, Muriel

    2014-01-01

    Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of “microgenderome” related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder. PMID:24627581

  16. Gut microbiome and liver diseases.

    PubMed

    Tilg, Herbert; Cani, Patrice D; Mayer, Emeran A

    2016-12-01

    The gut microbiota has recently evolved as a new important player in the pathophysiology of many intestinal and extraintestinal diseases. The liver is the organ which is in closest contact with the intestinal tract, and is exposed to a substantial amount of bacterial components and metabolites. Various liver disorders such as alcoholic liver disease, non-alcoholic liver disease and primary sclerosing cholangitis have been associated with an altered microbiome. This dysbiosis may influence the degree of hepatic steatosis, inflammation and fibrosis through multiple interactions with the host's immune system and other cell types