JTT-130, a Novel Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein, Suppresses Food Intake and Gastric Emptying with the Elevation of Plasma Peptide YY and Glucagon-Like Peptide-1 in a Dietary Fat-Dependent Manner

The proglucagon gene gives rise to multiple peptides that play diverse roles in the control of energy intake, gut motility, and nutrient disposal. Glucagon-like peptide-1 (GLP-1), a 30-amino-acid peptide regulates glucose homeostasis via control of insulin and glucagon secretion and by inhibition of gastric emptying and food intake. Oxyntomodulin (OXM) a 37-amino-acid peptide also derived from the proglucagon gene, binds to both the glucagon and GLP-1 receptor (GLP-1R); however, a separate OXM receptor has not yet been identified. Here we show that OXM, like other GLP-1R agonists, stimulates cAMP formation and lowers blood glucose after both oral and ip glucose administration, actions that require a functional GLP-1R. OXM also directly stimulates insulin secretion from murine islets and INS-1 cells in a glucose- and GLP-1R-dependent manner. Moreover, OXM ameliorates hyperglycemia and significantly reduces apoptosis in murine β-cells after streptozotocin administration and directly reduces apoptosis in thapsigargin-treated INS-1 cells. Unexpectedly, OXM, but not the GLP-1R agonist exendin-4, increased plasma levels of insulin after oral glucose administration. Moreover, OXM administered at doses that potently lower blood glucose had no effect on inhibition of gastric emptying but reduced food intake in WT mice. Taken together, these findings illustrate that although structurally distinct proglucagon-derived peptides such as GLP-1 and OXM engage the GLP-1R, OXM mimics some but not all of the actions of GLP-1R agonists in vivo. These findings may have implications for therapeutic efforts using OXM as a long-acting GLP-1R agonist for the treatment of metabolic disorders.

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Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00446.2012 ◽

2013 ◽

Vol 304 (7) ◽

pp. E677-E685 ◽

Cited By ~ 34

Author(s):

Melissa A. Burmeister ◽

Jennifer Ayala ◽

Daniel J. Drucker ◽

Julio E. Ayala

Keyword(s):

Food Intake ◽

Glucose Metabolism ◽

Dependent Manner ◽

Anorectic Effect ◽

Dependent Inhibition ◽

Glycolytic Inhibitor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Amp Activated Protein Kinase ◽

Mediated Reduction

Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.

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Do the Actions of Glucagon-Like Peptide-1 on Gastric Emptying, Appetite, and Food Intake Involve Release of Amylin in Humans?

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2133 ◽

2010 ◽

Vol 95 (5) ◽

pp. 2367-2375 ◽

Cited By ~ 23

Author(s):

Meena Asmar ◽

Michael Bache ◽

Filip K. Knop ◽

Sten Madsbad ◽

Jens J. Holst

Keyword(s):

Gastric Emptying ◽

Food Intake ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery

International Journal of Obesity ◽

10.1038/ijo.2016.121 ◽

2016 ◽

Vol 40 (11) ◽

pp. 1699-1706 ◽

Cited By ~ 83

Author(s):

M S Svane ◽

N B Jørgensen ◽

K N Bojsen-Møller ◽

C Dirksen ◽

S Nielsen ◽

...

Keyword(s):

Gastric Bypass ◽

Food Intake ◽

Bypass Surgery ◽

Peptide Yy ◽

Gastric Bypass Surgery ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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GPR119 Regulates Murine Glucose Homeostasis Through Incretin Receptor-Dependent and Independent Mechanisms

Endocrinology ◽

10.1210/en.2010-1047 ◽

2010 ◽

Vol 152 (2) ◽

pp. 374-383 ◽

Cited By ~ 44

Author(s):

Grace Flock ◽

Dianne Holland ◽

Yutaka Seino ◽

Daniel J. Drucker

Keyword(s):

Insulin Secretion ◽

Gastric Emptying ◽

Glucose Tolerance ◽

Glucose Homeostasis ◽

Peptide Yy ◽

Cell Receptor ◽

Dependent Manner ◽

Glucagon Like Peptide 1

Abstract G protein-coupled receptor 119 (GPR119) was originally identified as a β-cell receptor. However, GPR119 activation also promotes incretin secretion and enhances peptide YY action. We examined whether GPR119-dependent control of glucose homeostasis requires preservation of peptidergic pathways in vivo. Insulin secretion was assessed directly in islets, and glucoregulation was examined in wild-type (WT), single incretin receptor (IR) and dual IR knockout (DIRKO) mice. Experimental endpoints included plasma glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY. Gastric emptying was assessed in WT, Glp1r−/−, DIRKO, Glp2r−/−, and GPR119−/− mice treated with the GPR119 agonist AR231453. AR231453 stimulated insulin secretion from WT and DIRKO islets in a glucose-dependent manner, improved glucose homeostasis, and augmented plasma levels of GLP-1, GIP, and insulin in WT and Gipr−/−mice. In contrast, although AR231453 increased levels of GLP-1, GIP, and insulin, it failed to lower glucose in Glp1r−/− and DIRKO mice. Furthermore, AR231453 did not improve ip glucose tolerance and had no effect on insulin action in WT and DIRKO mice. Acute GPR119 activation with AR231453 inhibited gastric emptying in Glp1r−/−, DIRKO, Glp2r−/−, and in WT mice independent of the Y2 receptor (Y2R); however, AR231453 did not control gastric emptying in GPR119−/− mice. Our findings demonstrate that GPR119 activation directly stimulates insulin secretion from islets in vitro, yet requires intact IR signaling and enteral glucose exposure for optimal control of glucose tolerance in vivo. In contrast, AR231453 inhibits gastric emptying independent of incretin, Y2R, or Glp2 receptors through GPR119-dependent pathways. Hence, GPR119 engages multiple complementary pathways for control of glucose homeostasis.

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JTT-130, a Novel Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein, Improves Hyperglycemia and Dyslipidemia Independent of Suppression of Food Intake in Diabetic Rats

Journal of Diabetes Research ◽

10.1155/2014/803832 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Shohei Sakata ◽

Makoto Ito ◽

Yasuko Mera ◽

Tomohiko Sasase ◽

Hiromi Yamamoto ◽

...

Keyword(s):

Lipid Metabolism ◽

Treatment Group ◽

Food Intake ◽

Plasma Cholesterol ◽

Specific Inhibitor ◽

Microsomal Triglyceride Transfer Protein ◽

Diabetic Rats ◽

Glucose And Lipid Metabolism ◽

Zdf Rats ◽

Glucagon Like Peptide 1

We investigated the effects of JTT-130 on glucose and lipid metabolism independent of the suppression of feeding by comparing with pair-fed animals. Male Zucker diabetic fatty (ZDF) rats were divided into control, JTT-130 treatment, and pair-fed groups. The rats were fed with a regular powdered diet with or without JTT-130 as a food admixture for 6 weeks. We compared the effects on glucose and lipid metabolism in JTT-130 treatment group with those in pair-fed group.Results. Hyperglycemia in ZDF rats was prevented in both JTT-130 treatment and pair-fed groups, but the prevention in pair-fed group became poor with time. Moreover, reduction in plasma cholesterol levels was observed only in JTT-130 treatment group. JTT-130 treatment group showed improved glucose tolerance at 5 weeks after treatment and significant elevation of portal glucagon-like peptide-1 (GLP-1) levels. The hepatic lipid content in JTT-130 treatment group was decreased as compared with pair-fed group. Furthermore, pancreatic protection effects, such as an increase in pancreatic weight and an elevation of insulin-positive area in islets, were observed after JTT-130 treatment.Conclusions. JTT-130 improves hyperglycemia and dyslipidemia via a mechanism independent of suppression of food intake, which is ascribed to an enhancement of GLP-1 secretion and a reduction of lipotoxicity.

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Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.281.3.g752 ◽

2001 ◽

Vol 281 (3) ◽

pp. G752-G763 ◽

Cited By ~ 68

Author(s):

Feruze Y. Enç ◽

Neşe I˙meryüz ◽

Levent Akin ◽

Turgut Turoğlu ◽

Fuat Dede ◽

...

Keyword(s):

Gastric Emptying ◽

Peptide Yy ◽

Area Under The Curve ◽

Gut Hormones ◽

Random Order ◽

Mixed Meal ◽

Carbohydrate Absorption ◽

Plasma Response ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

We investigated the effect of acarbose, an α-glucosidase and pancreatic α-amylase inhibitor, on gastric emptying of solid meals of varying nutrient composition and plasma responses of gut hormones. Gastric emptying was determined with scintigraphy in healthy subjects, and all studies were performed with and without 100 mg of acarbose, in random order, at least 1 wk apart. Acarbose did not alter the emptying of a carbohydrate-free meal, but it delayed emptying of a mixed meal and a carbohydrate-free meal given 2 h after sucrose ingestion. In meal groups with carbohydrates, acarbose attenuated responses of plasma insulin and glucose-dependent insulinotropic polypeptide (GIP) while augmenting responses of CCK, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). With mixed meal + acarbose, area under the curve (AUC) of gastric emptying was positively correlated with integrated plasma response of GLP-1 ( r = 0.68 , P < 0.02). With the carbohydrate-free meal after sucrose and acarbose ingestion, AUC of gastric emptying was negatively correlated with integrated plasma response of GIP, implying that prior alteration of carbohydrate absorption modifies gastric emptying of a meal. The results demonstrate that acarbose delays gastric emptying of solid meals and augments release of CCK, GLP-1, and PYY mainly by retarding/inhibiting carbohydrate absorption. Augmented GLP-1 release by acarbose appears to play a major role in the inhibition of gastric emptying of a mixed meal, whereas CCK and PYY may have contributory roles.

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PACAP intraperitoneal treatment suppresses appetite and food intake via PAC1 receptor in mice by inhibiting ghrelin and increasing GLP-1 and leptin

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00190.2015 ◽

2015 ◽

Vol 309 (10) ◽

pp. G816-G825 ◽

Cited By ~ 9

Author(s):

John P. Vu ◽

Deepinder Goyal ◽

Leon Luong ◽

Suwan Oh ◽

Ravneet Sandhu ◽

...

Keyword(s):

Food Intake ◽

Feeding Behavior ◽

Peptide Yy ◽

Dark Phase ◽

Dependent Manner ◽

Pac1 Receptor ◽

Intraperitoneal Treatment ◽

Regulate Food Intake ◽

Feeding Parameters ◽

Glucagon Like Peptide 1

Pituitary adenylate cyclase-activating peptide (PACAP) is expressed within the gastroenteric system, where it has profound physiological effects. PACAP was shown to regulate food intake and thermogenesis centrally; however, PACAP peripheral regulation of appetite and feeding behavior is unknown. Therefore, we studied PACAP's effect on appetite and food intake control by analyzing feeding behavior and metabolic hormones in PAC1-deficient (PAC1−/−) and age-matched wild-type (WT) mice intraperitoneally injected with PACAP1–38 or PACAP1–27 before the dark phase of feeding. Food intake and feeding behavior were analyzed using the BioDAQ system. Active ghrelin, glucagon-like peptide-1 (GLP-1), leptin, peptide YY, pancreatic polypeptide, and insulin were measured following PACAP1–38 administration in fasted WT mice. PACAP1–38/PACAP1–27 injected into WT mice significantly decreased in a dose-dependent manner cumulative food intake and reduced bout and meal feeding parameters. Conversely, PACAP1–38 injected into PAC1−/− mice failed to significantly change food intake. Importantly, PACAP1–38 reduced plasma levels of active ghrelin compared with vehicle in WT mice. In PAC1−/− mice, fasting levels of active ghrelin, GLP-1, insulin, and leptin and postprandial levels of active ghrelin and insulin were significantly altered compared with levels in WT mice. Therefore, PAC1 is a novel regulator of appetite/satiety. PACAP1–38/PACAP1–27 significantly reduced appetite and food intake through PAC1. In PAC1−/− mice, the regulation of anorexigenic/orexigenic hormones was abolished, whereas active ghrelin remained elevated even postprandially. PACAP significantly reduced active ghrelin in fasting conditions. These results establish a role for PACAP via PAC1 in the peripheral regulation of appetite/satiety and suggest future studies to explore a therapeutic use of PACAP or PAC1 agonists for obesity treatment.

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Glucagon Like Peptide 1 and Evidence Around Diabetes Specific Nutrition

World Nutrition ◽

10.26596/wn.201910264-75 ◽

2019 ◽

Vol 10 (2) ◽

pp. 64-75

Author(s):

ANSHU JOSHI ◽

SAMEER RAO ◽

GANESH KADHE

Keyword(s):

Fatty Acids ◽

Insulin Secretion ◽

Gastric Emptying ◽

Food Intake ◽

Diabetes Management ◽

Monounsaturated Fatty Acids ◽

Complex Carbohydrate ◽

Soluble Fibre ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

There has been significant research and development in pharmaco-therapeutic molecules for management of type 2 diabetes mellitus (T2DM). Diabetes specific nutrition intervention & newer incretin-based therapies have gained a lot of attention. Since incretins play an essential role in augmenting the post-prandial release of insulin, it is important to understand the science behind incretins and modulation of same by diabetic-specific nutrition (DSN). The purpose of this article is to summarize the available science around glucagon like peptide 1 (GLP-1) and the known role of nutrition, particularly diabetes specific nutrition. Literature published in PubMed, Google scholar and Embase were studied up to the end of August 2018. The key words of GLP-1, T2DM and Nutrients were used in different combinations. It was found that macronutrient aspects of DSN like complex carbohydrate, soluble fibre, proteins and high monounsaturated fatty acids augment GLP-1 secretion from intestinal L-cells. This may be attributed to insulin-trophic effects of DSN as well as its effects in causing deceleration in gastric emptying and reducing food intake. Hence, it was concluded that augmenting GLP-1 secretion in response to the intake of certain nutrients helps in modulating insulin secretion, metabolic homeostasis as well as decelerating gastric emptying and reducing food intake. DSN increases endogenous GLP-1 secretion which in turn improves insulin secretion and sensitivity. Thus, integrating DSN in mainstay diabetes management plans may result in better glycaemic and metabolic controls, particularly when GLP-1 based therapies are concurrently in use. Key Messages: DSN containing complex carbohydrate, soluble fibre, proteins and high monounsaturated fatty acids (MUFAs) augments GLP-1 secretion which in turn improves insulin secretion and sensitivity.

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