The Physiology of Glucagon-like Peptide 1

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

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The glucagon-like peptide-1 metabolite GLP-1-(9–36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00576.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. E1118-E1123 ◽

Cited By ~ 60

Author(s):

Juris J. Meier ◽

Arnica Gethmann ◽

Michael A. Nauck ◽

Oliver Götze ◽

Frank Schmitz ◽

...

Keyword(s):

Gastric Emptying ◽

Plasma Concentrations ◽

Glucagon Secretion ◽

Postprandial Glucose ◽

Glucose Disposal ◽

C Peptide ◽

Postprandial Glycemia ◽

Insulin And Glucagon Secretion ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide 1 (GLP-1) lowers glycemia by modulating gastric emptying and endocrine pancreatic secretion. Rapidly after its secretion, GLP-1-(7–36) amide is degraded to the metabolite GLP-1-(9–36) amide. The effects of GLP-1-(9–36) amide in humans are less well characterized. Fourteen healthy volunteers were studied with intravenous infusion of GLP-1-(7–36) amide, GLP-1-(9–36) amide, or placebo over 390 min. After 30 min, a solid test meal was served, and gastric emptying was assessed. Blood was drawn for GLP-1 (total and intact), glucose, insulin, C-peptide, and glucagon measurements. Administration of GLP-1-(7–36) amide and GLP-1-(9–36) amide significantly raised total GLP-1 plasma levels. Plasma concentrations of intact GLP-1 increased to 21 ± 5 pmol/l during the infusion of GLP-1-(7–36) amide but remained unchanged during GLP-1-(9–36) amide infusion [5 ± 3 pmol/l; P < 0.001 vs. GLP-1-(7–36) amide administration]. GLP-1-(7–36) amide reduced fasting and postprandial glucose concentrations ( P < 0.001) and delayed gastric emptying ( P < 0.001). The GLP-1 metabolite had no influence on insulin or C-peptide concentrations. Glucagon levels were lowered by GLP-1-(7–36) amide but not by GLP-1-(9–36) amide. However, the postprandial rise in glycemia was reduced significantly (by ∼6 mg/dl) by GLP-1-(9–36) amide ( P < 0.05). In contrast, gastric emptying was completely unaffected by the GLP-1 metabolite. The GLP-1 metabolite lowers postprandial glycemia independently of changes in insulin and glucagon secretion or in the rate of gastric emptying. Most likely, this is because of direct effects on glucose disposal. However, the glucose-lowering potential of GLP-1-(9–36) amide appears to be small compared with that of intact GLP-1-(7–36) amide.

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Distribution and function of glucagon-like peptide 1 (GLP-1) in the digestive tract of mammals and the clinical use of its analogues

Medycyna Weterynaryjna ◽

10.21521/mw.6374 ◽

2023 ◽

Vol 76 (07) ◽

pp. 6374-2023 ◽

Cited By ~ 1

Author(s):

ALEKSANDRA GÓRSKA ◽

MARCIN B. ARCISZEWSKI

Keyword(s):

Type 2 Diabetes ◽

Food Intake ◽

Metabolic Diseases ◽

Biological Effects ◽

Glucagon Secretion ◽

The Body ◽

Reactive Hypoglycemia ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Recently, interest in glucagon-like peptide-1 (GLP-1) and other peptides derived from preproglucagon has increased significantly. GLP-1 is a 30-amino acid peptide hormone produced in L-type enteroendocrine cells as a response to food intake. GLP-1 is rapidly metabolized and inactivated by the dipeptidyl peptidase IV enzyme before the hormone leaves the intestine, which increases the likelihood that GLP-1 action is transmitted through sensory neurons in the intestine and liver through the GLP-1 receptor. The main actions of GLP-1 are to stimulate insulin secretion (i.e. act as incretin hormone) and inhibit glucagon secretion, thus contributing to the reduction of postprandial glucose spikes. GLP-1 also inhibits motility and gastrointestinal secretion, and therefore acts as part of the „small bowel brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these effects, GLP-1 or GLP-1 receptor agonists are now increasingly used to treat type 2 diabetes. Reduced GLP-1 secretion may contribute to the development of obesity, and excessive secretion may be responsible for postprandial reactive hypoglycemia. The use of GLP-1 agonists opens up new possibilities for the treatment of type 2 diabetes and other metabolic diseases. In the last two decades, many interesting studies covering both the physiological and pathophysiological role of GLP-1 have been published, and our understanding of GLP-1 has broadened significantly. In this review article, we have tried to describe our current understanding of how GLP-1 works as both a peripheral hormone and as a central neurotransmitter in health and disease. We focused on its biological effects on the body and the potential clinical application in relation to current research.

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The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect

Cardiovascular Diabetology ◽

10.1186/s12933-021-01412-5 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Enrique Z. Fisman ◽

Alexander Tenenbaum

Keyword(s):

Receptor Agonist ◽

Therapeutic Option ◽

Insulin Response ◽

Glucagon Secretion ◽

Long Term Effects ◽

Glucose Levels ◽

Lower Glucose ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Gip Receptor

AbstractIncretin hormones are peptides released in the intestine in response to the presence of nutrients in its lumen. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 stimulates insulin secretion, inhibits glucagon secretion at pancreatic α cells and has also extrapancreatic influences as slowing of gastric emptying which increases the feeling of satiety. GIP is the main incretin hormone in healthy people, causative of most the incretin effects, but the insulin response after GIP secretion in type 2 diabetes mellitus (T2DM) is strongly reduced. Therefore, in the past GIP has been considered an unappealing therapeutic target for T2DM. This conception has been changing during recent years, since it has been reported that resistance to GIP can be reversed and its effectiveness restored by improving glycemic control. This fact paved the way for the development of a GIP receptor agonist-based therapy for T2DM, looking also for the possibility of finding a combined GLP-1/GIP receptor agonist. In this framework, the novel dual GIP and GLP-1 receptor agonist tirzepatide seems to be not just a new antidiabetic medication. Administered as a subcutaneous weekly injection, it is a manifold single pharmacological agent that has the ability to significantly lower glucose levels, as well as improve insulin sensitivity, reduce weight and amend dyslipidemia favorably modifying the lipid profile. Tirzepatide and additional dual GLP-1/GIP receptor agonists that could eventually be developed in the future seem to be a promising furthest advance for the management of several cardiometabolic settings. Obviously, it is too early to be overly hopeful since it is still necessary to determine the long-term effects of these compounds and properly verify the potential cardiovascular benefits. Anyway, we are currently facing a novel and very appealing therapeutic option.

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

Metabolism ◽

10.1016/j.metabol.2009.10.021 ◽

2010 ◽

Vol 59 (7) ◽

pp. 988-992 ◽

Cited By ~ 11

Author(s):

Giovanni Pacini ◽

Karl Thomaseth ◽

Bo Ahrén

Keyword(s):

Insulin Clearance ◽

Cell Secretion ◽

Β Cell ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Postprandial glucose, insulin and glucagon-like peptide 1 responses to sucrose ingested with berries in healthy subjects

British Journal Of Nutrition ◽

10.1017/s0007114511004557 ◽

2011 ◽

Vol 107 (10) ◽

pp. 1445-1451 ◽

Cited By ~ 61

Author(s):

Riitta Törrönen ◽

Essi Sarkkinen ◽

Tarja Niskanen ◽

Niina Tapola ◽

Kyllikki Kilpi ◽

...

Keyword(s):

Healthy Subjects ◽

Serum Insulin ◽

Venous Blood ◽

Postprandial Glucose ◽

Carbohydrate Ingestion ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Meal Ingestion ◽

Single Blind ◽

Modest Effect

Berries are often consumed with sucrose. They are also rich sources of polyphenols which may modulate glycaemia after carbohydrate ingestion. The present study investigated the postprandial glucose, insulin and glucagon-like peptide 1 (GLP-1) responses to sucrose ingested with berries, in comparison with a similar sucrose load without berries. A total of twelve healthy subjects were recruited to a randomised, single-blind, placebo-controlled crossover study. They participated in two meal tests on separate days. The berry meal was a purée (150 g) made of bilberries, blackcurrants, cranberries and strawberries with 35 g sucrose. The control meal included the same amount of sucrose and available carbohydrates in water. Fingertip capillary and venous blood samples were taken at baseline and at 15, 30, 45, 60, 90 and 120 min after starting to eat the meal. Glucose, insulin and GLP-1 concentrations were determined from the venous samples, and glucose also from the capillary samples. Compared to the control meal, ingestion of the berry meal resulted in lower capillary and venous plasma glucose and serum insulin concentrations at 15 min (P = 0·021,P < 0·007 andP = 0·028, respectively), in higher concentrations at 90 min (P = 0·028,P = 0·021 andP = 0·042, respectively), and in a modest effect on the GLP-1 response (P = 0·05). It also reduced the maximum increases of capillary and venous glucose and insulin concentrations (P = 0·009,P = 0·011 andP = 0·005, respectively), and improved the glycaemic profile (P < 0·001 andP = 0·003 for capillary and venous samples, respectively). These results suggest that the glycaemic control after ingestion of sucrose can be improved by simultaneous consumption of berries.

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Molecular mechanisms underlying nutrient-stimulated incretin secretion

Expert Reviews in Molecular Medicine ◽

10.1017/s146239940900132x ◽

2010 ◽

Vol 12 ◽

Cited By ~ 102

Author(s):

Helen E. Parker ◽

Frank Reimann ◽

Fiona M. Gribble

Keyword(s):

Drug Discovery ◽

Molecular Mechanisms ◽

Fat Metabolism ◽

Potential Range ◽

Incretin Hormones ◽

Appetite Control ◽

K Cells ◽

Incretin Secretion ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in the intestinal epithelium in response to nutrient ingestion. The actions of GLP-1 and GIP – not only on local gut physiology but also on glucose homeostasis, appetite control and fat metabolism – have made these hormones an attractive area for drug discovery programmes. The potential range of strategies to target the secretion of these hormones therapeutically has been limited by an incomplete understanding of the mechanisms underlying their release. The use of organ and whole-animal perfusion techniques, cell line models and primary L- and K-cells has led to the identification of a variety of pathways involved in the sensing of carbohydrate, fat and protein in the gut lumen. This review focuses on our current understanding of these signalling mechanisms that might underlie nutrient responsiveness of L- and K-cells.

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Effects of GLP-1 and Incretin-Based Therapies on Gastrointestinal Motor Function

Experimental Diabetes Research ◽

10.1155/2011/279530 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 43

Author(s):

Chinmay S. Marathe ◽

Christopher K. Rayner ◽

Karen L. Jones ◽

Michael Horowitz

Keyword(s):

Inhibitory Action ◽

Current Knowledge ◽

Incretin Hormone ◽

Distal Small Intestine ◽

Gastrointestinal Motor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Antiobesity Agents ◽

Motor Actions

Glucagon-like peptide 1 (GLP-1) is a hormone secreted predominantly by the distal small intestine and colon and released in response to enteral nutrient exposure. GLP-1-based therapies are now used widely in the management of type 2 diabetes and have the potential to be effective antiobesity agents. Although widely known as an incretin hormone, there is a growing body of evidence that GLP-1 also acts as an enterogastrone, with profound effects on the gastrointestinal motor system. Moreover, the effects of GLP-1 on gastrointestinal motility appear to be pivotal to its effect of reducing postprandial glycaemic excursions and may, potentially, represent the dominant mechanism. This review summarizes current knowledge of the enterogastrone properties of GLP-1, focusing on its effects on gut motility at physiological and pharmacological concentrations, and the motor actions of incretin-based therapies. While of potential importance, the inhibitory action of GLP-1 on gastric acid secretion is beyond the scope of this paper.

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Intra-islet regulation of hormone secretion by glucagon-like peptide-1-(7--36) amide

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1995.269.6.g852 ◽

1995 ◽

Vol 269 (6) ◽

pp. G852-G860 ◽

Cited By ~ 2

Author(s):

R. S. Heller ◽

G. W. Aponte

Keyword(s):

Monoclonal Antibodies ◽

Insulin Secretion ◽

Hormone Secretion ◽

Glucagon Secretion ◽

Posttranslational Processing ◽

Alpha Cells ◽

Islet Hormone ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Peptide Product

Glucagon-like peptide (GLP)-1-(7--36) amide, a peptide product of the posttranslational processing of pancreatic and intestinal proglucagon, has been shown to regulate insulin secretion. Monoclonal antibodies to glucagon and GLP-1-(7--36) amide were generated to localize GLP-1-(7--36) amide in the pancreatic islets by immunocytochemistry and radioimmunoassay. GLP-1-(7--36) amide immunoreactivity was found in some, but not all, glucagon-containing alpha-cells. Displaceable receptor binding for GLP-1-(7--36) amide and nonamidated GLP-1-(7--37) on hormone secretion were investigated using isolated pancreatic islet preparations. GLP-1-(7--37) and -(7--36) amide significantly increased insulin and somatostatin release in the concentration range of 0.01-100 nM in 11.0 mM glucose. GLP-1-(7--37) and -(7--36) amide had no effect on glucagon secretion in the presence of 11.0 mM glucose. GLP-1-(7--36) amide was released from isolated islets in response to 2.25, 5.5, and 11.0 mM glucose. These results suggest that pancreatic GLP-1 may be important in the regulation of intra-islet hormone secretion.

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