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

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.

Download Full-text

Therapeutic Targets Underlying the Evolution of Potential Anti-Diabetic Agents: A Comprehensive Review

Current Diabetes Reviews ◽

10.2174/1573399818666211206100235 ◽

2021 ◽

Vol 18 ◽

Author(s):

Siddhita Tiwari ◽

Paranjeet Kaur ◽

Deepali Gupta ◽

Saumik Chaudhury ◽

Manish Chaudhary ◽

...

Keyword(s):

Type 2 Diabetes ◽

Beta Cell ◽

Glucose Level ◽

Glycogen Phosphorylase ◽

Dipeptidyl Peptidase ◽

The Body ◽

Dipeptidyl Peptidase 4 ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

: Type 2 Diabetes is termed as a chronic metabolic syndrome that occurs due to hyperglycaemia. Type 2 diabetes is growing worldwide really fast. Looking at all the circumstances, it was recognized that insulin check and Beta-cell brokenness are essential issues that are responsible for the unforeseen development of diabetes. Drugs for diabetes were found to have glucose level lessening impacts in the body and they were named as Glucagon-like peptide 1, amylin. Amylin is one of the hormones that show its action after having a meal; they have correlated activity to the pancreatic hormones. GLP-1 speedily corrupts via dipeptidyl-peptidase-4 in-vivo that leads to a decline in the said feasibility. Some other efficacious biological medicines that are being used for Type-2 Diabetes are 11beta-HSD-1 inhibitors or rivals in relation to glucocorticoids receptor, some other for reducing hepatic glucose level these are rival of glucagon receptor or maybe inhibitors to glycogen phosphorylase or fructose-1,6-biphosphatase, last but not least mounting urinary discarding of superfluity glucose those are SGLT inhibitors. Moreover, treatments related to Incretin can be glucagon-like peptide-1 [GLP-1] inhibitors and dipeptidyl peptidase 4 [DPP-4] inhibitors. Certain Non-incretin beta-cell stimulants are also in the phase of developments and they are glucokinase activators, G-protein-coupled receptors. These are soothing, antagonistic towards the oxidizing agent. Targets that cause glucose stimulant effect were glucose-6-phosphatase, glycogen phosphorylase and inhibition of same causes vice-versa. Some more novel targets are yet to be found; these superiors will additionally target metabolic ailment, as talking about the present situation it is one novel and primary clinical ailment that individual in the world estimated to suffer from the threat of 2nd type of diabetes.

Download Full-text

Pharmacotherapy for Type 2 Diabetes Mellitus: What’s Up and Coming in the Glucagon-Like Peptide-1 (GLP-1) Pipeline?

Journal of Pharmacy Practice ◽

10.1177/08971900211049032 ◽

2021 ◽

pp. 089719002110490

Author(s):

Mary J. Elder ◽

Emily J. Ashjian

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Glycemic Control ◽

Glucagon Secretion ◽

New Drugs ◽

Beneficial Effects ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is known to lower glucose levels, suppress glucagon secretion, and slow gastric emptying. These properties make GLP-1 an ideal target in treating type 2 diabetes mellitus (T2DM). There are many FDA-approved GLP-1 agonists on the market today, several of which have demonstrated benefit beyond improving glycemic control. Given the beneficial effects of GLP-1 agonists in patients with T2DM, new drugs are in development that combine the mechanism of action of GLP-1 receptor agonism with novel mechanisms and with drugs that promote GLP-1 secretion. These agents are designed to improve glycemic control and target greater body weight reduction. This article discusses new GLP-1 drugs in the pipeline for the treatment of T2DM.

Download Full-text

Improvement of metabolic state in an animal model of nutrition-dependent type 2 diabetes following treatment with S 23521, a new glucagon-like peptide 1 (GLP-1) analogue

Journal of Endocrinology ◽

10.1677/joe.1.05818 ◽

2005 ◽

Vol 184 (3) ◽

pp. 505-513 ◽

Cited By ~ 7

Author(s):

G Üçkaya ◽

P Delagrange ◽

A Chavanieu ◽

G Grassy ◽

M-F Berthault ◽

...

Keyword(s):

Type 2 Diabetes ◽

Food Intake ◽

High Energy ◽

Insulinogenic Index ◽

Β Cell ◽

Metabolic State ◽

Pancreatic Insulin ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide 1 (GLP-1) analogues are considered potential drugs for type 2 diabetes. We studied the effect of a novel GLP-1 analogue, S 23521 ([a8-des R36] GLP-1-[7–37]-NH2), on the metabolic state and β-cell function, proliferation and survival in the Psammomys obesus model of diet-induced type 2 diabetes. Animals with marked hyperglycaemia after 6 days of high-energy diet were given twice-daily s.c. injection of 100 μg/kg S 23521 for 15 days. Food intake was significantly decreased in S 23251-treated P. obesus; however, there was no significant difference in body weight from controls. Progressive worsening of hyperglycaemia was noted in controls, as opposed to maintenance of pre-treatment glucose levels in the S 23521 group. Prevention of diabetes progression was associated with reduced mortality. In addition, the treated group had higher serum insulin, insulinogenic index and leptin, whereas plasma triglyceride and non-esterified fatty acid levels were decreased. S 23521 had pronounced effect on pancreatic insulin, which was 5-fold higher than the markedly depleted insulin reserve of control animals. Immunohistochemical analysis showed islet degranulation with disrupted morphology in untreated animals, whereas islets from S 23521-treated animals appeared intact and filled with insulin; β-cell apoptosis was approximately 70% reduced, without a change in β-cell proliferation. S 23521 treatment resulted in a 2-fold increase in relative β-cell volume. Overall, S 23521 prevented the progression of diabetes in P. obesus with marked improvement of the metabolic profile, including increased pancreatic insulin reserve, β-cell viability and mass. These effects are probably due to actions of S 23521 both directly on islets and via reduced food intake, and emphasize the feasibility of preventing blood glucose deterioration over time in type 2 diabetes.

Download Full-text

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

Mediators of Inflammation ◽

10.1155/2013/591056 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Alessandra Puddu ◽

François Mach ◽

Alessio Nencioni ◽

Giorgio Luciano Viviani ◽

Fabrizio Montecucco

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Glucagon Secretion ◽

Advanced Glycation ◽

Chronic Hyperglycemia ◽

Gut Hormone ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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

Download Full-text

The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00665.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. E1038-E1046 ◽

Cited By ~ 95

Author(s):

Asger Lund ◽

Tina Vilsbøll ◽

Jonatan I. Bagger ◽

Jens J. Holst ◽

Filip K. Knop

Keyword(s):

Type 2 Diabetes ◽

Glucagon Secretion ◽

Tolerance Test ◽

Oral Glucose ◽

Intestinal Hormones ◽

Intravenous Glucose ◽

Glucagon Suppression ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Type 2 diabetes mellitus (T2DM) is associated with reduced suppression of glucagon during oral glucose tolerance test (OGTT), whereas isoglycemic intravenous glucose infusion (IIGI) results in normal glucagon suppression in these patients. We examined the role of the intestinal hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2) in this discrepancy. Glucagon responses were measured during a 3-h 50-g OGTT ( day A) and an IIGI ( day B) in 10 patients with T2DM [age (mean ± SE), 51 ± 3 yr; body mass index, 33 ± 2 kg/m2; HbA1c, 6.5 ± 0.2%]. During four additional IIGIs, GIP ( day C), GLP-1 ( day D), GLP-2 ( day E) and a combination of the three ( day F) were infused intravenously. Isoglycemia during all six study days was obtained. As expected, no suppression of glucagon occurred during the initial phase of the OGTT, whereas significantly ( P < 0.05) lower plasma levels of glucagon during the first 30 min of the IIGI ( day B) were observed. The glucagon response during the IIGI + GIP + GLP-1 + GLP-2 infusion ( day F) equaled the inappropriate glucagon response to OGTT ( P = not significant). The separate GIP infusion ( day C) elicited significant hypersecretion of glucagon, whereas GLP-1 infusion ( day D) resulted in enhancement of glucagon suppression during IIGI. IIGI + GLP-2 infusion ( day E) resulted in a glucagon response in the midrange between the glucagon responses to OGTT and IIGI. Our results indicate that the intestinal hormones, GIP, GLP-1, and GLP-2, may play a role in the inappropriate glucagon response to orally ingested glucose in T2DM with, especially, GIP, acting to increase glucagon secretion.

Download Full-text

Novel Approaches to the Treatment of Type 2 Diabetes

Journal of Pharmacy Practice ◽

10.1177/0897190008326578 ◽

2009 ◽

Vol 22 (3) ◽

pp. 320-332 ◽

Cited By ~ 3

Author(s):

Erin L. St. Onge ◽

Shannon A. Miller ◽

James R. Taylor

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Glucagon Secretion ◽

Current Evidence ◽

Β Cell Function ◽

Dipeptidyl Peptidase Iv Inhibitors ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Third Line

The emergence of the glucoregulatory hormone, glucagon-like peptide-1, has expanded our understanding of glucose homeostasis. The glucoregulatory actions of glucagon-like peptide-1 include enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to potentiate the effects of glucagon-like peptide-1 in those with type 2 diabetes. The glucagon-like peptide-1 analogs, such as exenatide, and dipeptidyl peptidase-IV inhibitors, such as sitagliptin, are currently available whereas others are in the final stages of development. These agents effectively reduce hemoglobin A1c while providing the other benefits associated with increased glucagon-like peptide-1. They also offer the potential to preserve the β-cell function. The effects on cardiovascular disease, if any, are unknown. Based on the current evidence, these agents represent viable second-and third-line options in the management of type 2 diabetes.

Download Full-text

Oral Semaglutide, the First Ingestible Glucagon-Like Peptide-1 Receptor Agonist: Could It Be a Magic Bullet for Type 2 Diabetes?

International Journal of Molecular Sciences ◽

10.3390/ijms22189936 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9936

Author(s):

Hwi Seung Kim ◽

Chang Hee Jung

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Receptor Agonist ◽

Body Weight Loss ◽

Glucagon Secretion ◽

Magic Bullet ◽

Early Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The gastrointestinal tract secretes gut hormones in response to food consumption, and some of these stimulate insulin secretion. Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone released from the lower digestive tract that stimulates insulin secretion, suppresses glucagon secretion, and decreases hunger. GLP-1 receptor agonist (GLP-1RA) mimics the action of endogenous GLP-1, consequently reversing hyperglycemia and causing weight reduction, demonstrating its efficacy as an antidiabetic and antiobesity agent. Previously restricted to injection only, the invention of the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate resulted in the development of oral semaglutide, the first ingestible GLP-1RA. Oral semaglutide demonstrated its efficacy in glycemic management and body weight loss with a low risk of hypoglycemia as a monotherapy and in combination with other hypoglycemic medications in its clinical trial programs named Peptide Innovation for Early Diabetes Treatment. Consistent with other injectable GLP-1RAs, gastrointestinal side effects were often reported. Additionally, cardiovascular safety was established by demonstrating that oral semaglutide was not inferior to a placebo in terms of cardiovascular outcomes. Thus, oral semaglutide represents a novel treatment option that is particularly well-suited for patients with type 2 diabetes and/or obesity.

Download Full-text