Volume 29, Issue 12 (3-2023)                   RJMS 2023, 29(12): 222-239 | Back to browse issues page

Research code: I-801
Ethics code: 1
Clinical trials code: ندارد

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Nikkar A, Fereidoni E, Karkhane A, Allahyari Fard N. Review of the Mechanism and Function of Glucagon-Like Peptide 1 (GLP-1) and GLP-1 Receptor Agonists in the Improvement of Type 2 Diabetes. RJMS 2023; 29 (12) :222-239
URL: http://rjms.iums.ac.ir/article-1-7473-en.html
National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran , allahyar@nigeb.ac.ir
Abstract:   (855 Views)
In 2019, the prevalence of diabetes was estimated at 463 million people, and it is predicted that its prevalence will reach 548 million people by 2045. The most common type of diabetes is type 2 diabetes (T2DM), which accounts for more than 90% of all diabetes cases and is the fifth leading cause of death in people aged 50 to 74 years (1). T2DM is a metabolic disorder that is associated with elevated blood glucose levels, insulin resistance, or relative insulin deficiency, and (2) is on the rise around the world due to progressive damage to beta cells (4). A combination of non-pharmacological measures (such as exercise and diet modification) and anti-diabetic drugs are commonly needed to improve glycemic control and slow disease progression (5). Incretin hormones are insulin-stimulating agents that are released from the gastrointestinal tract within minutes after eating (6,7). Intestinal function and incretin secretion have been reported to directly regulate pancreatic health (4). glucagon-like peptide 1 (GLP-1) is one of the types of incretins (7) that contains 42 amino acids and is synthesized in the L cells of the intestine by post-translational modifications of proglucagon by prohormone convertase 1 (PC1) (8,9). Recent evidences have shown that GLP-1 plays an important role in the regulation of glucose homeostasis (10-12). In several clinical trials, it has been observed that the adverse effects of incretin loss in patients with T2DM have improved after treatment with incretins or incretin agonists (13-15). In addition, evidences suggest that incretin-based therapies may have a positive effect on inflammation, cardiovascular and liver health, sleep, and the central nervous system (16). Intact GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) (20) and the resulting metabolite lacks insulinotropic activity (21). Therefore, less than 10% of the secreted GLP-1 is delivered to its target organs (23). using DPP-4 inhibitors (sitagliptin, vildagliptin) which prevent degradation of natural GLP-1, and synthesing DPP-4 resistant GLP-1 analogs (exenatide, liraglutide, exenatide LAR, albiglutide, D lixisenatide) are Two methods to overcome the short half-life defect of endogenous GLP-1 and achieve therapeutic benefits (25). The general effects of GLP-1 on metabolism include insulin secretion, glucagon inhibition, β cell preservation, suppression of gastric emptying, anorexia, weight loss, bone formation, and protection of certain organs (brain, heart, and kidney) (31). GLP-1 increases insulin sensitivity through several molecular mechanisms. These pathways are: 1- Reduction of oxidative stress through several molecular pathways (34-40), 2- Induction of insulin expression/secretion through various molecular mechanisms (40-42), 3- Improving insulin resistance due to inflammation by reducing pro-inflammatory mediators (43-45), 4- Increasing expression/localization of GLUT-4 in insulin-dependent tissues (46-49), 5- Improving the profile of plasma lipids, which leads to a decrease in insulin resistance due to dyslipidemia (50-54), 6- Improving the function of pancreatic beta cells through several molecular pathways (55-58), 7- Amplify insulin signal transmission in different stages (59-61), 8- Reducing endoplasmic reticulum stress (62,63). GLP-1 causes long-term glucose-lowering activity in a glucose-dependent manner, due to its insulinotropic action in pancreatic β cells (64). This activity of GLP-1 is partly mediated by interaction with β cells membrane GLP-1 receptors (65). In contrast, its non-insulinotropic function has been shown to have extra-pancreatic effects that may be useful in the prevention and treatment of diabetes-related complications and diseases independent of glycemic control (64). The results of studies have shown that exercise leads to the stimulation of GLP-1 secretion from intestinal L cells and α cells through an increase in IL-6 levels (71-73). GLP-1 (7-36) amide and GLP-1 (7-37) are two different biologically active isoforms of GLP-1 that are synthesized and secreted simultaneously in the body (74). Glucagon-like peptide 1 receptor (GLP1R) is a member of the GPCR (G protein-coupled receptor) glucagon receptor family found in pancreatic beta cells and brain neurons and is involved in controlling blood sugar levels by increasing insulin secretion (76-78). Glucagon-like peptide-1 receptor agonists are also known as incretin mimetics. These drugs are used to treat type 2 diabetes (85) and One of their advantages over older insulin-secreting stimulants, such as sulfonylureas or meglitinides, is that they have a lower risk of developing hypoglycemia (86). to overcome GLP-1 short duration of activity limitation, several modifications to the drug or its formulation are being developed. Approved GLP-1 receptor agonists are exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, and the GLP-1 receptor agonists under study are taspoglutide, efpeglenatide, and tirzepatide (87). GLP-1 analogs have a broad polytropic effect on metabolism. beneficial effects of GLP1R agonists consist of blood glucose regulation, weight loss through inhibition of food intake and gastric motility, stimulation of cell proliferation, reduction of inflammation and apoptosis, improvement of cardiovascular function, and neuroprotection (88). Liraglutide is an acyl GLP-1 agonist derived from the human GLP-1- (7-37), a less common form of endogenous GLP-1. It is a drug used to treat type 2 diabetes or obesity (90) and reduces meal-related hyperglycemia by increasing insulin secretion, delaying gastric emptying, and suppressing glucagon secretion during the meal. Liraglutide is resistant to metabolic degradation by peptidases with a plasma half-life of 13 hours (91,92). Exenatide is a 39 amino acid peptide with 50% amino acid homology with GLP-1 which has a longer half-life in vivo. It binds to the intact human GLP-1R in a manner similar to the human GLP-1 peptide (93,94). Lixisenatide is a  44 amino acids peptide with an amide group at its C terminal which is a GLP-1 receptor agonist used as a diet and exercise supplement to treat type 2 diabetes (95). Albiglutide is another GLP-1 agonist that can be used alone or in combination with other anti-diabetic drugs, including insulin, to treat type 2 diabetes in adults. According to an analysis in 2015, Albiglutide is less effective than other GLP-1 agonists in reducing glycated hemoglobin (HbA1c, an indicator of long-term blood glucose control) and weight loss (96). Dulaglutide is an adult diet supplement and exercise supplement for improving blood sugar control in adults with type 2 diabetes which can be used alone or in combination with other medicines for type 2 diabetes, especially metformin, sulfonylureas, thiazolidinediones, and insulin is taken with food. Dulaglutide is not recommended for the treatment of people with type 1 diabetes or patients with diabetic ketoacidosis, as these problems are due to the inability of islet cells to produce insulin, and one of the actions of Dulaglutide is to stimulate islet cells to produce more insulin (97). Semaglutide is chemically similar to human GLP-1 with 94% similarity and acts like GLP-1 because it increases insulin secretion and sugar metabolism. It is administered by subcutaneous injection in a pre-filled pen or orally. One of its advantages over other anti-diabetic drugs is that it has a long-lasting effect, so a once-weekly injection is sufficient. It has been shown to supplement diet and exercise to improve blood sugar control in adults with type 2 diabetes (98,99). Finally, GLP-1R activation leads to cAMP production and cAMP-dependent activation of protein kinase A (PKA) and Epac2 messenger pathways. These pathways are involved in a variety of intracellular events, including increased systolic calcium levels, altered ion channel activity, and increased exocytosis of insulin-containing granules, all of which participate in the stimulation of insulin secretion in a glucose-dependent manner. Current therapeutic approaches, including drastic lifestyle modifications and dietary and pharmacological interventions to control the global increase in metabolic disorders, including type 2 diabetes, are not sufficient. Therefore, a new method is needed to combat metabolic disorders. Although GLP-1 has several potentially beneficial effects on type 2 diabetes, it is not a suitable treatment for type 2 diabetes due to its short half-life. Therefore, due to the reduction of GLP-1 incretin hormone activity in patients with type 2 diabetes, incretin mimics have been developed as new therapeutic agents for the treatment of type 2 diabetes.
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Type of Study: review article | Subject: Endocrinology & Metabolism

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