Recently, incretin hormone-based therapies, including glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors, have become the main therapeutic tools in the hyperglycemia management in patients with type 2 diabetes mellitus. These therapeutic agents could fill an important gap in glycemic control for patients with type 2 diabetes because the incretin response is blunted in type 2 diabetes mellitus. GLP-1 analogues can be classified as exendin-4 backbone (Exenatide, Exenatide LAR and Lixisenatide) and human GLP-1 backbone (Liraglutide, Taspoglutide and Albiglutide). Among these, Exenatide, Exenatide LAR and Liraglutide are currently available. This review will focus on the clinical efficacies of GLP-1 analogues in glycemic control for patients with diabetes.
Diabetes Mellitus, Type 2 ; Glucagon ; Glucagon-Like Peptide 1 ; Humans ; Hyperglycemia ; Incretins ; Peptides ; Venoms ; Liraglutide

New therapeutics for type 2 diabetes using incretin hormone were introduced recently. Incretin-based therapies consist of two types: GLP-1 agonists mainly acting on the GLP-1 receptor and dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors). The former is resistant to DPP-4 and injectable. The latter is oral medications raising endogenous GLP-1 by inhibiting the degrading enzyme DPP-4. The incretin based therapies are promising and more commonly used due to their action and safety profile. Stimulation of insulin secretion by these drugs occurs in a glucose-dependent manner. Incretin based therapies have low risk for hypoglycemia. The subsequent review outlines evidence from selected clinical trials of the currently available GLP-1 agonists, exenatide and liraglutide, and DPP-4 inhibitors, sitagliptin and vildagliptin.
Adamantane ; Dipeptidyl-Peptidase IV Inhibitors ; Glucagon-Like Peptide 1 ; Hypoglycemia ; Incretins ; Insulin ; Nitriles ; Peptides ; Pyrazines ; Pyrrolidines ; Receptors, Glucagon ; Triazoles ; Venoms ; Glucagon-Like Peptide-1 Receptor ; Liraglutide ; Sitagliptin Phosphate

No abstract available.
Glucagon-Like Peptide 1*

OBJECTIVETo investigate the effects of activation of the GLP-1 receptor on the p38MAPK signaling pathway in hepatic stellate cells (HSCs).

METHODSHSCs were isolated and identified according to morphological features; the levels of GLP-1R protein were determined by western blotting.The HSCs were randomly divided into a control grouP (normal saline treatment) and experimental grouP(liraglutide treatment); after 120 hours, the expression of p38MAPK mRNA was examined by RT-PCR and of phosphorylated (p)-p38MAPK protein was detected by western blotting.

RESULTSGLP-1R proteins were detected in the HSCs. Compared with the control group, the experimental group showed significantly decreased p38MAPK mRNA and p-p38MAPK protein (both P < 0.01).

CONCLUSIONThe p38MAPK signaling pathway could be down-regulated when GLP-1R is activated in HSCs.

Cells, Cultured ; Glucagon-Like Peptide 1 ; analogs & derivatives ; pharmacology ; Glucagon-Like Peptide-1 Receptor ; Hepatic Stellate Cells ; metabolism ; Humans ; Liraglutide ; MAP Kinase Signaling System ; RNA, Messenger ; Receptors, Glucagon ; metabolism ; p38 Mitogen-Activated Protein Kinases ; metabolism

Glucagon-like peptide-1 (GLP-1) expression is shared by both intestinal cells and neurons of brainstem, which plays anorexigenic role on food intake. However, the exact source of physiological GLP-1 influencing food intake and pertinent mechanism of GLP-1 receptor agonists (GLP-1RA) remain unelucidated. In this study, the immediate early gene product c-Fos was chosen as the specific antigen for immunohistochemistry to show the certain areas of central nervous system (CNS) activation by the GLP-1RA. Thirty normal SD rats were randomly assigned to 3 groups, which were single intraperitoneally injected with Liraglutide (200 μg/kg), Exenatide (10 μg/kg) and saline, respectively. After injection, the amount of food intake and acute glycemic variation were assessed for comparison. The results showed that acute pharmacological dosage of GLP-1RA (Liraglutide or Exenatide) could significantly influence food intake. However, glycemic change indicated that the anorexic effect was dissociated with change in blood glucose in normal rats. Moreover, c-Fos was expressed significantly higher in major critical nuclei related to food intake in GLP-1RA groups when compared with the control group, and its expression was also found in spinal cord. The results suggested that acute administration of pharmacological doses of GLP-1 influences CNS via circulation and vagal pathways, especially on the arcuate nucleus (ARC) and the nucleus of solitary tract (NTS), and GLP-1 modulates autonomic nervous activities.
Animals ; Eating ; drug effects ; Exenatide ; pharmacology ; Glucagon-Like Peptide-1 Receptor ; agonists ; Liraglutide ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley

According to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes guideline for treatment of diabetes, glucagon-like peptide-1 receptor agonist (GLP-1 RA) is recommended in diabetic patients with established atherosclerotic cardiovascular disease. This recommendation is based on the results of recent cardiovascular outcome trials of this kind of medications. GLP-1 RAs have a glucose lowering effect with weight loss and a lower incidence of hypoglycemia, and can improve cardiovascular outcomes such as three-point major cardiovascular events composed of death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke. Also, several GLP-1 RAs have beneficial effects on renal outcomes, mainly due to improvement in macroalbuminuria. In addition, high-dose liraglutide (3 mg/day subcutaneous injection) showed efficacy for reducing body weight. Therefore GLP-1 RA may be effective in patients with established cardiovascular disease, chronic kidney disease, and/or metabolic syndrome.
Body Weight ; Cardiovascular Diseases ; Diabetes Mellitus ; Glucagon-Like Peptide 1 ; Glucagon-Like Peptide-1 Receptor ; Glucose ; Humans ; Hypoglycemia ; Incidence ; Kidney Diseases ; Liraglutide ; Myocardial Infarction ; Obesity ; Renal Insufficiency, Chronic ; Stroke ; Weight Loss

There have recently been many advances in obesity treatment, including lifestyle modifications and pharmacological and surgical treatments. Specifically, pharmacological strategies have improved significantly. However, the history of the development of medications aimed at weight loss is complicated. The Federal Drug Administration (FDA) withdrew anti-obesity drugs such as fenfluramine, dexfenfluramine, and phenylpropylamine due to their unwanted side effects. Moreover, sibutramine was voluntarily withdrawn from the market and a new drug, rimonabant, has been suspended in the middle of a clinical trial due to unacceptable side effects. The FDA has approved four new anti-obesity drugs in recent years. Lorcaserin is a selective 5-hydroxytryptamine receptor 2c (5-HT2c) agonist. The pharmacological mechanism of action of this drug is similar to fenfluramine and dexfenfluramine, but lorcaserin is specific for 5-HT2c, which are located almost exclusively in the central nervous system and are not found in heart valves. Three phase 3 clinical trials for lorcaserin have been published recently; weight reduction was successful and no side effects involving the heart were found. Furthermore, the FDA has also approved phentermine/topiramate controlled-release (PHEN/TPM CR), which is composed of a combination of immediate-release phentermine and controlled-release topiramate. Weight reduction achieved with PHEN/TPM CR was demonstrated to be better than all other anti-obesity drugs. Lastly, the combination therapy bupropion/naltrexone activates proopiomelanocortin neurons and inhibits opioid-mediated negative feedback by synergism. Similar to liraglutide, a long-acting analogue of the hormone glucagon-like peptide-1, this treatment showed significant weight loss and metabolic improvements. However, in addition to its efficacy, clinicians should consider its side effects before use.
Anti-Obesity Agents ; Central Nervous System ; Dexfenfluramine ; Fenfluramine ; Glucagon-Like Peptide 1 ; Heart ; Heart Valves ; Life Style ; Neurons ; Obesity* ; Phentermine ; Pro-Opiomelanocortin ; Serotonin ; Weight Loss ; Liraglutide

BACKGROUNDThe pathophysiology of type 2 diabetes is progressive pancreatic beta cell failure with consequential reduced insulin secretion. Glucotoxicity results in the reduction of beta cell mass in type 2 diabetes by inducing apoptosis. Autophagy is essential for the maintenance of normal islet architecture and plays a crucial role in maintaining the intracellular insulin content by accelerating the insulin degradation rate in beta cells. Recently more attention has been paid to the effect of autophagy in type 2 diabetes. The regulatory pathway of autophagy in controlling pancreatic beta cells is still not clear. The aim of our study was to evaluate whether liraglutide can inhibit apoptosis and modulate autophagy in vitro in insulinoma cells (INS-1 cells).

METHODSINS-1 cells were incubated for 24 hours in the presence or absence of high levels of glucose, liraglutide (a long-acting human glucagon-like peptide-1 analogue), or 3-methyadenine (3-MA). Cell viability was measured using the Cell Counting Kit-8 (CCK8) viability assay. Autophagy of INS-1 cells was tested by monodansylcadaverine (MDC) staining, an autophagy fluorescent compound used for the labeling of autophagic vacuoles, and by Western blotting of microtubule-associated protein I light chain 3 (LC3), a biochemical markers of autophagic initiation.

RESULTSThe viability of INS-1 cells was reduced after treatment with high levels of glucose. The viability of INS-1 cells was reduced and apoptosis was increased when autophagy was inhibited. The viability of INS-1 cells was significantly increased by adding liraglutide to supplement high glucose level medium compared with the cells treated with high glucose levels alone.

CONCLUSIONSApoptosis and autophagy were increased in rat INS-1 cells when treated with high level of glucose, and the viability of INS-1 cells was significantly reduced by inhibiting autophagy. Liraglutide protected INS-1 cells from high glucose level-induced apoptosis that is accompanied by a significant increase of autophagy, suggesting that liraglutide plays a role in beta cell apoptosis by targeting autophagy. Thus, autophagy may be a new target for the prevention or treatment of diabetes.

Animals ; Apoptosis ; drug effects ; Autophagy ; drug effects ; Cell Line, Tumor ; Cell Survival ; drug effects ; Glucagon-Like Peptide 1 ; analogs & derivatives ; pharmacology ; Glucose ; pharmacology ; Insulinoma ; pathology ; Liraglutide ; Rats

The Korean Ministry of Food and Drug Safety has approved three anti-obesity drugs for long-term management in the past decade. In addition, since 2019, bariatric surgery has been financially supported by National Health Insurance Service in Korea. In this review, the mechanisms of action and the clinical implications of the recently approved anti-obesity drugs, lorcaserin, naltrexone/bupropion, and liraglutide are explained. Lorcaserin stimulates proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons and inhibits neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, which results in the activation of melanocortin 3/4 receptors. Naltrexone/bupropion stimulates POMC neurons through bupropion; this stimulation is augmented by blocking the autoinhibitory mechanism of POMC with naltrexone. The hypophagic effect of liraglutide is mediated through the direct activation of POMC/CART neurons and the indirect suppression of NPY/AgRP neurons through γ-aminobutyric acid-dependent signaling, with adjunctive suppression of the mesolimbic dopamine reward system. In addition to liraglutide, another glucagon-like peptide-1 receptor agonist, semaglutide, is expected to be added to the list of anti-obesity drugs in the near future. In patients with obesity and high cardiovascular risk, lorcaserin was considered neutral and liraglutide was considered favorable, whereas inconclusive results were obtained for naltrexone/bupropion.
Anti-Obesity Agents ; Bariatric Surgery ; Bupropion ; Dopamine ; Glucagon-Like Peptide-1 Receptor ; Humans ; Korea ; Liraglutide ; Naltrexone ; National Health Programs ; Neurons ; Neuropeptide Y ; Obesity ; Pro-Opiomelanocortin ; Reward

The prevalence of type 2 diabetes mellitus (T2DM), which is associated with cardiovascular morbidity and mortality, is increasing worldwide. Although there have been advances in diabetes treatments that reduce microvascular complications (nephropathy, neuropathy, retinopathy), many clinical studies have found that conventional oral hypoglycemic agents and glucose control alone failed to reduce cardiovascular disease. Thus, incretin-based therapies including glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT-2Is) represent a new area of research, and may serve as novel therapeutics for treating hyperglycemia and modifying other cardiovascular risk factors. Recently, it has been confirmed that several drugs in these classes, including canagliflozin, empagliflozin, semaglutide, and liraglutide, are safe and possess cardioprotective effects. We review the most recent cardiovascular outcome trials on GLP-1RAs and SGLT-2Is, and discuss their implications for treating patients with T2DM in terms of protective effects against cardiovascular disease.
Canagliflozin ; Cardiovascular Diseases ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Glucagon-Like Peptide 1 ; Glucose ; Heart Failure ; Humans ; Hyperglycemia ; Hypoglycemic Agents ; Liraglutide ; Mortality ; Myocardial Ischemia ; Prevalence ; Risk Factors