Actions Of Glucagon-like Peptide-1 Receptor Agonists Research Articles

Anti-Inflammatory Effects of Glucagon-Like Peptide-1 Receptor Agonists via the Neuroimmune Axis.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have shown efficacy in the treatment of metabolic disease-related complications, partially attributable to their anti-inflammatory properties. However, the specific cell types and pathways involved in these effects were not fully understood. A recent study by Wong et al. demonstrated the importance of the brain GLP-1R in mediating the anti-inflammatory effects of GLP-1RAs in Toll-like receptor and sepsis-mediated inflammation. In this discussion, we review the existing literature on the action of GLP-1RAs in inflammation and explore the implications of these recent findings.

Агониcты рецепторов глюкагоноподобного пептида-1: возможности применения для лечения больных сахарным диабетом 2 типа

An article reviews the use of glucagon-like peptide-1 (GLP-1) receptor agonists for treatment of patients with type 2 diabetes mellitus associated with high cardiovascular risk, chronic heart failure with low left ventricular ejection fraction and diabetic nephropathy. The authors discuss the mechanisms of action of GLP-1 receptor agonists, their main advantages (significant hypoglycemic effect, organoprotection and improved cardiovascular and renal outcomes) and dosedependent side effects.

325-OR: ß-Arrestin 1 Regulates Glucagon-Like Peptide-1 Receptor Mediated Insulin Secretion in a Ligand-Dependent Manner

Incretin-based drugs are widely thought to act via a Gαs/adenylate cyclase (AC)/cAMP pathway in β-cells. This model has been challenged by data demonstrating various glucagon-like peptide 1 receptor (GLP-1R) ligands differentially activate multiple signaling pathways including Gαs, Gq, ERK, and β-arrestins. This ligand-mediated signaling bias implicates an array of intracellular mechanisms that regulate GLP-1R action and raises the possibility GLP-1R agonists can be optimized to enhance insulin secretion. We tested the hypothesis that β-arrestin 1 (βarr1), a critical GPCR effector, is necessary for the full insulinotropic action of GLP-1R agonists. The β-cell βarr1 knockout mice (βarr1βcell-/-) used here have reduced Arrb1 expression in the β-cell, but not α- or Δ-cells; Arrb2 expression was unaffected. Islets isolated from βarr1βcell-/- mice have increased glucose stimulated insulin secretion (GSIS) compared to controls. The enhanced GSIS in the knockout islets was ablated by the GLP-1R antagonist exendin-9. In addition, βarr1βcell-/-islets treated with GLP-1 or exendin 4 (Ex4) have increased insulin release compared to controls. Conversely, βarr1 deletion did not impact the insulinotropic actions of glucagon, which signals through both the GLP-1R and the glucagon receptor (GCGR). Moreover, control and βarr1βcell-/- islets produced similar insulin secretion in response to a GCGR specific agonist that does not signaling through GLP-1R and to glucose-dependent insulinotropic polypeptide. Together, these results indicate that βarr1 in β-cells selectively dampens the insulinotropic actions of the GLP-1R, but not the GCGR or GIP receptor. Thus, there is a specific interaction between the GLP-1R and βarr1 that points to divergent regulation between the insulinotropic class B G-protein coupled receptors in β-cells. This data implies that GLP-1R agonists that bias away from βarr1 may be more effective at stimulating insulin secretion. Disclosure J.D. Douros: None. K. Sloop: None. J. Campbell: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. D. D’Alessio: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Intarcia Therapeutics. Research Support; Self; Ansh Labs, Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novo Nordisk A/S. Funding 1F32DK115031-01

GLP-1 Receptor Agonists and Kidney Protection.

Type 2 diabetes mellitus (T2DM) is the leading cause of chronic kidney disease (CKD). Diabetic nephropathy (DN) is determined by specific pathological structural and functional alterations of the kidneys in patients with diabetes, and its clinical manifestations are albuminuria and decline of glomerular filtration rate (GFR). Apart from renin–angiotensin–aldosterone system (RAAS) inhibitors, no other drugs are currently available as therapy for diabetic kidney disease (DKD). Glucagon-like peptide-1 receptor (GLP-1R) agonists are a new class of anti-hyperglycemic drugs which have been demonstrated to prevent the onset of macroalbuminuria and reduce the decline of GFR in diabetic patients. These drugs may exert their beneficial actions on the kidneys through blood glucose- and blood pressure (BP)-lowering effects, reduction of insulin levels and weight loss. Clinical benefits of GLP-1R agonists were acknowledged due to data from large randomized phase III clinical trials conducted to assess their cardiovascular(CV) safety. These drugs improved renal biomarkers in placebo-controlled clinical studies, with effects supposed to be independent of the actions on glycemic control. In this review, we will focus on the actions of GLP-1R agonists on glucose metabolism and kidney physiology, and evaluate direct and indirect mechanisms through which these drugs may confer renal protection.

Pleiotropic effects of insulin and GLP-1 receptor agonists: Potential benefits of the association

The combination of basal insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is an emerging option for patients with type 2 diabetes (T2D). GLP-1RAs have been shown to improve glycaemic control with a low risk of hypoglycaemia and to promote body weight loss. However, GLP-1 receptors (GLP-1Rs) are widely expressed in extrapancreatic tissues and could sustain pleiotropic actions of GLP-1RAs beyond glycaemic control. The underlying molecular mechanisms maintaining these extrapancreatic actions of GLP-1 are complex, and involve GLP-1R signalling in both the brain and several peripheral tissues. The present review focuses specifically on the role of GLP-1RAs in the cardiovascular system and liver. Preclinical data in rodents and pilot studies in humans suggest that GLP-1RAs may have potential beneficial effects on heart function, blood pressure, postprandial lipaemia, liver steatosis and non-alcoholic steatohepatitis (NASH). Long-term studies are now warranted to determine the safety and clinical relevance of the association between insulin and GLP-1RAs in T2D.

Liraglutide improves pancreatic Beta cell mass and function in alloxan-induced diabetic mice.

Glucagon-like peptide-1 (GLP-1) receptor agonists potentiate glucose-induced insulin secretion. In addition, they have been reported to increase pancreatic beta cell mass in diabetic rodents. However, the precise mode of action of GLP-1 receptor agonists still needs to be elucidated. Here we clarify the effects of the human GLP-1 analog liraglutide on beta cell fate and function by using an inducible Cre/loxP-based pancreatic beta cell tracing system and alloxan-induced diabetic mice. Liraglutide was subcutaneously administered once daily for 30 days. The changes in beta cell mass were examined as well as glucose tolerance and insulin secretion. We found that chronic liraglutide treatment improved glucose tolerance and insulin response to oral glucose load. Thirty-day treatment with liraglutide resulted in a 2-fold higher mass of pancreatic beta cells than that in vehicle group. Liraglutide increased proliferation rate of pancreatic beta cells and prevented beta cells from apoptotic cells death. However, the relative abundance of YFP-labeled beta cells to total beta cells was no different before and after liraglutide treatment, suggesting no or little contribution of neogenesis to the increase in beta cell mass. Liraglutide reduced oxidative stress in pancreatic islet cells of alloxan-induced diabetic mice. Furthermore, the beneficial effects of liraglutide in these mice were maintained two weeks after drug withdrawal. In conclusion, chronic liraglutide treatment improves hyperglycemia by ameliorating beta cell mass and function in alloxan-induced diabetic mice.

Effect of liraglutide on proliferation and differentiation of human adipose stem cells

Glucagon-Like Peptide-1 (GLP-1) receptor agonists, used as glucose-lowering drugs, also induce weight loss by inhibiting food intake. The present study was aimed at the assessment of the in vitro effects of the GLP-1 receptor agonist liraglutide on proliferation and differentiation of human adipose stem cells (ASC) obtained from subcutaneous adipose tissue of morbidly obese subjects undergoing bariatric surgery.Liraglutide (10–100 nM) significantly inhibited ASC proliferation and viability, with a maximum effect at 6 days of culture (45% and 50%, for liraglutide 10 and 100 nM, respectively); the effect was reverted by exendin 9–39. Glucose uptake was significantly reduced by liraglutide in a dose dependent manner. Treatment with liraglutide reduced intracellular lipid accumulation in differentiating ASC, together with FABP-4 mRNA expression (−18%, −23%, −46%, for 1 nM, 10 nM and 100 nM, respectively), whereas it stimulated adiponectin (APN) expression (1.86-, 2.64-, 2.28-fold increase, for 1 nM, 10 nM and 100 nM, respectively).Liraglutide exerts effects on human adipose cell precursors, inhibiting proliferation and differentiation, while stimulating the expression of the insulin-sensitizing adipokine APN. These effects could contribute to the actions of GLP-1 receptor agonists on body weight and insulin sensitivity.