An emerging role of glucagon-like peptide-1 in preventing advanced-glycation-end-product-mediated damages in diabetes

Abstract

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 pancreatic β-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.

Figure 1

Beneficial effects of GLP-1 in pancreatic beta cells exposed to AGEs. The activation of the AGEs-RAGE axis in pancreatic beta cells increases oxidative stress that causes mitochondrial dysfunction, endoplasmic reticulum stress, and altered signal transduction. These detrimental effects modify gene expression leading to increased expression of RAGE and proapoptotic molecules, and downregulation of proteins involved in insulin gene expression, such as PDX-1, thus causing decreased insulin production and loss of glucose-stimulated insulin secretion (GSIS). Activation of GLP-1 signaling increases antioxidant defense thus counteracting formation of reactive oxygen species (ROS) and expression of RAGE, blocking the positive feedback loop that links RAGE activation with RAGE expression. Furthermore, GLP-1 maintaining pancreatic beta-cell function restores GSIS, thus contributing to reduce plasma glucose concentration and, consequently, formation of new AGEs.

Figure 2

Beneficial effects of GLP-1 in other cells exposed to AGEs. Detrimental effect of AGEs leads to cell dysfunction and, eventually, cell death. GLP-1, counteracting AGEs-induced damage with mechanisms reported in pancreatic beta cells, may contribute to reducing diabetic complications.