Trigger mechanisms in insulin resistance and diabetes mellitus development

Abstract

Type 2 diabetes mellitus characterized by chronic hyperglycaemia is caused by insulin resistance and β-cell dysfunction. Glycogen accumulation, due to impaired metabolism, contributes to this “glucotoxicity” via dysregulated biochemical pathways promoting β-cell dysfunction. Thus, long-term exposition of insulin-secreted cells or isolated islets together with increased free fatty acids (FFA) and glucose levels can cause insulin-induced glucose secretion depression, damage to insulin gene expression and apoptotic death of cells. It is known that, the main regulator of pancreatic β-cells functioning and regulator of insulin gene expression, synthesis and secretion of insulin is glucose. Glucose enters cells and progressively metabolizes, in particular, to pyruvate in a cycle of tricarboxylic acids, subjected to oxidative phosphorylation, during which formed adenosine triphosphate and reactive oxygen radicals (ROS). Although, when more glucose enters the cell, there are other ways in which extra glucose can be transferred to reserve and of the glucose molecules can form ROS. The release of excessive amounts of FFA leads to lipotoxicity, as lipids and metabolites produce ROS in the endoplasmic reticulum and mitochondria. This affects both adipose and non-fat tissue, making up its pathophysiology in many organs. This overview demonstrates that the insulin gene is expressed in pancreatic β-cells. Glucose is the main physiological regulator of insulin gene expression. It controls the effect of transcription factors, insulin mRNA stability, and transcription rate. Glucolipotoxicity mechanisms affect the transcription factors MafA and PDX-1. Important is the β-cells damaging, which is connected with the oxidative stress and the synthesis of ceramides.