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.

Pretreatment with Ajwa dates (Phoenix dactylifera Linn) prevents development of alloxan-induced diabetes in rats

“…The molecular pathogenesis of DM is explained by the development of insulin resistance resulting from excessive intake of carbohydrates resulting in a glucolipotoxic cell environment. 27 High carbohydrates proportion in Ajwa flesh group C may be, therefore, a possible reason for increased insulin resistance and HOMA-IR in this group. Antioxidants in Ajwa flesh were able to prevent the complete exhaustion of islets of Langerhans as a result of this high insulin demand, thereby allowing more insulin to be secreted to overcome this resistance.…”

Root extracts of Anacardium occidentale reduce hyperglycemia and oxidative stress in vitro

“…Glucose is the key regulator of insulin synthesis and secretion. However, exposure of β-cells to supraphysiological glucose concentration results in incessant stimulation of the cells leading to insulin store exhaustion and reduced insulin secretion, impaired insulin gene expression, generation of oxidative stress, and apoptosis of the cells [27]. Thus, managing hyperglycemia has become an inevitable factor for the prevention of diabetes and its associated complications.…”

Development and Characterization of Metformin Nanoparticles for the Effective Treatment of Diabetes Mellitus

“…Treatment with nanoparticles of metformin at a dose of 40mg/kg respectively, prevented this alteration in glycogen content of liver tissue, but could not normalize the content of glycogen of the non-diabetic control. This prevention or depletion of glycogen in the liver is possibly due to either stimulation of insulin release from β-cells 40 or due to the insulin mimetic activity of some components of the plants resulting in direct peripheral glucose uptake. Decreased enzymatic activity of Hexokinase, Glucokinase and substrate glucose-6-phosphate has been reported in diabetic animals resulting in depletion of liver and muscle glycogen [41][42][43] .The present study also had similar results.…”