Regulation of Glucose Production in the Pathogenesis of Type 2 Diabetes

Abstract

Purpose of review: Increased glucose production associated with hepatic insulin resistance contributes to the development of hyperglycemia in T2D. The molecular mechanisms accounting for increased glucose production remain controversial. Our aims were to review recent literature concerning molecular mechanisms regulating glucose production and to discuss these mechanisms in the context of physiological experiments and observations in humans and large animal models.

Recent findings: Genetic intervention studies in rodents demonstrate that insulin can control hepatic glucose production through both direct effects on the liver, and through indirect effects to inhibit adipose tissue lipolysis and limit gluconeogenic substrate delivery. However, recent experiments in canine models indicate that the direct effects of insulin on the liver are dominant over the indirect effects to regulate glucose production. Recent molecular studies have also identified insulin-independent mechanisms by which hepatocytes sense intrahepatic carbohydrate levels to regulate carbohydrate disposal. Dysregulation of hepatic carbohydrate sensing systems may participate in increased glucose production in the development of diabetes.

Keywords: ChREBP; Diabetes; Gluconeogenesis; Glucose 6 phosphate; Glucose production; Glycogenolysis.

Figure 1.

Insulin binds the Insulin receptor and activates AKT, which enhances glycogen synthesis by activating glycogen synthase (GS), and repressing glycogen phosphorylase (GP). Activated AKT also inhibits the transcription factor FOXO1 leading to decreased expression of gluconeogenic enzymes including glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (PCK1) and increased expression of glucokinase (GCK) which enhances hepatic glucose uptake. The transcription factor ChREBP senses cellular glucose-6-phosphate (G6P) levels and mediates cellular G6P homeostasis by enhancing expression of enzymes that dispose of G6P including G6PC and liver pyruvate kinase (Pklr). Enzymes labeled in red increase G6P production, whereas enzymes labeled in blue contribute to G6P disposal.