Glucokinase Inhibition: A Novel Treatment for Diabetes?

Abstract

Chronic hyperglycemia increases pancreatic β-cell metabolic activity, contributing to glucotoxicity-induced β-cell failure and loss of functional β-cell mass, potentially in multiple forms of diabetes. In this perspective we discuss the novel paradoxical and counterintuitive concept of inhibiting glycolysis, particularly by targeted inhibition of glucokinase, the first enzyme in glycolysis, as an approach to maintaining glucose sensing and preserving functional β-cell mass, thereby improving insulin secretion, in the treatment of diabetes.

Figure 1

Schematic representation of the conceived role of GCK in pancreatic β-cell function. A: Paradigmatic role of normal GCK in glucose metabolism-induced insulin secretion (middle). GCK-GOF mutations cause permanent hyperinsulinemia hypoglycemia of infancy (PHHI) (excessive insulin secretion, right arm), and heterozygous or homozygous GCK-LOF mutations cause MODY2 or ND (lower insulin secretion, left arm). B: In the early stages of diabetes, insulin resistance leads to rising blood glucose levels that induce an increase in glucose metabolism and insulin secretion (middle) and the onset of β-cell failure and reduced insulin secretion. By inducing further increases in glucose metabolism and insulin secretion, GCKAs will exacerbate the drive toward failure (right arm). Conversely, by reducing glucose metabolism from the hyperglycemic phase, GCKIs will preserve functional β-cell mass and slow the progression to failure (left arm).