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.