Unraveling the impaired incretin effect in obesity and type 2 diabetes: Key role of hyperglycemia-induced unscheduled glycolysis and glycolytic overload.

Glucagon-like peptide-1 (GLP-1) agonists and GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) co-agonists are major treatment options for subjects with obesity and patients with type 2 diabetes mellitus (T2DM). They counter without addressing the mechanistic cause of the impaired incretin effect associated with obesity and T2DM. Incretin effect impairment is characterized by decreased secretion of incretins from enteroendocrine cells and incretin resistance of pancreatic β-cells. It is linked to hyperglycemia. We present evidence that subversion of the gating of glucose entry into glycolysis, mainly by glucokinase (hexokinase-4), during persistent hyperglycemia in enteroendocrine cells, pancreatic β- and α-cells and appetite-regulating neurons contributes to the biochemical mechanism of the impaired incretin effect. Unscheduled glycolysis and glycolytic overload thereby produced decreases cell signalling of incretin secretion to glucose and other secretion stimuli and incretin receptor responses. This mechanism provides a guide for development of alternative therapies targeting recovery of the impaired incretin effect.