Targeting Pyruvate Kinase PEPs Up Insulin Secretion and Improves Glucose Homeostasis

The consensus model of glucose-stimulated insulin secretion (GSIS) holds that ATP generation by oxidative phosphorylation directly regulates K_ATP channel activity and thus insulin granule release, a concept inconsistent with bioenergetic principles. Here, Lewandowski et al. (2020) and Abulizi et al. (2020) report that regulation of GSIS is much more complex as different sources of ATP generation are essential to control this process, which can be targeted in vivo and additionally modulate hepatic glucose production. These findings establish an important new conceptual framework of GSIS and in vivo glucose homeostasis.