Beta-hydroxybutyrate Promotes Basal Insulin Secretion While Decreasing Glucagon Secretion in Mouse and Human Islets

Dietary carbohydrates raise blood glucose levels, and limiting carbohydrate intake improves glycemia in patients with type 2 diabetes. Low carbohydrate intake (< 25 g) allows the body to utilize fat as its primary fuel. As a consequence of increased fatty acid oxidation, the liver produces ketones to serve as an alternative energy source. beta-Hydroxybutyrate (beta HB) is the most abundant ketone. While beta HB has a wide range of functions outside of the pancreas, its direct effects on islet cell function remain understudied. We examined human islet secretory response to acute racemic beta HB treatment and observed increased insulin secretion at a low glucose concentration of 3 mM. Because beta HB is a chiral molecule, existing as both R and S forms, we further studied insulin and glucagon secretion following acute treatment with individual beta HB enantiomers in human and C57BL/6J mouse islets. We found that acute treatment with R-beta HB increased insulin secretion and decreased glucagon secretion at physiological glucose concentrations in both human and mouse islets. Proteomic analysis of human islets treated with R-beta HB over 72 hours showed altered abundance of proteins that may promote islet cell health and survival. Collectively, our data show that physiological concentrations of beta HB influence hormone secretion and signaling within pancreatic islets.