β-Hydroxybutyrate promotes basal insulin secretion while decreasing glucagon secretion in mouse and human islets

Dietary carbohydrates raise blood glucose and limiting carbohydrate intake improves glycemia in patients with T2D. 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. β-Hydroxybutyrate (βHB) is the most abundant ketone. While βHB has a wide range of functions outside of the pancreas, its effect on islet cell function remains understudied. In this study, we examined islet response to racemic βHB treatment, and observed an increase in insulin secretion in human islets treated with βHB at basal glucose concentrations (3 mM glucose). Because βHB is a chiral molecule, existing as both R and S forms, we further examined insulin and glucagon secretion following acute treatment with individual βHB enantiomers in human and C57BL6/J mouse islets. We found that acute treatment with R-βHB increases insulin secretion and decreases glucagon secretion at physiological glucose concentrations in human and mouse islets. Proteomic analysis of human islets treated with R-βHB over 72 h showed altered abundance of proteins that may promote islet cell health and survival. However, live cell imaging revealed that neither enantiomer of βHB protected dispersed mouse islet cells from cell death. Collectively, our data show that physiological concentrations of βHB influence hormone secretion and signaling within pancreatic islets.