Beta hydroxybutyrate alters beta cell identity and function in human islets

Fasting alters insulin secretion in humans and islet cell composition in mice. Fasting triggers ketogenesis, which increases beta hydroxybutyrate (BHB) levels. BHB is a signaling molecule that alters insulin secretion in primary islets. We hypothesized that BHB alters human islet cell composition and identity. Primary human islets were cultured with R-BHB or its non-metabolizable enantiomer, S-BHB. Human islets cultured with R-BHB, but not S-BHB, resulted in an increased C-peptide - glucagon + to C-peptide + glucagon - cell ratio, and an increased frequency of C-peptide + glucagon + bihormonal cells and NKX6.1 + glucagon + cells. Single-cell transcriptomics revealed upregulation of alpha cell identity genes in R-BHB treated islet beta cells. Alterations in beta cell identity were accompanied by increased basal insulin secretion in response to low glucose, and a reduced insulin stimulation index in response to high glucose. The differential effects of the two BHB enantiomers on islet cell composition indicated that ketone metabolism is involved in islet cell identity change. Supporting this hypothesis, a subpopulation of beta cells in islets treated with R-BHB characterized by low ketolysis genes, OXCT1 and ACAT1 , did not show altered alpha and beta cell identity genes. Additionally, primary islets from type 2 diabetes donors, which exhibited reduced OXCT1 and ACAT1 expression relative to donors without diabetes, did not display altered islet cell composition and beta cell function from R-BHB treatment. Our findings uncover a novel role of BHB in modulating beta cell identity, with potential implications for islet function in states with chronically elevated ketone concentrations.