Coordination of GPR40 and Ketogenesis Signaling by Medium Chain Fatty Acids Regulates Beta Cell Function

Diabetes prevalence increases with age, and beta-cell dysfunction contributes to the incidence of the disease. Dietary lipids have been recognized as contributory factors in the development and progression of the disease. Unlike long chain triglycerides, medium chain triglycerides (MCT) increase fat burning in animal and human subjects as well as serum C-peptide in type 2 diabetes patients. We evaluated the beneficial effects of MCT on beta-cells in vivo and in vitro. MCT improved glycemia in aged rats via beta-cell function assessed by measuring insulin secretion and content. In beta-cells, medium chain fatty acid (MCFA)-C10 activated fatty acid receptor 1 FFAR1/GPR40, while MCFA-C8 induced mitochondrial ketogenesis and the C8:C10 mixture improved beta cell function. We showed that GPR40 signaling positively impacts ketone body production in beta-cells, and chronic treatment with beta-hydroxybutyrate (BHB) improves beta-cell function. We also showed that BHB and MCFA help beta-cells recover from lipotoxic stress by improving mitochondrial function and increasing the expression of genes involved in beta-cell function and insulin biogenesis, such as Glut2, MafA, and NeuroD1 in primary human islets. MCFA offers a therapeutic advantage in the preservation of beta-cell function as part of a preventative strategy against diabetes in at risk populations.