Role of Prolyl 4-Hydroxylase in Pancreatic ß-cell Insulin Secretion

Abstract

Type 2 diabetes mellitus (T2D) is characterized by chronic hyperglycemia and peripheral insulin resistance. In response to elevated blood glucose levels, pancreatic β-cells release insulin which occurs in a biphasic manner. First-phase insulin secretion occurs via the KATP channel dependent pathway during the first 10 minutes after a glucose load. Second-phase insulin secretion, KATP channel-independent pathways, results in a slow and sustained release of insulin, which can last for several hours after a glucose load. The mechanisms underlying KATP channel independent pathways remain incompletely understood. It is suggested that anaperlosis, increased production of tricarboxylic acid (TCA) cycle intermediates, regulates second-phase insulin secretion. Anaplerotic pathways involve the production of cytosolic α-ketoglutarate (αKG) that may enhance prolyl 4-hydroxlase (PHD) activity. PHDs are well-established regulators of the hypoxia response pathway. However, PHD may play a role in insulin secretion with both short- and long-term effects through prolyl hydroxylation of key proteins. Inhibition of PHD via dimethyloxalylglycine (DMOG) decreased oxygen consumption rate (OCR) in both INS-1 832/13 cells and primary mouse islets. DMOG treated primary mouse islets demonstrated enhanced second-phase insulin secretion when stimulated with high glucose (HG). Intraperitoneal glucose tolerance tests (ipGTTs) in male C57BL/6J mice treated with DMOG revealed improved glucose tolerance during second-phase insulin secretion and improved insulin sensitivity during first-phase insulin secretion. The results presented in this thesis reveal that PHD plays a role in both first- and second-phase insulin secretion and may be a potential target for the treatment of T2D.