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.
Cite this version of the work
Sarah Janssen
(2017).
Role of Prolyl 4-Hydroxylase in Pancreatic ß-cell Insulin Secretion. UWSpace.
http://hdl.handle.net/10012/12284
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