Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor(s)

Dr. Ute Schwarz

Abstract

Cholesterol-lowering statins, or the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are one of the leading treatments for hypercholesterolemia and are recognized for their ability to prevent cardiovascular events. Though safe and effective for most, statin therapy has recently been associated with new-onset diabetes, with risk varying depending on potency and dose. Additionally, in vitro data suggest statin-mediated alterations in insulin secretion; however, the exact mechanism is currently unknown. Statins are known substrates of various membrane transporters belonging to the organic anion-transporting polypeptides (OATPs), on which they rely heavily for hepatic uptake and therapeutic efficacy. We have recently reported expression of OATP1B3 in healthy human pancreas, localized to insulin-secreting β cells in the islets of Langerhans. Given the evidence for statin-induced diabetes and potential expression of statin-transporting OATPs in the pancreas, we hypothesize that expression and activity of OATP transporters in pancreatic β cells regulate statin entry and contribute to statin-induced impairment of insulin secretion through disruption of mitochondrial function and ATP-dependent signalling. We demonstrated gene and protein expression of OATP1B3 and OATP2B1 in human adult islets, with differential distribution to α and β cells, respectively. Quantitative analysis showed variable co-localization of OATP1B3 with endocrine cells in relation to age. Our in vitro findings support a role of OATPs in mediating statin-induced impairment of insulin secretion and β cell function via mitochondrial dysfunction. Overall, our results suggest a link between pancreatic OATP expression and statin-induced effects on glucose-stimulated insulin secretion and provide novel insights into a currently unexplored mechanism.

Available for download on Saturday, June 01, 2019


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