Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Schwarz, Ute I.

Abstract

Statins are a class of cholesterol-lowering drugs which work by inhibiting the mevalonate pathway. Statin treatment has been linked to an increase in the risk of new-onset diabetes mellitus, and previous studies have suggested impairment in insulin secretion following statin treatment. Recent work from our laboratory confirmed the expression of organic anion transporting polypeptide 2B1 (OATP2B1), an important statin uptake transporter, in human pancreatic beta cells. Our study examined the role of OATP2B1 in statin-associated beta cell toxicity using INS-1 cells as a beta cell model. We showed that OATP2B1 augments cellular accumulation of rosuvastatin and atorvastatin, but not pravastatin. While rosuvastatin and atorvastatin led to a dose-dependent reduction in insulin secretion, OATP2B1 had no effect. However, OATP2B1 was found to facilitate statin-induced mitochondrial toxicity, apoptosis and ATP level reduction. In conclusion, our findings support an important role of OATP2B1-mediated statin uptake on beta cell toxicity but not insulin secretion.

Summary for Lay Audience

Statins are commonly prescribed cholesterol-lowering drugs. These statins work by reducing the amount of cholesterol synthesized in the liver. Recently, statin therapy has been linked to an increased risk of diabetes mellitus. Organic anion transporting polypeptide (OATP)2B1 is an important transport protein residing on the surface of many cell types, including insulin-secreting pancreatic beta cells, and helps bring many substances, including statins, into the cell. We sought to study the effect of OATP2B1 on the accumulation of statins inside cells, and possible toxicities caused by statins using a cell model, INS-1. We created INS-1 cells that express large amounts of OATP2B1, and we found that these cells had a higher accumulation of rosuvastatin and atorvastatin within the cells. While insulin secretion was impaired after treatment of INS-1 cells with increasing rosuvastatin and atorvastatin concentrations, OATP2B1 had no effect on insulin secretion. After treating the INS-1 cells with different statins at high concentrations, OATP2B1 enhanced known adverse effects of statins, including function of the mitochondria, the main site of energy or ATP production in cells, as well as increased markers of programmed cell death (apoptosis). In summary, our study highlighted a possible connection between the transport protein OATP2B1 and harmful effects on pancreatic beta cells caused by statins at very high doses.

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