Differential effects of OATP2B1 on statin accumulation and toxicity in a beta cell model

Abstract

An increased risk of new-onset diabetes mellitus has been recently reported for statin therapy, and experimental studies have shown reduced glucose-stimulated insulin secretion (GSIS) and mitochondrial dysfunction in beta cells with effects differing among agents. Organic anion transporting polypeptide (OATP) 2B1 contributes to hepatic uptake of rosuvastatin, atorvastatin and pravastatin, three known substrates. Since OATP2B1 is present in beta cells of the human pancreas, we investigated if OATP2B1 facilitates the local accumulation of statins in a rat beta cell model INS-1 832/13 (INS-1) thereby amplifying statin-induced toxicity. OATP2B1 overexpression in INS-1 cells via adenoviral transduction showed 2.5-, 1.8- and 1.4-fold higher cellular retention of rosuvastatin, atorvastatin and pravastatin, respectively, relative to LacZ control, while absolute intracellular concentration was about twice as high for the lipophilic atorvastatin compared to the more hydrophilic rosuvastatin and pravastatin. After 24 h statin treatment at high concentrations, OATP2B1 enhanced statin toxicity involving activation of intrinsic apoptosis (caspase 3/7 activation) and mitochondrial dysfunction (NADH dehydrogenase activity) following rosuvastatin and atorvastatin, which was partly reversed by isoprenoids. OATP2B1 had no effect on statin-induced reduction in GSIS, mitochondrial electron transport chain complex expression or caspase 9 activation. We confirmed a dose-dependent reduction in insulin secretion by rosuvastatin and atorvastatin in native INS-1 with a modest change in cellular ATP. Collectively, our results indicate a role of OATP2B1, which is abundant in human beta cells, in statin accumulation and statin-induced toxicity but not insulin secretion of rosuvastatin and atorvastatin in INS-1 cells.

Keywords:

• Rat beta cell model
• OATP2B1
• statin
• impaired insulin secretion
• apoptosis
• mitochondrial dysfunction

Acknowledgments

Authors would like to thank Richard B. Kim and Daniel B. Hardy (Western University) for helpful discussions and constructive feedback on this work.

Disclosure statement

The authors report no conflicts of interests.

Data availability statement

Data can be requested from the corresponding author via e-mail.

Additional information

Funding

This work was supported by Western University (Western Strategic Support for CIHR Success Award, R5193A01), Lawson Health Research Institute (Lawson Internal Research Fund - IRF) and by the Heart and Stroke Foundation Canada under Grants G-20-0029452 and G-22-0032139 (PI Schwarz UI).