Role of organic anion transporting polypeptides in pancreatic statin disposition and islet cell function in mice

Statins are widely prescribed and effective for reducing cardiovascular risk. However, their use has been associated with new-onset diabetes risk, involving impaired insulin secretion and sensitivity. Statins exert their lipid-lowering effect in the liver, where hepatic uptake is mediated by organic anion transporting polypeptides (OATPs). OATPs are also found in pancreatic islets, yet their importance to pancreas distribution and insulin secretion is unknown. The aim of this study was to investigate the role of OATPs in pancreatic statin distribution using the Oatp1a/1b cluster knockout (KO) mouse model, and to assess statin effects on islet cell function. We characterized Slco gene expression in adult mouse pancreas and islets, determined statin tissue distribution in Oatp1a/1b KO mice, assessed OATP-mediated statin uptake in HEK293T cells, and measured insulin secretion in rosuvastatin-treated primary mouse islets. All Slco1a/1b transcripts, except Slco1a5, were detected in pancreas and islets, with abundance of Slco1a6 in islets. Following oral statin dosing, KO mice exhibited reduced pancreas-to-plasma distribution ratios for atorvastatin, rosuvastatin, and pravastatin compared to wildtype, as was observed for liver and kidney. Almost all statins were Oatp1a1, Oatp1a4, and Oatp1a6 substrates. In islets, rosuvastatin reduced insulin secretion and content, whereas Oatp inhibition mitigated the latter effect. Our findings demonstrate expression of Oatp1a/1b transporters in pancreas and islets, their contribution to pancreas distribution of statins, and reduced insulin content. OATP-mediated statin distribution to the pancreas may represent a potential mechanism underlying statin-associated islet cell dysfunction. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (OATPs) are well known determinants of statin exposure and hepatic distribution, while their role in the pancreas is unknown. After confirming islet expression, we show reduced pancreas-to-plasma distribution ratios of oral atorvastatin, rosuvastatin, and pravastatin in Oatp1a/1b knockout mice versus wildtype, and reduced insulin content in rosuvastatin-treated isolated islets which was reversed by Oatp inhibition. Hence, Oatp1a/1b are key determinants of pancreatic statin disposition and Oatp-mediated statin uptake may contribute to β-cell dysfunction.