Abstract
Increasing evidence shows that statins increase the risk of new-onset diabetes mellitus, but the exact mechanism is not clearly known. Free fatty acid receptor 1 (FFA1) has been recognized to mediate insulin secretion, and pioglitazone has direct effects on glucose-stimulated insulin secretion in addition to the reversion of insulin resistance. In this study, we found that atorvastatin decreased potassium-stimulated insulin secretion and inhibited the expression of FFA1, PDX-1, and BETA2/NeuroD in INS-1 cells. Further study demonstrated that pioglitazone prevented the impairment of insulin secretion induced by atorvastatin and enhanced the expression of FFA1, PDX-1, and BETA2/NeuroD reduced by atorvastatin in INS-1 cells. In addition, the preventive effect of pioglitazone on atorvastatin-induced impairment of insulin secretion and the enhancement of the expression of PDX-1 and BETA2/NeuroD was abolished by knockdown of FFA1 using siRNA or the PLC inhibitor, U-73122, respectively. Ultimately, FFA1 may mediate the atorvastatin-induced pancreatic β-cell dysfunction and pioglitazone may ameliorate this deleterious effect through the upregulation of FFA1 expression.
Highlights
Statins are potent and specific competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), which is the rate-limiting enzyme that catalyses the conversion of HMG-CoA to mevalonate in the biosynthesis of cholesterol
Using Quantitative Real-Time PCR (qRT-PCR) and western blot assay, we demonstrated that treating INS-1 cells with different concentrations of atorvastatin for 24 h led to a dramatic decrease in Free fatty acid receptor 1 (FFA1) expression; the decrease in
The results in the present study showed that pioglitazone enhanced insulin secretion in INS-1 cells treated with atorvastatin for 24 h, but not in cells treated with atorvastatin and FFA1 siRNA/U-73122
Summary
Statins are potent and specific competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), which is the rate-limiting enzyme that catalyses the conversion of HMG-CoA to mevalonate in the biosynthesis of cholesterol. Statins are widely used as plasma cholesterol-lowering drugs and are efficient in the primary and secondary prevention of both atherosclerotic cardiovascular disease and stroke. Meta-analyses of previous studies [1,2,3] done with statins have shown that statins can dose-dependently increase the risk of new-onset diabetes mellitus (NODM). Diabetes has become a global epidemic disease. The exact mechanism of statin-induced NODM is not clearly known. Further studies on the mechanism of statin-induced NODM have important clinical significance
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