Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet β-cells

Abstract

1. Hypercholesterolaemia often occurs in patients with type 2 diabetes, who therefore encounter administration of HMG-CoA reductase inhibitors. Alteration of pancreatic β-cell function leading to an impaired insulin secretory response to glucose plays a crucial role in the pathogenesis of type 2 diabetes. Therefore, it is important to examine the effects of HMG-CoA reductase inhibitors on β-cell function. 2. Cytosolic Ca2+ concentration ([Ca2+](i)) plays a central role in the regulation of β-cell function. The present study examined the effects of HMG-CoA reductase inhibitors on the glucose-induced [Ca2+](i) signalling and insulin secretion in rat islet β-cells. 3. Simvastatin, a lipophilic HMG-CoA reductase inhibitor, at 0.1-3 μg ml-1 concentration-dependently inhibited the first phase increase and oscillation of [Ca2+](i) induced by 8.3 mM glucose in single β-cells. The less lipophilic inhibitor, simvastatin-acid, inhibited the first phase [Ca2+](i) increase but was two orders of magnitude less potent. The hydrophilic inhibitor, pravastatin (100 μg ml-1), was without effect on [Ca2+](i). 4. Simvastatin (0.3 μg ml-1), more potently than simvastatin-acid (30 μg ml-1), inhibited glucose-induced insulin secretion from islets, whereas pravastatin (100 μg ml-1) had no effect. 5. Whole-cell patch clamp recordings demonstrated a reversible inhibition of the β-cell L-type Ca2+ channels by simvastatin, but not by pravastatin. Simvastatin also inhibited the [Ca2+](i) increases by L-arginine and KCl, agents that act via opening of L-type Ca2+ channels. 6. In conclusion, lipophilic HMG-CoA reductase inhibitors can inhibit glucose-induced [Ca2+](i) signalling and insulin secretion by blocking L-type Ca2+ channels in β-cells, and their inhibitory potencies parallel their lipophilicities. Precaution should be paid to these findings when HMG-CoA reductase inhibitors are used clinically, particularly in patients with type 2 diabetes.