Simvastatin, but not Pravastatin, Blocks L-Type Ca2+ Channels In Rat Islet -Cells, Inhibiting Glucose-Induced Cytosolic Ca2+ Signaling and Insulin Release

Abstract

Patients with type 2 diabetes who have hypercholesterolemia frequently need to take HMG-CoA reductase inhibitors. A key factor in the pathophysiology of type 2 diabetes is altered pancreatic beta-cell activity, which results in a reduced ability of the pancreas to secrete insulin in response to glucose. The impact of HMG-CoA reductase inhibitors on -cell function must therefore be investigated. The regulation of -cell function is greatly influenced by the cytosolic Ca2+ concentration ([Ca2+]i). The current work looked at how HMG-CoA reductase inhibitors affected the [Ca2+]i signaling and insulin release that glucose-induced in rat islet -cells. Simvastatin, a lipophilic HMG-CoA reductase inhibitor, suppressed the initial phase increase and oscillation of [Ca2+]i caused by 8.3 mM glucose in single -cells at concentrations ranging from 0.1 to 3 g ml—1. The fewer Simvastatin-acid, a lipophilic inhibitor, decreased the first [Ca2+]i rise but was two orders of magnitude less effective. Pravastatin (100g ml—1), a hydrophilic inhibitor, has little impact on [Ca2+]. Simvastatin (0.3g ml–1) reduced glucose-induced insulin production from islets more effectively than simvastatin-acid (30g ml–1), whereas pravastatin (100g ml–1) had no effect. Simvastatin, but not pravastatin, showed a reversible blockage of the L-type Ca2+ channels in -cells in whole-cell patch clamp recordings. Simvastatin also prevented the opening of L-type Ca2+ channels, which is how L-arginine and HCl enhance [Ca2+] Conclusion: By blocking L-type Ca2+ channels in -cells, lipophilic HMG-CoA reductase inhibitors can prevent glucose-induced [Ca2+]i signaling and insulin secretion, and their inhibitory potencies are inversely correlated with their lipophilicities. Precaution must be takenWhen HMG-CoA reductase inhibitors are utilized in clinical settings, attention should be given to these findings, especially in type 2 diabetic patients.