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Inhibition by simvastatin, but not pravastatin, of glucose‐induced cytosolic Ca 2+ signalling and insulin secretion due to blockade of L‐type Ca 2+ channels in rat islet β‐cells
Author(s) -
Yada Toshihiko,
Nakata Masanori,
Shiraishi Tomoko,
Kakei Masafumi
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702397
Subject(s) - simvastatin , pravastatin , endocrinology , medicine , insulin , hmg coa reductase , islet , reductase , chemistry , hydroxymethylglutaryl coa reductase , cytosol , biology , biochemistry , cholesterol , enzyme
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. Cytosolic Ca 2+ concentration ([Ca 2+ ] 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 [Ca 2+ ] i signalling and insulin secretion in rat islet β‐cells. Simvastatin, a lipophilic HMG‐CoA reductase inhibitor, at 0.1–3 μg ml −1 concentration‐dependently inhibited the first phase increase and oscillation of [Ca 2+ ] i induced by 8.3 m M glucose in single β‐cells. The less lipophilic inhibitor, simvastatin‐acid, inhibited the first phase [Ca 2+ ] i increase but was two orders of magnitude less potent. The hydrophilic inhibitor, pravastatin (100 μg ml −1 ), was without effect on [Ca 2+ ] i . 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. Whole‐cell patch clamp recordings demonstrated a reversible inhibition of the β‐cell L‐type Ca 2+ channels by simvastatin, but not by pravastatin. Simvastatin also inhibited the [Ca 2+ ] i increases by L ‐arginine and KCl, agents that act via opening of L‐type Ca 2+ channels. In conclusion, lipophilic HMG‐CoA reductase inhibitors can inhibit glucose‐induced [Ca 2+ ] i signalling and insulin secretion by blocking L‐type Ca 2+ 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.British Journal of Pharmacology (1999) 126 , 1205–1213; doi: 10.1038/sj.bjp.0702397