Article date: March 1999
By: Toshihiko Yada, Masanori Nakata, Tomoko Shiraishi, Masafumi Kakei, in Volume 126, Issue 5, pages 1205-1213
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 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.
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.
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 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.
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.
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 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.
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.
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 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.
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.
British Journal of Pharmacology (1999) 126, 1205–1213; doi:10.1038/sj.bjp.0702397
DOI: 10.1038/sj.bjp.0702397
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