Received for publication June 5, 2006.
Revised August 24, 2006.
Accepted for publication September 20, 2006.

Calcium Channel Blocker, Azelnidipine, Reduces Glucose Intolerance in Diabetic Mice via Different Mechanism to Angiotensin Receptor Blocker, Olmesartan

Abstract

The potential combined effect and mechanism of calcium channel blockers (CCB) and angiotensin II type 1 (AT₁) receptor blockers (ARB) to improve insulin resistance were investigated in type 2 diabetic KK-Ay mice, focusing on their anti-oxidative action. Treatment of KK-Ay mice with a CCB, azelnidipine (3 mg/kg/day), or with an ARB, olmesartan (3 mg/kg/day), for 2 weeks lowered the plasma concentrations of glucose and insulin in fed state, attenuated the increase in plasma glucose in oral glucose tolerance test (OGTT), and increased 2-[³H]deoxy-D-glucose (2-[³H]DG) uptake into skeletal muscle with the increase in translocation of GLUT4 to the plasma membrane. Both blockers also decreased the in situ superoxide production in skeletal muscle. The decrease in plasma concentrations of glucose and insulin in fed state and superoxide production in skeletal muscle, GLUT4 translocation to the plasma membrane by azelnidipine was not significantly affected by co-administration of an antioxidant, tempol. However, those changes caused by olmesartan were further improved by tempol. Moreover, olmesartan enhanced the insulin-induced tyrosine-phosphorylation of IRS-1 induced in skeletal muscle, whereas azelnidipine did not change it. Co-administration of azelnidipine and olmesartan further decreased the plasma concentrations of glucose and insulin, improved OGTT, and increased 2-[³H]DG uptake in skeletal muscle. These results suggest that azelnidipine improved glucose intolerance mainly through inhibition of oxidative stress and enhanced the inhibitory effects of olmesartan on glucose intolerance, and the clinical possibility that the combination of CCB and ARB could be more effective than monotherapy in the treatment of insulin resistance.

Key words: AT1 receptor blocker, angiotensin, calcium channel blocker, glucose intolerance, glucose uptake, oxidative stress

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