Possible Synergistic Effect of ACE Inhibition and Calcium-Channel Blockade on Insulin Sensitivity in Insulin-Resistant Type II Diabetic Hypertensive Patients

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Abstract

Summary:

So-called insulin resistance is a frequent phenomenon and a marker of increased risk for both type II diabetes mellitus and atherosclerosis. Today, insulin resistance is widely understood as a tissue- and pathway-specific defect of insulin-stimulated glucose uptake into skeletal muscle that is compensated for by hyperinsulinemia, leading to a cluster of undesirable hypertensiogenic, diabetogenic, and atherogenic processes. Additional defects of insulin-stimulated muscle blood flow and cellular kation balance are presently attracting increasing awareness. Clinical and experimental evidence suggests that angiotensin-converting enzyme (ACE) inhibition ameliorates both insulin-stimulated skeletal-muscle glucose uptake and blood flow in insulin-resistant states by a direct stimulation of cellular glucose uptake, which appears to be kinin-mediated. This improvement of insulin sensitivity could mean not only improvement of glucose metabolism, but also reduction of chronically elevated serum insulin and the ensuing atherogenic consequences (hyper- and dyslipidemia, sympathetic overactivity, growth of vascular smooth-muscle cells, hypertension, etc.). Ca2+-channel blockers that do not increase heart rate appear to exert direct antiatherogenic effects while being metabolically neutral. Thus, the combination of Ca2+-channel blockade by sustained release verapamil and ACE inhibition by trandolapril in insulinresistant type II diabetic patients with essential hypertension appears to be promising in terms of possible synergistic effects. Therefore, presently we are conducting a double-blind, placebo-controlled, randomized study in 40 insulin-resistant patients who have NIDDM and mild essential hypertension and who, after a 4-week placebo run-in, receive either 180 mg verapamil SR, 1 mg trandolapril, a combination of both, or placebo in a single oral dose during an 8-week period. Target criteria are insulin sensitivity determined by isoglycemic hyperinsulinemic clamp and 24-h blood pressure determined by ambulatory blood pressure monitoring.

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