In patients with diabetes and coronary artery disease, the potential negative role of sulfonylurea drugs is under intensive investigation. We assessed the effects of treatment with glibenclamide or insulin on the extension of left ventricular myocardial dysfunction induced by acute ischemia. Nineteen consecutive patients with type 2 diabetes and coronary artery disease entered the study. Each patient was randomly assigned to either insulin or glibenclamide therapy. Treatment was crossed over after 12 weeks and maintained for another 12 weeks. At the end of each treatment, left ventricular myocardial function at rest and during dipyridamole infusion was studied by two-dimensional echocardiography under the same conditions of metabolic control. Glibenclamide or insulin treatment did not influence the rest values of left ventricular dimensions, left ventricular ejection fraction (LVEF), or wall motion score index (WMSI). Dipyridamole infusion, in patients receiving glibenclamide treatment, decreased LVEF (43 ± 7 vs. 37 ± 12%, P < 0.005) and increased WMSI (1.4 ± 0.28 vs. 1.98 ± 0.24, P < 0.001) compared with baseline values; during insulin treatment, LVEF (46 ± 8 vs. 45 ± 11%, NS) and WMSI (1.4 ± 0.29 vs. 1.6 ± 0.4, NS) did not change significantly. Peak stress LVEF was higher (45 ± 11 vs. 37 ± 12%, P < 0.001) and WMSI lower (1.6 ± 0.4 vs. 1.98 ± 0.24, P < 0.001) in patients receiving insulin. The results indicate that in patients with type 2 diabetes and coronary artery disease, ischemic myocardial dysfunction induced by dipyridamole infusion is less severe during treatment with insulin than with glibenclamide. Restitution of a preconditioning mechanism in insulin-treated patients may be the potential beneficial mechanism.