Blunted insulin-stimulated endothelial function may be a mechanism for the development of atherothrombotic disease in type 2 diabetes, but it is unknown whether hypoglycemic drug therapy can modulate this abnormality. We studied patients with type 2 diabetes and stable ischemic heart disease (n = 28) and lean, healthy control subjects (n = 31). Forearm blood flow was measured by venous occlusion plethysmography during dose-response studies of acetylcholine (ACh) and sodium nitroprusside (SNP) infused into the brachial artery. In the patients and 10 healthy control subjects, ACh was repeated after intrabrachial infusion of insulin. Patients were restudied after 2 months of insulin therapy with four daily subcutaneous injections (treatment group, n = 19) or without hypoglycemic drug therapy (time control group, n = 9). Insulin infusion raised venous serum insulin in the forearm to high physiological levels (133 +/- 14.6 mU/l in patients) with a minor increase in systemic venous serum insulin. This increased the ACh response by 149 +/- 47, 110 +/- 33, 100 +/- 45, and 106 +/- 44% during the four ACh doses in healthy control subjects (P < 0.0001) but had no effect in patients (P = 0.3). After 2 months, HbA(1c) in the treatment group had decreased from 10.0 +/- 0.4 to 7.5 +/- 0.2%. Although neither the ACh response (P = 0.09) nor the SNP response (P = 0.4) had changed significantly, insulin stimulation had a significant effect, as the ACh response increased by 58 +/- 25, 84 +/- 66, 120 +/- 93, and 69 +/- 36% (P = 0.0002). In the time control group, insulin stimulation remained without effect after 8 weeks (P = 0.7). In conclusion, insulin therapy partly restores insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart disease.