Diabetic patients are often treated with a lipid lowering statin and an ACE inhibitor or angiotensin receptor antagonist against hypertension or albuminuria. These drugs may also improve glucose tolerance, but the mechanism for this remains elusive. We now studied whether these drugs and the fatty acid palmitate influence insulin secretion in vivo in rats through effects on islet blood perfusion. Whole pancreatic blood flow was markedly increased by captopril and irbesartan, and decreased by palmitate. Islet blood flow was significantly and preferentially enhanced by captopril, irbesartan, and pravastatin, and suppressed by palmitate. Both captopril and irbesartan raised serum insulin concentrations significantly. However, glycemia was not affected in any group. In conclusion, the present study suggests that a local pancreatic RAS and pravastatin may be selectively controlling pancreatic islet blood flow and thereby influencing insulin secretion. The antidiabetic actions of statins and RAS inhibitors might in part occur through the beneficial direct islet effects shown here. Conversely, free fatty acids that are elevated in type 2 diabetic patients may contribute to an impaired nutritive islet blood flow and thereby further aggravate the diabetic state by limiting the supply of insulin needed to curb hyperglycemia.