Hypoglycemia induced by alcohol ingestion is a well known problem in diabetic patients. However, the mechanisms underlying this phenomenon have largely remained elusive. Since insulin secretion in vivo can be rapidly tuned by changes in pancreatic microcirculation, we evaluated the influence of acute alcohol administration on pancreatic islet blood flow and dynamic changes in insulin secretion and glycemia in the rat. Ethanol (10%) or saline was intravenously injected as a bolus into Wistar rats, yielding serum ethanol concentrations of 8 mmol/l. Measurements of pancreatic blood flow were performed by a microsphere technique in combination with a freeze-thawing technique after 10 minutes of injection. Ethanol preferentially and significantly increased pancreatic islet blood flow approx four-fold, while not influencing whole pancreatic blood flow. The alcohol also augmented late phase insulin secretion and induced late hypoglycemia upon intraperitoneal glucose tolerance tests. The nitric oxide synthase inhibitor N--nitro-L-arginine methyl ester and atropine prevented the increased pancreatic islet blood flow, enhanced insulin secretion, and hypoglycemia evoked by ethanol. Our findings thus demonstrate that ethanol acutely exerts substantial influences on pancreatic microcirculation by evoking a massive redistribution of pancreatic blood flow from the exocrine into the endocrine part via mechanisms mediated by nitric oxide and vagal stimuli, augmenting late phase insulin secretion, and thereby evoking hypoglycemia. This effect may in part underlie the well known hypoglycemic properties of alcohol in diabetic patients or in alcoholics with hepatic failure.