Objective: Constant exposure of pancreatic islets to high levels of glucose or free fatty acids can lead to irreversible beta-cell dysfunction, a process referred to as glucotoxicity or lipotoxicity, respectively. In this context a role for nitric oxide generated by pancreatic islet has been suggested. The present investigation examined whether the route of glucose administration, i.e., given orally (OG) or infused intravenously (IVG), could have any effect on the expression and activity of inducible nitric oxide synthase (iNOS) in pancreatic islets. Methods: Rats were infused with glucose (50%) or Intralipid intravenously for 24 h or given glucose orally. A freely fed control group (FF) was also included. At 24 h rats were killed and blood samples were drawn for analysis of plasma insulin, glucagon, and glucose. Pancreatic islets were harvested from each animal and investigated for the occurrence of iNOS by the use of confocal microscopy, western blot, and high-performance liquid chromatographic analysis. The effect of intravenously infused glucose was then compared with the effect of an intravenous infusion of Intralipid (IL). Results: Plasma insulin levels were markedly decreased after 24 h of infusion of glucose (IVG group) or Intralipid (IL group) compared with the FF or OG group. Plasma glucagon and glucose levels were markedly increased in the IVG group, whereas both parameters were decreased in the IL group. No significant differences in plasma insulin, glucagon, or glucose were found between the OG and FF groups. Immunocytochemical (confocal microscopy), western blot, and biochemical (high-performance liquid chromatographic) analyses showed that a sustained increase in plasma level of glucose or free fatty acids by an intravenous infusion of either nutrient for 24 h resulted in a marked expression and activity of iNOS in pancreatic islets. No sign of iNOS expression could, however, be detected in the islets of FF control or OG rats. Conclusion: The data suggest that impaired beta-cell function found after 24 It of an intravenous infusion of glucose or Intralipid might be mediated, at least in part, by the induction of iNOS in pancreatic islets. This may subsequently result in an exclusive production of nitric oxide, which is deleterious for beta-cells. (C) 2006 Elsevier Inc. All rights reserved.