Basic nutritional investigation Selective induction of inducible nitric oxide synthase in pancreatic islet of rat after an intravenous glucose or intralipid challenge Mats Ekelund, M.D., Ph.D. a , Saleem S. Qader, M.D., Ph.D. a , Javier Jimenez-Feltstrom, Ph.D. b , and Albert Salehi, Ph.D. b, * a Department of Surgery, Division of Diabetes, Metabolism and Endocrinology, University of Lund, Lund, Sweden b Department of Experimental Medical Sciences, Division of Diabetes, Metabolism and Endocrinology, University of Lund, Lund, Sweden Manuscript received September 27, 2005; accepted December 23, 2005. Abstract: Objective: Constant exposure of pancreatic islets to high levels of glucose or free fatty acids can lead to irreversible -cell dysfunction, a process referred to as glucotoxicity or lipotoxicity, respec- tively. 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 -cell function found after 24 h 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 -cells. © 2006 Elsevier Inc. All rights reserved. Keywords: Pancreatic islets; Insulin secretion; Inducible nitric oxide synthase; Glucose challenge Introduction It is well known that the gastrointestinal tract harbors hor- mones that contribute to the control of insulin secretion [1–3]. The route of glucose administration is important for -cell function and insulin secretion. It has been shown that more insulin is secreted in response to an oral glucose challenge than in response to an equivalent intravenous (IV) glucose chal- lenge [1]. Thus, an oral glucose load is metabolized faster than an equivalent IV glucose load. It is also known that sustained increased plasma glucose (hyperglycemia) or free fatty acid (FFA) levels (hyperlipidemia) negatively affect pancreatic -cell response to glucose challenge, a process that has been referred to as glucotoxicity or lipotoxicity, respectively [4–6]. This study was supported by grants from the Swedish Research Council (K2006-04X), NOVO Nordic, the Albert Påhlsson, the Swedish Diabetes Foundation, and the Crafoord Foundation. * Corresponding author. Tel.: +46-46222-7586; fax: +46-46222-7763. E-mail address: salehi@farm.lu.se (A. Salehi). Nutrition 22 (2006) 652– 660 www.elsevier.com/locate/nut 0899-9007/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2006.01.006