title: Interleukin-1 reduces the glycolytic utilization of glucose by pancreatic islets and reduces glucokinase mRNA content and protein synthesis by a nitric oxide-dependent mechanism.
abstract: Culture of rat pancreatic islets with interleukin-1 (IL-1) results in up-regulation of the inducible isoform of nitric oxide synthase and overproduction of nitric oxide (NO). This is associated with reversible inhibition of both glucose-induced insulin secretion and islet glucose oxidation, and these effects are prevented by the inducible nitric oxide synthase inhibitor NG-monomethylarginine. IL-1 also induces accumulation of nonesterified arachidonic acid in islets by an NO-dependent mechanism, and one potential explanation for that effect would involve an IL-1-induced enhancement of islet glycolytic flux. We have therefore examined effects of IL-1 on islet glycolytic utilization of glucose and find that culture of islets with IL-1 in medium containing 5.5 mM glucose results in suppression of islet glucose utilization subsequently measured at glucose concentrations between 6 and 18 mM. The IL-1-induced suppression of islet glucose utilization is associated with a decline in islet glucokinase mRNA content, as determined by competitive reverse transcriptase-polymerase chain reaction, and in glucokinase protein synthesis, as determined by immuoprecipitation experiments, and all of these effects are prevented by NG-monomethylarginine. These findings suggest that IL-1 can down-regulate islet glucokinase, which is the primary component of the islet glucose-sensor apparatus, by an NO-dependent mechanism. Because reductions in islet glucokinase levels are known to cause a form of type II diabetes mellitus, these observations raise the possibility that factors which increase islet NO levels might contribute to development of glucose intolerance.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
authors.forename: M
authors.initials: M
authors.lastname: Landt
authors.forename: A
authors.initials: A
authors.lastname: Bohrer
authors.forename: S
authors.initials: S
authors.lastname: Ramanadham
authors.forename: D M
authors.initials: DM
authors.lastname: Kipnis
authors.forename: J
authors.initials: J
authors.lastname: Turk
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D017665:Hydroxyl Radical / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007375:Interleukin-1; D012333:RNA, Messenger; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D019001:Nitric Oxide Synthase; D005941:Glucokinase; D005947:Glucose