title: Differential sensitivity to beta-cell secretagogues in cultured rat pancreatic islets exposed to human interleukin-1 beta.
abstract: The early stages of insulin-dependent diabetes mellitus are characterized by a selective inability to secrete insulin in response to glucose, coupled to a better response to nonnutrient secretagogues. The deficient glucose response may be a result of the autoimmune process directed toward the beta-cells. Interleukin-1 (IL-1) has been suggested to be one possible mediator of immunological damage of the beta-cells. In the present study we characterized the sensitivity of beta-cells to different secretagogues after human recombinant IL-1 beta (rIL-1 beta) exposure. Furthermore, experiments were performed to clarify the biochemical mechanisms behind the defective insulin response observed in these islets. Rat pancreatic islets were isolated and kept in tissue culture (medium RPMI-1640 plus 10% calf serum) for 5 days. The islets were subsequently exposed to 60 pM human recombinant IL-1 beta during 48 h in the same culture conditions as above and examined immediately after IL-1 exposure. The rIL-1 beta-treated islets showed a marked reduction of glucose-stimulated insulin release. Stimulation with arginine plus different glucose concentrations, and leucine plus glutamine partially counteracted the rIL-1 beta-induced reduction of insulin release. The activities of the glycolytic enzymes hexokinase, glucokinase, and glyceraldehyde 3-phosphate dehydrogenase, were similar in control and IL-1-exposed islets. Treatment with IL-1 also did not impair the activities of NADH+- and NADPH+-dependent glutamate dehydrogenase, glutamate-aspartate transaminase, glutamate-alanine transaminase, citrate synthase, and NAD+-linked isocitrate dehydrogenase. The oxidation of D-[6-14C]glucose and L-[U-14C]leucine were decreased by 50% in IL-1-treated islets. Furthermore, there was a significant decrease in the ratios of [2-14C]pyruvate oxidation/[1-14C]pyruvate decarboxylation and L-[U-14C]leucine oxidation/L-[1-14C]leucine decarboxylation, indicating that IL-1 decreases the proportion of generated acetyl-coenzyme-A residues undergoing oxidation. However, in the presence of IL-1 there was a significant increase in L-[U-14C]glutamate oxidation. These combined observations suggest that exposure to IL-1 induces a preferential decrease in glucose-mediated insulin release and mitochondrial glucose metabolism. This mitochondrial dysfunction seems to reflect an impairment in proximal steps of the Krebs cycle. It is conceivable that the IL-1-induced suppression and shift in islet metabolism can be an explanation for the beta-cell insensitivity to glucose observed in the early phases of human and experimental insulin-dependent diabetes mellitus.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Sweden.
authors.forename: D L
authors.initials: DL
authors.lastname: Eizirik
authors.forename: S
authors.initials: S
authors.lastname: Sandler
authors.forename: A
authors.initials: A
authors.lastname: Hallberg
authors.forename: K
authors.initials: K
authors.lastname: Bendtzen
authors.forename: A
authors.initials: A
authors.lastname: Sener
authors.forename: W J
authors.initials: WJ
authors.lastname: Malaisse
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D002478:Cells, Cultured; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004338:Drug Combinations / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D007930:Leucine / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D004338:Drug Combinations; D007328:Insulin; D007375:Interleukin-1; D011773:Pyruvates; D005973:Glutamine; D001120:Arginine; D007521:Isocitrate Dehydrogenase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005969:Glutamate Dehydrogenase; D002950:Citrate (si)-Synthase; D006593:Hexokinase; D005941:Glucokinase; D007930:Leucine; D005947:Glucose