Suppression of bank vole pancreatic islet function by proinflammatory cytokines.
Bank voles kept in captivity may develop diabetes. We recently characterized beta-cell function of pancreatic islets from normal and glucose intolerant/diabetic bank voles. These animals had features of both human type 1 and type 2 diabetes. Cytokines may impair beta-cell function in both types of diabetes. Presently, we studied how pancreatic islets isolated from normal, i.e. glucose tolerant bank voles are affected by proinflammatory cytokines in vitro. Islets were exposed to hIL-1beta (25U/ml) alone or in combination with hTNF-alpha (1000U/ml)+mIFN-gamma (1000U/ml) for 48h, whereupon islet functions were assessed. Cytokines markedly reduced insulin gene expression and the (pro)insulin biosynthesis rate, which was accompanied by a profound depletion of the islet insulin content. The cytokines did not affect the culture medium insulin accumulation and the glucose oxidation rate, but caused a modest increase in medium nitrite, an indicator of nitric oxide (NO) generation. Cytokine-induced decrease in islet insulin content was not prevented by the preferential inducible NO synthase inhibitor aminoguanidine. These findings suggest that the reduction in islet insulin content is not attributed to enhanced exocytosis or related to altered glucose metabolism, but is rather due to a decline in insulin production. The suppressive effects of islet functions elicited by cytokines seem to be mediated by an NO-independent mechanism. In relation to previous studies on cytokine effects on islets from various species, the bank vole islets show a pattern which more resembles human islets than rat or murine islets.
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. Martin.Blixt@mcb.uu.se
Martin
M
Blixt
Bo
B
Niklasson
Stellan
S
Sandler
D000818:Animals; D003411:Arvicolinae / Q000378:metabolism* / Q000502:physiology; D003920:Diabetes Mellitus / Q000378:metabolism; D018149:Glucose Intolerance / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007328:Insulin; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma