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Interleukin-6 Affects Insulin Secretion and Glucose Metabolism of Rat Pancreatic Islets in Vitro^*

STELLAN SANDLER, KLAUS BENDTZEN, DÉCIO L. EIZIRIK and MICHAEL WELSH

Department of Medical Cell Biology, Uppsala University (S.S., D.L.E., M.W.), Uppsala, Sweden; and Laboratory of Medical Immunology, Rigshospitalet, University Hospital (KB.) Copenhagen, Denmark

Abstract

Recently it has been postulated that interleukin-1 (IL-1) locally released by infiltrating mononuclear cells may destroy the pancreatic B cells during the development of insulindependent diabetes mellitus. Since IL-1 is a potent inducer of interleukin-6 (IL-6) in various cells, it is conceivable that IL-6 is a second mediator of the IL-1 action. In the present study the effects of IL-6 alone or in combination with IL-1 were studied on pancreatic islet function in vitro after tissue culture and compared with the effects observed after exposure to IL-1 only. Rat pancreatic islets were cultured in medium RPMI1640 + 10% calf serum with or without the addition of human recombinant IL-6 (500–5000 pg/ml) for 48 h. The medium insulin accumulation was increased by 40–50% after culture with 500–2000 pg/ml IL-6, but was similar to the controls at 5000 pg/ml. When islets were cultured for 18 h only, also 5000 pg/ml IL-6 stimulated the medium insulin accumulation. IL-6 did not affect the islet insulin content and the rates of islet (pro)insulin and total protein biosynthesis. It inconsistently decreased the islet DNA content. In short-term experiments after 48-h culture with IL-6, there was a dose-dependent inhibition of the glucosestimulated insulin release. On the other hand, islets cultured with IL-6 (5000 pg/ml) exhibited an elevated glucose oxidation and oxygen uptake, but a lower ATP content at 16.7 mM glucose and an unaffected glucose utilization and glutamine oxidation compared to the controls. This raises the possibility that IL-6 had induced a condition with an increased energy expenditure, resulting in an enhanced mitochondrial metabolism of glucose. Islets cultured with human recombinant IL-1β (25 units/ml) showed a strong inhibition of the insulin accumulation in the culture medium and of glucose-stimulated insulin release and a marked decrease in the islet DNA and insulin content. A combination of IL-1 (25 U/ml) + IL-6 (1000 pg/ml) did not alter the inhibitory action of IL-1 alone. The present findings thus show that IL-6 induces a dissociation between insulin secretion and glucose oxidation in islets in vitro. This has not been observed in islets exposed to IL-1, which suggests that IL-6 does not solely mediate the inhibitory effects of IL-1 on islet function. However, a role for IL-6 in the process of B cell suppression and destruction during the course of insulin-dependent diabetes mellitus cannot be excluded. (Endocrinology 126: 1288–1294, 1990)

Footnotes

^* This work was supported by grants from the Swedish Medical Research Council (12X–109; 12X–8273), the Swedish Diabetes Association, the Swedish Society of Medicine, the Nordic Insulin Fund, Aage-Louis Hansens Mindefond, the Juvenile Diabetes Foundation International, the Hoechst Diabetes Foundation, Magnus Bergvalls Stiftelse, the Torsten and Ragnar Soderbergs Foundation, the Danish Medical Research Council and the Danish Biotechnology Program. D.L.E. and M.W. are recipients of a Postdoctoral and a Career Development Award Fellowship, respectively, from the Juvenile Diabetes Foundation International.

Address correspondence and reprint requests to: Dr. Stellan Sandier, Department of Medical Cell Biology, Biomedicum, P.O. Box 571, S-751 23 Uppsala, Sweden.

Received September 11, 1989.

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