METABOLISM AND BETA-CELL FUNCTION OF RAT PANCREATIC-ISLETS EXPOSED TO HUMAN INTERLEUKIN-1-BETA IN THE PRESENCE OF A HIGH GLUCOSE-CONCENTRATION

It has been postulated that one of the factors causing immune-mediated pancreatic β-cell destruction in insulin-dependent diabetes mellitus (IDDM) is interleukin-1 (IL-1). Rat pancreatic islets exposed to human recombinant IL-1β (rIL-1β) for 48 h in vitro exhibit a markedly reduced glucose-stimulated insulin secretion. Also, a deleterious effect of glucose on β-cell function, especially under conditions of a reduced β-cell mass, which may exist in the early phase of IDDM has been suggested. In this study the response of rat pancreatic islets in vitro to a combination of the cytokine and high glucose concentration have therefore been assessed. Thus, islets were cultured for 48 h at either 11.1 or 56 mM glucose with or without 25 U/ml rIL-1β. Exposure to the cytokine reduced the islet DNA content at both glucose concentrations by 20-25%. In short-term incubations in the absence of rIL-1β after the preceding culture with the cytokine, the glucose-stimulated insulin release was reduced by 70% in islets cultured at 11.1 mM glucose and by only 40% after culture at 56 mM glucose, when compared to the corresponding control islets. The utilization of D-[5-3H]glucose, i.e., the catabolism of glucose in the glycolytic pathway, was the same in all groups of islets. However, the D-[6-14C]glucose oxidation rate, i.e., the metabolism of glucose in the Krebs cycle, was reduced by about 65% in rIL-1β exposed islets kept at 11.1 mM glucose and 46% in islets cultured at 56 mM glucose. The islet ATP content was reduced by about 40-45% by rIL-1β at both glucose concentrations and also the ratio ATP/ADP was reduced. The rIL-1β exposed islets maintained at 11.1 mM glucose failed to increase their oxygen uptake in response to glucose, whereas 56 mM glucose cultured islets showed a similar respiratory pattern as their controls. The islets exposed to rIL-1β exhibited also a 50-60% reduction in their cAMP content. In control islets cultured at 56 mM glucose a slight decrease in their glucose oxidation rates and a lowering in the ATP/ADP ratio was recorded. Taken together the present results point towards a disturbed glucose metabolism in the mitochondria of β-cells exposed to rIL-1β. However, a high glucose concentration does not appear to further deteriorate β-cell function when present together with rIL-1β, but rather to counteract some of the effects of rIL-1β. The findings also suggest a slightly impairing effect of a very high glucose concentration on islet function, although it remains unclear if such an effect is of pathophysiological relevance. © 1990.