Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets?

Different degrees of P-cell failure and apoptosis are present in type I and type 2 diabetes. It has been recently suggested that high glucose-induced beta-cell apoptosis in type 2 diabetes shares a final common pathway with type I diabetes, involving interleukin-1 beta (IL-1 beta) production by beta-cells, nuclear factor-kappa B (NF-kappa B) activation, and death via Fas-FasL. The aim of this study was to test whether human islet exposure to high glucose in vitro, or to the type 2 diabetes environment in vivo, induces IL-1 beta expression and consequent activation of NF-kappa B-dependent genes. Human islets were isolated from five normoglycemic organ donors. The islets were cultured for 48 h to 7 days at 5.6, 11, or 28 mmol/l glucose. For comparative purposes, islets were also exposed to IL-1 beta. Gene mRNA expression levels were assessed by real-time RT-PCR in a blinded fashion. Culture of the human islets at 11 and 28 mmol/l glucose induced a four- to fivefold increase in medium insulin as compared with 5.6 mmol/l glucose, but neither IL-1 beta nor IL-1 receptor antagonist (IL-1ra) expression changed. IL-1 beta and IL-1ra protein release to the medium was also unchanged. Stimulated human monocytes, studied in parallel, released > 50-fold more IL-1 beta than the islets. There was also no glucose-induced islet Fas expression. Expression of the NF-kappa B-dependent genes I kappa B-alpha and monocyte chemoattractant protein (MCP)-1 was induced in human islets by IL-1 beta but not by high glucose. In a second set of experiments, human islets were isolated from seven type 2 diabetic patients and eight control subjects. The findings on mRNA levels were essentially the same as in the in vitro experiments, namely the in vivo diabetic state did not induce IL-1 beta, Fas, or MCP-1 expression in human islets, and also did not modify IL-1ra expression. The present findings suggest that high glucose in vitro, or the diabetic milieu in vivo, does not induce IL-1 beta production or NF-kappa B activation in human islets. This makes it unlikely that locally produced IL-1 beta is an important mediator of glucotoxicity to human islets and argues against the IL-1 beta-NF-kappa B-Fas pathway as a common mediator for P-cell death in type 1 and type 2 diabetes.