Increased interleukin (IL)-1β messenger ribonucleic acid expression in β-cells of individuals with type 2 diabetes and regulation of IL-1β in human islets by glucose and autostimulation

Context: Elevated glucose levels impair islet function and survival, and it has been proposed that intraislet expression of IL-1 beta contributes to glucotoxicity. Objective: The objective was to investigate IL-1 beta mRNA expression in near-pure beta-cells of patients with type 2 diabetes (T2DM) and study the regulation of IL-1 beta by glucose in isolated human islets. Methods: Laser capture microdissection was performed to isolate beta-cells from pancreas sections of 10 type 2 diabetic donors and nine controls, and IL-1 beta mRNA expression was analyzed using gene arrays and PCR. Cultured human islets and fluorescence-activated cell sorter-purified human beta-cells were used to study the regulation of IL-1 beta expression by glucose and IL-1 beta. Results: Gene array analysis of RNA from beta-cells of individuals with T2DM revealed increased expression of IL-1 beta mRNA. Real-time PCR confirmed increased IL-1 beta expression in six of 10 T2DM samples, with minimal or no expression in nine control samples. In cultured human islets, IL-1 beta mRNA and protein expression was induced by high glucose and IL-1 beta autostimulation and decreased by the IL-1 receptor antagonist IL-1Ra. The glucose response was negatively correlated with basal IL-1 beta expression levels. Autostimulation was transient and nuclear factor-kappa B dependent. Glucose-induced IL-1 beta was biologically active and stimulated IL-8 release. Low picogram per milliliter concentrations of IL-1 beta up-regulated inflammatory factors IL-8 and IL-6. Conclusion: Evidence that IL-1 beta mRNA expression is up-regulated in beta-cells of patients with T2DM is presented, and glucose-promoted IL-1 beta autostimulation may be a possible contributor.