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

Abstract

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