Pioglitazone and Sodium Salicylate Protect Human β-Cells against Apoptosis and Impaired Function Induced by Glucose and Interleukin-1β

Abstract

Decreased functional β-cell mass in type 1 and type 2 diabetes is due to β-cell apoptosis and impaired secretory function suggested to be mediated, in part, by immune- and/or high-glucose-induced production of IL-1β acting through the nuclear factor κB (NFκB)/Fas pathway. The aim of this study was to determine whether two drugs believed to block NFκB activation, the thiazolidinedione (glitazone) pioglitazone and the nonsteroidal antiinflammatory drug sodium salicylate, can protect human β-cells against the toxic effects of IL-1β and high glucose in vitro. Human islets were maintained in culture 2–4 d at 100 mg/dl (5.5 mm) glucose with or without (control) IL-1β or at 600 mg/dl (33.3 mm) glucose. IL-1β and 600 mg/dl glucose increased β-cell apoptosis and abolished short-term glucose-stimulated insulin secretion. Both drugs protected partially against loss of glucose-stimulated insulin secretion and prevented completely increased apoptosis caused by IL-1β or 600 mg/dl glucose. IL-1β secretion from islets was increased by 4-d culture at 600 mg/dl, and this was blocked by pioglitazone. Both drugs prevented activation of β-cell NFκB by high glucose. Pioglitazone and sodium salicylate thus protect human islets against the detrimental effects of IL-1β and high glucose by blocking NFκB activation and may therefore be useful in retarding the manifestation and progression of diabetes.