Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta.
Decreased functional beta-cell mass in type 1 and type 2 diabetes is due to beta-cell apoptosis and impaired secretory function suggested to be mediated, in part, by immune- and/or high-glucose-induced production of IL-1beta acting through the nuclear factor kappaB (NFkappaB)/Fas pathway. The aim of this study was to determine whether two drugs believed to block NFkappaB activation, the thiazolidinedione (glitazone) pioglitazone and the nonsteroidal antiinflammatory drug sodium salicylate, can protect human beta-cells against the toxic effects of IL-1beta 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-1beta or at 600 mg/dl (33.3 mm) glucose. IL-1beta and 600 mg/dl glucose increased beta-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-1beta or 600 mg/dl glucose. IL-1beta secretion from islets was increased by 4-d culture at 600 mg/dl, and this was blocked by pioglitazone. Both drugs prevented activation of beta-cell NFkappaB by high glucose. Pioglitazone and sodium salicylate thus protect human islets against the detrimental effects of IL-1beta and high glucose by blocking NFkappaB activation and may therefore be useful in retarding the manifestation and progression of diabetes.
Zeender
E
E
Department of Genetic Medicine and Development, University Medical Centre, Geneva CH-1211, Switzerland.
Maedler
K
K
Bosco
D
D
Berney
T
T
Donath
M Y
MY
Halban
P A
PA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D000077205:Pioglitazone; D012980:Sodium Salicylate / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007004:Hypoglycemic Agents; D007328:Insulin; D007375:Interleukin-1; D016328:NF-kappa B; D045162:Thiazolidinediones; D009569:Nitric Oxide; D005947:Glucose; D012980:Sodium Salicylate; D000077205:Pioglitazone