Oxidative stress and beta-cell dysfunction.
Diabetes mellitus type 1 and 2 (T1DM and T2DM) are complex multifactorial diseases. Loss of beta-cell function caused by reduced secretory capacity and enhanced apoptosis is a key event in the pathogenesis of both diabetes types. Oxidative stress induced by reactive oxygen and nitrogen species is critically involved in the impairment of beta-cell function during the development of diabetes. Because of their low antioxidant capacity, beta-cells are extremely sensitive towards oxidative stress. In beta-cells, important targets for an oxidant insult are cell metabolism and K(ATP) channels. The oxidant-evoked alterations of K(ATP) channel activity seem to be critical for oxidant-induced dysfunction because genetic ablation of K(ATP) channels attenuates the effects of oxidative stress on beta-cell function. Besides the effects on metabolism, interference of oxidants with mitochondria induces key events in apoptosis. Consequently, increasing antioxidant defence is a promising strategy to delay beta cell failure in (pre)-diabetic patients or during islet transplantation. Knock-out of K(ATP) channels has beneficial effects on oxidant-induced inhibition of insulin secretion and cell death. Interestingly, these effects can be mimicked by sulfonylureas that have been used in the treatment of T2DM for many years. Loss of functional K(ATP) channels leads to up-regulation of antioxidant enzymes, a process that depends on cytosolic Ca(2+). These observations are of great importance for clinical intervention because they show a possibility to protect beta-cells at an early stage before dramatic changes of the secretory capacity and loss of cell mass become manifest and lead to glucose intolerance or even overt diabetes.
Drews
Gisela
G
Department of Pharmacology and Clinical Pharmacy, University of Tübingen, Auf der Morgenstelle 8, Tübingen, Germany. gisela.drews@uni-tuebingen.de
Krippeit-Drews
Peter
P
Düfer
Martina
M
D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology*