Oxidative stress and beta-cell dysfunction

Abstract

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.

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat

“…In patients with type 2 diabetes, there is, over time, a progressive loss of beta cells due to increased apoptosis [39][40][41][42]. This increase in cell death is thought to be a consequence, at least in part, of glucolipotoxicity and associated oxidative stress [20,21,43,44]. There is, nonetheless, much that remains unknown regarding the mechanisms of beta cell loss as diabetes progresses.…”

“…Patients with type 2 diabetes lose a significant portion of their beta cell mass over time [18,19], and this is believed to be at least in part a consequence of oxidative stress [20,21]. Various lines of indirect evidence suggest that pharmacological interventions that augment glucokinase activity may favour mechanisms that slow or prevent beta cell loss [22,23] or promote beta cell proliferation in vivo [3,[24][25][26][27].…”

Mitochondrial succinate dehydrogenase is involved in stimulus-secretion coupling and endogenous ROS formation in murine beta cells

“…For pheochromocytoma cells, it has been shown that short-term application of 3-NPA induces a concentration-dependent elevation of ROS [32], whereas others did not detect any effect in the same cell line [33]. As oxidative stress plays an important role in beta cell failure during development and progression of type 2 diabetes [34], we monitored ROS accumulation. Our data demonstrate that 3-NPA had no acute effect on intracellular ROS and even reduced ROS concentration after an exposure time of 1 h (Fig.…”

Oxidative Stress in Diabetes Mellitus: Is There a Role for Hypoglycemic Drugs and/or Antioxidants?

“…With persistent hyperglycemia, disproportionate amounts of glucose are delivered to the cells. This results in enhanced glucose flux through glycolysis and the tricarboxylic acid (TCA) cycle (Drews et al, 2010). This leads to an overdrive of the mitochondrial electron transport chain, which generates greater amounts of O 2 •− more than mitochondrial SOD can dismutase , Brand, 2010.…”