Diabetes associated cell stress and dysfunction: role of mitochondrial and non‐mitochondrial ROS production and activity

Abstract

It is now widely accepted, given the current weight of experimental evidence, that reactive oxygen species (ROS) contribute to cell and tissue dysfunction and damage caused by glucolipotoxicity in diabetes. The source of ROS in the insulin secreting pancreatic β-cells and in the cells which are targets for insulin action has been considered to be the mitochondrial electron transport chain. While this source is undoubtably important, we provide additional information and evidence for NADPH oxidase-dependent generation of ROS both in pancreatic β-cells and in insulin sensitive cells. While mitochondrial ROS generation may be important for regulation of mitochondrial uncoupling protein (UCP) activity and thus disruption of cellular energy metabolism, the NADPH oxidase associated ROS may alter parameters of signal transduction, insulin secretion, insulin action and cell proliferation or cell death. Thus NADPH oxidase may be a useful target for intervention strategies based on reversing the negative impact of glucolipotoxicity in 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].…”

Preventive Effects of Flavonoids on Alloxan-Induced Diabetes Mellitus in Rats

“…Certain studies have found increased lipid peroxides or ROS and oxidative stress (or both) in different animal models of diabetes (Anjaneyulu and Chopra 2004;Mehta et al 2006). However, the results in clinical practice are not unequivocal and the usefulness of antioxidant therapy in diabetic patients is not convincing (Newsholme et al 2007). …”

Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice

“…On the other hand, the shunting of fatty acid towards esterification may provide a protective mechanism against the detrimental effects of lipid overload and elevated β-oxidation [29][30][31][32]. This may prevent the build-up of ROS or products of incomplete β-oxidation, such as specific acylcarnitine esters, which have been linked to insulin resistance [33,34]. A reduction in β-oxidation in association with improved insulin sensitivity has been described predominantly in muscle [31,34] and is in direct contrast to other findings indicating a positive role for β-oxidation [35][36][37].…”