Usurping the mitochondrial supremacy: Extramitochondrial sources of reactive oxygen intermediates and their role in beta cell metabolism and insulin secretion

Abstract

Insulin secretion from pancreatic beta cells is a process dependent on metabolism. While oxidative stress is a well-known inducer of beta cell toxicity and impairs insulin secretion, recent studies suggest that low levels of metabolically-derived reactive oxygen intermediates (ROI) also play a positive role in insulin secretion. Glucose metabolism is directly correlated with ROI production, particularly in beta cells in which glucose uptake is proportional to the extracellular concentration of glucose. Low levels of exogenously added ROI or quinones, which stimulate ROI production, positively affect insulin secretion, while antioxidants block insulin secretion, suggesting that ROI activate unidentified redox-sensitive signal transduction components within these cells. The mitochondria are one source of ROI: increased metabolic flux increases mitochondrial membrane potential resulting in electron leakage and adventitious ROI production. A second source of ROI are cytosolic and plasma membrane oxidoreductases which oxidize NAD(P)H and directly produce ROI through the reduction of molecular oxygen. The mechanism of ROI-mediated potentiation of insulin secretion remains an important topic for future study.

Keywords::

• Pancreatic islets
• glycolysis
• NAD(P)H
• mitochondrial shuttles
• cytosolic oxidoreductases

Acknowledgements

The authors thank Dr Katherine A. Burns and Professor M. Meow for helpful comments and support in manuscript preparation. J. P. Gray is a professor at the US Coast Guard Academy. The views here are his own and not necessarily those of the Coast Guard or other branches of the US government.

Declaration of interest

Funding was provided by the American Diabetes Association Junior Faculty Award 7-08-JF-18 (EH), The Center for Advanced Studies of the US Coast Guard Academy (JPG), and the Alexander Trust Fund (JPG). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.