Can insulin secreting pancreatic β-cells provide novel insights into the metabolic regulation of the DNA damage response?

Abstract

Insulin, produced by pancreatic β-cells, is responsible for the control of whole-body glucose metabolism. Insulin is secreted by pancreatic β-cells in a tightly regulated process that is controlled by the serum level of glucose, glucose sensing and glucose oxidative metabolism. The regulation of intermediary metabolism in β-cells is unique as these cells oxidize glucose to CO₂ on substrate supply while mitochondrial oxidative metabolism occurs on demand, for the production of intermediates or energy production, in most cell types. This review discusses recent findings that the regulation of intermediary metabolism by nitric oxide attenuates the DNA damage response (DDR) and DNA damage-dependent apoptosis in a β-cell selective manner. Specific focus is placed on the mechanisms by which iNOS derived nitric oxide (low micromolar levels) regulates DDR activation via the inhibition of intermediary metabolism. The physiological significance of the association of metabolism, nitric oxide and DDR signaling for cancer biology and diabetes is discussed.

Keywords: Beta cell; DNA damage response; Islet; Metabolism; Mitochondria; Nitric oxide; Oxidation.