What is it about?
We revealed that NADPH oxidase , isoform NOX4, produces hydrogen peroxide upon glucose intake into the pancreatic beta cells. When NOX4 was ablated in mice, the first phase of insulin secretion was blocked. In pancreatic islets from NOX4 knockout mice, insulin secretion as responding to glucose was rescued either by NOX4 overexpression or by the addition of H2O2. Patch-clamped INS-1E cells with silenced NOX4 did not close the ATP-sensitive K+channel upon glucose addition. Moreover, 2- ketoisocaproate (i.e. 2-oxoisocaproate, OIC) stimulated insulin secretion in INS-1E cells, and even in NOX4-knockout mice and pancreatic islets, but in not in cells silenced for branched chain ketoacid dehydrogenase or treated with mitochondrial matrix-targeted antioxidant SkQ1. This means that in case of OIC, metabolism of OIC in mitochondria produces also superoxide, which after conversion to H2O2 provides mitochondrial redox signaling for closing of the ATP-sensitive K+channel. In conclusion, the essential requirement of redox signaling for insulin secretion in vivo can be provided either by NOX4 or by mitochondrial sources
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Why is it important?
Not only the cell metabolic status (reflected by the increased ATP/ADP ratio) is linked to the insulin exocytosis, but also the redox status, determined by the existing rates of H2O2 release into the cytosol. This is very important for all considerations and analyses of impaired redox homeostasis and/or insulin secretion in diabetic pancreatic beta cells. Since there is a diminished antioxidant defense in pancreatic beta-cells, the repeatable NOX4-produced H2O2 at glucose-stimulated insulin secretion in vivo could be gradually transformed into oxidative stress, reflecting the high beta-cell vulnerability. This could potentially contribute to diabetic etiology. The cytosol-targeted antioxidant therapy, which should inevitably suppress GSIS, seems to be irrelevant for these early stages of diabetes. Tuning down the essential H2O2 release at GSIS would instead amplify pre-diabetes symptoms instead of preventing them. In contrast, we may predict that mitochondria-targeted antioxidants should not harm the physiological redox signaling (except that of oxoacids) and might cure the premature oxidative stress in the matrix at the pre-diabetic stage.
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This page is a summary of: Glucose-Stimulated Insulin Secretion Fundamentally Requires H2O2 Signaling by NADPH Oxidase 4, Diabetes, April 2020, American Diabetes Association, DOI: 10.2337/db19-1130.
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