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.


Surprisingly, merely the ablation of a single NOX4 gene generated in mice the onset of insulin resistance. We can speculate that the pancreatic beta-cells must emit an as yet unknown stress signal (directly or via the immune system, inducing the peripheral insulin resistance. We hypothesize that such a putative stress signal is induced by the insufficient identity checking or autocrine self-maintenance of beta-cells in NOX4KO mice. The beta-cell identity checking can be even mediated by the same redox signaling which acts upon KATP-dependent insulin exocytosis. We suggest that its source is H2O2 produced by NOX4. This may hypothetically contribute to the “correct” beta-cell identity-checking signal, which also primarily maintains sufficient insulin gene expression. For NOX4 knockout mice, the diet over time stimulates insulin release stimulated with fatty acids and ketoacidsor other secretagogues, hence these sectretagogues might be sufficient. However, since the NOX4-mediated redox signaling is impaired, they lack the NOX4-induced “correct” beta-cell identity-checking signal. We speculate that the lack of this signal evokes an as yet unknown stress signal for the periphery. All these aspects must be investigated and either to be confirmed, modified or excluded.

Petr Jezek
Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Prague, 14220, Czech Republic

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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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