Beta-Cell-Specific Expression of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 5 Aggravates High-Fat Diet-Induced Impairment of Islet Insulin Secretion in Mice

Karim Bouzakri; Christelle Veyrat-Durebex; Chet Holterman; Caroline Arous; Charlotte Barbieux; Domenico Bosco; Jordi Altirriba; Mohamed Alibashe; Benjamin B Tournier; Jenny E Gunton; Sarah Mouche; William Bietiger; Alexis Forterre; Thierry Berney; Michel Pinget; Gerhard Christofori; Christopher Kennedy; Ildiko Szanto

doi:10.1089/ars.2018.7579

Beta-Cell-Specific Expression of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 5 Aggravates High-Fat Diet-Induced Impairment of Islet Insulin Secretion in Mice

Antioxid Redox Signal. 2020 Mar 20;32(9):618-635. doi: 10.1089/ars.2018.7579.

Authors

Karim Bouzakri^{1

2}, Christelle Veyrat-Durebex³, Chet Holterman⁴, Caroline Arous^{1

3}, Charlotte Barbieux⁵, Domenico Bosco⁵, Jordi Altirriba⁶, Mohamed Alibashe⁵, Benjamin B Tournier⁷, Jenny E Gunton^{8

9}, Sarah Mouche^{3

10}, William Bietiger², Alexis Forterre², Thierry Berney¹¹, Michel Pinget², Gerhard Christofori¹², Christopher Kennedy⁴, Ildiko Szanto^{10

13}

Affiliations

¹ Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
² Centre Européen d'Etude du Diabète, Strasbourg, France.
³ Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
⁴ Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, Canada.
⁵ Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
⁶ Laboratory of Metabolism, Department of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland.
⁷ Vulnerability Biomarkers Unit, Division of General Psychiatry, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland.
⁸ Centre for Diabetes, Obesity and Endocrinology, Westmead Millennium Institute, The University of Sydney, Sydney, Australia.
⁹ Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, Australia.
¹⁰ Department of Internal Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
¹¹ Division of Transplantation, Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland.
¹² Department of Biomedicine, University of Basel, Basel, Switzerland.
¹³ Diabetes Center of the Faculty of Medicine at the University of Geneva, Geneva, Switzerland.

PMID: 31931619
DOI: 10.1089/ars.2018.7579

Abstract

Aims: Nicotinamide adenine dinucleotide phosphate oxidases (NOX-es) produce reactive oxygen species and modulate β-cell insulin secretion. Islets of type 2 diabetic subjects present elevated expression of NOX5. Here, we sought to characterize regulation of NOX5 expression in human islets in vitro and to uncover the relevance of NOX5 in islet function in vivo using a novel mouse model expressing NOX5 in doxycycline-inducible, β-cell-specific manner (RIP/rtTA/NOX5 mice). Results:In situ hybridization and immunohistochemistry employed on pancreatic sections demonstrated NOX5 messenger ribonucleic acid (mRNA) and protein expressions in human islets. In cultures of dispersed islets, NOX5 protein was observed in somatostatin-positive (δ) cells in basal (2.8 mM glucose) conditions. Small interfering ribonucleic acid (siRNA)-mediated knockdown of NOX5 in human islets cultured in basal glucose concentrations resulted in diminished glucose-induced insulin secretion (GIIS) in vitro. However, when islets were preincubated in high (16.7 mM) glucose media for 12 h, NOX5 appeared also in insulin-positive (β) cells. In vivo, mice with β-cell NOX5 expression developed aggravated impairment of GIIS compared with control mice when challenged with 14 weeks of high-fat diet. Similarly, in vitro palmitate preincubation resulted in more severe reduction of insulin release in islets of RIP/rtTA/NOX5 mice compared with their control littermates. Decreased insulin secretion was most distinct in response to theophylline stimulation, suggesting impaired cyclic adenosine monophosphate (cAMP)-mediated signaling due to increased phosphodiesterase activation. Innovation and Conclusions: Our data provide the first insight into the complex regulation and function of NOX5 in islets implying an important role for NOX5 in δ-cell-mediated intraislet crosstalk in physiological circumstances but also identifying it as an aggravating factor in β-cell failure in diabetic conditions.

Keywords: NADPH oxidase; NOX5; beta cell; diabetes; insulin; islet; somatostatin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Diet, High-Fat / adverse effects
Female
Humans
Insulin Secretion / drug effects
Islets of Langerhans / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
NADPH Oxidase 5 / genetics*
NADPH Oxidase 5 / metabolism

Substances

NADPH Oxidase 5
NOX5 protein, human