title: The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice.
abstract: In type 2 diabetes, it has been proposed that pancreatic beta-cell dysfunction is promoted by oxidative stress caused by NADPH oxidase (NOX) overactivity. Five different NOX enzymes (NOX1-5) have been characterized, among which NOX1 and NOX2 have been proposed to negatively affect beta-cells, but the putative role of NOX4 in type 2 diabetes-associated beta-cell dysfunction and glucose intolerance is largely unknown. Therefore, we presently investigated the importance of NOX4 for high-fat diet or HFD-induced glucose intolerance using male C57BL/6 mice using the new NOX4 inhibitor GLX351322, which has relative NOX4 selectivity over NOX2. In HFD-treated male C57BL/6 mice a two-week treatment with GLX351322 counteracted non-fasting hyperglycemia and impaired glucose tolerance. This effect occurred without any change in peripheral insulin sensitivity. To ascertain that NOX4 also plays a role for the function of human beta-cells, we observed that glucose- and sodium palmitate-induced insulin release from human islets in vitro was increased in response to NOX4 inhibitors. In long-term experiments (1-3 days), high-glucose-induced human islet cell reactive oxygen species (ROS) production and death were prevented by GLX351322. We propose that while short-term NOX4-generated ROS production is a physiological requirement for beta-cell function, persistent NOX4 activity, for example, during conditions of high-fat feeding, promotes ROS-mediated beta-cell dysfunction. Thus, selective NOX inhibition may be a therapeutic strategy in type 2 diabetes.
authors.affiliation: a Science for Life Laboratory, Department of Medical Cell Biology , Uppsala University , Uppsala , Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Anvari
authors.affiliation: b Glucox Biotech AB , Stockholm , Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Wikström
authors.affiliation: b Glucox Biotech AB , Stockholm , Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Walum
authors.affiliation: a Science for Life Laboratory, Department of Medical Cell Biology , Uppsala University , Uppsala , Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Welsh
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000188:drug therapy*; D057166:High-Throughput Screening Assays; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000209:etiology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; D017382:Reactive Oxygen Species; D013876:Thiophenes; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: NADPH oxidase; NOX inhibitor; beta-cell death; glucose intolerance; human islet; insulin release; reactive oxygen radical