The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice

Abstract

The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice.. (11) http://dx.doi.org/10. 3109/10715762.2015.1067697 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. EA and PW performed the experiments. PW, EW and NW designed the experiments, analyzed the results and wrote the manuscript. Free radical research, 49 2 ABSTRACTIn Type 2 diabetes, it has been proposed that pancreatic beta-cell dysfunction is promoted by oxidative stress caused by NADPH oxidase (NOX) over-activity. 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 (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 longterm experiments (1-3 days), high glucose-induced human islet cell ROS production and death were prevented by GLX351322. We propose that whilst short-term NOX4-generated ROS production is a physiological requirement for beta-cell function, persistent NOX4-activity, e.g. during conditions of high-fat feeding, promotes ROSmediated beta-cell dysfunction. Thus, selective NOX-inhibition may be a therapeutic strategy in Type 2 diabetes.3

Long‐Term Measures of Dyslipidemia, Inflammation, and Oxidative Stress in Rats Fed a High‐Fat/High‐Fructose Diet

“…These results suggested that NADPH oxidase-mediated oxidative stress may contribute to glucose intolerance and liver injury during high-fat diet feeding. In addition and in agreement with such hypothesis, a novel NADPH oxidase inhibitor, the GLX351322, was reported to counteract glucose intolerance in high-fat diettreated C57BL/6 mice (Anvari et al, 2015). Another team , catalase and glutathione peroxidase [GPx] (c) parameters were determined.…”

“…These results suggested that NADPH oxidase‐mediated oxidative stress may contribute to glucose intolerance and liver injury during high‐fat diet feeding. In addition and in agreement with such hypothesis, a novel NADPH oxidase inhibitor, the GLX351322, was reported to counteract glucose intolerance in high‐fat diet‐treated C57BL/6 mice (Anvari et al, ). Another team (Yang et al, ) has reported that oral administration of Salidroside prevented liver injury in the NASH model, through its antioxidant actions to suppress oxidative stress and the free radical‐generating Nox2 in liver.…”

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

“…Our proposition is that the antioxidant drugs used to date are highly unlikely to be able to combat the high levels of b-cell oxidative stress driven continuously by b-cell intrinsic and local environmental factors. One possible approach is to target NADPH oxidases with proof or principle preclinical studies suggesting that the targeting of NOX2 or NOX4 could improve b-cell function , Anvari et al 2015. Our observations that IL22 drives a strong intrinsic antioxidant program in b-cells that decreases production and increases degradation of ROS and RNS open a new pathway to promoting b-cell resilience to oxidative stress caused by lipids, cytokines and protein misfolding.…”

Therapeutic potential of NADPH oxidase 1/4 inhibitors

“…A number of compounds, including interfering peptides, have been described as NOX inhibitors and have been recently reviewed in detail (Gatto et al , , Altenhofer et al , ) (Table ). Compounds more recently published include thioridazine, an N‐substituted phenothiazine, with non‐isoform selective NOX activity (Seredenina et al , ); GLX351322, a NOX4‐selective inhibitor (Anvari et al , ); and GSK2795039, a direct NOX2 inhibitor (Hirano et al , ) (Table ). Two of the older compounds that have been widely used as NOX inhibitors are diphenyleneidonium (DPI) and apocynin.…”