Mechanism of Action
A new Target for Diabetes Treatment: NAD(P)H-oxidase
The benefits of the potential therapy of Glucox Biotech are that it effectively increase glucose uptake in muscle and dramatically improves insulin sensitivity and thus remove the probable cause of the blunted insulin response. This is in a way the opposite effect of what drugs on the market do when stimulating insulin secretion from pancreatic cells.
Chronic hyperglycaemia is the main cause of increased oxidative stress in type 2 diabetes patients. The over-production of oxygen free radicals, ROS, and nitric oxide radicals leads to the damage of many cellular compounds including lipids, proteins and nucleic acids.
Glucox Biotech’s development compounds are designed to inhibit one of the main enzymes involved in ROS production, NAD(P)H-oxidase (isoenzyme NOX4), thus aiming to reduce ROS production in diabetic subjects. NAD(P)H-oxidase related ROS has repeatedly been identified by several independent scientists as a key component in insulin resistance and the development of diabetes complications.
Based on its scientific excellence, favourable IP-position and with a strong mission, Glucox Biotech aims to develop and produce the next generation safe and beneficial therapy for present and future diabetes suffers.
The role of NAD(P)H-oxidase in different indications
In vivo experiments – in mouse and rat models – made by Glucox have indicate that NAD(P)H-oxidase inhibition improves glucose sensitivity. Literature support may be found in e. g.: Evans LE et al., 2003, Diabetes 52, 1-8, Wei Y et al., 2006 J Biol Chem 281, 35137-35146, Bloch K et al., 2009 PNAS 106, 14385-14390.
Regarding the development of diabetic complication, the involvement of Nox4 in nephropathy, in podocytes response to high glucose concentrations is relevant: Sedeek M et al., Am J Physiol Renal Physiol. 2010 Dec; 299(6); Eid AA et al., J Biol Chem. 2010 Nov 26; 285(48).
The connection of NOX4 in mitochondrial dysfunction in “the aging heart” is very interesting (Tetsuro Ago et al., AGING, December 2010, vol.2 No 12). The review Maejima Y et al., 2011 “Regulation of myocardial growth and death by NADPH oxidase” point to NOX4 as a candidate for myocardial cell death also”NADPH oxidase 4 is a major source of oxidative stress in the failing heart” Kuroda J et al., PNAS USA 2010 Aug 31; 107.
Endothelial dysfunction is a crucial step in the pathogenesis of cardiovascular diseases and diabetes. There is a strong connection of NADPH oxidase and dysfunctional endothelial cells – “Activation of NF-kappaB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation (NOX4 knockdown by siRNA)” Maloney E et al., Arterioscler Throm Vasc Biol. 2009 sep;29(9). Thus – the implication of the connection of fatty acids and cellular inflammation.
NOX4-dependent H2O2 production contributes to glutamate toxicity in primary cortical neurons, Ha JS et al., Exp Cell Res. 2010 Jun 10; 316(10)