The maintenance of a low NADH/NAD+ ratio might be achieved by preserving the complex I activity from the inhibitory effects of cardio lipin peroxidation and sustained glutathionylation, for which the maintenance of high GSH/GSS ratios would be beneficial. The resultant increase in NAD+ levels might impact favorably insulin resistance in diabetes and obesity by decreasing the levels of incomplete products of fat oxidation that impairs insulin signaling.
This would be the result of enhanced deacetylation of key enzymes involved in fatty acid oxidation and mitochondrial bioenergetic metabolism, including the complex I by itself. This would create a virtuous cycle that might lead to sustained improvement of complex I activity and increased NAD+ generation, leading to decreased production of ROS and decreased lipid peroxidation Regarding to the hypothesis that beneficial effects on glucose homeostasis could be achieved by enhancing complex I activity, it could be argued that complex I inhibition is beneficial rather than deleterious for the treatment of diabetes, since it has been proposed that met formin, the first choice drug for the treatment of type 2 diabetes, de creases blood glucose by a mechanism involving the inhibition of complex I activity, decreased ATP/AMP ratio, stimulation of AMP-ac tivated protein kinase (AMPK), and AMPK -mediated inhibition of gluconeogenesis and activation of glycolysis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686634/
Thus, the en hancement of complex I activity might lead to a contrary outcome in glucose levels with respect to metformin. However, there are some data questioning the role of complex I inhibition in the hypoglycemic action of metformin, including the very high concentrations of metformin that are used in vitro to inhibit complex I, way out of the range of the concentrations found in the plasma of individuals treated with this drug, besides the lack of complex I inhibition detected in biopsies of skeletal muscle from diabetic patients treated with metformin.
Moreover, if complex I inhibition drives to AMPK activation, it turns out that the chronic administration of metformin would lead to deleterious outcomes, since sustained activation of AMPK in mice carrying a mutation in γ2, a regulatory AMPK subunit, causes hyperphagia, obesity, steatosis and impaired insulin secretion . Thus, long-term complex I inhibition may have deleterious metabolic consequences not only by increasing the NADH/NAD+ ratio, but also by other unrelated mechanisms.