There is strong scientific evidence showing a primary role of aldose reductase, the first enzyme of the polyol pathway, in the cascade of metabolic imbalances responsible for the detrimental effects of hyperglycemia.
We have recently demonstrated that aldose reductase (AR, AKR1B1) is an obligatory mediator of oxidative and inflammatory signals induced by growth factors, cytokines and hyperglycemia.
Hyperglycemia invoke number of pathways resulting in development of diabetic retinopathy (DR), including protein kinase C activation, increased expression of VEGF, advanced glycation end product (AGEs) formation and activation of polyol pathway, among which the pathophysiology of aldose reductase (ALR2) of the polyol pathway is evident by more than a decade of research.
Increased AR expression during hyperglycemia and oxidative stress is found to be correlated with the increase in PKC expression and activity in both condition.
The most involved mechanisms are inhibition of intestinal alpha-glucosidase and alpha-amylase, lens aldose reductase, oxidative stress protection, inhibition of formation of advanced glycation end products, inhibition of aldose reductase, lowering plasma glucose levels, altering enzyme activity of hexokinases and glucose-6-phosphate, synthesizing and releasing of insulin, postprandial hyperglycemia inhibition, stimulation of GLUT-4, decreasing activity of G6P, lowering the level of skeletal hexokinases, etc.
Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents.
In summary, the present study demonstrated AKR1B1 played a vital role in astrocytes proliferation through Akt pathway, associated with the metabolism of hyperglycemia induced by SCI.
Diarylmethanon, bromophenol and diarylmethane compounds: Discovery of potent aldose reductase, α-amylase and α-glycosidase inhibitors as new therapeutic approach in diabetes and functional hyperglycemia.
Supporting synergy between hyperglycemia and hAR were the even more pronounced changes in these parameters in <i>Akita<sup>+/-</sup></i> /hAR mice, which had atherosclerosis progression in spite of normolipidemia.
Aldose reductase (AR) inhibitors play a vital importance as a potential therapeutic and preventive medicine when it comes to hyperglycemia associated diabetic complications.
We present a novel mechanism for miR-24 downregulation through hyperglycemia-induced activation of aldose reductase, reactive oxygen species, and c-Myc.
These results indicate that high AR expression in the context of hyperglycemia and insulin deficiency may constitute a risk factor that could predispose the lens to disturbances in signaling through the ERK and JNK pathways and thereby alter the balance of cell growth and apoptosis that is critical to lens transparency and homeostasis.
Together, these results clearly demonstrated that hyperglycemia-induced TonEBP plays a crucial role in increasing AR and PKCδ levels and leading to apoptotic death.
AR also negatively regulates RUNX2-dependent vascular remodeling in an EC wounded monolayer assay, which is reversed by specific AR inhibition in hyperglycemia.
AR activity as photometrically determined by NADPH consumption was effectively inhibited by the AR inhibitor epalrestat. oxLDL-dependent AR upregulation was further increased under hyperglycemic conditions (30 mmol/L D-glucose) as compared to osmotic control, suggesting a synergistic effect of hyperlipidemia and hyperglycemia.
In addition, treatment with quercetin appears to reduce the osmotic stress induced by hyperglycaemia, as assessed by polyol pathway enzyme aldose reductase.
There was a highly significant correlation between increased aldose reductase (ALR2) expression, CAT, CuZnSOD, and GPX mRNA levels under HG conditions and polymorphisms of ALR2 in the patients with nephropathy (P < 0.00001).
The accumulation of advanced glycosilation end products (AGEPs), the activation of isoforms of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycaemia damages vessels.Growth factors (i.e.
The accumulation of advanced glycosylated end-products (AGEs), the activation of isoform(s) of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycemia damages tissue.