Aldose reductase (ALR2) has been the target of therapeutic intervention for over 40 years; first, for its role in long-term diabetic complications and more recently as a key mediator in inflammation and cancer.
There are 15 human AKRs of these AKR1B1, AKR1C1-1C3, AKR1D1, and AKR1B10 have been implicated in diabetic complications, steroid hormone dependent malignancies, bile acid deficiency and defects in retinoic acid signaling, respectively.
As part of our ongoing search for natural sources of therapeutic and preventive agents for diabetic complications, we evaluated the inhibitory effects of components of the fruit of Xanthium strumarium (X. strumarium) on aldose reductase (AR) and galactitol formation in rat lenses with high levels of glucose.
Aldose reductase (AR), an enzyme mediating the first step in the polyol pathway of glucose metabolism, is associated with complications of diabetes mellitus and increased cardiac ischemic injury.
Glucose over-utilization through the polyol pathway has been linked to tissue-based pathologies associated with diabetes complications, which make the development of a potent aldose reductase inhibitor an obvious and attractive strategy to prevent or delay the onset and progression of the complications.
Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.
The newly discovered RSOR has certain structural and functional similarities to AKR1B and seems to be relevant to the renal complications of diabetes mellitus.
The identified protein is designated as RSOR because it is renal-specific with properties of an oxido-reductase, and like ALR2 it may be relevant in the renal complications of diabetes mellitus.
These results suggest that NO may be an endogenous regulator of aldose reductase, and consequently the polyol pathway of glucose metabolism; which has been implicated in the pathogenesis of secondary diabetic complications.
One of the alleles (Z-2) was found to be associated with early onset of retinopathy in patients with non-insulin-dependent diabetes (P = 0.007), suggesting that aldose reductase or a gene in the close vicinity may be involved in the pathogenesis of this diabetic complication.
Since aldose reductase is the first and ratelimiting enzyme of the polyol pathway, it is predicted that restriction fragment length polymorphisms at the aldose reductase gene locus may influence catalytic activity and determine individual susceptibility to the diabetic complications.
The result should facilitate refined structural analysis and the development of new specific aldose reductase inhibitors for the treatment of diabetic complications.
The haptoglobin (Hp) genotype is associated with type 2 diabetes related complications including increased risk for cerebrovascular pathology and worse cognitive performance.
Prolonged autoimmune injures in the retinal territory will triggers and maintains a low-grade chronic inflammation process, microvascular alterations, glial proliferation and subsequent fibrosis and worse, progressive apoptosis of the photoreceptor neurons.Patients with long-standing DM disturbances in retinal BRBs suffer of alterations in the enzymatic pathways of polyunsaturated fatty acids (PUFAs), increase release of free radicals and pro-inflammatory molecules and subsequently incremented levels of vascular endothelial growth factor.
Neuroimaging was completed in 94 participants of the Pittsburgh Epidemiology of Diabetes Complications study with Hp genotyping available (mean age, 49; duration, 41 years).