Aldose reductase, ocular diabetic complications and the development of topical Kinostat®

Abstract

Diabetes mellitus (DM) is a major health problem with devastating effects on ocular health in both industrialized and developing countries. The control of hyperglycemia is critical to minimizing the impact of DM on ocular tissues because inadequate glycemic control leads to ocular tissue changes that range from a temporary blurring of vision to permanent vision loss. The biochemical mechanisms that promote the development of diabetic complications have been extensively studied. As a result, a number of prominent biochemical pathways have been identified. Among these, the two-step sorbitol pathway has been the most extensively investigated; nevertheless, it remains controversial. To date, long-term pharmacological studies in animal models of diabetes have demonstrated that the onset and development of ocular complications that include keratopathy, retinopathy and cataract can be ameliorated by the control of excess metabolic flux through aldose reductase (AR). Clinically the alleles of AR have been linked to the rapidity of onset and severity of diabetic ocular complications in diabetic patient populations around the globe. In spite of these promising preclinical and human genetic rationales, several clinical trials of varying durations with structurally diverse aldose reductase inhibitors (ARIs) have shown limited success or failure in preventing or arresting diabetic retinopathy. Despite these clinical setbacks, topical ARI Kinostat(®) promises to find a home in clinical veterinary ophthalmology where its anticipated approval by the FDA will present an alternative treatment paradigm to cataract surgery in diabetic dogs. Here, we critically review the role of AR in diabetes mellitus-linked ocular disease and highlight the development of Kinostat(®) for cataract prevention in diabetic dogs. In addition to the veterinary market, we speculate that with further safety and efficacy studies in humans, Kinostat(®) or a closely related product could have a future role in treating diabetic keratopathy.

Multivalorization of apple pomace towards materials and chemicals. Waste to wealth

“…2% of dry AP. The determination of carbohydrates in the extracts by ion chromatography indicates mainly the presence of fructose, that accounts for 80% of the total, 17% sorbitol, and in smaller quantities glucose, sucrose, xylose, arabitol and arabinose, all of them substances of biological interest, for example is well known the effect on caries of arabitol under controlled application (Nouman et al, 2016) or on diabetes derived diseases (Kador et al, 2016). al., 2012).…”

Identification of Protein Biomarkers for Diabetic Retinopathy using Sequence Mining Techniques

“…Sequences contain most useful primary data with the information of proteins [27]. Two-step sorbitol pathway has been widely studied for diabetes complications while continuous pharmacological studies in animals showed inception and growth of ocular complications including keratopathy, retinopathy and cataract [28]. Diabetic retinopathy is a microcirculatory disease of retina and several evidences indicates that in diabetic retinopathy retinal neurodegeneration is an early encounter which engages in microcirculatory abnormalities that occurs in diabetic retinopathy [29].…”

Biochemical mechanisms of cataract in diabetes mellitus

“…In diabetic patients, the production of sorbitol takes place more quickly compared to nondiabetic patients, which is then converted under the action of sorbitol dehydrogenase to fructose. Studies performed on laboratory animals have reported that intracellular accumulation of polyols generates liquefaction of lens, leading to opacities of the lens [12,13].…”