Search

Background The success of 5α-reductase inhibitors in the 1990s vindicated the role of androgens and cast doubt on the role of diet in androgenetic alopecia (AGA). However, poor glucose control and high cholesterol are now recognised as comorbidities, which are salient characters of the ‘western diet’. Scope and approach In glucose potentiated hair loss, continuous monosaccharide flux to the liver promotes the polyol pathway, causing fatty liver and attenuating synthesis of sex hormone binding globulin, accommodating the increased ratio of dihydrotestosterone (DHT) to testosterone. The scalp of the balding phenotype is characterised by overactive PPAR-γ receptors, increased fatty acid synthesis, enlarged sebaceous glands and sebum secretions. Sebum feeds lipophilic bacteria, such as Propionibacterium acnes, which augment the expression of prostaglandin-type (PGD2 & 15d-PGJ2) ligands of PPAR-γ and increase local insulin sensitivity via Akt/mTOR pathways. In hyperglycaemic events the androgen dependent polyol pathway depletes glucose and generates purine by-products that antagonise adenosine receptors. Mitochondrial reactive oxygen species accumulate, and ATP levels reduce, slowing gluconeogenesis in the outer root sheath keratinocytes of the hair follicle. Furthermore, the current commentary suggests that an important mineral in hair health is magnesium, which is relevant to both glucose and cholesterol potentiated hair loss. Magnesium deficiency not only reinforces insulin resistance, but in cholesterol potentiated hair loss, local magnesium dependent monooxygenase enzymes that metabolise cholesterol and vitamin D are impaired. Furthermore, magnesium deficient muscles at the occipital and temporal region of the skull create mechanical strain against the galea aponeurotica. Key findings and conclusions Taking all of this into consideration, treatment options for androgenetic alopecia should include a low cholesterol and low glycaemic index diet, improved glucose control, and fortification with magnesium. Furthermore, the current narrative does not endorse severe caloric restriction for obvious health reasons.

The prevalence and incidence of diabetes mellitus (DM) are increasing worldwide bringing with it a significantly higher rate of complications. Various mechanisms such as carbonyl stress, polyol pathway, oxidative stress, hexosamine pathways, diacylglycerol/protein kinase-C activation, etc., are responsible for the pathogenesis of DM and its complications. Persistent hyperglycaemia and inhibition of metabolising and detoxifying enzymes lead to the excessive synthesis of carbonyl compounds such as methylglyoxal, glyoxal, and 3-deoxyglucosone, resulting in carbonyl stress. The substrates, metabolizing and detoxifying enzymes of carbonyl compounds are discussed. The mechanistic roles of carbonyl compounds and advanced glycation end products (AGEs) in atherosclerosis, insulin resistance, thrombogenicity, and endothelial dysfunction in animal and cell culture model of DM and patients with DM are summarised. Because of the essential role of carbonyl stress, therapeutics are aimed at scavenging, metabolizing, detoxifying, and inhibiting carbonyl compounds or AGEs so that their harmful effects are minimized. Clinically used drugs, plants extracts and miscellaneous chemical with antiglycation properties are used in an animal model of DM to alleviates the impact of carbonyl compounds. Extensive clinical trials with derivatisation of available antiglycation agents to increase the bioavailability and decrease side effects are warranted further.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by impaired glucose homeostasis, insulin resistance and hyperglycemia. Among its serious multisystemic complications is diabetic retinopathy (DR), which develops slowly and often insidiously. This disorder-the most common cause of vision loss in working-age adults-is characterized by functional and morphological changes in the retina. It results from the exacerbation of ischemic and inflammatory conditions prompted by alterations in the blood vessels, such as the development of leukostasis, thickening of the basement membrane, retinal neovascularization and fibrovascular tissue formation at the vitreoretinal interface. The pathogenic alterations are usually triggered at the biochemical level, involving a greater activity in 4 pathways: the polyol pathway, the hexosamine pathway, the formation of advanced glycation end-products and the activation of protein kinase C isoforms. When acting together, these pathways give rise to increased levels of reactive oxygen species and decreased levels of endogenous antioxidant agents, thus generating oxidative stress. All current therapies are aimed at the later stages of DR, and their application implies side effects. One possible strategy for preventing the complications of DM is to counteract the elevated superoxide production stemming from a high level of blood glucose. Accordingly, some treatments are under study for their capacity to reduce vascular leakage and avoid retinal ischemia, retinal neovascularization and macular edema. The present review summarizes the biochemical aspects of DR and the main approaches for treating it.

Prolonged hyperglycemia generates advanced glycation end-products (AGEs), which are believed to be involved in the pathogenesis of diabetic complications. In the present study, we developed a polyclonal antibody against fructose-modified proteins (Fru-P antibody) and identified its epitope as glucoselysine (GL) by NMR and LC-electrospray ionization (ESI)- quadrupole TOF (QTOF) analyses and evaluated its potential role in diabetes sequelae. Although the molecular weight of GL was identical to that of fructoselysine (FL), GL was distinguishable from FL because GL was resistant to acid hydrolysis, which converted all of the FLs to furosine. We also detected GL in vitro when reduced BSA was incubated with fructose for 1 day. However, when we incubated reduced BSA with glucose, galactose, or mannose for 14 days, we did not detect GL, suggesting that GL is dominantly generated from fructose. LC-ESI-MS/MS experiments with synthesized [(13)C(6)]GL indicated that the GL levels in the rat eye lens time-dependently increase after streptozotocin-induced diabetes. We observed a 31.3-fold increase in GL 8 weeks after the induction compared with nondiabetic rats, and Nϵ-(carboxymethyl)lysine and furosine increased by 1.7- and 21.5-fold, respectively, under the same condition. In contrast, sorbitol in the lens levelled off at 2 weeks after diabetes induction. We conclude that GL may be a useful biological marker to monitor and elucidate the mechanism of protein degeneration during progression of diabetes.

Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC50 values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC50 values of 0.52 ± 0.04 and 0.19 ± 0.03 μM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC50 value of 3.14 ± 0.02 μM).

Background Diabetes mellitus is a chronic metabolic disorder associated with persistent increased level of glucose in the blood. According to a report by World Health Organisation (WHO), prevalence of diabetes among adults over 18 years of age had reached to 8.5% in year 2014 which was 4.7% in 1980s. The Prolong increased level of glucose in blood leads to development of microvascular (blindness, nephropathy and neuropathy) and macrovascular (cardiovascular and stroke) degenerative complications because of uncontrolled level of glucose in blood. This also leads to the progression of oxidative stress and affecting metabolic, genetic and haemodynamic system by activation of polyol pathway, protein kinase C pathway, hexosamine pathway and increases advanced glycation end products (AGEs) formation. Diabetes mellitus and its associated complications are one of the major leading causes of mortality worldwide. Various natural products like alkaloids, glycosides, flavonoids, terpenoids and polyphenols are reported for their activity in management of diabetes and its associated diabetic complications. Tannins are systematically studied by many researchers in past few decades for their effect in diabetes and its complications. Aim The present review was designed to compile the data of tannins and their beneficial effects in the management of diabetic complications. Method Literature search was performed using various dataset like pubmed, EBSCO, proQuest Scopus and selected websites including the National Institutes of Health (NIH) and the World Health Organization (WHO). Results Globally, more than 400 natural products have been investigated in diabetes and its complications. Tannins are the polyphenolic compounds present in many medicinal plants and various dietary sources like fruits, nuts, grains, spices and beverages. Various reports have shown that compounds like gallic acid, ellagic acid, catechin, epicatechin and procynidins from medicinal plants play major role in controlling progression of diabetes and its related complications by acting on molecular pathways and key targets involved in progression. Many chemists used above mentioned phyto-constituents as a pharmacophore for the developing new chemical entities having higher therapeutic benefits in management of diabetic complications. Conclusion This review focuses on the role of various tannins in prevention and management of diabetic complications like diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and diabetic cardiomyopathy. It will help researchers to find some leads for the development of new cost effective therapy using dietary source for the management of diabetic complications.

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. Subtle involvement of ALR2 in invoking various pathways of diabetic complications has caused an increase in attention towards the identification of novel aldose reductase inhibitors (ARIs). Numerous ARIs of different classes were employed in the treatment of diabetic complications initially, but few came into light as drugs. Though no ALR2 inhibitor has been used for the treatment or control of DR, Epalrestat has been used worldwide for treating diabetic neuropathy. This review critically analyses different treatments available for diabetic retinopathy, their limitations and the importance of the development of novel inhibitors of ALR2 that could prevent progression of DR, by causing a direct or indirect effect on controlling factors associated with DR.

Oxidative stress and inflammation interact in the development of diabetic atherosclerosis. Intracellular hyperglycemia promotes production of mitochondrial reactive oxygen species (ROS), increased formation of intracellular advanced glycation end-products, activation of protein kinase C, and increased polyol pathway flux. ROS directly increase the expression of inflammatory and adhesion factors, formation of oxidized-low density lipoprotein, and insulin resistance. They activate the ubiquitin pathway, inhibit the activation of AMP-protein kinase and adiponectin, decrease endothelial nitric oxide synthase activity, all of which accelerate atherosclerosis. Changes in the composition of the gut microbiota and changes in microRNA expression that influence the regulation of target genes that occur in diabetes interact with increased ROS and inflammation to promote atherosclerosis. This review highlights the consequences of the sustained increase of ROS production and inflammation that influence the acceleration of atherosclerosis by diabetes. The potential contributions of changes in the gut microbiota and microRNA expression are discussed. Keywords: Atherosclerosis, Diabetes mellitus, Reactive oxygen species, Gut microbiota, MicroRNA

Over activated molecular target ALR2 of polyol pathway and oxidative stress are two well established pathological indicators in diabetic complications. In present study, mutual prodrugs of Epalrestat and natural product based antioxidants were designed, synthesized and evaluated. In silico techniques such as molecular dynamic simulations and quantum mechanical approaches, considering human esterase enzyme (hCE1) as the site of hydrolytic cleavage were employed in designing of these mutual prodrugs. Geometrical parameters (distance and Burgi-Dunitz angle favorable for nucleophilic attack) and quantum mechanical parameters (HOMO-LUMO energy gap), which govern the hydrolytic cleavage of ester prodrugs by esterase enzyme were calculated. Further, on the basis of in silico analysis, mutual prodrugs were synthesized and considering the values of in silico parameters, EPL-GUA (3g) was evaluated for its in vivo antioxidant activity. Results suggested that 3g possess significant antioxidant activity intermediary to control and Epalrestat. Thus, this study has concluded that these mutual prodrugs could be optimized to develop molecules for the management of diabetic complications.

Aldose reductase, the pivotal enzyme in the polyol pathway, has been widely investigated as an enzyme critically involved in the onset and progression of various pathologies associated with diabetes mellitus. Investigation of the inhibitory effect of tara [Caesalpinia spinosa (Molina) Kuntze] pods extract on aldose reductase revealed that its n-butanol fraction exhibits excellent aldose reductase inhibitory activity in vitro and ex vivo. Methyl gallate and pistafolin B were isolated from the n-butanol fraction of the tara pod methanolic extract as the main contributors for its aldose reductase inhibition, guided by affinity-based ultrafiltration-high performance liquid chromatography, with pistafolin B being the more potent inhibitor of the two. In vitro and in silico results demonstrated that pistafolin B is a mixed-type inhibitor that can bind to the aldose reductase active site rapidly, preventing substrate access and product formation (IC50, 0.198 mM; Ki, 0.34 mM). Ex vivo experiments indicated that pistafolin B can penetrate the eye lens and successfully inhibit aldose reductase under hyperglycaemic conditions, thus preventing the accumulation of sorbitol and the subsequent osmotic stress.

We have a large body of evidence showing that hyperglycemia is a cardiovascular risk factor and that its reduction decreases the risk for cardiovascular events. Indeed, epidemiological studies have clearly shown that hyperglycemia is a strong and independent factor for cardiovascular disease. In addition, we have many pathophysiological studies demonstrating the direct role of hyperglycemia in the development of atherosclerosis. Hyperglycemia, by stimulating protein kinase C, increases the production of pro-inflammatory cytokines, of adhesion molecules and of endothelin-1 and, by stimulating the polyol pathway, promotes the oxidative stress. Furthermore, chronic hyperglycemia leads to the accumulation of advanced glycation end-products that modify the structure of the arterial wall and, as a consequence, will increase the risk for the development of atherosclerosis. Moreover, prolonged intervention studies have shown that reduction of hyperglycemia is associated with a significant decrease in the risk for major cardiovascular events. Thus, hyperglycemia is a cardiovascular risk factor which is characterized by the fact that it induces profound modifications of the arterial wall and that it is necessary to correct hyperglycemia during enough time to obtain a cardiovascular benefit.

Novel derivatives of spiroimidazolidinedione were synthesized and evaluated as hypoglycemic agents through binding to sulfonylurea receptor 1 (SUR1) in pancreatic beta-cells. Their selectivity index was calculated against both aldehyde reductase (ALR1) and aldose reductase (ALR2). Aldehyde reductase is a key enzyme in the polyol pathway that is involved in the etiology of the secondary diabetic complications. All structures were confirmed by microanalysis and by IR, 1H NMR, 13C NMR and EI-MS spectroscopy. The investigated compounds were subjected to molecular docking and an in silico prediction study to determine their free energy of binding (ΔG) values and predict their physicochemical properties and drug-likeness scores. Compound 1′-(5-chlorothiophene-2-ylsulfonyl)spiro[cyclohexane-1,5′-imidazolidine]-2′,4′-dione showed IC50 0.47 µM and 79% reduction in blood glucose level with a selectivity index 127 for ALR2.

Objective Ketohexokinase (KHK), a primary enzyme in fructose metabolism, has two isoforms, namely, KHK-A and KHK-C. Previously, we reported that renal injury was reduced in streptozotocin-induced diabetic mice which lacked both isoforms. Although both isoforms express in kidney, it has not been elucidated whether each isoform plays distinct roles in the development of diabetic kidney disease (DKD). The aim of the study is to elucidate the role of KHK-A for DKD progression. Materials and Methods Diabetes was induced by five consecutive daily intraperitoneal injections of streptozotocin (50 mg/kg) in C57BL/6J wild-type mice, mice lacking KHK-A alone (KHK-A KO), and mice lacking both KHK-A and KHK-C (KHK-A/C KO). At 35 weeks, renal injury, inflammation, hypoxia, and oxidative stress were examined. Metabolomic analysis including polyol pathway, fructose metabolism, glycolysis, TCA (tricarboxylic acid) cycle, and NAD (nicotinamide adenine dinucleotide) metabolism in kidney and urine was done. Results Diabetic KHK-A KO mice developed severe renal injury compared to diabetic wild-type mice, and this was associated with further increases of intrarenal fructose, dihydroxyacetone phosphate (DHAP), TCA cycle intermediate levels, and severe inflammation. In contrast, renal injury was prevented in diabetic KHK-A/C KO mice compared to both wild-type and KHK-A KO diabetic mice. Further, diabetic KHK-A KO mice contained decreased renal NAD+ level with the increase of renal hypoxia-inducible factor 1-alpha expression despite having increased renal nicotinamide (NAM) level. Conclusion These results suggest that KHK-C might play a deleterious role in DKD progression through endogenous fructose metabolism, and that KHK-A plays a unique protective role against the development of DKD.

Traditionally, the leading hypothesis regarding the development of obesity involves caloric imbalance, whereby the amount of calories consumed exceeds the amount of calories burned which causes obesity. Another hypothesis for why we get fat has surfaced in the last decade which is the idea that the overconsumption of added sugars and refined carbohydrates induce insulin resistance and high insulin levels causing obesity. While insulin is a fat-storing hormone, this hypothesis does not explain visceral adiposity, or why certain people are found to have fat stored in and around their organs. We propose a new mechanism for body fattening, particular visceral adiposity. This hypothesis involves the overconsumption of fructose, which leads to inflammation in all cells that metabolize it rapidly. When fructose is metabolized in subcutaneous adipocytes, the subsequent inflammation leads to an increase in intracellular cortisol in order to help squelch the inflammation. Unfortunately, the increase in intracellular cortisol leads to an increased flux of fatty acids out of the subcutaneous adipocytes allowing more substrate for fat storage into visceral fat tissue. Moreover fructose-induced inflammation in the liver also leads to increased intracellular cortisol via an upregulation of 11-B hydroxysteroid dehydrogenase type 1 causing increased fat storage in the liver (i.e., fatty liver). In essence, the fructose-induced inflammatory cortisol response causes "thin on the outside, fat on the inside" (TOFI). Furthermore, fructose in the brain, either from fructose uptake via the blood brain barrier or endogenous formation from glucose via the polyol pathway stimulates an increased release of cortisol causing hepatic gluconeogenesis leading to overall insulin resistance and further body fattening. This review paper will discuss in detail the hypothesis that fructose-induced inflammation and cortisol activation causes visceral adiposity.

The prevalence of diabetes is continuously increasing in the recent decades. Persistent hyperglycaemia, hyperinsulinemia and the subsequent oxidative stress result in diabetic complications, primarily categorized as microvascular (nephropathy, retinopathy and neuropathy) and macrovascular (cardiomyopathy) complications. The complications are prevalent in both type 1 and type 2 diabetic patients. Polyol pathway, elevated AGE production, PKC activation and hexosamine pathway are indeed the critical pathways involved in the progression of diabetic complications. Silent information regulator 2 or SIR2 or more commonly known as sirtuins are NAD+ dependent histone deacetylase. SIRT1, a member of the sirtuin family has been extensively studied for its role in lifespan extension and needs to be explored for its beneficial effects in diabetic complications. Moreover, it is also known to regulate the activity of other proteins and transcription factors. One such substrate of SIRT1 is FOXOs transcription factor which has gained much attention as the mediator of various cellular processes such as cell cycle arrest and proliferation, DNA repair and metabolism. It has been reported that SIRT1 regulates the activity of FOXOs, whereas few recent advances also suggest a role FOXOs in governing the activity of SIRT1, which permits for a crosstalk between SIRT1 and FOXOs. Therefore, the focus of the present review is to describe and explore the interaction between SIRT1 and FOXOs, predominantly FOXO1 and FOXO3 and to understand the underlying mechanism of SIRT1-FOXOs in controlling and alleviating diabetic complications. Thus, this crosstalk suggests that SIRT1 and FOXOs may serve as potential therapeutic targets in treating diabetic complications.

Objective NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. While it is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage, little is known regarding the effects of prolonged non-canonical NRF2 activation in diabetes. The goal of this study was to determine the role and mechanisms of prolonged NRF2 activation in arsenic diabetogenicity. Methods To test this, we utilized an integrated transcriptomic and metabolomic approach to assess diabetogenic changes in the livers of wild type, Nrf2−/−, p62−/−, or Nrf2−/−; p62−/− mice exposed to arsenic in the drinking water for 20 weeks. Results In contrast to canonical oxidative/electrophilic activation, prolonged non-canonical NRF2 activation via p62-mediated sequestration of KEAP1 increases carbohydrate flux through the polyol pathway, resulting in a pro-diabetic shift in glucose homeostasis. This p62- and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis occurs through the upregulation of four novel NRF2 target genes, ketohexokinase (Khk), sorbitol dehydrogenase (Sord), triokinase/FMN cyclase (Tkfc), and hepatocyte nuclear factor 4 (Hnf4A). Conclusion We demonstrate that NRF2 and p62 are essential for arsenic-mediated insulin resistance and glucose intolerance, revealing a pro-diabetic role for prolonged NRF2 activation in arsenic diabetogenesis., Highlights • The role of non-canonical activation of the Nrf2 signaling pathway in type II diabetes has not been determined. • Chronic activation of Nrf2 promotes a pro-diabetic shift in the liver polyol pathway that increases blood glucose levels. • Four newly identified Nrf2 target genes are responsible for the diabetogenic shift in liver carbohydrate metabolism.

Persistent hyperglycaemia coupled with inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). Present study examined the therapeutic potential of taraxerol isolated from the methanol extract of Abroma augusta leaf against DN using rodent model of type 2 diabetes (T2D). T2D was experimentally induced by high fat diet and a single low-single dose of streptozotocin (35mg/kg, i.p.). Accumulation of serum creatinine, urea, and uric acid, activation of lactate dehydrogenase and creatinin kinase, and release of urinary albumin represented the glomerular damage and the progression of nephropathy in T2D rats. Taraxerol (20mg/kg, p.o.) treatment significantly reinstated the aforementioned changes in biochemical parameters near to normalcy. Molecular mechanism studies demonstrated an impaired signaling cascade, IRS1/PI3K/Akt/AMPK/GLUT4/GSK3β, of glucose metabolism in the skeletal muscle and increase in serum levels of pro-inflammatory cytokines, CRP and MCP1 in T2D rats. Activation of polyol pathway, enhanced production of AGEs, up-regulation of NF-κB/PKCs/PARP signaling, and renal fibrosis was also observed in T2D rats. Taraxerol (20mg/kg, p.o.) treatment stimulated glucose metabolism in skeletal muscle, regulated blood glycaemic status and lipid profile in the sera, reduced the secretion of pro-inflammatory cytokines, and restored the renal physiology in T2D rats. Histological assessments were also in agreement with the above findings. Molecular docking study again supported the probable interactions of taraxerol with PKCβ, PKCδ, NF-κB, PARP, PI3K, IRS, Akt and AMPK. In silico ADME study predicted the drug-likeness character of taraxerol. Results suggest a possibility of taraxerol to be a new therapeutic agent for DN in future.

Diabetic nephropathy (DN) is the most common and serious complication in diabetes mellitus, but the efficacy of available strategies for preventing this disorder remains poor. The aim of this study was to investigate the possible beneficial effects of 1-acetyl-5-phenyl-1H-pyrrol-3-ylacetate (APPA), an aldose reductase inhibitor, on DN. In the present study, a model of rat glomerular mesangial cells (HBZY-1) damaged by high glucose was used to confirm the protective effects of APPA in vitro. Then, a rat model of streptozotocin-induced diabetes was used to assess the effects of APPA in vivo. APPA increased viability and reduced apoptosis in HBZY-1 cells. In vivo, APPA improved the signs of DN as determined by measurements of blood glucose, urinary microalbumin, serum total antioxidant capacity, serum catalase activity, serum glutathione levels, and serum total superoxide dismutase activity. Hematoxylin and eosin staining of kidney tissue confirmed the protective effect. Moreover, APPA reduced the levels of transforming growth factor-β1, collagen IV, and laminin in HBZY-1cells incubated in high glucose, and in serum in DN rats. In summary, APPA can effectively prevent apoptosis and the symptoms of streptozotocin-induced diabetes by inhibiting the polyol pathway in rats. This suggests that APPA could be a potential drug in treating DN.

The effect of Radix Scutellariae treated on type 2 diabetic rats has been investigated by a liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) based urinary quantitative approach. In this research, multiple reactions monitoring mode of MS/MS in LC–MS/MS analysis was used to quantitatively analyze the concentrations of 7 endogenous compounds in urine of normal control group, type 2 diabetic model group and Radix Scutellariae -treated group, and multivariate statistical analysis was utilized for MS data processing. The above-mentioned three groups can be distinguished via pattern recognition. The obtained results indicated that Radix Scutellariae affect the urinary metabolic profiling of type 2 diabetic rats on the polyol pathway, protein glycation reaction and amino acids metabolism pathway. According to these results, Radix Scutellariae should have the pharmacological effect on preventing or delaying the onset and progression of diabetes and its complications.

Aldose reductase (ALR2), a NADPH-dependent reductase, is the first and rate-limiting enzyme of the polyol pathway of glucose metabolism and is implicated in the pathogenesis of secondary diabetic complications. In the last decades, this enzyme has been targeted for inhibition but despite the numerous efforts made to identify potent and safe ALR2 inhibitors, many clinical candidates have been a failure. For this reason the research of new ALR2 inhibitors highly effective, selective and with suitable pharmacokinetic properties is still of great interest. In this paper some new N-(aroyl)-N-(arylmethyloxy)alanines have been synthesized and tested for their ability to inhibit ALR2. Some of the synthesized compounds exhibit IC50 in the low micromolar range and all have proved to be highly selective towards ALR2. The N-(aroyl)-N-(arylmethyloxy)-α-alanines are a promising starting point for the development of new ALR2 selective drugs with the aim of delaying the onset of diabetic complications.

Fructose-containing added sugars, such as sucrose and high-fructose corn syrup, have been experimentally, epidemiologically, and clinically shown to be involved in the current epidemics of obesity and diabetes. Here we track this history of intake of sugar as it relates to these epidemics. Key experimental studies that have identified mechanisms by which fructose causes obesity and diabetes are reviewed, as well as the evidence that the uricase mutation that occurred in the mid-Miocene in ancestral humans acted as a “thrifty gene” that increases our susceptibility for fructose-associated obesity today. We briefly review recent evidence that obesity can also be induced by nondietary sources of fructose, such as from the metabolism of glucose (from high-glycemic carbohydrates) through the polyol pathway. These studies suggest that fructose-induced obesity is driven by engagement of a “fat switch” and provide novel insights into new approaches for the prevention and treatment of these important diseases.

There are many kinds of diabetic complications, and the pathogenesis are complex, including oxidative stress response, polyol pathway, nitric oxide theory, glucose transporter and other mechanisms. The molecular mechanisms are interacted to increase the occurrence of chronic complications in patients with diabetes. In this paper, the interaction effect between these mechanisms is reviewed in detail to provide scientific theoretical basis for the development and design of clinical antidiabetic drugs.

Fructose is associated with the biochemical alterations that promote the development of metabolic syndrome (MetS), nonalcoholic fatty liver disease, and type 2 diabetes. Its consumption has increased in parallel with MetS. It is metabolized by the liver, where it stimulates de novo lipogenesis. The triglycerides synthesized lead to hepatic insulin resistance and dyslipidemia. Fructose-derived advanced glycation end products (AGEs) may be involved via the Maillard reaction. Fructose has not been a main focus of glycation research because of the difficulty in measuring its adducts, and, more importantly, because although it is 10 times more reactive than glucose, its plasma concentration is only 1% of that of glucose. In this focused review, I summarize exogenous and endogenous fructose metabolism, fructose glycation, and in vitro, animal, and human data. Fructose is elevated in several tissues of diabetic patients where the polyol pathway is active, reaching the same order of magnitude as glucose. It is plausible that the high reactivity of fructose, directly or via its metabolites, may contribute to the formation of intracellular AGEs and to vascular complications. The evidence, however, is still unconvincing. Two areas that have been overlooked so far and should be actively explored include the following: 1) enteral formation of fructose AGEs, generating an inflammatory response to the receptor for AGEs (which may explain the strong association between fructose consumption and asthma, chronic bronchitis, and arthritis); and 2) inactivation of hepatic AMP-activated protein kinase by a fructose-mediated increase in methylglyoxal flux (perpetuating lipogenesis, fatty liver, and insulin resistance). If proven correct, these mechanisms would put the fructose-mediated Maillard reaction in the limelight again as a contributing factor in chronic inflammatory diseases and MetS.

Hyperglycemic stress activates polyol pathway and aldose reductase (AR) key enzyme responsible for generating secondary complications during diabetes. In this study the therapeutic potential of phloretin, epigallocatechin 3-gallate (EGCG) and [6]-gingerol were evaluated for anti-glycating and AR inhibitory activity in vitro and in vivo systems. Human retinal pigment epithelial (HRPE) cells were induced with high glucose supplemented with the phloretin, EGCG and [6]-gingerol. Aldose reductase activity, total advanced glycation end products (AGEs) and enzyme inhibitor kinetics were assessed. Male C57BL/6J mice were randomly assigned to one of the different treatments (bioactive compounds at 2 concentrations each) with either a low fat diet or high fat diet (HFD). After sixteen weeks, AGE accumulation and AR activity was determined in heart, eyes and kidney. High glucose induced toxicity decreased cell viability compared to the untreated cells and AR activity increased to 2–5 folds from 24 to 96h. Pre-treatment of cells with phloretin, EGCG and [6]-gingerol improved cell viability and inhibited AR activity. The enzyme inhibition kinetics followed a non-competitive mode of inhibition for phloretin and EGCG whereas [6]-gingerol indicated uncompetitive type of inhibition against AR. Data from the animal studies showed high plasma glucose levels in HFD group over time, compared to the low fat diet. HFD group developed cataract and AR activity increased to 4 folds compared to the group with low fat diet. Administration of EGCG, phloretin and [6]-gingerol significantly reduced blood sugar levels, AGEs accumulation, and AR activity. These findings could provide a basis to consider using the selected dietary components alone or in combination with other therapeutic approaches to prevent diabetes-related complications in humans. Qatar national Research Fund

High-fat diet (HFD) promotes the oxidative stress formation, which in turn has hazardous effects on reproductive system and fertility. The objective of this study was to evaluate the protective effect of Caralluma fimbriata on high-fat diet-induced oxidative stress in the testis of rat. Male Wistar rats were randomly divided into five groups: Control (C), Control treated with CFE (C+ CFE), High fat diet fed (HFD), High fat diet fed treated with CFE (HFD+CFE) and High fat diet fed treated with Metformin (HFD+Met). CFE was orally administered (200mg/kg body weight) for 90days to groups-C+CFE and HFD+CFE rats. The effects of HF-diet on the reproductive organs were determined by measuring relative and absolute testes and epididymal fat pads weights. Regarding testes antioxidant status, high-fat fed rats showed higher levels of lipid peroxidation, protein oxidation, polyol pathway enzymes and lower GSH levels and lower activities of antioxidants, while CFE treatment prevented all these observed abnormalities. The present study clearly indicates that CFE offers a significant protection against HF-diet induced testicular oxidative stress in rats.

Purpose Tephrosia purpurea (T. purpurea) has been reported to prevent cataract formation in senile cataract model as well as proven effective in STZ induced type 1 diabetes. Aldose reductase (AR) is a key enzyme in the intracellular polyol pathway responsible for the development of diabetic cataract. Objective To investigate the effects of T. purpurea in the light of inhibition of aldose reductase enzyme in polyol pathway. Methods We studied the effects of alcoholic extract and flavonoid fraction of T. purpurea in streptozotocin (STZ, 45 mg/kg, i.v.)-induced type I diabetic cataract in rats. The animals were divided into five groups as control, control treated with alcoholic and flavonoid fraction, diabetic control and diabetic treated with alcoholic and flavonoid fraction. In-vitro aldose reductase inhibitory activity was also evaluated. Further, molecular docking study was performed with crystal structure of aldose reductase and its known chemical constituents of the plant. Results The IC50 value of alcoholic extract for aldose reductase inhibition was found to be 209.13 μg/ml, and that of flavonoid fraction was found to be 46.73 μg/ml. Administration of STZ produced significantly abnormal levels of serum glucose, serum insulin, soluble protein and antioxidants in the lens homogenate. Treatment with alcoholic extract and flavonoid fraction of T. purpurea were able to normalize these levels. Some of the active constituents of T. purpurea showed significant interactions with aldose reductase enzyme in molecular docking studies. Conclusions Our data suggested that both the extracts might be helpful in delaying the development of diabetic cataract due to the presence of rutin and quercetin. This beneficial effect may be due to its significant inhibition of aldose reductase enzyme and anti-oxidant activity.

Objectives We evaluated the effects of S-allylcysteine (SAC) on biomarkers of the polyol pathway in streptozotocin-nicotinamide (STZ-NA)-induced diabetes in rats. Methods Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (55 mg kg −1 bw −1 ) and NA (110 mg kg −1 bw −1 ). SAC (150 mg kg −1 bw −1 ) was orally administered to the rats with diabetes for 45 days to assess its effects on blood glucose, insulin, insulin resistance, glycated hemoglobin, aldose reductase (AR), sorbitol dehydrogenase (SDH), sorbitol, fructose, thiobarbituric acid-reactive substances (TBARS), hydroperoxide, hemoglobin and glutathione (GSH). Results On SAC administration in the rats with diabetes, the levels of blood glucose, insulin resistance, glycated hemoglobin, AR, SDH, sorbitol, fructose, TBARS and hydroperoxide increased significantly (p Conclusions The results indicate that SAC prevents complications of diabetes by reducing the influx of glucose in the polyol pathway, thereby elevating the GSH level and reducing the activities of AR and SDH. Therefore, SAC may have imperative implications for the deterrence and early treatment of type 2 diabetes.

Huntington's disease (HD) is a genetically-mediated neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein (Htt) through lengthening of its polyglutamine tract, thus initiating a cascade that ultimately leads to premature death. However, neurodegeneration typically manifests in HD only in middle age, and mechanisms linking the causative mutation to brain disease are poorly understood. Brain metabolism is severely perturbed in HD, and some studies have indicated a potential role for mutant Htt as a driver of these metabolic aberrations. Here, our objective was to determine the effects of HD on brain metabolism by measuring levels of polar metabolites in regions known to undergo varying degrees of damage. We performed gas-chromatography/mass spectrometry-based metabolomic analyses in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine matched controls. In each patient, we measured metabolite content in representative tissue-samples from eleven brain regions that display varying degrees of damage in HD, thus identifying the presence and abundance of 63 different metabolites from several molecular classes, including carbohydrates, amino acids, nucleosides, and neurotransmitters. Robust alterations in regional brain-metabolite abundances were observed in HD patients: these included changes in levels of small molecules that play important roles as intermediates in the tricarboxylic-acid and urea cycles, and amino-acid metabolism. Our findings point to widespread disruption of brain metabolism and indicate a complex phenotype beyond the gradient of neuropathologic damage observed in HD brain.

Background Polyol pathway and protein glycation are implicated in establishing secondary complications in diabetes. Their relative contribution to the process needs to be evaluated. It is essential to understand why some aldose reductase inhibitors (ARIs) trials are successful while some have failed and to study their effect on protein glycation. Methods Aldose reductase (AR) was assayed using xylose as substrate; protein glycation was evaluated using total and specific fluorescence, fructoseamine and protein bound carbonyl content (PCO) measurements. Long term studies were carried out on streptozotocin induced diabetic rats for evaluation of urine parameters, tissue fluorescence. Anti-cataract action was studied by lens culture studies. Results Epalrestat, a commercial ARI was also found to possess potent glycation inhibitory action. Long term experiments revealed strong protein glycation with higher concentration of citronellol (ARI) demonstrating shift in glucose flux. Treatment with epalrestat and limonene revealed improved urine parameters and tissue fluorescence. Lens culture studies revealed cataract formation at higher inhibition of AR while no lens opacity was observed at lower citronellol concentration and with limonene and epalrestat. Conclusion Strong inhibition of AR shifts the glucose flux to protein glycation causing damage. ARIs possessing protein glycation inhibition are more useful in amelioration of secondary complications.

Diabetic retinopathy, a severe sight-threatening complication of diabetes mellitus, accounts for a large number of cases of acquired, yet potentially avoidable, blindness. The principal mechanism of its pathogenesis appears to be alterations in the microvasculature of retina as the result of hyperglycemia. The elevated concentration of blood glucose is a harbinger of numerous molecular changes. These lead to various responses that result in microangiopathy. Oxidative stress, one such response, is attributed to disruption in the homeostasis of free radical production during the various vital processes such as the electron transport chain reaction and the scavenging mechanisms designed to neutralize these damaging molecules. This imbalance has been linked to the pathophysiology of diabetic retinopathy. Excessive formation of free radicals influences almost all pathways involved in normal human physiology. Thus, hyperglycemia-induced oxidative stress is one of the factors associated with biochemical changes. These changes are further responsible for the various structural and functional abnormalities seen in diabetic retinopathy.

Sugar induced cataractogenesis and visual impairment is more prominent ophthalmic problem in humans suffering from diabetes. Flavonoids have been identified as one of the therapeutically important class of phytochemicals possessing myriad of biological activities. Analyzing the anti-cataract effects of flavonoids from natural sources is an important aspect owing to their bioavailability in variety of dietary sources. In the present study a panel of ten dietary flavonoids like 3, 6-dihydroxy flavone, 3, 7-dihydroxy flavone, chrysin, 3-hydroxy-7-methoxy flavone, apigenin, genistein, baicalein, galangin, Biochanin-A, and diosmin were evaluated for their anti-cataract effects in sugar induced lens model studies. Series of parameters like role of flavonoids in glycation induced lens opacity, protein aggregation measurements, carbonyl group formation: a biochemical marker of glycation reaction, non-tryptophan fluorescence: a marker of formation of advanced glycation end products (AGEs) and assessment of (experimental and in silico) aldose reductase inhibition: a key enzyme of polyol pathway involved in cataractogenesis. The results of the study clearly demonstrated the impressive anti-cataract activity of chrysin followed by significant activity by apigenin, baicalein and genistein. The results of the present study may find applications in formulation of functional foods and neutraceuticals for the management of diabetic cataract.

The purpose of this study was to investigate whether and how topical nerve growth factor (NGF) attenuates streptozotocin (STZ)-induced diabetic cataracts in vivo. Rats were randomly divided into three groups, including the normal control rat group, STZ-induced diabetic cataract rat group (DM group), and STZ-induced diabetic cataract rat group treated with 200 μg/mL recombinant rat β-NGF (DM + NGF group). Cataract formation was evaluated by portable slit lamp biomicroscopy following pupil dilation at 8 weeks. The expression levels of NGF, aldose reductase (AR), and Na+/K+-ATPase in the lens epithelial cells (LECs) of the three groups were measured in the presence or absence of topical NGF. TUNEL-positive LECs were quantified to determine if hyperglycemia caused LEC apoptosis. At 8 weeks, the mean cataract score in the control group was significantly lower than that in DM and DM + NGF groups, and the score in the DM + NGF group was significantly lower than that in the DM group. At the equatorial zone and anterior central zone of lens, NGF and Na+/K+-ATPase expression levels were significantly decreased in the DM group; however, they were partially restored in the DM + NGF group. At the equatorial zone and anterior central zone of lens, AR expression and TUNEL-positive apoptotic LECs were significantly increased in the DM group compared with the control group, however, they were significantly decreased in the DM + NGF group. In conclusion, topical NGF could delay the progression of diabetic cataracts by attenuating polyol pathway activation and increasing Na+/K+-ATPase protein levels.

Chronic non-communicable diseases are one of the major human health challenges in the 21st century. Fermented apple juice rich in polyphenols has a beneficial effect on the prevention of non-communicable diseases. This review illustrates that the fermentation process involved in biotransformation significantly changes the composition and content of polyphenols in cloudy apple juice related to apple varieties, fermentation types, and fermentation strains. The enzymatic transformation reaction converts polyphenols into small molecules phenolic compounds with higher biologically activity. These small molecular weight active substances could help prevent cardiovascular disease and type 2 diabetes mellitus by mediating the AMPK pathway, the Nrf2 signaling pathway, the polyol pathway, and the NF-κB pathway. Moreover, this review is intended to provide a systematic theoretical basis for researchers to further study the bioactive function of fermented apple juice for the first time.

Recurrent infections are one of the common morbidities in Type 2 Diabetes (T2D) subjects. Bidirectional activation of innate immune cells such as neutrophils and glucose metabolism in T2D conditions leads to a pro-inflammatory milieu and reduced neutrophil function, which can be a potential cause for recurrent infections. In pathological conditions of sterile inflammation associated T2D, neutrophils form constitutive extracellular traps (NETs) due to hyperglycemia and respond poorly to infections. The present study was aimed at understanding the cellular and metabolic consequences, and NETs formation in T2D. We show that glucose induces NADPH oxidase derived reactive oxygen species and further citrullinates the histones to form weaker NETs leading to reduced response to lipopolysaccharide (LPS). Untargeted metabolomics analysis in neutrophils cultured under high glucose and from T2D subjects revealed enrichment of polyol pathway intermediates (1-anhydrosorbitol) and reduced glutathione metabolism products (cysteinylglycine). NADPH is an absolute requirement for three independent pathways of formation of 1-anhydrosorbitol via aldose reductase under excess glucose, induction of glutathione synthesis and glucose induced NETs formation. During T2D and in presence of high glucose, there is a competition for NADPH between these processive reactions, which leads to its insufficiency to produce NETs in response to LPS. Interestingly, supplementation of NADPH and pharmacological inhibitor of aldose reductase, ranirestat, restored NETs formation in presence of LPS. Our study provides novel insights on the metabolic reprogramming of neutrophils, which may lead to susceptibility of T2D subjects to infections.

Aldose reductase (AR) catalyzes the NADPH-dependent reduction of glucose to sorbitol in the polyol pathway which plays an important role in the development of diabetic complications including cataract, retinopathy, nephropathy, and neuropathy. AR has been considered as an important target to heal these long-term diabetic complications and for this reason the design and development of new AR inhibitors is an important approach in modern medicinal chemistry. In the current study, new 4-aryl-2-[2-((3,4-dihydro-2H-1,5-benzodioxepine-7-yl)methylene)hydrazinyl]thiazole derivatives (1-12) were synthesized and screened for their inhibitory effects on AR which was purified by diverse chromatographic methods with a yield of 1.40% and a specific activity of 2.00 EU/mg. All compounds were determined as promising AR inhibitors with their Ki values in the range of 0.018±0.005 μM-3.746±1.321 μM compared to the quercetin (Ki= 7.025±1.780 μM). In particular, 4-(4-cyanophenyl)-2-[2-((3,4-dihydro-2H-1,5-benzodioxepin-7-yl)methylene)hydrazinyl]thiazole (3) was detected as the most potential AR inhibitor in this series with the Ki constant value of 0.018±0.005 µM and the compound showed competitive AR inhibition. The cytotoxic effects of compounds 1-12 were investigated on L929 mouse fibroblast (healthy) cells using MTT assay and all these compounds were defined as non-cytotoxic agents against L929 cells. Molecular docking studies which were employed to determine the affinity of compounds 1-12 into the active site of AR highlighted that the thiazole scaffolds of all these compounds presented π-π stacking interactions with Trp20 and Phe122. According to both in vitro and in silico assays, these potential AR inhibitors may have great importance in the prevention of diabetic microvascular conditions.

Diabetes is a chronic disease, characterized by hyperglycemia, which refers to the elevated levels of glucose in the blood, due to the inability of the body to produce or use insulin effectively. Chronic hyperglycemia levels lead to macrovascular and microvascular complications. The macrovascular complications consist of peripheral artery disease (PAD), cardiovascular diseases (CVD) and cerebrovascular diseases, while the microvascular complications comprise of diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy and diabetic neuropathy. Vascular endothelial dysfunction plays a crucial role in mediating both macrovascular and microvascular complications under hyperglycemic conditions. In diabetic microvasculature, the intracellular hyperglycemia causes damage to the vascular endothelium through - (i) activation of four biochemical pathways, namely the Polyol pathway, protein kinase C (PKC) pathway, advanced glycation end products (AGE) pathway and hexosamine pathway, all of which commutes glucose and its intermediates leading to overproduction of reactive oxygen species, (ii) dysregulation of growth factors and cytokines, (iii) epigenetic changes which concern the changes in DNA as a response to intracellular changes, and (iv) abnormalities in non-coding RNAs, specifically microRNAs. This review will focus on gaining an understanding of the molecular complexities underlying the vascular complications in diabetes mellitus, to increase our understanding towards the development of new mechanistic therapeutic strategies to prevent or treat diabetes-induced vascular complications.

Ethnopharmacological relevance Fructus Arctii is the dried ripe fruit of Arctium lappa L. (family Asteraceae). It is a well-known Chinese Materia Medica that was included in the Chinese pharmacopoeia because of its traditional therapeutic actions, such as heat removal, detoxification, and elimination of swelling. Since ancient times Fructus Arctii has been used extensively in a number of classical drug formulas to treat type 2 diabetes mellitus. Modern pharmacological studies have shown that certain components of Fructus Arctii have multiple physiological activities on type 2 diabetes and its complications. Aim of the study We have reported the inhibitory effect of total lignans from Fructus Arctii (TLFA) on aldose reductase, the key enzyme in the polyol pathway, which is considered to be closely related to the onset of diabetic retinopathy (DR). The present study aimed to observe the preventive and therapeutic effects of TLFA on DR in Streptozotocin (STZ)-induced DR rats. Materials and methods TLFA was prepared from Fructus Arctii and its content was determined using UV spectrophotometry. The DR model was induced by STZ in Wistar rats. For DR prevention, the animals were gavaged once daily for 9 weeks with TLFA (1.38, 0.69, and 0.35 g/kg/day) as soon as they were confirmed as diabetes models. Pathological changes to retinal tissues and the expression of vascular endothelial growth factor (VEGF) and protein kinase C (PKC) in the retina were detected after TLFA treatment. The effects of TLFA on blood glucose levels and body weight were also observed. For DR treatment, the animals were gavaged once daily for 12 weeks with TLFA (1.38 and 0.69 g/kg/day) at 3 months after they were confirmed as diabetes models. The therapeutic effect was studied using quantitative detection of blood-retina barrier (BRB) breakdown via an Evans Blue leakage assay. Results For DR prevention, after 9 weeks of TLFA administration, histopathological examination of retinal tissue showed that TLFA improved the lesions in the retina. Changes to retinal microstructures such as capillaries, ganglion cells, bipolar cells, and the membrane disk examined by electron microscopy further confirmed that TLFA has a preventive effect on retinopathy. Terminal deoxynucleotidyl Transferase-mediated dUTP nick end labeling (TUNEL) detection showed that TLFA could inhibit retinal cell apoptosis in the diabetic rats, and fasting blood glucose (FBG) levels of rats in the TLFA-treated groups decreased during the experiment. For DR treatment, after 3 months of administration, the amount of dye leakage in the TLFA-administered groups was reduced by more than 50% compared with that in the model group, which indicated that TLFA has a therapeutic effect on middle and late DR. Messenger RNA (mRNA) expression of VEGF and PKCβ2 in the retina detected by real-time fluorescent quantitative reverse transcription-polymerase chain reaction (FQ-RT-PCR) showed that TLFA could inhibit the expression of them, which was consistent with the results of immunohistochemistry (IHC). Conclusion TLFA has a preventive and therapeutic effect on DR. Its mechanism of action on DR is related to inhibiting PKC activation and blocking VEGF elevation.

Neuropathy, or damage to the nerves of the peripheral nervous system, is a debilitating yet surprisingly common and complex condition. Diabetic peripheral neuropathy (DPN) is a prevalent, disabling condition. The damage of the central or peripheral nervous system results in neuropathic pain and which is also triggered by primary lesion and dysfunction of the nerves system. There is still limited knowledge about the factors that initiate and maintain neuropathic pain. It poses a significant challenge for clinicians as it is often diagnosed late when patients present with advanced consequences. The chronic hyperglycaemia activates various downsream cascasdes like polyol pathway, increasing glycation in non-enzymatic with several structural proteins that further alter Protein Kinase C activity, increases oxidative stress as well as alteration in Peroxisome proliferator-activated receptor gamma (PPAR-γ) activation that all are interrelated for the development and cause of neuropathy. Multifactorial risk factor reduction, targeting glycaemia, blood pressure and lipids can reduce the progression of DPN. Different therapies are also used for managing diabetic neuropathy and neuropathic pain includes anticonvulsants, opioids, antidepressants, aldose reuptake inhibitors. The current treatment of DPN is largely symptomatic. A number of novel potential candidates, including erythropoietin analogues, angiotensin II receptor type 2 antagonists, and sodium channel blockers are currently being evaluated in phase II clinical trials. Future studies are needed to further explore this relationship with implications for new treatments for this common disease.

Diabetic neuropathy (DN) is one of the most common and severe manifestations of diabetes mellitus. The mechanisms underlying the structural, functional and metabolic changes in diabetic neuropathy have been under study for a long time. In this review the biochemistry and implications of the four pathways responsible for the development of DN, polyol pathway; increased AGEs (advanced glycation end-products) formation; activation of PKC (protein kinase C) and hexosamine pathway have been discussed. Experimental and clinical evidences suggest a close link between neurodegeneration and oxidative stress which serves as a unifying mechanism, thus linking the four pathways. Recent studies indicate that oxidative stress mediated DNA damage causes poly(ADP-ribose) polymerase (PARP) overactivation and reduced activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a factor common to all the four pathways. The exact mechanism of PARP mediated cell death in DN needs further investigation. Based on current studies neuroprotective and antioxidant therapy have been suggested as potential treatment and preventive solutions for DN.

Summary Objective To examine the relationship between osteoarthritis (OA) and type 2 diabetes mellitus (DM). Methods OA cartilage from DM and non-DM patients undergoing knee replacement were stimulated by IL-1β for 24 h and release of interleukin-6 (IL-6) and prostaglandin E 2 (PGE 2 ) was measured. Primary cultured murine chondrocytes were stimulated for 24 and 72 h with or without IL-1β (5 ng/mL) under normal-glucose (5.5 mM) or high-glucose (25 mM) conditions. The expression and release of pro-inflammatory mediators (IL-6, cyclooxygenase 2 [COX2]/PGE 2 ) were analyzed by quantitative RT-PCR and ELISA/EIA. Glucose uptake was assessed with ( 14 C)-2-deoxyglucose. Reactive oxygen species (ROS) and nitric oxide (NO) production were measured. To analyze the mechanism of IL-1β-induced inflammation, cells were pretreated or treated with inhibitors of glucose transport (cytochalasin B), the polyol pathway (epalrestat), mitochondrial oxidative stress (MitoTEMPO) or nitric oxide synthase (l-NAME). Results With IL-1β stimulation, IL-6 and PGE 2 release was greater in human DM than non-DM OA cartilage (2.7- and 3-fold, respectively) ( P In vitro , with IL-1β stimulation, IL-6 and COX2 mRNA expression, IL-6 and PGE 2 release, and ROS and NO production were greater under high-than normal-glucose conditions in cultured chondrocytes. IL-1β–increased IL-6 release was reduced with cytochalasin B, epalrestat, l-NAME or MitoTEMPO treatment (−45%, −62%, −38% and −40%, respectively). Conclusion OA cartilages from DM patients showed increased responsiveness to IL-1β–induced inflammation. Accordingly, high glucose enhanced IL-1β–induced inflammation in cultured chondrocytes via oxidative stress and the polyol pathway. High glucose and diabetes may thus participate in the increased inflammation in OA.

Introduction Type 2 diabetes mellitus is a polygenic metabolic syndrome characterized by impaired carbohydrate and lipid metabolism. Diabetes mellitus is commonly associated with secondary disorders such as obesity and genetic predisposition. Prolonged hyperglycemia can also lead to secondary complications such as cataractogenesis, retinopathy and nephropathy through the induction of the polyol pathway. Ficus hispida (FH) is a medium size tree found in India, Sri Lanka and the Andaman Islands in damp localities. Traditionally, different parts of the FH plant have been used in the treatment of various diseases and disorders. Methodology FH bark was sequentially extracted using different organic solvents ranging from non polar to polar. Glucose uptake assays were performed using 2-deoxy- d -1-[ 3 H] for the FH extracts. Fluorimetric analysis was adopted to assess the aldose reductase inhibitory effect. The gene and protein level expression of the markers were analyzed using RT-PCR and Western blot analysis. Results F. hispida methanolic extract (FHME) showed an enhancement in the glucose uptake and upregulated the gene and protein level expression of IRβ, IRS-1, PI3K, GLUT4 and PPARγ. Comparison with wortmannin, a specific PI3K inhibitor confirmed that the active FHME recruits glucose uptake through a PI3K dependent pathway. Subsequently, FHME possesses a significant aldose reductase inhibitory activity. Conclusion The current study emphasizes the cellular level mechanism of FHME on glucose transport in L6 myotubes and the inhibition of aldose reductase activity.

Aldose reductase, the key enzyme of the polyol pathway, plays a crucial role in the development of long term complications affecting diabetic patients. Nevertheless, the expedience of inhibiting this enzyme to treat diabetic complications has failed, due to the emergence of side effects from compounds under development. Actually, aldose reductase is a Janus-faced enzyme which, besides ruling the polyol pathway, takes part to the antioxidant defence mechanism of the body. In this work we report the evidence that a novel class of compounds, characterized by a pyrazolo[1,5-a]pyrimidine core and a ionisable fragment, is able to modulate differently the catalytic activity of the enzyme, depending on the presence of specific substrates like sugar, toxic aldehydes and glutathione conjugates of toxic aldehydes. These compounds stand out as the first example of aldose reductase differential inhibitors (ARDIs), intended to target long term diabetic complications while leaving unaltered the detoxifying role of the enzyme.

Type-2 diabetes and obesity-related metabolic abnormalities are major risk factors for the development of colon cancer. In the present study, we examined the effects of polyol pathway enzyme aldose reductase (AR) inhibitor, fidarestat, on the development of azoxymethane (AOM)-induced colonic premalignant lesions in C57BL/KsJ-db/db obese mice. Our results indicate that fidarestat given in the drinking water caused a significant reduction in the total number of colonic premalignant lesions in the AOM treated obese mice. Further, the expression levels of PKC-β2, AKT, COX-2 and iNOS in the colonic mucosa of AOM-treated mice were significantly decreased by fidarestat. The serum levels of IL-1α, IP-10, MIG, TNF-α and VEGF are significantly suppressed in AOM + fidarestat treated obese mice. Fidarestat also decreased the expression of COX-2, iNOS, XIAP, survivin, β-catenin and NF-κB in high glucose-treated HT29 colon cancer cells. In conclusion, our results indicate that fidarestat inhibits the development of colonic premalignant lesions in an obesity-related colon cancer and is chemopreventive to colorectal carcinogenesis in obese individuals.

Introduction Hyperactivation of the polyol pathway (PP) contributes to development of diabetic complications such as diabetic cardiomyopathy (DbCM). Aldose reductase (AR), the rate-controlling enzyme in the PP, catalyzes NADPH-dependent reduction of glucose to sorbitol. Under hyperglycemic and ischemic conditions, PP activation causes intracellular sorbitol accumulation leading to osmotic stress, cell death and diabetic complications. Previous AR inhibitors (ARI) failed due to safety or lack of efficacy. AT-001 is a novel oral ARI with optimized specificity and affinity for AR. Objectives To assess cardioprotective activity of AT-001 in an animal model of DbCM and safety, tolerability and target engagement in a phase 1/2 clinical study. Preclinical Methods and Results The cardioprotective effect of AT-100 was studied in transgenic mice expressing human levels of AR (Tg hAR) and rendered diabetic with streptozotocin (55 mg/kg for 5d). Mice were treated with AT-001 40 mg/kg, n=6 or vehicle (V, n=6) for 3d prior to cardiac ischemia reperfusion (IR) injury induced by ligation and reperfusion of the left anterior descending (LAD) coronary artery. Control non-DM Tg hAR mice (non-DM, n=9) were also subjected to IR injury. After 48h recovery mice were euthanized and infarct area and fractional shortening (FS) assessed. Mean (±SD) infarct area (ratio of infarcted to total left ventricular area) was significantly lower in AT-001 (35.3±2.7) vs. non-DM (43±2) and V (59.1±0.8); P Clinical methods and Results The phase 1/2 study consisted of single and multiple oral ascending doses (SAD, n=8 per group) of 5, 10, 20 and 40 mg/kg once daily (QD) and multiple doses (MAD) of placebo (Pbo) or AT-001 5, 20, 40 mg/kg QD or 20 mg/kg twice daily for 7d. Subjects with type 2 diabetes (T2DM), age 18-75 and HbA1c 5.0-8.5% were allocated to AT-001 (n=8) or Pbo (n=2) in each dose cohort. AT-001 was well-tolerated with no drug-related AEs. AR inhibition and target engagement were demonstrated by dose-dependent decreases in sorbitol in AT-001 (up to -50 % change from baseline) vs. Pbo subjects (-3 % change). Maximum inhibition was between 2-4 h and lasted several hours. Conclusions AT-001 significantly attenuated or prevented cardiac damage in a relevant animal model and was safe, well-tolerated and reduced sorbitol levels in T2DM subjects. These findings support clinical development in DbCM.

Aims Chronic hyperglycaemia activates the polyol pathway of glucose metabolism thereby stimulating the activation aldose reductase enzyme that in turn initiates a cascade of deleterious events, eventually, leading to nerve damage or neuropathy. Marine macroalgae and their isolated chemical constituents have been found to possess potential antidiabetic activity and have proved beneficial in the treatment of diabetes. In this study the neuroprotective effect of polyphenols isolated from the red macroalga Symphyocladia latiuscula was evaluated in experimental diabetic peripheral neuropathy. Main methods The polyphenolic fraction from Symphyocladia latiuscula was isolated. Diabetic peripheral neuropathy (DPN) was induced in animals by intraperitoneal injection of streptozotocin (45 mg/kg, b. w) and maintained for 6 weeks followed by treatment with SLPP or epalrestat. Nerve Conduction Velocity (NCV) and Compound Muscle Action Potential (CMAP) were measured using a non-invasive method followed by muscular grip strength test. Sciatic nerve aldose reductase activity, sorbitol accumulation, Na+K+-ATPase activity, production of pro-inflammatory cytokines and expression of AR and PKC were assessed. Key findings The Symphyocladia latiuscula polyphenols (SLPP) were found to inhibit aldose reductase activity as well as their expression in diabetic animals thereby improving the NCV, CMAP and muscle grip strength. Improvements in the sciatic nerve Na+K+-ATPase activity and intraneural accumulation of sorbitol, an index of aldose reductase overactivity, were evident with SLPP treatment. The production of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and expression of protein kinase C (PKC) were also diminished. Significance The data suggest that the polyphenols of Symphyocladia latiuscula have neuroprotective potential against experimental DPN.

Objective Activation of polyol pathway based on increased activity of aldose reductase (AR) has been implicated in the development of diabetic complications including diabetic autonomic neuropathy (DAN). The relationship between DAN and hyperglycemia-induced activation of polyol pathway is still uncertain. In the present study, we investigate the association between aldose reductase activity and diabetic autonomic neuropathy by measuring AR level in red blood cells (RBC). Method In this study, 145 subjects with diabetes with or without DAN and 32 subjects without diabetes have been included. All subjects have been investigated for autonomic function tests and RBC aldose reductase activity. DAN was defined if results of any 2 of the tests of parasympathetic function were abnormal. RBC aldose reductase level was determined spectrophotometrically and expressed as unit/g of hemoglobin. The values were expressed as mean ± standard deviation, and ANOVA test has been applied for comparison between groups. Results RBC aldose reductase activity was found to be significantly higher in people with diabetes with autonomic neuropathy in comparison to people with diabetes without autonomic neuropathy and healthy individuals without diabetes. Aldose reductase (AR) level ranges from 0.8 units/g Hb to 14.2 units/g Hb. The mean AR level was 8.6±2.95 units in subjects of DM with autonomic neuropathy, while mean AR level was 4.1±1.78 units and 2.0±0.89 units in people with diabetes without neuropathy and normal healthy individuals, respectively (p Conclusions High aldose reductase activity is associated with the presence of autonomic neuropathy in subjects of type 2 DM.

Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes, and are major risk factors for foot ulceration and amputation. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue, but importantly, neurodegenerative changes are precipitated by compromised nerve vascular supply. Experiments in animal models of diabetic neuropathy suggest that similar metabolic sequelae affect neurons and vasa nervorum endothelium. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes such as elevated protein kinase C, nuclear factor κB and p38 mitogen activated protein kinase signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Nitrosative stress and the induction of the enzyme poly (ADP-ribose) polymerase form one important link between physiological stressors such as reactive oxygen species and the pro-inflammatory mechanisms. Recently, evidence points to endoplasmic stress and the unfolded protein response as forming another crucial link. This review focuses on the aetiopathogenesis of neurovascular changes in diabetic neuropathy, elucidated in animal studies, and on putative therapeutic targets the majority of which have yet to be tested for efficacy in clinical trials.

Diabetic retinopathy (DR) is a common chronic complication of diabetes and remains the leading cause of blindness in working-aged people. Hyperglycemia increases glucose flux through the polyol pathway, in which aldose reductase converts glucose into intracellular sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase (SDH). The accelerated polyol pathway triggers a cascade of events leading to retinal vascular endothelial dysfunction and the eventual development of DR. Polymorphisms in the gene encoding aldose reductase have been consistently associated with DR. However, only two studies have analyzed the relationship between polymorphisms in the gene encoding SDH (SORD) and DR. In this case-control study, we investigated whether the -888G > C polymorphism (rs3759890) in the SORD gene is associated with the presence or severity of DR in 446 Caucasian-Brazilians with type 2 diabetes (241 subjects with and 205 subjects without DR). The -888G > C polymorphism was also examined in 105 healthy Caucasian blood donors, and the genotyping of this polymorphism was carried out by real-time PCR. The genotype and allele frequencies of the -888G > C polymorphism in patients with type 2 diabetes were similar to those of blood donors (G allele frequency = 0.16 in both groups of subjects). Similarly, the genotype and allele frequencies in patients with DR or the proliferative form of DR were similar to those of patients without this complication (P > 0.05 for all comparisons). Thus, our findings suggest that the -888G > C polymorphism in the SORD gene is not involved in the pathogenesis of DR in type 2 diabetes.