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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 review presents data on the pathogenesis of diabetic retinopathy. The importance of increasing the activity of the polyol pathway of glucose metabolism, non-enzymatic glycation of proteins, activation of protein kinase C, carbonic anhydrase, hemodynamic changes and the activity of the renin-angiotensin system in the development of diabetes and its microvascular complications is indicated. Particular attention is paid to the role of oxidative stress, growth factors, as well as metabolic syndrome and obesity in the development and progression of diabetic retinopathy.

Cardiovascular disease is one of the leading causes of mortality in diabetes. High fructose consumption has been linked with the development of diabetes and cardiovascular disease. Serum and cardiac tissue fructose levels are elevated in diabetic patients, and cardiac production of fructose via the intracellular polyol pathway is upregulated. The question of whether direct myocardial fructose exposure and upregulated fructose metabolism have potential to induce cardiac fructose toxicity in metabolic stress settings arises. Unlike tightly-regulated glucose metabolism, fructose bypasses the rate-limiting glycolytic enzyme, phosphofructokinase, and proceeds through glycolysis in an unregulated manner. In vivo rodent studies have shown that high dietary fructose induces cardiac metabolic stress and functional disturbance. In vitro, studies have demonstrated that cardiomyocytes cultured in high fructose exhibit lipid accumulation, inflammation, hypertrophy and low viability. Intracellular fructose mediates post-translational modification of proteins, and this activity provides an important mechanistic pathway for fructose-related cardiomyocyte signaling and functional effect. Additionally, fructose has been shown to provide a fuel source for the stressed myocardium. Elucidating the mechanisms of fructose toxicity in the heart may have important implications for understanding cardiac pathology in metabolic stress settings.

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.

Modern lifestyle, changing eating habits and reduced physical work have been known to culminate into making diabetes a global pandemic. Hyperglycemia during the course of diabetes is an important causative factor for the development of both microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (coronary artery disease, stroke and peripheral artery disease) complications. In this article, we summarize several mechanisms accountable for the development of both microvascular and macrovascular complications of diabetes. Several metabolic and cellular events are linked to the augmentation of oxidative stress like the activation of advanced glycation end products (AGE) pathway, polyol pathway, Protein Kinase C (PKC) pathway, Poly-ADP Ribose Polymerase (PARP) and hexosamine pathway. Oxidative stress also leads to the production of reactive oxygen species (ROS) like hydroxyl radical, superoxide anion and peroxides. Enhanced levels of ROS rescind the anti-oxidant defence mechanisms associated with superoxide dismutase, glutathione and ascorbic acid. Moreover, ROS triggers oxidative damages at the level of DNA, protein and lipids, which eventually cause cell necrosis or apoptosis. These physiological insults may be related to the microvascular complications of diabetes by negatively impacting the eyes, kidneys and the brain. While underlying pathomechanism of the macrovascular complications is quite complex, hyperglycemia associated atherosclerotic abnormalities like changes in the coagulation system, thrombin formation, fibrinolysis, platelet and endothelial function and vascular smooth muscle are well proven. Since hyperglycemia also modulates the vascular inflammation, cytokines, macrophage activation and gene expression of growth factors, elevated blood glucose level may play a central role in the development of macrovascular complications of diabetes. Taken collectively, chronic hyperglycemia and increased production of ROS are the miscreants for the development of microvascular and macrovascular complications of diabetes.

Chronic hyperglycemia induces activation of the polyol-sorbitol pathway, which is a major contributor to microvascular complications like stroke. The current study was designed to elucidate the therapeutic role of α-glucose inhibitor in chronic hyperglycemia-induced impaired polyol pathway and associated micro-complications. Male albino-Wistar rats (200-250 g) were treated with voglibose 10 mg kg-1 day-1 /p.o. for 2 weeks before middle cerebral artery occlusion; 72 hr after surgery, neurological score was evaluated and blood was collected for the assessment of various serum biochemical parameters like CRP, CK-MB, LDH, lipid profile, and blood glucose levels. In the end, brain samples were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity oxidative stress-related parameters, aldose reductase activity, and gene expression studies. Results from the present study indicate that pre-treatment with voglibose showed significant improvement in lipid parameters but did not impact glucose levels. Voglibose has shown a statistically significant (p

Hyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization of glucose levels delays its progression. In hyperglycemia, hexokinase is saturated and excess glucose is metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies to reduce retinal polyol accumulation for the prevention of DR have been elusive because of low sorbitol dehydrogenase levels in the retina and inadequate inhibition of aldose reductase. Using systemic and conditional genetic inactivation, we targeted the primary facilitative glucose transporter in the retina, Glut1, as a preventative therapeutic in diabetic male and female mice. Unlike WT diabetics, diabeticGlut1+/−mice did not display elevated Glut1 levels in the retina. Furthermore, diabeticGlut1+/−mice exhibited ameliorated ERG defects, inflammation, and oxidative stress, which was correlated with a significant reduction in retinal sorbitol accumulation. Retinal pigment epithelium-specific reduction of Glut1 did not prevent an increase in retinal sorbitol content or early hallmarks of DR. However, like diabeticGlut1+/−mice, reduction of Glut1 specifically in the retina mitigated polyol accumulation and diminished retinal dysfunction and the elevation of markers for oxidative stress and inflammation associated with diabetes. These results suggest that modulation of retinal polyol accumulation via Glut1 in photoreceptors can circumvent the difficulties in regulating systemic glucose metabolism and be exploited to prevent DR.SIGNIFICANCE STATEMENTDiabetic retinopathy affects one-third of diabetic patients and is the primary cause of vision loss in adults 20-74 years of age. While anti-VEGF and photocoagulation treatments for the late-stage vision threatening complications can prevent vision loss, a significant proportion of patients do not respond to anti-VEGF therapies, and mechanisms to stop progression of early-stage symptoms remain elusive. Glut1 is the primary facilitative glucose transporter for the retina. We determined that a moderate reduction in Glut1 levels, specifically in the retina, but not the retinal pigment epithelium, was sufficient to prevent retinal polyol accumulation and the earliest functional defects to be identified in the diabetic retina. Our study defines modulation of Glut1 in retinal neurons as a targetable molecule for prevention of diabetic retinopathy.

Diabetes mellitus is one of the most widely spread non-infectious cats and dogs diseases and in modern times it is reaching epidemic levels. The purpose of the research was to determine enzymes activity, which is a marker of liver’s functional activity: alanine aminotransferase, asparagine aminotransferase, alkaline phosphatase and sorbitol dehydrogenase in cats suffering from diabetes mellitus, and another purpose was to study the dynamics of sorbitol dehydrogenase activity. Two groups of cats aged 5–7 years old (males and females) 10 cats in each group were formed for the research. A control group comprised clinically healthy animals, experimental group comprised animals diagnosed with diabetes mellitus. The results of the research showed that in cats of the experimental group the glucose content was 3.31 times as high as in cats of a control group. Fructosamine characterizes the duration of hyperglycemia and in cats diagnosed with diabetes mellitus its content overshot the control indices by 32 %, that testifies to a long-standing increase in glucose amount. Because of diabetes mellitus, water-salt metabolism is damaged, for instance blood osmolality is increased. The determination of enzymes activity showed that transaminase activity doubled, whereas the alkaline phosphatase activity increased by 25 %. The concentration of total bilirubin increased more than three-fold as compared to the control. The sorbitol dehydrogenase activity in cats diagnosed with diabetes mellitus was in 2.25 times higher as compared to the animals in a control group. The activity of this enzyme, contrary to transaminase activity, is increased during the first days after hepatic dysfunction symptoms. Thus, in cats diagnosed with diabetes mellitus, liver function abnormality is developed which is manifested in activity changes of alanine aminotransferase, asparagine aminotransferase, alkaline phosphatase in the increase in bilirubin concentration as well as in the increase of sorbitol dehydrogenase activity. This enzyme is a valuable biochemical marker of liver function abnormality on the early stages of pathology development.

Astaxanthin (ATX) is a marine carotenoid known for its powerful antioxidant and neuroprotective properties. In this study, we investigated the in vitro and in vivo potential inhibitory effect of ATX on the aldose reductase (AR) activity, a key enzyme in the polyol pathway responsible for the pathogenesis of diabetic complications including diabetic retinopathy (DR). The gerbil Psammomys obesus (P. ob.), an animal model for type 2 diabetes and DR has been used. The erythrocyte and retinal AR activity of P. ob. individuals were, respectively, assessed monthly and at the 7th month during a 7‐month hypercaloric diet (HD) using a NADPH oxidation method. Meanwhile, the body weight and blood glucose of the gerbils were monitored. After 7 months, P. ob. individuals were fed with ATX (4.8 mg/kg of body weight) once a day for 1 week. The results showed that the HD‐fed animals developed significant obesity and hyperglycemia in comparison with controls. Erythrocyte AR activity showed a progressive and significant increase in the HD‐fed group compared with controls. Retinal AR activity was higher in the 7‐month HD‐fed group compared with controls. Erythrocyte AR activity was markedly decreased after ATX‐treatment in vitro and in vivo. These findings suggested that ATX inhibited the erythrocyte AR activity and could be used for DR prevention and/or early treatment.

Alpha-lipoic acid (ALA) is a substantial antioxidant in the prevention of diabetes and diabetes complications. It can regenerate other antioxidants like vitamin E, vitamin C, Coenzyme Q10 and glutathione and is often known as a universal antioxidant. Antioxidants play a role in diabetes treatment due to hyperglycemia-induced stimulation of the polyol pathway and formation of advanced glycation end products (AGE) and reactive oxygen species (ROS). Clinical trials examining alpha-lipoic acid supplementation on diabetic neuropathy, nephropathy, cardiomyopathy and erectile dysfunction display positive results, particularly in pain amelioration in neuropathy, asymmetric dimethylarginine reductions in nephropathy and improved oscillatory potential and contrast sensitivity in retinopathy. In diabetic cardiomyopathy (DCM), ALA offers protection through inhibition of NF-kB activation, reduction of fas-ligand and decrease in matrix metalloproteinase-2. This comprehensive review summarises and provides an understanding of the importance of alpha- lipoic acid supplementation to prevent diabetes complications.

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.

Purpose of review Excessive sugar and particularly fructose consumption has been proposed to be a key player in the pathogenesis of metabolic syndrome and kidney disease in humans and animal models. However, besides its dietary source, fructose can be endogenously produced in the body from glucose via the activation of the polyol pathway. In this review, we aim to describe the most recent findings and current knowledge on the potential role of endogenous fructose production and metabolism in disease. Recent findings Over the recent years, the activation of the polyol pathway and endogenous fructose production has been observed in multiple tissues including the liver, renal cortex, and hypothalamic areas of the brain. The activation occurs during the development and progression of metabolic syndrome and kidney disease and results from different stimuli including osmotic effects, diabetes, and ischemia. Even though the potential toxicity of the activation of the polyol pathway can be attributed to several intermediate products, the blockade of endogenous fructose metabolism either by using fructokinase deficient mice or specific inhibitors resulted in marked amelioration of multiple metabolic diseases. Summary New findings suggest that fructose can be produced in the body and that the blockade of tis metabolism could be clinically relevant for the prevention and treatment of metabolic syndrome and kidney disease.

Hyperglycemia of diabetes mellitus leads to the activation of the polyol way of oxidation of glucose with the activation of the enzymes of aldose reductase and sorbitol dehydrogenase and of their coenzymes NADPH and NAD, which triggers the mechanism of formation of sorbitol. The consequences of these changes lead to microangiopathy of the tissues of the kidneys, which may be one of the pathogenetic mechanisms of diabetic nephropathy. In an accessible literature, the role of coenzymes of sorbitol pathway in the development of diabetic nephropathy is not sufficiently defined. The purpose of the study was to study the content of NAD and NADPH coenzymes, their correlation, and their role in the mechanism of kidney damage in diabetes mellitus and to predict the possible correction of these changes with the NAD-nicotinamide derivative. The study was conducted on a model of streptotrozectinic diabetes mellitus (single administration of streptozotocin in a dose of 60 mg per 1 kg of body weight). Four weeks after induction of diabetes, nicotinamide (100 mg per 1 kg body weight) was injected. The level of glucose was determined by the Accu-chek (Roshe Diagnostics, Switzerland) glucose meter. The content of NAD and NADH was determined in the non-protein extracts. The statistical analysis was carried out using the Microsoft Excel statistical analysis program. The difference between the indicators was considered statistically significant (p

Peripheral neuropathy is the most prevalent chronic complication of diabetes mellitus. Good glycemic control can delay the appearance of neuropathic symptoms in diabetic patients but it is not sufficient to prevent or cure the disease. Therefore therapeutic approaches should focus on attenuation of pathogenetic mechanisms responsible for the nerve injury. Considering the role of polyol pathway in the etiology of diabetic neuropathy, we evaluated the effect of a novel efficient and selective aldose reductase inhibitor, 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (cemtirestat), on symptoms of diabetic peripheral neuropathy in Zucker Diabetic Fatty (ZDF) rats. Since the age of 5 months, male ZDF rats were orally administered cemtirestat, 2.5 and 7.5 mg/kg/day, for two following months. Thermal hypoalgesia was evaluated by tail flick and hot plate tests. Tactile allodynia was determined by a von Frey flexible filament test. Two-month treatment of ZDF rats with cemtirestat (i) did not affect physical and glycemic status of the animals; (ii) partially inhibited sorbitol accumulation in red blood cells and the sciatic nerve; (iii) markedly decreased plasma levels of thiobarbituric acid reactive substances; (iv) normalized symptoms of peripheral neuropathy with high significance. The presented findings indicate that inhibition of aldose reductase by cemtirestat is not solely responsible for the recorded improvement of the behavioral responses. In future studies, potential effects of cemtirestat on consequences of diabetes that are not exclusively dependent on glucose metabolism via polyol pathway should be taken into consideration.

Diabetic nephropathy (DN) is a common complication of diabetes, and it is also the main cause of chronic renal failure. Physiological/pathological changes mediated by high glucose are the main factors causing injury of DN, including the enhancement of polyol pathway, the accumulation of advanced glycation products (AGEs), and the activation of protein kinase C (PKC) and transforming growth factor-β (TGF-β) signals. In addition, the abnormal activation of renin-angiotensin system (RAS) and oxidative stress are also involved. Melatonin is a physiological hormone mainly secreted by the pineal gland which has been proved to be related to diabetes. Studies have shown that exogenous melatonin intervention can reduce blood glucose and alleviate high glucose mediated pathological damage. At the same time, melatonin also has a strong antioxidant effect, and can inhibit the activation of RAS. Therefore, it is of great significance to explore the therapeutic effect and value of melatonin on DN.

Diabetes is a leading cause of cardiovascular morbidity and mortality. Despite numerous treatments for cardiovascular disease (CVD), for patients with diabetes, these therapies provide less benefit for protection from CVD. These considerations spur the concept that diabetes-specific, disease-modifying therapies are essential to identify especially as the diabetes epidemic continues to expand. In this context, high levels of blood glucose stimulate the flux via aldose reductase (AR) pathway leading to metabolic and signaling changes in cells of the cardiovascular system. In animal models flux via AR in hearts is increased by diabetes and ischemia and its inhibition protects diabetic and non-diabetic hearts from ischemia-reperfusion injury. In mouse models of diabetic atherosclerosis, human AR expression accelerates progression and impairs regression of atherosclerotic plaques. Genetic studies have revealed that single nucleotide polymorphisms (SNPs) of the ALD2 (human AR gene) is associated with diabetic complications, including cardiorenal complications. This Review presents current knowledge regarding the roles for AR in the causes and consequences of diabetic cardiovascular disease and the status of AR inhibitors in clinical trials. Studies from both human subjects and animal models are presented to highlight the breadth of evidence linking AR to the cardiovascular consequences of diabetes.

Diabetes is associated with cardiac metabolic disturbances and increased heart failure risk. Plasma fructose levels are elevated in diabetic patients. A direct role for fructose involvement in diabetic heart pathology has not been investigated. The goals of this study were to clinically evaluate links between myocardial fructose and sorbitol (a polyol pathway fructose precursor) levels with evidence of cardiac dysfunction, and to experimentally assess the cardiomyocyte mechanisms involved in mediating the metabolic effects of elevated fructose. Fructose and sorbitol levels were increased in right atrial appendage tissues of type 2 diabetic patients (2.8- and 1.5-fold increase respectively). Elevated cardiac fructose levels were confirmed in type 2 diabetic rats. Diastolic dysfunction (increased E/e’, echocardiography) was significantly correlated with cardiac sorbitol levels. Elevated myocardial mRNA expression of the fructose-specific transporter, Glut5 (43% increase), and the key fructose-metabolizing enzyme, Fructokinase-A (50% increase) was observed in type 2 diabetic rats (Zucker diabetic fatty rat). In neonatal rat ventricular myocytes, fructose increased glycolytic capacity and cytosolic lipid inclusions (28% increase in lipid droplets/cell). This study provides the first evidence that elevated myocardial fructose and sorbitol are associated with diastolic dysfunction in diabetic patients. Experimental evidence suggests that fructose promotes the formation of cardiomyocyte cytosolic lipid inclusions, and may contribute to lipotoxicity in the diabetic heart.

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus. There is much evidence showing that a high level of mitochondrial overproduction of reactive oxygen species in the diabetic retina contributes in modifying cellular signalling and leads to retinal cell damage and finally to the development of DR pathogenesis. In the last few decades, it has been reported that vitamin D is involved in DR pathogenesis. Vitamin D, traditionally known as an essential nutrient crucial in bone metabolism, has also been proven to be a very effective antioxidant. It has been demonstrated that it modulates the production of advanced glycosylated end products, as well as several pathways including protein kinase C, the polyol pathway leading to the reduction of free radical formation. It prevents the translocation of nuclear factor kappa B, preventing the inflammatory response, acting as an immunomodulator, and modulates autophagy and apoptosis. In this review, we explore the molecular mechanisms by which vitamin D protects the eye from oxidative stress, in order to evaluate whether vitamin D supplementation may be useful to mitigate the deleterious effects of free radicals in DR.

Diabetic retinopathy is a major cause of ocular complications in patients with type 1 and type 2 diabetes in developed countries. Due to the continued increase in the number of people with obesity and diabetes in the United States of America and globally, the incidence of diabetic retinopathy is expected to increase significantly in the coming years. Diabetic retinopathy is widely accepted as a combination of neurodegenerative and microvascular changes; however, which change occurs first is not yet understood. Although the pathogenesis of diabetic retinopathy is very complex, regulated by numerous signaling pathways and cellular processes, maintaining glucose homeostasis is still an essential component for normal physiological functioning of retinal cells. The maintenance of glucose homeostasis is finely regulated by coordinated interplay between glycolysis, Krebs cycle, and oxidative phosphorylation. Glycolysis is the most conserved metabolic pathway in biology and is tightly regulated to maintain a steady-state concentration of glycolytic intermediates; this regulation is called scheduled or regulated glycolysis. However, an abnormal increase in glycolytic flux generates large amounts of intermediate metabolites that can be shunted into different damaging pathways including the polyol pathway, hexosamine pathway, diacylglycerol-dependent activation of the protein kinase C pathway, and Amadori/advanced glycation end products (AGEs) pathway. In addition, disrupting the balance between glycolysis and oxidative phosphorylation leads to other biochemical and molecular changes observed in diabetic retinopathy including endoplasmic reticulum-mitochondria miscommunication and mitophagy dysregulation. This review will focus on how dysregulation of glycolysis contributes to diabetic retinopathy.

Hyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization of glucose levels delays its progression. In hyperglycemia, hexokinase is saturated and excess glucose is metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies to reduce retinal polyol accumulation for the prevention of DR have been elusive due to low sorbitol dehydrogenase levels in the retina and inadequate inhibition of aldose reductase. Using systemic and conditional genetic inactivation, we targeted the primary facilitative glucose transporter in the retina, Glut1, as a preventative therapeutic in diabetic male and female mice. Unlike wildtype diabetics, diabetic Glut1+/− mice did not display elevated Glut1 levels in the retina. Furthermore, diabetic Glut1+/− mice exhibited ameliorated ERG defects, inflammation and oxidative stress, which was correlated with a significant reduction in retinal sorbitol accumulation. RPE-specific reduction of Glut1 did not prevent an increase in retinal sorbitol content or early hallmarks of DR. However, like diabetic Glut1+/− mice, reduction of Glut1 specifically in retinal neurons mitigated polyol accumulation and completely prevented retinal dysfunction and the elevation of markers for oxidative stress and inflammation associated with diabetes. These results suggest that modulation of retinal polyol accumulation via Glut1 in photoreceptors can circumvent the difficulties in regulating systemic glucose metabolism and be exploited to prevent DR.SignificanceDiabetic retinopathy (DR) affects one third of diabetic patients and is the primary cause of vision loss in adults aged 20-74. While anti-VEGF and photocoagulation treatments for the late-stage vision threatening complications can prevent vision loss, a significant proportion of patients do not respond to anti-VEGF therapies and mechanisms to stop progression of early-stage symptoms remain elusive. Glut1 is the primary facilitative glucose transporter for the retina. We determined that a moderate reduction in Glut1 levels, specifically in retinal neurons, but not the RPE, was sufficient to prevent retinal polyol accumulation and the earliest functional defects to be identified in the diabetic retina. Our study defines modulation of Glut1 in retinal neurons as a targetable molecule for prevention of DR.

The objective of this study was to investigate whether juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease (NAFLD), cholestasis, and gut dysbiosis would develop histological and metabolic markers of neurodegeneration in the frontal cortex (FC) and whether supplementing probiotics would influence the response to the diet. Twenty-eight juvenile Iberian pigs were fed for 10 wk either a control (CON) or high-fructose high-fat (HFF) diet with or without a commercial probiotic mixture. Compared with CON, HFF-fed pigs had a decreased number of neurons and an increase in reactive astrocytes in FC tissue. There was also a decrease in one-carbon metabolites choline and betaine and a marked accumulation of bile acids, cholesteryl esters, and polyol pathway intermediates in FC of HFF-fed pigs, which were associated with markers of neurodegeneration and accentuated with the severity of NAFLD. Betaine depletion in FC tissue was negatively correlated with choline-derived phospholipids in colon content, whereas primary conjugated bile acids in FC were associated with cholestasis. Plasma kynurenine-to-tryptophan quotient, as a marker of indoleamine 2,3-dioxygenase activity, and intestinal dysbiosis were also correlated with neuronal loss and astrogliosis. Recognition memory test and FC levels of amyloid-β and phosphorylated Tau did not differ between diets, whereas probiotics increased amyloid-β and memory loss in HFF-fed pigs. In conclusion, our results show evidence of neurodegeneration in FC of juvenile Iberian pigs and establish a novel pediatric model to investigate the role of gut-liver-brain axis in diet-induced NAFLD.

Obesity and metabolic syndrome are strongly associated with cancer, and these disorders may share a common mechanism. Recently, fructose has emerged as a driving force to develop obesity and metabolic syndrome. Thus, we assume that fructose may be the mechanism to explain why obesity and metabolic syndrome are linked with cancer. Clinical and experimental evidence showed that fructose intake was associated with cancer growth and that fructose transporters are upregulated in various malignant tumors. Interestingly, fructose metabolism can be driven under low oxygen conditions, accelerates glucose utilization, and exhibits distinct effects as compared to glucose, including production of uric acid and lactate as major byproducts. Fructose promotes the Warburg effect to preferentially downregulate mitochondrial respiration and increases aerobic glycolysis that may aid metastases that initially have low oxygen supply. In the process, uric acid may facilitate carcinogenesis by inhibiting the TCA cycle, stimulating cell proliferation by mitochondrial ROS, and blocking fatty acid oxidation. Lactate may also contribute to cancer growth by suppressing fat oxidation and inducing oncogene expression. The ability of fructose metabolism to directly stimulate the glycolytic pathway may have been protective for animals living with limited access to oxygen, but may be deleterious toward stimulating cancer growth and metastasis for humans in modern society. Blocking fructose metabolism may be a novel approach for the prevention and treatment of cancer.

One of the major public health issues is the rising prevalence of cataracts, a primary reason for preventable blindness. The causes for the development of age-related cataracts and accelerated cataractogenesis in diabetes are multifactorial. Hence, this study was designed to examine the status and relationship between the three majorly associated molecular events, namely, oxidative stress, non-enzymatic glycation, and polyol pathway in age-related cataracts with and without diabetes. A total of 472 subjects were distributed into four groups: non-diabetic subjects with clear lens (135), diabetic subjects with clear lens (40), non-diabetic subjects with cataract (174), and diabetic subjects with cataract (123). Cataracts were graded by slit-lamp examination according to the Lens Opacities Classification System III. Age at onset of cataract, type of opacity, anthropometric measurements, and sociodemographic characteristics were recorded, and clinical profile was examined. Plasma oxidative stress markers were assessed by estimating the lipid peroxidation end product malondialdehyde, protein oxidation products protein carbonyls, and DNA oxidative damage marker 8-hydroxy-2-deoxyguanosine. Plasma advanced glycation end products index, erythrocyte aldose reductase activity, and sorbitol levels were evaluated. After adjusting for age, plasma malondialdehyde levels were significantly higher in diabetic cataracts (P 0.001) and non-diabetic cataract subjects (P 0.05), compared to non-diabetic subjects with clear lens. Plasma advanced glycation end products index was significantly higher (P 0.05) only in diabetic cataracts, but not in non-diabetic subjects with cataracts. Aldose reductase activity and sorbitol levels were significantly higher (P 0.001) in both diabetic and non-diabetic subjects with cataract compared to non-diabetic subjects with clear lens. The data indicated that plasma lipid peroxidation in age-related cataracts was independent of diabetes. An association of pronounced glycation was observed only in diabetic cataracts but not in non-diabetic cataracts and polyol flux between diabetic cataracts and non-diabetic cataracts was comparable.

Background: Chronic hyperglycemia and related complications involving peripheral nerves in diabetes are one of the most severe microvascular complications with an average prevalence of 50–60%. Diabetic neuropathy is among the vascular disorders of diabetes, the most debilitating and crippled, lethal condition impacting patients’s quality of life. Methods: In the present review article, several hypotheses associated with the pathogenesis of Diabetic Peripheral Neuropathy (DPN) have been introduced, among them metabolic pathways associated with polyol pathway, oxidative stress, production of reactive oxygen species (ROS) amplified under chronic hyperglycemic conditions and activation of transcription factor Nuclear factor-κB (NF- κB). The review article also possesses pathogenetic and pharmacologic treatments along with others, including acupressure, lidocaine, and capsaicin for DPN. Conclusion: It may be concluded that we can combat the pathogenesis of DPN with different suggested treatments.

Reductive stress is defined as a condition of sustained increase in cellular glutathione/glutathione disulfide and NADH/NAD+ ratios. Reductive stress is emerging as an important pathophysiological event in several diseased states, being as detrimental as is oxidative stress. Occurrence of reductive stress has been documented in several cardiomyopathies and is an important pathophysiological factor particularly in coronary artery disease and myocardial infarction. Excess activation of the transcription factor, Nrf2-the master regulator of the antioxidant response-, consequent in most cases to defective autophagy, can lead to reductive stress. In addition, hyperglycemia-induced activation of the polyol pathway can lead to increased NADH/NAD+ ratio, which might translate into increased levels of hydrogen sulfide-via enhanced activity of cystathionine β-synthase-that would fuel reductive stress through inhibition of mitochondrial complex I. Reductive stress may be either a potential weapon against cancer priming tumor cells to apoptosis or a cancer's ally promoting tumor cell proliferation and making tumor cells resistant to reactive oxygen species-inducing drugs. In non-cancer pathological states reductive stress is definitely harmful paradoxically leading to reactive oxygen species overproduction via excess NADPH oxidase 4 activity. In face of the documented occurrence of reductive stress in several heart diseases, there is much less information about the occurrence and effects of reductive stress in skeletal muscle tissue. In the present review we describe relevant results emerged from studies of reductive stress in the heart and review skeletal muscle conditions in which reductive stress has been experimentally documented and those in which reductive stress might have an as yet unrecognized pathophysiological role. Establishing whether reductive stress has a (patho)physiological role in skeletal muscle will hopefully contribute to answer the question whether antioxidant supplementation to the general population, athletes, and a large cohort of patients (e.g. heart, sarcopenic, dystrophic, myopathic, cancer, and bronco-pulmonary patients) is harmless or detrimental.

Background: Recent epidemiological and experimental studies have shown that obesity is a major risk factor for Colorectal Cancer (CRC). Regular intake of high fat-containing diet can promote obesity and metabolic syndrome by increasing the insulin resistance and inflammatory response which contribute to carcinogenesis. Previously, we have shown that inhibition of polyol pathway enzyme aldose reductase (AR) prevents carcinogens- and inflammatory growth factorsinduced CRC. However, the effect of AR inhibition on a high-fat diet (HFD)-induced formation of intestinal polyps in Apc-deficient Min (multiple intestinal neoplasia; ApcMin/+) mice is not known. Methods: We examined the effect of AR inhibitor, fidarestat on the HFD-induced formation of preneoplastic intestinal polyps in ApcMin/+ mice which is an excellent model of colon cancer. Results: APCMin/+ mice fed for 12 weeks of HFD caused a significant increase in the formation of polyps in the small and large intestines and fidarestat given along with the HFD prevented the number of intestinal polyps. Fidarestat also decreased the size of the polyps in the intestines of HFDtreated APC Min mice. Further, the expression levels of beta-catenin, PCNA, PKC-β2, P-AKT, Pp65, COX-2, and iNOS in the small and large intestines of HFD-treated mice significantly increased, and AR inhibitor prevented it. Conclusion: Our results thus suggest that fidarestat could be used as a potential chemopreventive drug for intestinal cancers due to APC gene mutations.

Diabetic retinopathy (DR) is a retinal disease which is one of the most severe complications occuring due to diabetes mellitus and is a major cause of blindness. Patients who have diabetes mellitus for number of years develop characteristic group of lesions in the retina which leads to Diabetic retinopathy. It is a multifactorial condition occuring due to complex cellular interactions between biochemical and metabolic abnormalities taking place in all retinal cells. Considerable research efforts in the past 20 years have suggested that the microvasculature of the retina responds to hyperglycemia through a number of biochemical changes, which includes polyol pathway, protein kinase C activation, upregulation of advanced glycation end products formation and renin angiotensin system activation. Various previous studies had suggest that interaction of these biochemical changes may cause a cascade of events, such as apoptosis, oxidative stress, inflammation and angiogenesis which can lead to the damage of a diabetic retina, causing DR. This highlights that oxidative stress, inflammation, angiogenesis-related factors triggers the occurrence of retinal complication in diabetes are highlighted. Keywords: Diabetic retinopathy, Oxidative stress, Inflammation, Angiogenesis

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.

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.

Vascular endothelium plays a role in capillary transport of nutrients and drugs and regulates angiogenesis, homeostasis, as well as vascular tone and permeability as a major regulator of local vascular homeostasis. The present study has been designed to investigate the role of endothelium in metabolic disorders. The endothelium maintains the balance between vasodilatation and vasoconstriction, procoagulant and anticoagulant, prothrombotic and antithrombotic mechanisms. Diabetes mellitus causes the activation of aldose reductase, polyol pathway and advanced glycation-end-product formation that collectively affect the phosphorylation status and expression of endothelial nitric oxide synthatase (eNOS) and causes vascular endothelium dysfunction. Elevated homocysteine levels have been associated with increase in LDL oxidation, generation of hydrogen peroxides, superoxide anions that increased oxidative degradation of nitric oxide. Hyperhomocysteinemia has been reported to increase the endogenous competitive inhibitors of eNOS viz L-N-monomethyl arginine (L-NMMA) and asymmetric dimethyl arginine (ADMA) that may contribute to vascular endothelial dysfunction. Hypercholesterolemia stimulates oxidation of LDL cholesterol, release of endothelins, and generation of ROS. The increased cholesterol and triglyceride level and decreased protective HDL level, decreases the activity and expression of eNOS and disrupts the integrity of vascular endothelium, due to oxidative stress. Hypertension also stimulates release of endothelins, vasoconstrictor prostanoids, angiotensin II, inflammatory cytokines, xanthine oxidase and, thereby, reduces bioavailability of nitric oxide. Thus, the cellular and molecular mechanisms underlying diabetes mellitus, hyperhomocysteinemia, hypercholesterolemia hypertension and hyperuricemia leads to an imbalance of phosphorylation and dephosphorylation status of lipid and protein kinase that cause modulation of vascular endothelial L-arginine/nitric oxide synthetase (eNOS), to produce vascular endothelium dysfunction.

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.

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.

Acute kidney injury is associated with high mortality, especially in intensive care unit patients. The polyol pathway is a metabolic route able to convert glucose into fructose. Here we show the detrimental role of endogenous fructose production by the polyol pathway and its metabolism through fructokinase in the pathogenesis of ischaemic acute kidney injury (iAKI). Consistent with elevated urinary fructose in AKI patients, mice undergoing iAKI show significant polyol pathway activation in the kidney cortex characterized by high levels of aldose reductase, sorbitol and endogenous fructose. Wild type but not fructokinase knockout animals demonstrate severe kidney injury associated with ATP depletion, elevated uric acid, oxidative stress and inflammation. Interestingly, both the renal injury and dysfunction in wild-type mice undergoing iAKI is significantly ameliorated when exposed to luteolin, a recently discovered fructokinase inhibitor. This study demonstrates a role for fructokinase and endogenous fructose as mediators of acute renal disease.

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.

Despite overall reductions in heart disease prevalence, the risk of developing heart failure has remained 2-fold greater among people with diabetes. Growing evidence has supported that fluctuations in glucose level and uptake contribute to cardiovascular disease (CVD) by modifying proteins, DNA, and gene expression. In the case of glucose, clinical studies have shown that increased dietary sugars for healthy individuals or poor glycemic control in diabetic patients further increased CVD risk. Furthermore, even after decades of maintaining tight glycemic control, susceptibility to disease progression can persist following a period of poor glycemic control through a process termed "glycemic memory." In response to chronically elevated glucose levels, a number of studies have identified molecular targets of the glucose-mediated protein posttranslational modification by the addition of an O-linked N-acetylglucosamine to impair contractility, calcium sensitivity, and mitochondrial protein function. Additionally, elevated glucose contributes to dysfunction in coupling glycolysis to glucose oxidation, pentose phosphate pathway, and polyol pathway. Therefore, in the "sweetened" environment associated with hyperglycemia, there are a number of pathways contributing to increased susceptibly to "breaking" the heart of diabetics. In this review we will discuss the unique contribution of glucose to heart disease and recent advances in defining mechanisms of action.

A new study identifies sorbitol dehydrogenase (SORD) deficiency as a slowly progressive hereditary motor axonopathy caused by a genetic defect in the second step of the polyol pathway, thus leading to elevated tissue and blood sorbitol. SORD deficiency is the most common recessive cause of neuropathy, for which therapeutic intervention with aldose reductase inhibitors may have potential.

Background: Diabetes Mellitus (DM) is a metabolic disorder, caused by impaired carbohydrate metabolism makes many changes in the blood vessels affecting the response of endothelium and the smooth muscles. Polyol pathway activation, protein non-enzymatic glycosylation and increased ROSs(reactive oxidative species) play an important role in the complications of diabetes.Ozone activates glucose metabolism that results in increasing content of 2,3diphosphoglycerate in erythrocytes which provides better oxygen supply into the tissues. Patients with diabetes mellitus have the so called glycosylated hemoglobin forming very strong bonds with oxygen, thus, inducing hypoxia and determining the severity of the disease. That is why hypoxia control with the help of ozone therapy is of the key importance in the course of treatment. Conclusion: Ozone therapy appears to be an effective method for DM treatment. The reason is inozone mechanisms when it can perform a number of processes, which provide its positive effect.

Here we demonstrate biallelic mutations in sorbitol dehydrogenase (SORD) as the most frequent recessive form of hereditary neuropathies. We identified 45 cases from 38 families across multiple ethnicities, carrying a particular nonsense mutation in SORD, c.753delG; p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state with a second variant. With an allele frequency of 0.004 in healthy controls, the p.Ala253GlnfsTer27 variant represents one of the most common pathogenic alleles in humans. SORD is an enzyme that converts sorbitol into fructose, in the two-step polyol pathway that has been implicated in diabetic neuropathy. In patient-derived fibroblasts, we find a complete loss of SORD protein as well as increased intracellular sorbitol. Also, serum fasting sorbitol level was over 100 times higher in patients homozygous for the p.Ala253GlnfsTer27 mutation compared to healthy individuals. In Drosophila, we show that loss of SORD orthologues causes synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a potentially treatable cause in a significant fraction of patients with inherited neuropathies and may contribute to a better understanding of the pathophysiology of diabetic neuropathy.

Fructose is a ketohexose and sweetest among all the natural sugars. Like other reducing sugars, it reacts readily with the amino- and nucleophilic groups of proteins, nucleic acids and other biomolecules resulting in glycation reactions. The non-enzymatic glycation reactions comprise Schiff base formation, their Amadori rearrangement followed by complex and partly incompletely understood reactions culminating in the formation of Advance Glycation End products (AGEs). The AGEs are implicated in complications associated with diabetes, cardiovascular disorders, Parkinson’s disease, etc. Fructose is highly reactive and forms glycation products that differ both in structure and reactivity as compared to those formed from glucose. Nearly all tissues of higher organisms utilize fructose but only a few like the ocular lens, peripheral nerves erythrocytes and testis have polyol pathway active for the synthesis of fructose. Fructose levels rarely exceed those of glucose but, in tissues that operate the polyol pathway, its concentration may rise remarkably during diabetes and related disorders. Diet contributes significantly to the body fructose levels however, availability of technologies for the large scale and inexpensive production of fructose, popularity of high fructose syrups as well as the promotion of vegetarianism have resulted in a remarkable increase in the consumption of fructose. In vivo glycation reactions by fructose, therefore, assume remarkable significance. The review, therefore, aims to highlight the uniqueness of glycation reactions with fructose and its role in some pathophysiological situations.

International audience; Alterations of renal endothelial cells play a crucial role in the initiation and progression of diabetic kidney disease. High glucose per se, as well as glucose by-products, induce endothelial dysfunction in both large vessels and the microvasculature. Toxic glucose by-products include advanced glycation end products (AGEs), a group of modified proteins and/or lipids that become glycated after exposure to sugars, and glucose metabolites produced via the polyol pathway. These glucose-related endothelio-toxins notably induce an alteration of the glomerular filtration barrier by increasing the permeability of glomerular endothelial cells, altering endothelial glycocalyx, and finally, inducing endothelial cell apoptosis. The glomerular endothelial dysfunction results in albuminuria. In addition, high glucose and by-products impair the endothelial repair capacities by reducing the number and function of endothelial progenitor cells. In this review, we summarize the mechanisms of renal endothelial toxicity of high glucose/glucose by-products, which encompass changes in synthesis of growth factors like TGF-β and VEGF, induction of oxidative stress and inflammation, and reduction of NO bioavailability. We finally present potential therapies to reduce endothelial dysfunction in diabetic kidney disease.

Hyperglycemia is considered a key risk factor for development of diabetic complications including neuropathy. 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. Aldose reductase is thus considered a significant drug target. We investigated the effects of cemtirestat, a novel aldose reductase inhibitor, in the streptozotocin-induced rat model of uncontrolled type 1 diabetes in a 4-month experiment. Markedly increased sorbitol levels were recorded in the erythrocytes and the sciatic nerve of diabetic animals. Osmotic fragility of red blood cells was increased in diabetic animals. Indices of thermal hypoalgesia were significantly increased in diabetic rats. Tactile allodynia, recorded in diabetic animals in the early stages, turned to mechanical hypoalgesia by the end of the experiment. Treatment of diabetic animals with cemtirestat (i) reduced plasma triglycerides and TBAR levels; (ii) did not affect the values of HbA1c and body weights; (iii) reversed erythrocyte sorbitol accumulation to near control values, while sorbitol in the sciatic nerve was not affected; (iv) ameliorated indices of the erythrocyte osmotic fragility; and (v) attenuated the symptoms of peripheral neuropathy more significantly in the middle of the experiment than at the end of the treatment. Taking into account the lipid metabolism as an interesting molecular target for prevention or treatment of diabetic peripheral neuropathy, the triglyceride-lowering effect of cemtirestat should be considered in future studies. The most feasible mechanisms of triglyceride-lowering action of cemtirestat were suggested.

Dietary, fructose-containing sugars have been strongly associated with the development of nonalcoholic fatty liver disease (NAFLD). Recent studies suggest that fructose also can be produced via the polyol pathway in the liver, where it may induce hepatic fat accumulation. Moreover, fructose metabolism yields uric acid, which is highly associated with NAFLD. Here, using biochemical assays, reporter gene expression, and confocal fluorescence microscopy, we investigated whether uric acid regulates aldose reductase, a key enzyme in the polyol pathway. We evaluated whether soluble uric acid regulates aldose reductase expression both in cultured hepatocytes (HepG2 cells) and in the liver of hyperuricemic rats and whether this stimulation is associated with endogenous fructose production and fat accumulation. Uric acid dose-dependently stimulated aldose reductase expression in the HepG2 cells, and this stimulation was associated with endogenous fructose production and triglyceride accumulation. This stimulatory mechanism was mediated by uric acid-induced oxidative stress and stimulation of the transcription factor nuclear factor of activated T cells 5 (NFAT5). Uric acid also amplified the effects of elevated glucose levels to stimulate hepatocyte triglyceride accumulation. Hyperuricemic rats exhibited elevated hepatic aldose reductase expression, endogenous fructose accumulation, and fat buildup that was significantly reduced by co-administration of the xanthine oxidase inhibitor allopurinol. These results suggest that uric acid generated during fructose metabolism may act as a positive feedback mechanism that stimulates endogenous fructose production by stimulating aldose reductase in the polyol pathway. Our findings suggest an amplifying mechanism whereby soft drinks rich in glucose and fructose can induce NAFLD.

Aims Although there is evidence linking sugar-sweetened beverage (SSB) intake with the development of cardio-metabolic diseases, the underlying mechanisms remain unclear. The current study therefore evaluated the effects of SSB consumption by establishing a unique in-house in vivo experimental model. Main methods Male Wistar rats were divided into two groups: a) one consuming a popular local SSB (SSB- Jive), and b) a control group (Control-water) for a period of three and six months (n = 6 per group), respectively. Rats were gavaged on a daily basis with an experimental dosage amounting to half a glass per day (in human terms) (SSB vs. water). Cardiac function was assessed at baseline (echocardiography) and following ex vivo ischemia-reperfusion of the isolated perfused working rat heart. Oral glucose tolerance tests and mitochondrial respiratory analyses were also performed. In addition, the role of non-oxidative glucose pathways (NOGPs), i.e. the polyol pathway, hexosamine biosynthetic pathway (HBP) and PKC were assessed. Key findings These data show that SSB intake: a) resulted in increased weight gain, but did not elicit major effects in terms of insulin resistance and cardiac function after three and six months, respectively; b) triggered myocardial NOGP activation after three months with a reversion after six months; and c) resulted in some impairment in mitochondrial respiratory capacity in response to fatty acid substrate supply after six months. Significance SSB intake did not result in cardiac dysfunction or insulin resistance. However, early changes at the molecular level may increase risk in the longer term.

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.

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.

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.