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Polyol Pathway (polyol + pathway)
Selected AbstractsFructose-mediated non-enzymatic glycation: sweet coupling or bad modificationDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2004Casper G. Schalkwijk Abstract The Maillard reaction is a process in which reducing sugars react spontaneously with amino groups in proteins to advanced glycation endproducts (AGEs). Although an elevated level of glucose had been thought to play a primary role in the Maillard reaction, on a molecular basis, glucose is among the least reactive sugars within biological systems. The formation of AGEs is now also known to result from the action of various metabolites other than glucose, which are primarily located intracellularly and participate in the non-enzymatic glycation reaction at a much faster rate, such as fructose, trioses and dicarbonyl compounds. In this review, we considered the glycation reaction with particular attention to the potential role of fructose and fructose metabolites. The two sources for fructose are an exogenous supply from the diet and the endogenous formation from glucose through the aldose reductase pathway. Despite its ,eightfold higher reactivity, the contribution of extracellular glycation by fructose is considerably less than that by glucose, because of the low plasma concentration of fructose (5 mmol/L glucose vs 35 µmol/L fructose). Intracellularly, fructose is elevated in a number of tissues of diabetic patients in which the polyol pathway is active. In the cells of these tissues, the concentrations of fructose and glucose are of the same magnitude. Although direct evidence is not yet available, it is likely that the high reactivity of fructose and its metabolites may substantially contribute to the formation of intracellular AGEs and may contribute to alterations of cellular proteins, dysfunction of cells and, subsequently, to vascular complications. Copyright © 2004 John Wiley & Sons, Ltd. [source] The role of taurine in diabetes and the development of diabetic complicationsDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2001Svend Høime Hansen Abstract The ubiquitously found ,-amino acid taurine has several physiological functions, e.g. in bile acid formation, as an osmolyte by cell volume regulation, in the heart, in the retina, in the formation of N -chlorotaurine by reaction with hypochlorous acid in leucocytes, and possibly for intracellular scavenging of carbonyl groups. Some animals, such as the cat and the C57BL/6 mouse, have disturbances in taurine homeostasis. The C57BL/6 mouse strain is widely used in diabetic and atherosclerotic animal models. In diabetes, the high extracellular levels of glucose disturb the cellular osmoregulation and sorbitol is formed intracellularly due to the intracellular polyol pathway, which is suspected to be one of the key processes in the development of diabetic late complications and associated cellular dysfunctions. Intracellular accumulation of sorbitol is most likely to cause depletion of other intracellular compounds including osmolytes such as myo -inositol and taurine. When considering the clinical complications in diabetes, several links can be established between altered taurine metabolism and the development of cellular dysfunctions in diabetes which cause the clinical complications observed in diabetes, e.g. retinopathy, neuropathy, nephropathy, cardiomyopathy, platelet aggregation, endothelial dysfunction and atherosclerosis. Possible therapeutic perspectives could be a supplementation with taurine and other osmolytes and low-molecular compounds, perhaps in a combinational therapy with aldose reductase inhibitors. Copyright © 2001 John Wiley & Sons, Ltd. [source] Aldose reductase gene is associated with diabetic macroangiopathy in Japanese Type 2 diabetic patientsDIABETIC MEDICINE, Issue 8 2006A. Watarai Abstract Aims The aldose reductase (AR) gene, a rate-limiting enzyme of the polyol pathway, has been investigated as a candidate gene in determining susceptibility to diabetic microangiopathy. However, the association of the AR gene with diabetic macroangiopathy has not been investigated. Therefore, the present study was conducted to determine whether genetic variations of AR may determine susceptibility to diabetic macroangiopathy. Methods There were 378 Type 2 diabetic patients enrolled in this study. A single nucleotide polymorphism in the promoter region (C-106T) was genotyped and the AR protein content of erythrocytes measured by ELISA. Results There were no significant differences in genotypic or allelic distribution in patients with or without ischaemic heart diseases, but there was a significant increase in the frequency of the CT + TT genotype and T allele in patients with stroke (P = 0.019 and P = 0.012). The erythrocyte AR protein content was increased in patients with the CT and TT genotype compared with those with the CC genotype. After adjustment for age, duration of diabetes, body mass index, systolic blood pressure, HbA1c, and serum creatinine, triglycerides, and total cholesterol in multivariate logistic-regression models, the association between this AR genotype and stroke remained significant. Conclusions Our results suggest that the CT or TT genotype of the AR gene might be a genetic marker of susceptibility to stroke in Type 2 diabetic patients. This observation might contribute to the development of strategies for the prevention of stroke in Type 2 diabetic patients. [source] Association of aldose reductase gene Z+2 polymorphism with reduced susceptibility to diabetic nephropathy in Caucasian Type 1 diabetic patientsDIABETIC MEDICINE, Issue 8 2004M. Lajer Abstract Aims The Z,2 allele of the (AC)n polymorphism in the aldose reductase gene (ALR2) confers increased risk of microvascular diabetic complications, whereas the Z+2 allele has been proposed to be a marker of protection. However data are conflicting. Therefore, we investigated whether this polymorphism is associated with diabetic nephropathy and retinopathy in Type 1 diabetes mellitus in a large case,control study and a family-based analysis. Methods A total of 431 Type 1 diabetic patients with diabetic nephropathy and 468 patients with longstanding Type 1 diabetes and persistent normoalbuminuria were genotyped for the case,control study. In addition, 102 case trios and 98 control trios were genotyped for a family-based study. Results Thirteen different alleles were identified. In the case,control study, the Z+2 allele frequency was significantly higher in the normoalbuminuric diabetic than in patients with diabetic nephropathy (0.17 vs. 0.11, P = 0.008), suggesting a protective function of the Z+2 allele. No significant increase in the frequency of the putative risk allele Z,2 was found in patients with diabetic nephropathy vs. controls (0.39 vs. 0.36). No association with diabetic retinopathy was found. Although the results of the transmission of the Z,2 and Z+2 alleles in the independent family-based study were consistent with the association study, the number of informative families was limited and thus differences were not statistically significant. Conclusions The Z+2 allele of the ALR2 promoter polymorphism is associated with a reduced susceptibility to diabetic nephropathy in Danish Type 1 diabetic patients, suggesting a minor role for the polyol pathway in the pathogenesis of diabetic kidney disease. No association of the ALR2 polymorphism with diabetic retinopathy was found. [source] Oxidative stress: A cause and therapeutic target of diabetic complicationsJOURNAL OF DIABETES INVESTIGATION, Issue 3 2010Eiichi Araki Abstract Oxidative stress is defined as excessive production of reactive oxygen species (ROS) in the presence of diminished anti-oxidant substances. Increased oxidative stress could be one of the common pathogenic factors of diabetic complications. However, the mechanisms by which hyperglycemia increases oxidative stress are not fully understood. In this review, we focus on the impact of mitochondrial derived ROS (mtROS) on diabetic complications and suggest potential therapeutic approaches to suppress mtROS. It has been shown that hyperglycemia increases ROS production from mitochondrial electron transport chain and normalizing mitochondrial ROS ameliorates major pathways of hyperglycemic damage, such as activation of polyol pathway, activation of PKC and accumulation of advanced glycation end-products (AGE). Additionally, in subjects with type 2 diabetes, we found a positive correlation between HbA1c and urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), which reflects mitochondrial oxidative damage, and further reported that 8-OHdG was elevated in subjects with diabetic micro- and macro- vascular complications. We recently created vascular endothelial cell-specific manganese superoxide dismutase (MnSOD) transgenic mice, and clarified that overexpression of MnSOD in endothelium could prevent diabetic retinopathy in vivo. Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia-induced mtROS production by the induction of PPAR, coactivator-1, (PGC-1,) and MnSOD and/or activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK,PGC-1, pathway. Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00013.x, 2010) [source] Correction of protein kinase C activity and macrophage migration in peripheral nerve by pioglitazone, peroxisome proliferator activated-,-ligand, in insulin-deficient diabetic ratsJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Shin-Ichiro Yamagishi Abstract Pioglitazone, one of thiazolidinediones, a peroxisome proliferator-activated receptor (PPAR)-, ligand, is known to have beneficial effects on macrovascular complications in diabetes, but the effect on diabetic neuropathy is not well addressed. We demonstrated the expression of PPAR-, in Schwann cells and vascular walls in peripheral nerve and then evaluated the effect of pioglitazone treatment for 12 weeks (10 mg/kg/day, orally) on neuropathy in streptozotocin-diabetic rats. At end, pioglitazone treatment improved nerve conduction delay in diabetic rats without affecting the expression of PPAR-,. Diabetic rats showed suppressed protein kinase C (PKC) activity of endoneurial membrane fraction with decreased expression of PKC-,. These alterations were normalized in the treated group. Enhanced expression of phosphorylated extracellular signal-regulated kinase detected in diabetic rats was inhibited by the treatment. Increased numbers of macrophages positive for ED-1 and 8-hydroxydeoxyguanosine-positive Schwann cells in diabetic rats were also corrected by the treatment. Pioglitazone lowered blood lipid levels of diabetic rats, but blood glucose and nerve sorbitol levels were not affected by the treatment. In conclusion, our study showed that pioglitazone was beneficial for experimental diabetic neuropathy via correction of impaired PKC pathway and proinflammatory process, independent of polyol pathway. [source] Diabetic neuropathies: components of etiologyJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2008David R. Tomlinson Abstract This review examines the putative role of glucose in the etiology of diabetic neuropathies. Excessive glucose generates several secondary metabolic anomalies , principally oxidative stress (via both the polyol pathway and glucoxidation) and non-enzymic glycation of macromolecules. The latter is also facilitated by glucoxidation. These metabolic deviations trigger cellular responses that are inappropriate to normal function. Principal among these are neurotrophic deficits and phosphorylation of mitogen-activated protein kinases (MAPK). Downstream of these events are aberrant ion channel function and disordered gene expression, leading to changes in cellular phenotype. This leads directly to disordered nerve conduction, a recognised early clinical sign, and indirectly, via as yet undisclosed links, to sensory loss and axonopathy. Recent work also links MAPK activation to the development of neuropathic pain. [source] Rat lens aldose reductase inhibitory constituents of Nelumbo nucifera stamensPHYTOTHERAPY RESEARCH, Issue 10 2006Soon Sung Lim Abstract Aldose reductase, the principal enzyme of the polyol pathway, has been shown to play an important role in the complications associated with diabetes. A methanol extract of the stamens of Nelumbo nucifera Gaertn. was shown to exert an inhibitory effect on rat lens aldose reductase (RLAR), and thus was fractionated using several organic solvents, including dichloromethane, ethyl acetate and n -butanol. The ethyl acetate-soluble fraction, which manifested potent RLAR-inhibitory properties, was then purified further via repeated measures of silica gel and Sephadex LH-20 column chromatography. Thirteen flavonoids: kaempferol (1) and seven of its glycosides (2,9), myricetin 3,,5,-dimethylether 3- O - , - d -glucopyranoside (10), quercetin 3- O - , - d -glucopyranoside (11) and two isorhamnetin glycosides (12, 13) were isolated from N. nucifera, as well as four non-flavonoid compounds: adenine (14), myo -inositol (15), arbutin (16) and , -sitosterol glucopyranoside (17). These compounds were all assessed with regard to their RLAR-inhibitory properties. Among the isolated flavonoids, those harboring 3- O - , - l -rhamnopyranosyl-(1,6)- , - d -glucopyranoside groups in their C rings, including kaempferol 3- O - , - l -rhamnopyranosyl-(1,6)- , - d -glucopyranoside (5) and isorhamnetin 3- O - , - l -rhamnopyranosyl-(1,6)- , - d -glucopyranoside (13), were determined to exhibit the highest degree of rat lens aldose reductase inhibitory activity in vitro, evidencing IC50 values (concentration required for a 50% inhibition of enzyme activity) of 5.6 and 9.0 µm, respectively. Copyright © 2006 John Wiley & Sons, Ltd. [source] | ||||||||||