Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that the gene encoding aldose reductase, the enzyme that converts glucose to sorbitol, may confer susceptibility to microvascular disease. The aim of this study therefore, was to investigate the relationship between the aldose reductase gene and type 2 diabetic microvascular complications such as diabetic nephropathy and retinopathy. DNA from 127 Korean patients with type 2 diabetes was typed for an (AC)(n) dinucleotide repeat polymorphic marker at the 5'-end of the aldose reductase gene using polymerase chain reaction. No significant difference in the frequency of the putative risk allele Z-2 was found in patients of nephropathy and retinopathy groups compared with the uncomplicated group (32.2, 34.1 vs. 25.1%, respectively, P>0.05). Similarly, no difference was found in the frequency of the putative protective allele Z+2 among any of the study groups. In conclusion, the results of the study in Korean type 2 diabetic patients do not support the hypothesis that polymorphism at the 5' end of the aldose reductase gene contributes to the susceptibility to diabetic microvascular complications.
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PMID:(AC)(n) polymorphism of aldose reductase gene and diabetic microvascular complications in type 2 diabetes mellitus. 1179 81

Diabetic nephropathy is a major cause of end stage renal failure. Non-insulin dependent diabetes mellitus (NIDDM) is more prevalent in our country than insulin dependent diabetes mellitus (IDDM). Nephropathy can be classified in IDDM patients in 5 stages which have been elaborated here. The major intervention to prevent or reduce the rate of progress in diabetic nephropathy is control of blood sugar, control of blood pressure, use of angiotensin converting enzyme inhibitors, restricting dietary protein intake, treatment with inhibitors of the formation of advanced glycosylation end products, treatment with aldose reductase inhibitors and treatment of dyslipidaemia. Once the patient of diabetic nephropathy reaches the end stage renal disease, renal replacement therapy is needed. The different modalities of renal replacement therapy are: Haemodialysis, continuous ambulatory peritoneal dialysis, kidney transplantation and kidney and pancreas transplantation. Renal replacement therapy in diabetics has to be individualised from patient to patient. Kidney transplantation is at present the option of choice.
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PMID:Diabetic nephropathy--prevention and treatment. 1240 75

Diabetes is a major cause of mortality and morbidity due to the long term microvascular complications of this disease. There is now convincing evidence to show that genetic factors together with elevated blood glucose play an important role in the susceptibility to diabetic nephropathy as well as retinopathy. The polyol pathway is thought to play an important role in the pathogenesis of diabetic microvascular complications. Aldose reductase is the first and rate-limiting enzyme of the polyol pathway. Polymorphisms in the promoter region as well as elsewhere in the gene have been associated with susceptibility to nephropathy, retinopathy as well as diabetic neuropathy. These associations have been replicated in patients with either type 1 or type 2 diabetes mellitus as well as across ethnic groups. These polymorphisms in the promoter region are also associated with expression of the gene. Although clinical trials using inhibitors of aldose reductase to treat diabetic microvascular complications have largely been unsuccessful, the identification of the susceptibility genes may help in the design of future drug regimens.
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PMID:Polymorphisms of the aldose reductase gene and susceptibility to diabetic microvascular complications. 1287 Nov 36

To study the genetic variation in 5'-regulatory region of aldose reductase (AR) gene that might influence expression and the relationship between variations and diabetic complication (DC), PCR-single stranded conformational polymorphism (SSCP) was used to screen the 5'-regulatory region of AR gene in Chinese patients with type 2 diabetes mellitus. A novel mutation, C(-167) --> A substitution which created a new CCAAT box was found only in two diabetic patients. These two patients have no retinopathy, and the AR activity of their erythrocytes was within low range in patients without DC. The DNA segments of AR wild type and mutant were subcloned into pCAT reporter vector, and CAT assays were performed to assess promoter activity. The interaction between the DNA segments and nuclear proteins was determined by using competitive gel electrophoretic mobility shift assay (EMSA). The transcriptional activity of mutant (5.7% +/-2.9%) was lower than that of wild type (15.7% +/- 4.1%) (P<0.01), and the mobility shift of mutant was also slower than that of wild type. The results indicated the mutation C(-167) -->A in AR gene might prevent or delay the development of DC by repressing the expression of AR gene.
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PMID:Effect of a novel mutation in 5'-regulatory region of aldose reductase gene on its expression. 1451 7

The expression of nephropathy in type 2 diabetes has several levels of abnormalities. To define the primary abnormalities of diabetic nephropathy, we conducted an autopsy study of 186 consecutive patients with type 2 diabetes to determine correlations among the aldose reductase gene, renal histopathologies, extracellular matrix, glomerular function, and clinical characteristics. Compared with cases of near-normal renal structure (n = 51) and atypical diabetic glomerulopathy (n = 75), patients with classic diabetic glomerulopathy (n = 60) had advanced glomerular disease, as reflected by elevated plasma creatinine levels (133.2 +/- 59.8 vs. 166.0 +/- 65.7 vs. 243.8 +/- 82.6 micromol/l; P < 0.001), glomerular matrix fractions (20.8 +/- 6.7 vs. 33.5 +/- 16.8 vs. 39.2 +/- 14.3%; P < 0.001), and risk of renal failure (odds ratio [OR] 1 vs. 3.5 vs. 21.4; P < 0.001). Compared with noncarriers of the aldose reductase z-2 allele (n = 92) and z-2 heterozygotes (n = 77), z-2 homozygotes (n = 17) had elevated plasma creatinine (164.1 +/- 73.7 vs. 190.6 +/- 60.9 vs. 241.1 +/- 86.2 micromol/l; P < 0.001) and an increased risk of classic diabetic glomerulopathy (OR 1 vs. 0.9 vs. 3.3; P = 0.026). Overexpression of transforming growth factor-beta1, mesangial cell transdifferentiation by expression of alpha-smooth muscle actin, and aberrant deposition of collagen type IV, fibronectin, and laminin were found in classic diabetic glomerulopathy. These data suggest genetic, biochemical, pathophysiological, and clinical correlations among the aldose reductase gene, extracellular matrix, classic diabetic glomerulopathy, and renal insufficiency. Gene mutation, cellular transdifferentiation, growth factor upregulation, extracellular matrix expansion, and glomerular filtration impairment are the primary abnormalities in type 2 diabetic patients with nephropathy.
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PMID:Association of glomerulopathy with the 5'-end polymorphism of the aldose reductase gene and renal insufficiency in type 2 diabetic patients. 1550 80

We have developed an animal model of diabetic sympathetic autonomic neuropathy which is characterized by neuroaxonal dystrophy (NAD), an ultrastructurally distinctive axonopathy, in chronic streptozotocin (STZ)-diabetic rats. Diabetes-induced alterations in the sorbitol pathway occur in sympathetic ganglia and therapeutic agents which inhibit aldose reductase or sorbitol dehydrogenase improve or exacerbate, respectively, diabetes-induced NAD. The sorbitol dehydrogenase inhibitor SDI-711 (CP-470711, Pfizer) is approximately 50-fold more potent than the structurally related compound SDI-158 (CP 166,572) used in our earlier studies. Treatment with SDI-711 (5 mg/kg/day) for 3 months increased ganglionic sorbitol (26-40 fold) and decreased fructose content (20-75%) in control and diabetic rats compared to untreated animals. SDI-711 treatment of diabetic rats produced a 2.5- and 4-5-fold increase in NAD in the SMG and ileal mesenteric nerves, respectively, in comparison to untreated diabetics. Although SDI-711 treatment of non-diabetic control rat ganglia increased ganglionic sorbitol 40-fold (a value 8-fold higher than untreated diabetics), the frequency of NAD remained at control levels. Levels of ganglionic sorbitol pathway intermediates in STZ-treated rats (a model of type 1 diabetes) and Zucker Diabetic Fatty rats (ZDF, a genetic model of type 2 diabetes) were comparable, although STZ-diabetic rats develop NAD and ZDF-diabetic rats do not. SDI failed to increase diabetes-related ganglionic NGF above levels seen in untreated diabetics. Initiation of Sorbinil treatment for the last 4 months of a 9 month course of diabetes, substantially reversed the frequency of established NAD in the diabetic rat SMG without affecting the metabolic severity of diabetes. These findings indicate that sorbitol pathway-linked metabolic alterations play an important role in the development of NAD, but sorbitol pathway activity, not absolute levels of sorbitol or fructose per se, may be most critical to its pathogenesis.
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PMID:A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes. 1575 58

Biological properties of renal-specific oxidoreductase (RSOR), characteristics of its promoter, and underlying mechanisms regulating its expression in diabetes were analyzed. RSOR expression, normally confined to the renal cortex, was markedly increased and extended into the outer medullary tubules in db/db mice, a model of type 2 diabetes. Exposure of LLCPK cells to d-glucose resulted in a dose-dependent increase in RSOR expression and its enzymatic activity. The latter was related to one of the glycolytic enzymes, myo-inositol oxygenase. The increase in activity was in proportion to serum glucose concentration. The RSOR expression also increased in cells treated with various organic osmolytes, e.g., sorbitol, myoinositol, and glycerolphosphoryl-choline and H(2)O(2). Basal promoter activity was confined to -1,252 bp upstream of ATG, and it increased with the treatment of high glucose and osmolytes. EMSAs indicated an increased binding activity with osmotic-, carbohydrate-, and oxidant-response elements in cells treated with high glucose and was abolished by competitors. Supershifts, detected by anti-nuclear factor of activated T cells, and carbohydrate-response-element-binding protein established the binding specificity. Nuclear factor of activated T cells tonicity-enhancer-binding protein and carbohydrate-response-element-binding protein had increased nuclear expression in cells treated with high glucose. The activity of osmotic-response element exhibited a unique alternate binding pattern, as yet unreported in osmoregulatory genes. Data indicate that RSOR activity is modulated by diverse mechanisms, and it is endowed with dual properties to channel glucose intermediaries, characteristic of hepatic aldehyde reductases, and to maintain osmoregulation, a function of renal medullary genes, e.g., aldose reductase, in diabetes.
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PMID:Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience. 1633 Jul 53

Diabetic retinopathy is a sight-threatening chronic complication of diabetes mellitus and is the leading cause of acquired blindness in adults. The -106C>T polymorphism in the promoter region of the aldose reductase (AR) gene has been shown to be associated with the susceptibility to diabetic nephropathy in type 2 diabetes, but the findings regarding the occurrence of diabetic retinopathy are conflicting. In this case-control study, we investigated whether the -106C>T polymorphism in the AR gene is involved in the development and progression of diabetic retinopathy in 579 Brazilians with type 2 diabetes (424 Caucasian- and 155 African-Brazilians). Patients underwent a clinical and laboratory evaluation consisting of a questionnaire, physical examination, assessment of diabetic complications and laboratory tests. Genotype analysis was performed using the polymerase chain reaction followed by digestion with restriction enzyme. Logistic regression analysis was used to control for independent risk factors associated with diabetic retinopathy. There were no differences in either genotype or allele frequencies for the -106C>T polymorphism between type 2 diabetic patients with or without diabetic retinopathy, in both ethnic groups. However, the CC genotype was associated with an increased risk of having proliferative diabetic retinopathy in Caucasian-Brazilians with type 2 diabetes (odds ratio (OR)=2.04; 95% confidence interval (CI)=1.21-3.45; P=0.007), independently of other risk factors associated with this complication. Thus, our results show that the -106CC genotype (-106C>T polymorphism) in the AR gene is related to the progression of diabetic retinopathy in Caucasian-Brazilians with type 2 diabetes.
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PMID:The -106CC genotype of the aldose reductase gene is associated with an increased risk of proliferative diabetic retinopathy in Caucasian-Brazilians with type 2 diabetes. 1654 77

Diabetic polyneuropathy (DPN) is the most common late diabetic complication, and is more frequent and severe in the type 1 diabetic population. Currently, no effective therapy exists to prevent or treat this complication. Hyperglycemia remains a major therapeutic target when dealing with DPN in both type 1 and type 2 diabetes, and should be supplemented by aldose reductase inhibition and antioxidant treatment. However, in the past few years, preclinical and clinical data have indicated that factors other than hyperglycemia contribute to DPN, and these factors account for the disproportionality of prevalence of DPN between the two types of diabetes. Insulin and C-peptide deficiencies have emerged as important pathogenetic factors and underlie the acute metabolic abnormalities, as well as serious chronic perturbations of gene regulatory mechanisms, impaired neurotrophism, protein-protein interactions and specific degenerative disorders that characterize type 1 DPN. It has become apparent that in insulin-deficient conditions, such as type 1 diabetes and advanced type 2 diabetes, both insulin and C-peptide must be replaced in order to gain hyperglycemic control and to combat complications. As with any chronic ailment, emphasis should be on the prevention of DPN; as the disease progresses, metabolic interventions, be they directed against hyperglycemia and its consequences or against insulin/ C-peptide deficiencies, are likely to be increasingly ineffective.
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PMID:Pathological mechanisms involved in diabetic neuropathy: can we slow the process? 1662 19

Bone disease in patients with type 2 diabetes mellitus (DM) is characterized by low bone turnover, resulting from either impaired secretion of parathyroid hormone or osteoblasts dysfunction. We have reported that intracellular sorbitol accumulation via. sorbitol pathway might be involved in the development of osteoblast dysfunction and osteoclast formation, as evidenced by either in vitro or in vivo study. The importance of metabolic pathway is further supported by the protective effect of aldose reductase inhibitor against the development of galactose-induced bone diseases in vivo and of functional impairments of human osteoblasts-like MG-63 cells. In conclusion, sorbotol pathway might be important in the development of low bone turnover disease in DM patients, and thus aldose reductase inhibitor might be clinically useful in the protection against the development of bone diseases in DM patients.
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PMID:[Effect of aldose reductase on the abnormality of calcium metabolism in diabetic patients]. 1688 45


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