Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a prospective cohort study, the authors examined risk factors for progression of distal symmetric polyneuropathy (DSP) in type 1 (insulin-dependent) diabetes mellitus. The study population consisted of participants in the Sorbinil Retinopathy Trial, a randomized trial of aldose reductase inhibition among patients aged 18-56 years with type 1 diabetes mellitus of 1-15 years' duration. Diagnosis of DSP was based on standardized clinical neurologic evaluation. A total of 407 participants who did not have definite DSP at randomization and had at least one follow-up visit were included in the analysis. Stepwise Cox proportional hazards models were used to examine the independent contribution of baseline variables to progression of DSP. During follow-up (median, 40 months), 68 participants (17%) showed progression to definite DSP. After adjustment for age and treatment assignment, independent predictors of progression to definite DSP were total glycosylated hemoglobin (relative risk (RR) for increase of one percentage point = 1.25; 95% confidence interval (CI) 1.12, 1.39), height (RR associated with being one inch (2.54 cm) taller = 1.15; 95% CI 1.05, 1.26), cigarette smoking (ever vs. never) (RR = 1.87; 95% CI 1.09, 3.21), and female gender (RR = 2.26; 95% CI 1.09, 4.67). These data indicate that, in addition to the previously established role for total glycosylated hemoglobin, other factors including height, cigarette smoking, and female gender may also be independent risk factors for progression of DSP in type 1 diabetes mellitus.
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PMID:Risk factors for progression of distal symmetric polyneuropathy in type 1 diabetes mellitus. Sorbinil Retinopathy Trial Research Group. 1058 75

The polyol pathway has been considered important in the development of diabetes long-term complications. Diabetic patients with microvascular disease have increased gene expression and enzyme activity, which may be due to variants in the aldose reductase gene. An association of an intragenic BamHI polymorphic site with diabetic retinopathy and nephropathy has been suggested, but the BamHI site has not been confirmed. In the current study, long template PCR-RFLP and DNA sequencing were used to ascertain its existence. A single substitution of A to C at 95th nucleotide of intron 8 was identified. This polymorphism was investigated in 164 adolescents with type 1 diabetes in whom diabetic retinopathy was assessed by stereoscopic retinal photography. Both the wild haplotype B and homozygote BB were significantly more common in the adolescents with retinopathy than in those without retinopathy (P = 0.018 and 0.002, respectively). We also confirmed an association between a previously described (CA)n repeat sequence and retinopathy in these adolescents (P < 0.0005). However, there was no association between the two polymorphisms.
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PMID:An aldose reductase intragenic polymorphism associated with diabetic retinopathy. 1072 95

The role of genetic investigations in diabetes one can describe in aspect of their role in the pathogenesis of type 1 and type 2 as well as in pathogenesis of chronic complications and gene therapy of diabetes. There is not only one gene responsible for type 1 diabetes. Similarly there are many gene-candidates in type 2 diabetes. Only in 6 types of MODY the genes responsible for beta-cell dysfunction were described. In diabetic complications some role e.g. in retinopathy may be played by genes of growth factors, heparan sulfate synthesis as well as genes of adrenergic receptor beta 3. In diabetic nephropathy the genes of renin synthesis, converting enzyme, aldose reductase or angiotensin receptor can be of importance. It should be emphasized that identification of human genome and genes responsible for diabetes can contribute to introduction of gene therapy in diabetes.
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PMID:[The role of genetic studies in finding the etiopathogenesis of diabetes mellitus]. 1129 31

Diabetic Nephropathy (DN) is the commonest cause of end-stage renal failure (ESRF) in the Western world. Diabetic nephropathy follows a well outline clinical course, starting with microalbuminuria through proteinuria, azotaemia and culminating in ESRF. Before the onset of overt proteinuria, there are various renal functional changes including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules. Basement-membrane thickening and mesangial expansion have long been recognized as pathological hallmark of diabetes. It has been postulated that DN occurs as a result of the interplay of metabolic and hemodynamic factors in the renal microcirculation. There is no doubt that there is a positive relationship between hyperglycaemia, which is necessary but not sufficient, and microvascular complications. The accumulation of advanced glycosylated end-products (AGEs), the activation of isoform(s) of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycemia damages tissue. PKC is one of the key signaling molecules in the induction of the vascular pathology of diabetes. The balance between extracellular matrix production and degradation is important in this context. Transforming growth factor-beta (TGF-beta) appears to play a pivotal role in accumulation in the diabetic kidney. Hemodynamic disturbances are believed to be directly responsible for the development of glomerulosclerosis and its attendant proteinuria. There is familial clustering of diabetic kidney disease. A number of gene loci have been investigated to try to explain the genetic susceptibility to diabetic nephropathy. The genes coding for components of renin-angiotensin system have drawn special attention, due to the central role that this system plays in the regulation of blood pressure, sodium metabolism, and renal hemodynamics. Endothelial dysfunction is closely associated with the development of diabetic retinopathy, nephropathy and atherosclerosis, both in IDDM and in NIDDM. The pathogenesis of diabetic nephropathy is not clarified completely yet.
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PMID:Pathogenesis of diabetic nephropathy. 1146 May 89

Diabetic nephropathy can develop in up to one-third of patients with type 1 diabetes and approximately 25% of patients with type 2 diabetes. This complication is important as it not only leads to renal failure but is associated with a high risk of coronary artery disease and other vascular complications. Although hyperglycaemia is necessary for the development of diabetic nephropathy, it is not sufficient, genetic factors also being important. This is evidenced by studies showing that only a subgroup of patients are at risk of nephropathy and that nephropathy clusters in families. The genes involved in susceptibility to diabetic nephropathy have yet to be identified. Most studies to date have been case-control in design, and there have been conflicting results. Genes suggested as having a role include those encoding angiotensin-1 converting enzyme, apolipoprotein E, heparan sulphate and aldose reductase. In order to clarify the role of these and other candidate genes in nephropathy, association studies in families are necessary. Because of the large number required, this will require international collaboration. A genetic marker for nephropathy would enable the earlier detection of this complication, thus facilitating screening and targeted intervention. An understanding of the role of susceptibility genes will ultimately allow the development of novel therapeutic strategies.
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PMID:Genetics of diabetic nephropathy. 1155 75

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

There is increasing evidence implicating genetic factors in the susceptibility to diabetic microvascular complications. Recent studies suggest that increased expression of the cytokine vascular endothelial growth factor (VEGF) may play a role in the pathogenesis of diabetic complications. A number of polymorphisms in the promoter region of the VEGF gene have been identified. The aim was to investigate whether an 18 base pair (bp) deletion (D)/insertion (I) polymorphism at position -2549 in the promoter region of the VEGF gene is associated with the susceptibility to diabetic microvascular complications. Two hundred and thirty-two patients with type 1 diabetes mellitus (T1DM) and 141 normal healthy controls were studied. The D/D genotype was significantly increased in those patients with nephropathy (n=102) compared to those with no complications after 20 years duration of diabetes (uncomplicated, n=66) (40.2% vs. 22.7%, respectively, chi(2)=5.5, P<.05). The combination of polymorphisms of VEGF together with the aldose reductase (ALR2) gene showed that in the nephropaths, 8 of the 83 subjects had the VEGF I allele together with the Z+2 5'ALR2 allele compared with 27 of the 62 uncomplicated patients (chi(2)=26.7, P<.00001). The functional role of the D/I polymorphism was examined by cloning the region into a luciferase reporter assay system and transient transfection into HepG2 cells. The construct containing the 18 bp deletion had a 1.95-fold increase in transcriptional activity compared with its counterpart that had the insert (P<.01). These results suggest that polymorphisms in the promoter region of the VEGF gene together with the ALR2 may be associated with the pathogenesis of diabetic nephropathy.
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PMID:Polymorphisms of the vascular endothelial growth factor and susceptibility to diabetic microvascular complications in patients with type 1 diabetes mellitus. 1250 48

Increased flux of glucose through the polyol pathway may cause generation of excess reactive oxygen species (ROS), leading to tissue damage. Abnormalities in expression of enzymes that protect against oxidant damage may accentuate the oxidative injury. The expression of catalase (CAT), CuZn superoxide-dismutase (CuZnSOD), glutathione peroxidase (GPX), and Mn superoxide-dismutase (MnSOD) mRNA was quantified in peripheral blood mononuclear cells-obtained from 26 patients with type 1 diabetes and nephropathy, 15 with no microvascular complications after 20 years' duration of diabetes, and 10 normal healthy control subjects-that were exposed in vitro to hyperglycemia (HG) (31 mmol/l D-glucose). Under HG, there was a twofold increase in the expression of CAT, CuZnSOD, and GPX mRNA in the patients without complications and the control subjects versus patients with nephropathy (P < 0.0001), and MnSOD did not change in any of the groups. The aldose reductase inhibitor zopolrestat partially restored the levels of CAT, CuZnSOD, and GPX mRNA in the patients with nephropathy (P < 0.05). There was a highly significant correlation between increased aldose reductase (ALR2) expression, CAT, CuZnSOD, and GPX mRNA levels under HG conditions and polymorphisms of ALR2 in the patients with nephropathy (P < 0.00001). In conclusion, these results suggest that high glucose flux through aldose reductase inhibits the expression of antioxidant enzymes.
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PMID:The response of antioxidant genes to hyperglycemia is abnormal in patients with type 1 diabetes and diabetic nephropathy. 1260 29

The determination of several of aldose reductase-inhibitor complexes at subatomic resolution has revealed new structural details, including the specific interatomic contacts involved in inhibitor binding. In this article, we review the structures of the complexes of ALR2 with IDD 594 (resolution: 0.66 angstrom, IC50 (concentration of the inhibitor that produced half-maximal effect): 30 nM, space group: P2(1)), IDD 393 (resolution: 0.90 angstrom, IC50: 6 nM, space group: P1), fidarestat (resolution: 0.92 angstrom, IC50: 9 nM, space group: P2(1)) and minalrestat (resolution: 1.10 angstrom, IC50: 73 nM, space group: P1). The structures are compared and found to be highly reproductible within the same space group (root mean square (RMS) deviations: 0.15 approximately 0.3 angstrom). The mode of binding of the carboxylate inhibitors IDD 594 and IDD 393 is analysed. The binding of the carboxylate head can be accurately determined by the subatomic resolution structures, since both the protonation states and the positions of the atoms are very precisely known. The differences appear in the binding in the specificity pocket. The high-resolution structures explain the differences in IC50, which are confirmed both experimentally by mass spectrometry measures of VC50 and theoretically by free energy perturbation calculations. The binding of the cyclic imide inhibitors fidarestat and minalrestat is also described, focusing on the observation of a Cl(-) ion which binds simultaneously with fidarestat. The presence of this anion, binding also to the active site residue His110, leads to a mechanism in which the inhibitor can bind in a neutral state and then become charged inside the active site pocket. This mechanism can explain the excellent in vivo properties of cyclic imide inhibitors. In summary, the complete and detailed information supplied by the subatomic resolution structures can explain the differences in binding energy of the different inhibitors.
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PMID:Subatomic and atomic crystallographic studies of aldose reductase: implications for inhibitor binding. 1509 1

The first subatomic resolution structure of a 36 kDa protein [aldose reductase (AR)] is presented. AR was cocrystallized at pH 5.0 with its cofactor NADP+ and inhibitor IDD 594, a therapeutic candidate for the treatment of diabetic complications. X-ray diffraction data were collected up to 0.62 A resolution and treated up to 0.66 A resolution. Anisotropic refinement followed by a blocked matrix inversion produced low standard deviations (<0.005 A). The model was very well ordered overall (CA atoms' mean B factor is 5.5 A2). The model and the electron-density maps revealed fine features, such as H-atoms, bond densities, and significant deviations from standard stereochemistry. Other features, such as networks of hydrogen bonds (H bonds), a large number of multiple conformations, and solvent structure were also better defined. Most of the atoms in the active site region were extremely well ordered (mean B approximately 3 A2), leading to the identification of the protonation states of the residues involved in catalysis. The electrostatic interactions of the inhibitor's charged carboxylate head with the catalytic residues and the charged coenzyme NADP+ explained the inhibitor's noncompetitive character. Furthermore, a short contact involving the IDD 594 bromine atom explained the selectivity profile of the inhibitor, important feature to avoid toxic effects. The presented structure and the details revealed are instrumental for better understanding of the inhibition mechanism of AR by IDD 594, and hence, for the rational drug design of future inhibitors. This work demonstrates the capabilities of subatomic resolution experiments and stimulates further developments of methods allowing the use of the full potential of these experiments.
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PMID:Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A. 1514 78


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