Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The reactive vascular-injuring amino acid homocysteine was previously shown to be increased in plasma in diabetic patients with clinical signs of nephropathy. In this study, plasma homocysteine was measured in type 1 diabetic patients with normoalbuminuria (n = 22), microalbuminuria (n = 40) and proteinuria (n = 14) in order to investigate whether plasma homocysteine levels are increased already at the stage of incipient nephropathy, i.e. microalbuminuria. Furthermore, patients were characterized according to the degree of retinopathy. Plasma homocysteine in the whole population (n = 76) was related to B-Folate (r = 0.38, p < 0.01), S-Creatinine (r = 0.55, p < 0.001), S-Urea (r = 0.37, p < 0.01), U-Albumin (r = 0.46, p < 0.001), urinary N-acetyl-beta- glucosaminidase (r = 0.40, p < 0.001), systolic blood pressure (r = 0.36, p < 0.01) and diabetes duration (r = 0.44, p < 0.001). There were no differences in plasma homocysteine levels between patients with normoalbuminuria (8.0 +/- 1.7 mumol l-1; mean +/- SD) and those with microalbuminuria (9.1 +/- 3.4 mumol l-1). However, patients with clinical signs of nephropathy had higher plasma homocysteine levels (12.9 +/- 5.7 mumol l-1, p < 0.01) compared to the other two groups. There was no association between plasma homocysteine levels and different degrees of retinopathy. Thus, the present study does not show any relation between plasma homocysteine levels and early stages of diabetic nephropathy or retinopathy indicating that elevated concentrations of plasma homocysteine does not explain the increased risk for atherosclerosis observed in patients with microalbuminuria.
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PMID:Lack of association between plasma homocysteine levels and microangiopathy in type 1 diabetes mellitus. 770 67

The high risk of cardiovascular disease in patients with diabetes mellitus, particularly in those with nephropathy, is not completely explained by classical risk factors. A high plasma homocysteine concentration is an independent risk factor for cardiovascular disease but information on its association with diabetes is limited. Fasting homocysteine concentrations were measured in the plasma of 165 diabetic patients (75 with insulin-dependent [IDDM]; 90 with non-insulin-dependent diabetes [NIDDM]) and 56 non-diabetic control subjects. Other measurements included the prevalence of diabetic complications, glycaemic control, lipid and lipoprotein levels, vitamin status and renal function tests. Patients with NIDDM had higher homocysteine levels than control subjects, whereas IDDM patients did not (9.2 +/- 4.5 vs 7.7 +/- 2 micromol/l, p < 0.01; and 7.0 +/- 3 vs 7.4 +/- 2 micromol/l, NS). Univariate correlations and multiple regression analysis showed albumin excretion rate to be the parameter with the strongest independent association with homocysteine. Patients with both types of diabetes and nephropathy had higher plasma homocysteine concentrations than those without nephropathy. Increases of homocysteine in plasma were related to increases in the severity of the nephropathy. Fasting hyperhomocysteinaemia was considered as the mean of the plasma homocysteine for all control subjects (7.5 +/- 2.1 micromol/l) + 2 SD (cut-off = 11.7 micromol/l). Nephropathy was present in 80 % of diabetic patients with fasting hyperhomocysteinaemia. In conclusion, increases in fasting homocysteine in diabetic patients are associated with increased albumin excretion rate, especially in those with NIDDM, thus providing a potential new link between microalbuminuria, diabetic nephropathy and cardiovascular disease.
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PMID:Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease? 1009 95

A missense mutation in the methylenetetrahydrofolate reductase gene (MTHFR), C677T, results in a thermolabile variant with reduced activity. Elevated levels of homocysteine have been recognized as a risk factor for vascular disease. Insulin-dependent diabetes mellitus (IDDM) is characterized by a higher prevalence of vascular complications. We analyzed the frequency of C677T MTHFR in IDDM and control groups. The genotype distribution did not differ between control subjects (n = 297) and IDDM patients (n = 392) (chi(2) = 5.413, df = 2, P > 0.05). The MTHFR T677T genotype was found significantly more frequently in IDDM patients with diabetic nephropathy (0.216) compared with the IDDM patients without nephropathy (0.056); the odds ratio was 2.635 (95% CI 1.768-3.927). Thus, we suggest that the T677T genotype of the MTHFR gene is an independent risk factor for diabetic nephropathy in IDDM.
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PMID:Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy in IDDM patients. 1056 65

The development of diabetic nephropathy shows marked variation among individuals. Not only hyperglycemia, but also genetic factors may contribute to the development of diabetic nephropathy. Methylenetetrahydrofolate reductase (MTHFR) is involved in remethylation of homocysteine to methionine. Decreased activity of MTHFR which can result in hyperhomocysteinemia may lead to cerebrovascular disease and coronary artery disease. Recently, a common C to T mutation at nucleotide position 677 of the MTHFR gene (MTHFR677CT) has been reported to be correlated with hyperhomocysteinemia and the severity of coronary artery disease as macroangiopathy. In the present study, we recruited 173 of Japanese type II diabetic patients with proliferative diabetic retinopathy who would be exposed to long-term hyperglycemia, and examined the contribution of the MTHFR gene polymorphism to the development of diabetic nephropathy as microangiopathy. The frequency of the mutated allele was 43.3% in patients with nephropathy (n = 105) versus 41.9% in those without nephropathy (n = 68). The genotype frequencies were +/+, 16.2%; +/-, 54.3%; -/-, 29.5% in patients with nephropathy versus +/+, 13.2%; +/-, 57.4%; -/-, 29.4% in those without nephropathy (+ indicates the presence of the mutation). The MTHFR genotype and allele frequencies were not significantly different between patients with and without nephropathy. Therefore, we conclude that the MTHFR gene polymorphism is not associated with the development of diabetic nephropathy in Japanese type II diabetic patients.
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PMID:No association between MTHFR gene polymorphism and diabetic nephropathy in Japanese type II diabetic patients with proliferative diabetic retinopathy. 1076 3

The vascular-injuring amino acid homocysteine was previously shown to be increased in plasma in type 1 diabetic patients with clinical signs of nephropathy. Previous studies have also shown an inconsistent relationship between the development of diabetic nephropathy and retinopathy, indicating different pathogenetic mechanisms. In this study, plasma homocysteine was measured in 25 type 1 diabetic patients with a well-characterized form of severe retinopathy. Furthermore, a group of 24 type 1 diabetic patients with similar age at onset of diabetes and diabetes duration with no or minimal background retinopathy were investigated, in order to determine whether plasma homocysteine levels are different from those in patients with severe retinopathy. Patients with severe retinopathy did not have higher plasma levels of homocysteine (13.9 micromol/L; 5.9-30.7, median and range) than those without retinopathy (10.4 micromol/L; 5.7-18.9). Within the group of patients with severe retinopathy, increased homocysteine levels were confined to the patients (19.9 micromol/L; 10.0-30.7, n=9) with serum creatinine levels > 100 micromol/L, compared to those patients (9.6; 5.9-14.3 micromol/L, n=15) with a serum creatinine below 100 micromol/L. None of the patients without or with minimal background retinopathy had serum creatinine levels > 100 micromol/L. We conclude that diabetic retinopathy is not associated with increased plasma homocysteine levels, but plasma homocysteine accumulates, probably owing to reduced glomerular filtration, in diabetic patients with signs of nephropathy. In these patients, the promoting effect of nephropathy on the development of retinopathy does not seem to be mediated through homocysteine.
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PMID:Severe retinopathy in type 1 diabetic patients is not related to the level of plasma homocysteine. 1088 88

The erythrocyte concentrations of the body's chief physiologic methyl donor S-adenosylmethionine (SAM) and of its metabolite and inhibitor S-adenosylhomocysteine (SAH), the plasma concentrations of total homocysteine (tHcy), and the activity of N(5,10) methylenetetrahydrofolate reductase (MTHFR) in lymphocytes were determined in healthy subjects and patients with diabetes mellitus without complications and at various stages of diabetic nephropathy, categorized according to the degree of progression of the disease. These groups were as follows: 1, control; 2, diabetics with no complications; 3, patients with albuminuria; 4, patients with an elevated plasma creatinine; and 5, patients on dialysis. No parameter studied exhibited significant differences between the type 1 and the type 2 diabetics. In control subjects, the blood concentrations of SAM were proportional to the activity of MTHFR; in diabetics, it was not. Consistent with previous observations, progression of nephropathy was accompanied by increased concentrations of tHcy. Increased erythrocyte concentrations of SAH, decreased erythrocyte concentrations of SAM, SAM/SAH ratios, and lymphocyte MTHFR activity also accompanied disease progression. The blood concentrations of SAH paralleled those of tHcy, while the concentrations of SAM showed a bimodal relationship with those of tHcy. These results provide further evidence that alterations in the blood concentrations of SAM and related compounds are abnormal in patients with diabetes, particularly in those with nephropathy. The deficiency of SAM may lead to methyl deficiencies, which may contribute to the high morbidity and mortality in patients with diabetic nephropathy. We have also demonstrated a decrease in lymphocyte MTHFR activity in patients with advanced nephropathy, suggesting that hyperhomocysteinemia in these patients may be due to a generalized metabolic abnormality. Further studies are needed to determine the pathogenesis of these abnormalities and whether they are present in renal failure due to causes other than diabetes or whether they are specific to diabetic nephropathy.
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PMID:Blood S-adenosylmethionine concentrations and lymphocyte methylenetetrahydrofolate reductase activity in diabetes mellitus and diabetic nephropathy. 1155 31

Among patients with diabetic nephropathy, the decline in glomerular filtration rate (GFR) varies substantially, ranging from 2 to 20 mL/min per year. Identification of predictors of progression in diabetic nephropathy is important. Plasma total homocysteine (tHcy) rises with urinary albumin excretion rate in diabetes, and plasminogen activator inhibitor-1 (PAI-1) has been correlated with increased matrix accumulation in various glomerulopathies. In this prospective observational cohort study, we evaluated the importance of baseline tHcy and PAI-1 as predictors of the rate of decline in GFR. Baseline tHcy and PAI-1 were measured in 157 type 1 diabetic patients with diabetic nephropathy (92 men; mean age, 41 +/- 10 years; mean diabetes duration, 27 +/- 8 years; median GFR, 80 mL/min/1.73 m(2) [range, 23 to 143 mL/min/1.73 m(2)]). Hereafter, GFR was measured yearly with a plasma clearance technique for at least 3 years (median, 7 years [range, 3.0 to 8.3 years]). The mean rate of decline in GFR was 3.7 +/- 0.3 mL/min per year. A linear regression analysis revealed a borderline significant relationship between rate of decline in GFR and tHcy (P = 0.069) and PAI-1 (P = 0.087). Analysis of the rate of decline in GFR and tertiles of tHcy and PAI-1 revealed that increasing levels of tHcy were correlated with a significantly faster decline in GFR (P = 0.025), whereas increasing levels of PAI-1 were not. After adjustment for other well-established risk factors for progression of nephropathy in a multiple linear regression analysis, however, neither tHcy levels nor PAI-1 levels were independent predictors of rate of decline in GFR.
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PMID:Progression of diabetic nephropathy: role of plasma homocysteine and plasminogen activator inhibitor-1. 1172 78

Hyperhomocysteinemia is known to be associated with many of the occlusive vascular diseases including ischemic heart disease. Elevated plasma total homocysteine (t-Hcy) is also remarkably common among patients with moderate to severe renal failure. The purpose of this study was to investigate the role of homocysteine (Hcy) in the pathogenesis of diabetic nephropathy in the rat. Additionally, any effect of aminoguanidine (AG), an inhibitor of advanced glycation end product (AGE) formation, on the onset of nephropathic symptoms and on the concentrations of Hcy was searched for. Diabetes was induced in male Wistar albino rats (6 months old) by a single injection of 50 mg x kg (-1)streptozotocin (STZ) into the penile vein. Animals with blood glucose levels higher than 350 mg x dl (-1)72 h after STZ injection were included in the study. Age-matched rats receiving a single dose of citrate buffer served as controls. One half of the control and diabetic groups received AG via drinking water (1 g l (-1)). The experimental period lasted for ten weeks. Animals were killed by cardiac venipuncture after 24 hour urine samples were collected. Serum t-Hcy was quantified using HPLC, and urinary GAGs using the spectrophotometric 1,9-dimethyl methylene blue dye method. Serum glucose, protein, creatinine and total sulfydryl (t-SH) measurements, and urinary protein determinations were carried out spectrophotometrically. In diabetic rats, serum t-Hcy levels were significantly decreased (P< 0.001), and were negatively correlated with the urinary protein concentration (r= -0.67, P< 0.05). Urinary GAG levels were also increased in diabetic rats (P< 0.001). AG neither affected the t-Hcy levels, nor ameliorated the nephropathic symptoms. These results indicate that diabetic nephropathy is not linked to homocysteinemia in the rat.
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PMID:A study on the relationship between homocysteine and diabetic nephropathy in rats. 1188 23

Homocysteinemia is an independent risk factor for cardiovascular disease, but information on its association with type 2 diabetes and mild renal dysfunction is limited. Plasma total homocysteine (tHcy) concentration is partly determined by renal plasma clearance. Serum cystatin C (Cys C) concentration has been introduced as a marker of renal function, specifically as an indicator of glomerular filtration rate (GFR). The aim of this study was to explore the relationships among tHcy, creatinine clearance (Ccr), serum Cys C, and microalbuminuria in a population with type 2 diabetes. Fasting plasma tHcy, serum homocysteine-related vitamins (folate and vitamin B12), serum Cys C, serum creatinine, urine microalbumin, and creatinine clearance were determined in 75 type 2 diabetic patients and 40 healthy control subjects. The patients were assigned to two groups based on urinary albumin excretion (UAE): normoalbuminuric (NAU, UAE < 30 mg/24 hr, n = 35) and microalbuminuric (MAU, UAE 30-300 mg/24 hr, n = 40). Ccr was calculated using the Cockroft-Gault formula. Plasma Hcy levels were determined by HPLC with fluorescence detection and serum Cys C by automated particle enhanced immunoturbidimetry. Plasma tHcy levels were significantly higher in normoalbuminuric and microalbuminuric patients than in controls (10.64 +/- 0.53, 13.29 +/- 0.78, 6.91 +/- 0.37 mmol/L, respectively). Serum Cys C levels in microalbuminuric diabetics were higher than in normoalbuminurics and controls (1.36 +/- 0.06, 1.12 +/- 0.04, 1.10 +/- 0.06 mg/ L, respectively). Positive correlations were noted between tHcy and Cys C levels in normoalbuminuric and microalbuminuric diabetics (r = 0.72, r = 0.64, respectively). Homocysteine and creatinine concentrations were correlated in both diabetic groups (r = 0.89, r = 0.93, NAU and MAU, respectively). Elevated plasma total homocysteine concentrations in type 2 diabetics suggest an association between homocysteinemia and deterioration of renal function, evidenced by increased serum creatinine and Cys C, Ccr, and microalbuminuria. These findings implicate homocysteinemia in the relationship between diabetic nephropathy and cardiovascular complications of diabetes.
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PMID:Association between homocysteinemia and renal function in patients with type 2 diabetes mellitus. 1217 91

The T/T genotype of the methylenetetrahydrofolate reductase C677 T gene polymorphism is associated with elevated homocysteine levels and presumably with increased atherosclerotic risk. We evaluated the interaction between this gene polymorphism and end-stage diabetic nephropathy on the observed prevalence of macroangiopathy in type 2 diabetes mellitus. The methylenetetrahydrofolate reductase 677 C/T genotypes were determined in 174 type 2 diabetic patients: 80 with and 94 without renal failure due to diabetic nephropathy. In the patients with renal failure, the T/T genotype and T allele were significantly associated with macroangiopathy (T/T; 31 % vs. 2 %, P = 0.0001 T allele; 59 % vs. 29 %, P = 0.00014), whereas the associations were not significant in the patients without renal failure. In the multiple logistic regression analysis, age (10 years OR 4.05 [1.79 - 9.31], P < 0.0005) and 677 T allele (6.84 [2.12 - 22.05], P = 0.0013) were significantly associated with macroangiopathy in the patients with renal failure. In conclusion, this study demonstrated that the 677 T/T genotype and T allele of MTHFR were significantly associated with macroangiopathy in type 2 diabetic patients with renal failure. The MTHFR 677 T allele, together with renal dysfunction due to diabetic nephropathy, could be a strong risk factor for atherosclerotic disease.
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PMID:The association between end-stage diabetic nephropathy and methylenetetrahydrofolate reductase genotype with macroangiopathy in type 2 diabetes mellitus. 1278 86


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