Plasma N-terminal pro-B-type natriuretic peptide and mortality in type 2 diabetes.

AIMS/HYPOTHESIS: Raised N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with a poor cardiac outcome in non-diabetic populations. Elevated NT-proBNP predicts excess morbidity and mortality in diabetic patients with an elevated urinary albumin excretion rate. This study investigated the prognostic value of NT-proBNP in a cohort of type 2 diabetic patients. SUBJECTS, MATERIALS AND METHODS: In a prospective observational follow-up study, 315 type 2 diabetic patients with normoalbuminuria (n=188), microalbuminuria (n=80) and macroalbuminuria (n=47) at baseline were followed for a median (range) of 15.5 (0.2-17.0) years. Plasma NT-proBNP concentrations were determined by immunoassay at baseline. Endpoints were overall and cardiovascular mortality. RESULTS: Of the patients, 162 died (51%), 119 of them (74%) due to cardiovascular causes. All-cause mortality was increased in patients with NT-proBNP in the second and third tertiles (hazard ratios [95% CI] compared with the first tertile, 1.70 [1.08-2.67] and 5.19 [3.43-7.88], p<0.001). These associations persisted after adjustment for urinary albumin excretion rate, glomerular filtration rate and conventional cardiovascular risk factors (covariate adjusted hazard ratios 1.46 [0.91-2.33] and 2.54 [1.56-4.14], p<0.001). This increased mortality was attributable to more cardiovascular deaths in the second and third NT-proBNP tertile (unadjusted hazard ratios 1.63 [0.96-2.77] and 4.88 [3.01-7.91], p<0.001; covariate adjusted 1.37 [0.79-2.37] and 2.26 [1.27-4.02], p=0.01). When patients with normo-, micro- and macroalbuminuria were analysed separately, NT-proBNP levels above the median (62 ng/l) were consistently associated with increased overall and cardiovascular mortality in all three groups (p<0.001). CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes, elevated circulating NT-proBNP is a strong predictor of the excess overall and cardiovascular mortality, this predictor status being independent of urinary albumin excretion rate and conventional cardiovascular risk factors.

Plasma N-terminal pro-brain natriuretic peptide as an independent predictor of mortality in diabetic nephropathy.

AIMS/HYPOTHESIS: Raised N-terminal pro-brain natriuretic peptide (NT-proBNP) is independently associated with an increased risk of death in chronic heart failure and acute coronary syndromes in nondiabetic populations. Diabetic nephropathy is characterised by an increased risk of cardiovascular morbidity and mortality. This study investigated the prognostic value of NT-proBNP in a large cohort of type 1 diabetic patients with and without diabetic nephropathy. METHODS: In a prospective observational follow-up study, 198 type 1 diabetic patients with overt diabetic nephropathy (122 men, age [mean+/-SD] 41+/-10 years, duration of diabetes 28+/-8 years, GFR 74+/-33 ml min(-1)) and a matched control group of 188 patients with longstanding type 1 diabetes and persistent normoalbuminuria (114 men, age 43+/-10 years, duration of diabetes 27+/-9 years) were followed for 9.3 (0.0-9.5) years. Plasma NT-proBNP concentration was determined by immunoassay at baseline. RESULTS: In patients with diabetic nephropathy, plasma NT-proBNP concentration was elevated to (median [range]) 110 (5-79640) ng l(-1) vs. 27 (5-455) ng l(-1) in normoalbuminuric patients (p<0.0001). Among patients with nephropathy, 39 (39%) patients with plasma NT-proBNP concentrations above the median and 12 (12%) with values below the median died from any cause (unadjusted hazard ratio 3.86 [95% CI 2.02-7.37], p<0.0001; covariate-adjusted hazard ratio 2.28 [1.04-4.99], p=0.04). This lower mortality rate was attributable to fewer cardiovascular deaths: 31 (31%) and 7 (7%) above and below the median NT-proBNP level respectively (unadjusted hazard ratio 5.25 [2.31-11.92], p<0.0001; covariate-adjusted hazard ratio 3.81 [1.46-9.94], p=0.006). CONCLUSIONS/INTERPRETATION: Elevated circulating NT-proBNP is a new independent predictor of the excess overall and cardiovascular mortality in diabetic nephropathy patients without symptoms of heart failure.

Association of aldose reductase gene Z+2 polymorphism with reduced susceptibility to diabetic nephropathy in Caucasian Type 1 diabetic patients.

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.

Effect of short-term hyperglycaemia on haemodynamics in type 1 diabetic patients.

OBJECTIVES: Mechanisms underlying glucose-mediated development and progression of diabetic complications are incompletely understood. We tested the impact of short-term hyperglycaemia on systemic blood pressure and regulatory hormones in type 1 diabetic patients. DESIGN AND METHODS: We included 18 patients [13 men, mean (SEM) diabetes duration 10 (1) years] without signs of autonomic neuropathy or renal complications in a randomized single-blinded cross-over trial using insulin-glucose clamp technique. Patients were clamped for 90 min to blood glucose of 5 mmol L(-1) (euglycaemia) and 15 mmol L(-1) (hyperglycaemia) in random order. Blood pressure was measured noninvasively every 5 min (Takeda TM2421 device). Regulatory hormones were determined at the end of each clamp period. RESULTS: Systolic blood pressure increased [mean (95% CI)] 3 (1, 5) mmHg during hyperglycaemia from 123 (SEM 2) during euglycaemia, P=0.01. Diastolic blood pressure remained unchanged at 78 (2) mmHg. Hyperglycaemia reduced plasma concentrations of: renin [14 (4, 23)%, P=0.02], angiotensin II [17 (8, 25)%, P<0.01] and adrenaline [20 (10, 29)%, P<0.01]. Plasma concentration of atrial natriuretic peptide increased by 11 (6, 17) pg mL(-1) (P<0.01) from 43 (2) pg mL(-1). We calculated a median (range) increase in extracellular volume and plasma volume (PV) of 2.6 (0.7-5.3)% and 5.0 (-4.7 to 8.6)%, respectively. CONCLUSIONS: In type 1 diabetic patients without signs of autonomic neuropathy short-term hyperglycaemia induced a modest increase in systolic blood pressure and suppression of the renin-angiotensin system, possibly caused by PV expansion because of fluid shift from intra- to extracellular compartment.

Long-term renoprotective effect of nisoldipine and lisinopril in type 1 diabetic patients with diabetic nephropathy.

OBJECTIVE: To compare the long-term effect on kidney function of a long-acting calcium antagonist (nisoldipine) versus a long-acting ACE inhibitor (lisinopril) in hypertensive type 1 diabetic patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: We performed a 4-year prospective, randomized, double-dummy controlled study comparing nisoldipine (20-40 mg once a day) with lisinopril (10-20 mg once a day). The study was double-blinded for the first year and single-blinded thereafter. The study included 51 hypertensive type 1 diabetic patients with diabetic nephropathy. Three patients dropped out during the first month; results for the remaining 48 patients are presented. RESULTS: At baseline, the two groups were comparable: glomerular filtration rate (GFR) was 85 +/- 5 and 85 +/- 6 ml x min(-1) x [1.73 m](-2); mean 24-h ambulatory blood pressure was 108 +/- 3 and 105 +/- 2 mmHg, and albuminuria was 1,554 mg/24 h (95% CI 980-2,465) and 1,033 mg/24 h (760-1,406) in the lisinopril and nisoldipine groups, respectively. Mean 24-h arterial blood pressure during the study did not differ between the lisinopril and nisoldipine groups (100 +/- 2 and 103 +/- 1 mmHg, respectively). The time-course of albuminuria differed between groups (P < 0.001). Whereas initiation of treatment with lisinopril resulted in a reduction from baseline albuminuria by 52% (95% CI 14-73), albuminuria in the nisoldipine group did not change throughout the study GFR declined in a biphasic manner with an initial (0-6 months) reduction of 1.3 +/- 0.3 ml x min(-1) x month(-1) in the lisinopril group compared with 0.2 +/- 0.4 ml x min(-1) x month(-1) in the nisoldipine group (P < 0.01). The subsequent sustained decline (6 to 48 months or the end of treatment) was identical in the two groups: 0.5 +/- 0.1 ml min(-1) x month(-1) (NS). Two patients in the lisinopril group and three patients in the nisoldipine group entered therapy for end-stage renal failure. CONCLUSIONS: Long-term treatment with lisinopril or nisoldipine has similar beneficial effects on progression of diabetic nephropathy in hypertensive type 1 diabetic patients.

Plasminogen activator inhibitor-1 and apolipoprotein E gene polymorphisms and diabetic angiopathy.

BACKGROUND: A point mutation in the plasminogen activator inhibitor-1 (PAI-1) gene and a three-allelic variation in the apolipoprotein-E (ApoE) gene have been suggested as risk factors for the development of diabetic micro- and macrovascular complications. METHODS: We studied 198 type 1 diabetic patients with diabetic nephropathy [121 men, age (mean+/-SD) 41+/-10 years, diabetes duration 28+/-8 years] and 192 patients with persistent normoalbuminuria (118 men, age 43+/-10 years, diabetes duration 27+/-9 years). RESULTS: Male patients with nephropathy had elevated plasma PAI-1 levels [geometric mean (95% CI)], 70 (62-79) ng/ml, compared with normoalbuminuric men, 43 (38-47) ng/ml, P<0.001. Even though nephropathic patients with the 4G4G genotype tended to have higher plasma PAI-1 levels, P=0.06, no difference in allele frequency (4G/5G) was seen between patients with and without nephropathy: 0.538/0.462 vs 0.539/0.461, respectively. Nor did ApoE allele frequencies (epsilon2/epsilon3/epsilon4) differ between nephropathic and normoalbuminuric patients: 0.099/0.749/0. 152 vs 0.081/0.745/0.174, respectively. Genotype distributions were also similar, n.s. Coronary heart disease was more prevalent (36%) among nephropathic patients carrying the atherogenic epsilon4-allele compared with 12% in patients with the epsilon3,epsilon3 genotype, P<0.001. No associations between diabetic retinopathy and PAI-1 or ApoE polymorphisms were observed, n.s. CONCLUSIONS: The ApoE polymorphism may accelerate the development of coronary heart disease often seen in Caucasian patients with type 1 diabetes and diabetic nephropathy, a condition characterized by elevated plasma PAI-1 in men. Neither the PAI-1 nor the ApoE gene polymorphism contributes to the genetic susceptibility to diabetic nephropathy or retinopathy.

Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy.

BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM). The study consisted of five periods, each lasting two months. The patients received losartan 50 mg, losartan 100 mg, enalapril 10 mg, enalapril 20 mg, and placebo in random order. At the end of each period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. RESULTS: Both doses of losartan and enalapril reduced albuminuria (P < 0.05) and mean arterial blood pressure (MABP; P < 0.05), whereas GFR remained stable. Albuminuria was reduced by 33% (95% CI, 12 to 51) on losartan 50 mg, 44% (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61) on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril 20 mg, and MABP fell by 9 +/- 2, 8 +/- 2, 6 +/- 3, and 11 +/- 3 mm Hg (mean +/- SEM), respectively. No significant differences were found between the effects of losartan 100 mg and enalapril 20 mg. HbA1C and sodium intake remained unchanged throughout the study, whereas a significant rise in serum potassium occurred during ACE inhibition. CONCLUSION: The angiotensin II subtype 1 receptor antagonist, losartan, reduces albuminuria and MABP similar to the effect of ACE inhibition. These results indicate that the reduction in albuminuria and blood pressure during ACE inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy.

The Trp64Arg amino acid polymorphism of the beta3-adrenergic receptor gene does not contribute to the genetic susceptibility of diabetic microvascular complications in Caucasian type 1 diabetic patients.

OBJECTIVE: The beta3-adrenergic receptor is involved in regulation of microvascular blood flow. A missense mutation (Trp64Arg) in the beta3-adrenergic receptor gene has been suggested as a risk factor for proliferative retinopathy in Japanese type 2 diabetic patients. The aim of the present study was to evaluate the contribution of this polymorphism to the development of microangiopathic complications in Caucasian type 1 diabetic patients. SUBJECTS AND METHODS: We studied the relationship between the Trp64Arg polymorphism in type 1 diabetic patients with nephropathy (204 men/132 women, age 42.8 +/- 11.0 years, diabetes duration 28 +/- 9 years) and in type 1 diabetic patients with persistent normoalbuminuria (118 men/73 women, age 42.6 +/- 10.2 years, diabetes duration 27 +/- 8 years). Proliferative retinopathy was present in 254 patients (48%), while 66 patients (13%) had no diabetic retinopathy. RESULTS: There were no differences in Trp64Arg genotype distribution between type 1 diabetic patients with diabetic nephropathy and type 1 diabetic patients with normoalbuminuria: 295 (88%)/38 (11%)/3 (1%) vs 161 (84%)/30 (16%)/- had Trp/Trp, Trp/Arg or Arg/Arg genotype respectively. Odds ratio (95% CI) of nephropathy in carriers of the mutation was 0.75 (0.45-1.25). No associations between the Trp64Arg polymorphism and simplex or proliferative retinopathy were revealed either. The frequency of the Arg-allele was 0.069 in patients with proliferative retinopathy, 0.066 in patients with simplex retinopathy and 0.090 in patients with no signs of diabetic retinopathy, NS. CONCLUSIONS: The Trp64Arg polymorphism of the beta3-adrenergic receptor gene does not contribute to the genetic susceptibility to diabetic nephropathy in Caucasian type 1 diabetic patients. Nor does our study support previous findings of an association between this variant and proliferative retinopathy.

Differential display competitive polymerase chain reaction: an optimal tool for assaying gene expression.

Gene discovery, i.e. detection of genes whose expression is affected in diseases or by different treatments of cells or animals, has become the focus of much genetic research. The technologies that are used to detect changes in expression level include polymerase chain reaction (PCR)-based subtraction methods, arrays of cDNA clones on chips or filters, serial analysis of gene expression, and differential display. In this paper we show that differential display can be used to investigate global gene expression in situations where a few genes change expression levels such as exposure of MCF7 cells to estradiol, and in more complex situations such as neuronal differentiation of human NTERA2 cells which affects a large number of genes. Furthermore, we show that differential display can replace Northern blotting and RNase protection as a tool to study the expression level of a specific gene in many samples. Results obtained by differential display can be stored in databases, where the identity of a band (gene or mRNA name) can be linked with information about the primer combination displaying the band and a gel image showing the band pattern, which is all the information that is needed to compare the expression level of this gene in other samples.

Development of a semisynthetic cheese medium for fungi using chemometric methods.

The growth, color formation, and mycotoxin production of six cheese-related fungi were studied on nine types of natural cheeses and 24 semisynthetic cheese media and compared using principal component analysis. The semisynthetic cheese media contained various amounts of Ca, K, Mg, Na, P, Fe, Cu, Zn, lactate, lactose, and casein. A robust well-defined and easily prepared semisynthetic cheese medium was developed for Penicillium commune, the most frequently occurring contaminant on semihard cheese. Growth experiments on the medium were repeatable and reproducible. The medium was also suitable for Penicillium camemberti. The medium had the following composition: 100 g of casein, 8.3 g of 90% lactate, 7.9 g of lactose, 7.3 g of CaCl2.2H2O, 2.6 g of MgSO4.7H2O, 26.0 g of NaCl, 20 g of agar, 0.025 g of FeSO4.7H2O, 0.004 g of CuSO4.5H2O, and water to a total weight of 1 kg. The semisynthetic cheese medium was less suitable for Penicillium roqueforti, Penicillium discolor, Penicillium verrucosum, and Aspergillus versicolor. However, another semisynthetic cheese medium could be recommended for P. roqueforti and P. discolor. That medium had higher contents of P (5000 ppm, wt/wt), K (5000 ppm), and Zn (50 ppm) and lower contents of Na (2700 ppm), Fe (1 ppm), Cu (0.1 ppm), and casein (1%).

Increased plasma apolipoprotein (a) levels in IDDM patients with diabetic nephropathy.

OBJECTIVE: The relative mortality from cardiovascular disease (CVD) is increased 40-fold in IDDM patients suffering from diabetic nephropathy as compared with nondiabetic subjects on average. We assessed the potential contribution of dyslipidemia in general and elevated serum apolipoprotein (a) [apo(a)] in particular to CVD in nephropathic patients with IDDM. RESEARCH DESIGN AND METHODS: We investigated 199 IDDM patients with diabetic nephropathy and 192 normoalbuminuric IDDM patients matched for sex, age, diabetes duration, and BMI. RESULTS: The prevalence of CVD was 30 and 12% in patients with and without nephropathy, respectively (P < 0.001). The level of apo(a) was significantly higher in patients with nephropathy, 189 (20-2,350) U/l as compared with the normoalbuminuric group, 103 (20-1,940) U/l (P < 0.005). The prevalence of plasma apo(a) > 300 U/l (at-risk level for cardiovascular pathogenicity) was 38% (31-45) vs. 22% (16-28) in patients with and without nephropathy, respectively (P < 0.0005). In nephropathic patients, the prevalence of plasma apo(a) > 300 U/l was raised in patients with CVD (48%, 36-61%) as compared with patients without (34%, 26-42%) (P = 0.05). Furthermore, the serum concentrations of the following apolipoproteins and lipids were higher in patients with nephropathy as compared with normoalbuminuric patients: apoB 1.33 +/- 0.37 vs. 1.06 +/- 0.26 g/l; total cholesterol 5.6 +/- 1.2 vs. 4.8 +/- 0.9 mmol/l; and triglycerides 1.22 (0.31-9.87) vs. 0.77 (0.28-3.05) mmol/l, P < 0.0001. Multiple logistic regression analysis of cardiovascular risk factors revealed that plasma apo(a) concentration > 300 U/l is an independent risk factor for coronary heart disease, odds ratio 1.86 (1.03-3.36) (P < 0.05). CONCLUSIONS: Dyslipidemia and raised plasma concentrations of apo(a), particularly > 300 U/l, may contribute to the enhanced morbidity and mortality from CVD characteristically observed in IDDM patients with diabetic nephropathy.

[Low birth weight--increased risk of diabetic nephropathies?]. / Lav fødselsvaegt--øget risiko for diabetisk nefropati?

It has been demonstrated that intrauterine growth retardation gives rise to a reduction in nephron number. Oligonephropathy has been suggested to enhance the risk for expression of renal disease following exposure to potentially injurious renal stimuli. In a case-control study we investigated if low birth weight is a risk factor for development of diabetic nephropathy in 184 IDDM patients with diabetic nephropathy (persistent albuminuria > 300 mg/24 hours) and 182 normoalbuminuric (< 30 mg/24 hours) patients. In women with birthweight < 10 th centile (< or = 2,700 g, n = 16) 75% had nephropathy compared to only 35% among patients > 90 th centile (> or = 4,000 g, n = 17) (p = 0.05). In men with birth-weight < 10th centile (< or = 2,910 g, n = 22) the prevalence of nephropathy: 50%, was similar to the prevalence among patients > 90th centile (> or = 4,200 g, n = 24) 54%. Mean weight at birth were similar in patients with and without diabetic nephropathy. Men with diabetic nephropathy were significantly shorter than men with normoalbuminuria (176.9 (7.1) vs 179.4 (6.5), p < 0.01). In conclusion, our study supports the hypothesis that genetic predisposition or factors operating in utero or early childhood, or both, contribute to the development of diabetic nephropathy.

Fish oil in diabetic nephropathy.

OBJECTIVE: Recent studies in nondiabetic kidney diseases suggest that dietary supplementation with n-3 polyunsaturated fatty acids (fish oil) may have beneficial effects on albuminuria, kidney function, arterial blood pressure, and dyslipidemia. Therefore, we evaluated the long-term effect of fish oil in diabetic nephropathy. RESEARCH DESIGN AND METHODS: A 1-year double-blind randomized controlled study comparing fish oil (4.6 g n-3 fatty acids/day) with placebo (olive oil) was performed in an outpatient clinic in a tertiary referral center. Thirty-six normotensive IDDM patients with diabetic nephropathy were included; 18 were treated with fish oil. Seven patients dropped out (four received fish oil), and results for the remaining 29 are presented. Albuminuria (enzyme immunoassay), glomerular filtration rate (51Cr-labeled EDTA plasma clearance), 24-h ambulatory blood pressure, and lipid profile were determined every 6 months. RESULTS: Albuminuria increased by 22% (1-46%) (mean [95% CI]) in the fish oil group vs. 15% (-11-49%) in the placebo group (NS). Glomerular filtration rate decreased from 116 +/- 7 to 105 +/- 7 ml.min-1.1.73 m-2 (mean +/- SE) vs. from 108 +/- 6 to 103 +/- 7, fish oil and placebo, respectively (NS). No significant changes occurred in 24-h ambulatory blood pressure: from 141 +/- 4/82 +/- 2 mmHg to 142 +/- 5/83 +/- 2 vs. from 140 +/- 4/78 +/- 2 to 144 +/- 4/80 +/- 3, fish oil and placebo, respectively (NS). In the fish oil group, serum triglycerides (median [range]) decreased from 0.97 (0.5-4.0) mmol/l to 0.8 (0.4-3.0) vs. from 1.01 (0.4-2.0) to 1.09 (0.4-2.0) in the placebo group (P < 0.05) and VLDL cholesterol decreased from 0.45 (0.23-1.88) to 0.37 (0.21-1.43) mmol/l vs. from 0.44 (0.21-0.94) to 0.41 (0.17-1.94) (P < 0.05), but total and LDL cholesterol rose in the fish oil compared with the placebo group. CONCLUSIONS: Our study does not suggest that fish oil has beneficial effects on albuminuria, kidney function, blood pressure, and dyslipidemia in normotensive IDDM patients suffering from diabetic nephropathy.

Angiotensin-II type 1 receptor gene polymorphism and diabetic microangiopathy.

BACKGROUND: Genotypic abnormalities of the renin-angiotensin system have been suggested as risk factors for the development of hypertension, diabetic nephropathy and proliferative retinopathy. Most of the known actions of angiotensin-II are exerted through the angiotensin-II type 1 receptor, which is present particularly in vascular smooth muscle cells, myocardium and the kidney. A transversion of adenine to cytosine at nucleotide position 1166 in the gene coding for the angiotensin-II type 1 receptor has been associated with hypertension in the non-diabetic population. METHODS: We studied the relationship between the A1166-->C polymorphism in the angiotensin-II type 1 receptor gene in patients with insulin dependent diabetes mellitus (IDDM) and diabetic nephropathy (121 men, 77 women, age 41 +/- 10 years, diabetes duration 27 +/- 8 years) and in IDDM patients with normoalbuminuria (116 men, 74 women, age 43 +/- 10 years, diabetes duration 27 +/- 8 years). 156 patients (40%) had proliferative retinopathy, 67 patients (17%) had no diabetic retinopathy. RESULTS: There was no difference in genotype distribution between IDDM patients with diabetic nephropathy and normoalbuminuria 103 (52%) / 81 (41%) / 14 (7%) vs. 97 (51%) / 80 (42%) / 13 (7%) had AA/AC/CC genotypes, respectively. The allele frequencies (A/C) in patients with nephropathy (0.73/0.27) and patients with normoalbuminuria (0.72/0.28) were also similar. No difference in genotype distribution between IDDM patients with proliferative retinopathy and without diabetic retinopathy was found either: 77 (50%) / 66 (42%) / 13 (8%) vs. 42 (63%) / 22 (33%) / 3 (4%) had AA/AC/CC genotypes, respectively. CONCLUSIONS: The A1166-->C polymorphism in the angiotensin-II type 1 receptor gene does not contribute to the genetic susceptibility to diabetic nephropathy or proliferative retinopathy in caucasian IDDM patients.

Angiotensinogen gene polymorphisms in IDDM patients with diabetic nephropathy.

Genotypic abnormalities of the renin-ANG system have been suggested as a risk factor for the development of diabetic nephropathy. Cleavage of angiotensinogen is the rate-limiting step in the activation of the renin-ANG system. The TT genotype of a polymorphism encoding threonine instead of methionine (M235T) has been associated not only with increased plasma angiotensinogen concentration but also with essential hypertension. In addition, a polymorphism in the angiotensinogen gene substituting methionine for threonine (T174M) has been associated with hypertension in nondiabetic populations. We studied the relationship between these polymorphisms in the angiotensinogen gene in IDDM patients with diabetic nephropathy (121 men, 74 women, age 40.9 +/- 10 years, diabetes duration 27 +/- 8 years). There was no difference in M235T genotype distribution between IDDM patients with diabetic nephropathy and those with normoalbuminuria: 73/97/25 (37/50/13%) vs. 67/95/23 (36/52/12%) had MM/MT/TT genotypes, respectively. No difference in distribution of T174M genotypes between nephropathic and normoalbuminuric IDDM patients was observed either: 148/44/1 (77/23/0.5%) vs. 141/42/2 (76/23/1%) had TT/TM/MM genotypes, respectively. In patients with nephropathy, systolic blood pressure was higher (161 +/- 22 mmHg [mean +/- SD]) in patients carrying TT genotype of the M235T angiotensinogen polymorphism as compared with patients with MM or MT genotypes (150 +/- 23 mmHg; P = 0.03). We conclude that neither the M235T nor the T174M polymorphism in the angiotensinogen gene contributes to genetic susceptibility to diabetic nephropathy in white IDDM patients, whereas the TT genotype of the M235T is associated with elevated blood pressure in patients with diabetic nephropathy.

Low birth weight. A risk factor for development of diabetic nephropathy?

It has been demonstrated that intrauterine growth retardation, defined as birth weight below the 10th percentile, gives rise to a reduction in nephron number. Oligonephropathy has been suggested to increase the risk for systemic and glomerular hypertension in adult life as well as enhance risk for expression of renal disease after exposure to potentially injurious renal stimuli. The aim of this study was to determine if low birth weight is a risk factor for development of diabetic nephropathy. In a case-control study, we investigated 184 (110 men) insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy (persistent albuminuria > 300 mg/24 h) (age [mean +/- SD] 41.0 +/- 9.3 years, duration of diabetes 26.9 +/- 8.2 years) and 182 (111 men) normoalbuminuric (< 30 mg/24 h) IDDM patients (age 42.1 +/- 9.8 years, duration of diabetes 25.8 +/- 8.6 years). Information about weight at birth was obtained from the midwife's original registrations. In women below the 10th percentile in birth weight (< or = 2,700 g, n = 16), 75% had nephropathy compared with only 35% among patients whose birth weights were above the 90th percentile (> or = 4,000 g, n = 17) (P = 0.05). In men below the 10th percentile in birth weight (< or = 2,910 g, n = 22), the prevalence of patients with nephropathy (50%) was similar to the prevalence among patients above the 90th percentile in birth weight (> or = 4,200 g, n = 24) (54%).(ABSTRACT TRUNCATED AT 250 WORDS)

Insertion/deletion polymorphism in the angiotensin-I-converting enzyme gene is associated with coronary heart disease in IDDM patients with diabetic nephropathy.

Insulin-dependent diabetic (IDDM) patients with diabetic nephropathy have a highly increased morbidity and mortality from coronary heart disease. An insertion (I) /deletion (D) polymorphism in the angiotensin-I-converting enzyme (ACE) gene has been shown to be associated with coronary heart disease. Therefore, we have investigated the role of this ACE/ID polymorphism in 198 IDDM patients with diabetic nephropathy and 190 normoalbuminuric IDDM patients. The prevalence of myocardial infarction and other coronary heart disease was significantly elevated in patients with nephropathy, 19% (38/198) vs 8% (15/190), p < 0.001. In the nephropathic group 12 of 63 (19%), 23 of 95 (24%), and 3 of 40 (7.5%) patients with the DD, ID and II genotypes, respectively had a history of coronary heart disease, II vs DD and ID, p < 0.05 when compared to nephropathic patients without coronary heart disease. Multiple logistic regression analysis of the risk factors associated with coronary heart disease in univariate analysis revealed that the II genotype acts as an independent protective factor against coronary heart disease, odds ratio II/DD + ID 0.27 (95% confidence interval 0.07-0.97, p < 0.05). There was no difference in genotype or allele frequency (D/I) between patients with and without nephropathy, 0.56/0.44 in both groups, but plasma ACE concentration was elevated in patients with nephropathy 609 (151-1504) ng/ml as compared to patients with normoalbuminuria, 428 (55-1630) ng/ml, p < 0.001. We suggest that ACE/ID polymorphism may influence the frequency of life-threatening cardiac complications in IDDM patients suffering from diabetic nephropathy, a condition characterized by increased plasma ACE concentration.

Lack of relationship between an insertion/deletion polymorphism in the angiotensin I-converting enzyme gene and diabetic nephropathy and proliferative retinopathy in IDDM patients.

Genotypic abnormalities of the renin-angiotensin system have been suggested as a risk factor for the development of diabetic nephropathy and proliferative retinopathy. We studied the relationship between an insertion(I)/deletion (D) polymorphism in the angiotensin-converting enzyme (ACE) gene in insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy (121 men and 77 women, age 40.9 +/- 10 years, diabetes duration 27 +/- 8 years) and in IDDM patients with normoalbuminuria (118 men and 74 women, age 42.7 +/- 10 years, diabetes duration 26 +/- 8 years). A total of 155 patients (40%) had proliferative retinopathy, and 67 patients (17%) had no diabetic retinopathy. There was no difference in genotype distribution between IDDM patients with diabetic nephropathy and those with normalbuminuria: 63 (32%)/95 (48%)/40 (20%) vs. 67 (35%)/77 (41%)/46 (24%) had DD/ID/II genotypes, respectively. Patients with nephropathy had higher plasma ACE levels (609 [151-1,504] micrograms/l) compared with patients with normoalbuminuria (428 [55-1,630] micrograms/l) (P < 0.001). Multiple linear regression analysis revealed that the plasma ACE level in patients with nephropathy is partially determined by ACE/ID polymorphism, mean arterial blood pressure, and glomerular filtration rate (r2 = 0.30, P < 0.001). There was no difference in genotype distribution between IDDM patients with proliferative retinopathy and those without diabetic retinopathy: 52 (34%)/74 (48%)/29 (19%) vs. 26 (39%)/25 (37%)/16 (24%) had DD/ID/II genotypes, respectively. There was also no difference in plasma ACE concentration detected among patients with no, simplex, or proliferative retinopathy.(ABSTRACT TRUNCATED AT 250 WORDS)