Glucose metabolism in relatives of type 1 diabetic patients with albuminuria.

OBJECTIVE: Diabetic nephropathy in type 1 diabetes is associated with familial aggregation of diabetes. In order to explore the mechanisms behind this association, we assessed glucose metabolism in glucose-intolerant relatives of type 1 diabetic patients with (ALB+) or without (ALB-) elevated urinary albumin excretion rate (UAER). METHODS: Glucose tolerance and insulin secretion were assessed using an oral glucose tolerance test (OGTT) and insulin sensitivity was measured with the short insulin tolerance test (ITT). RESULTS: One hundred and fourteen parents and siblings of 43 type 1 diabetic patients with ALB+ (UAER > or = 20 microg/min) were identified and 93 parents and siblings of 39 patients with ALB- (UAER < 20 microg/min). From this pool, a further selection was made of those (25 and 13 relatives of patients with ALB+ and ALB-, respectively) with mild abnormalities of glucose metabolism (fasting plasma glucose < 7.8 mmol/L; 2 h plasma glucose > or = 7.8 mmol/L in the OGTT). No difference in insulin sensitivity was discernible between the two groups of relatives (KITT 3.3 +/- 1.0 vs. 3.2 +/- 1.0%/min, p=NS). Although there were no significant differences in the incremental areas under glucose or insulin curves (AUC) between relatives of ALB+ and ALB- in the OGTT, the insulin secretory response to the rise in plasma glucose was impaired in relatives of patients with ALB+ (insulin AUC/glucose AUC: 7.1 [1.1-30.8] vs. 9.8 [3.6-52.2], p=0.039). CONCLUSIONS: Glucose-intolerant relatives of patients with elevated UAER seem to be characterized by impaired insulin secretion. Genetic or environmental factors related to impaired insulin secretion may be important in the development of diabetic nephropathy.

Increased secretion of TGF-beta1 by peripheral blood mononuclear cells from patients with Type 1 diabetes mellitus with diabetic nephropathy.

AIMS: To study transforming growth factor (TGF)-beta1 secretion by peripheral blood mononuclear cells (PBMC) from Type 1 diabetic patients with and without nephropathy. METHODS: Thirty normoalbuminuric Type 1 diabetic patients (urinary albumin excretion rate (AER) < 20 microg/min), 12 microalbuminuric (AER 20-200 microg/min), 10 nephropathic (AER > 200 microg/min), and 13 non-diabetic individuals were recruited. TGF-beta1 secretion by PBMC was measured by enzyme immunoassay (EIA) after 48 h culture with and without phytohaemagglutinin (PHA) (5 microg/ml). RESULTS: After 48 h culture, the highest TGF-beta1 levels secreted by unstimulated PBMC were found in patients with nephropathy (median 6.2 (range 0.9-20.0) ng/ml) when compared to patients with normal albumin excretion (4.1 (0.2-11.3) ng/ml), microalbuminuria (1.8 (0.2-6.4) ng/ml) and healthy controls (1.0 (0.2-7.0) ng/ml); P = 0.02 for the three diabetic groups and P = 0.006 for all groups. At 48 h, the PHA-stimulated TGF-beta1 levels were 12.4 (2.9-30.0) ng/ml in nephropathic, 7.3 (0.5-21.2) ng/ml in normoalbuminuric, and 5.5 (0.5-27.6) ng/ml in microalbuminuric patients (P = 0.05). A correlation was observed between TGF-beta1 and diastolic blood pressure in the subgroup of patients with incipient and overt nephropathy (r = 0.45, P = 0.04). CONCLUSIONS: Type 1 diabetic patients with overt nephropathy show increased TGF-beta1 secretion by PBMC. Diastolic blood pressure levels correlated with TGF-beta1 secretion in diabetic patients with nephropathy. Increased TGF-beta1 secretion by PBMC may be associated with renal and vascular disease in Type 1 diabetes mellitus.

No evidence of an exaggerated albuminuric response to physical exercise in non-diabetic siblings of type 1 diabetic patients with diabetic nephropathy.

Substantial evidence suggests a role for genetic factors in the development of diabetic nephropathy in both type 1 and type 2 diabetes. In support of this view, non-diabetic relatives of type 2 diabetic patients with nephropathy have been found to display abnormalities of urinary albumin excretion rate (AER) both when measured at rest and during physical exercise. The aim of the present study was to assess the albuminuric response to physical exercise in non-diabetic relatives of type 1 diabetic patients with nephropathy. AER was measured from urine collections performed (i) overnight, (ii) during an oral glucose tolerance test (OGTT), and (iii) during a submaximal bicycle ergometer test in 21 and 24 non-diabetic siblings of type 1 diabetic patients with (DN+; AER > 200 microg/min) and without diabetic nephropathy (DN-; AER < 20 microg/min). No difference was found in AER (median [range]) measured overnight (DN+ vs DN-: 3.8 [1.3-24.1] vs 3.5 [2.0-21.0] microg/min; P=NS), during the OGTT (DN+ vs DN-: 6.3 [3.2-26.0] vs 4.8 [1.9-15.7] microg/min; P = NS) or during the exercise test (DN+ vs DN-: 44.8 [7.0-535] vs 30.0 [3.4-1614] microg/min; P = NS). In conclusion, we found no evidence of an exaggerated albuminuric response to physical exercise in non-diabetic relatives of type 1 diabetic patients with nephropathy. This differs from previous findings in type 2 diabetes and may suggest differences in the mode of inheritance of albuminuria between type 1 and type 2 diabetes.

Albuminuria in nondiabetic relatives of IDDM patients with and without diabetic nephropathy.

BACKGROUND: In non-insulin-dependent diabetes mellitus (NIDDM), there is a clustering of an elevated urinary albumin excretion rate (U-AER) in nondiabetic relatives of albuminuric patients. Whether this is also the case in insulin-dependent diabetes mellitus (IDDM) is unknown. METHODS: Overnight U-AER was measured in 186 nondiabetic first-degree relatives of 80 IDDM patients with diabetic nephropathy (U-AER > 200 microg/min or 300 mg/24 hours; DN+) and in 52 relatives of 25 IDDM patients without nephropathy (U-AER < 20 microg/min; DN-). The two groups of relatives were comparable regarding gender distribution, age, obesity, blood pressure, prevalence of antihypertensive therapy, and smoking habits. RESULTS: No difference was found in overnight U-AER between relatives of patients with DN+ and DN- [median (range), 3.4 (0.1 to 372) vs. 4.0 (0.2 to 62) microg/min, respectively, P = NS]. The proportion of relatives with a U-AER = 10 microg/min was 12% in DN+ compared with 8% in DN- (P = NS). Among relatives of DN+, those with antihypertensive treatment (AHT+) had higher U-AER compared with those without [AHT+ vs. AHT-, 5.0 (0.5 to 372) vs. 3.4 (0.1 to 26.5) microg/min, P < 0.01], a phenomenon that was not seen among relatives of DN-[AHT + vs. AHT-, 3.6 (2.1 to 24.3) vs. 4.0 (0. 2 to 61.5) microg/min, P = NS]. However, this analysis was impaired by the small number of relatives of DN- with hypertension (N = 7). CONCLUSIONS: In IDDM, we found no clustering of elevated U-AER in nondiabetic relatives of patients with nephropathy. This is different from what has been reported in NIDDM, and suggests heterogeneity in the genesis of albuminuria in diabetes.

Cardiovascular morbidity and early mortality cluster in parents of type 1 diabetic patients with diabetic nephropathy.

OBJECTIVE: A familial predisposition was proposed to be a determinant of the increased morbidity and mortality from cardiovascular disease in type 1 diabetic patients with diabetic nephropathy. The insertion allele of an insertion/deletion polymorphism in the ACE (ACE/ID) gene seems to protect against coronary heart disease in nondiabetic and diabetic subjects. The aim of the present study was to evaluate these hypotheses in parents of a large group of type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: We investigated cardiovascular morbidity and mortality of parents of 163 type 1 diabetic patients with nephropathy and parents of 163 sex- and age-matched normoalbuminuric patients with type 1 diabetes. RESULTS: Kaplan-Meier curves showed that total parental mortality was significantly increased in parents of type 1 diabetic patients with nephropathy (121 of 244 [ approximately 50%] ) as compared with parents of normoalbuminuric type 1 diabetic patients (119 of 269 [approximately 44%]) (P = 0.008 [log-rank test]) partially due to an increase in cardiovascular deaths (48 of 244 [approximately 20%] vs. 42 of 269 [approximately 16%], P<0.05). In addition, more patients with nephropathy, as compared with the normoalbuminuric group, had at least one parent with fatal/nonfatal cardiovascular disease (46% [95% CI 38-54] vs. 36% [28-44], P = 0.05). Fathers of patients homozygous for the I-allele of the ACE/ID polymorphism had significantly less myocardial infarction as compared with other genotypes (P = 0.03), regardless of the nephropathic state of the offspring. CONCLUSIONS: Cardiovascular morbidity and early mortality clusters in parents of type 1 diabetic patients with diabetic nephropathy The ACE/ID polymorphism helps explain the increased morbidity from cardiovascular disease.

The impact of a family history of Type II (non-insulin-dependent) diabetes mellitus on the risk of diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus.

AIMS/HYPOTHESIS: There is substantial evidence for a role of genetic factors in the development of diabetic nephropathy. In Pima Indians, a link between susceptibility to diabetic nephropathy and Type II (non-insulin-dependent) diabetes mellitus has been proposed. In this study, our aim was to examine the association between a family history of Type II diabetes and diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus. METHODS: In a cross-sectional case-control study, we assessed the prevalence of Type II diabetes in the parents of 137 Type I diabetic patients with diabetic nephropathy (albuminuria > 300 microg/min in two of three overnight urine collections) compared with the parents of 54 Type I diabetic patients without nephropathy (albuminuria < 20 microg/min). RESULTS: Thirty-four (25 %) of the patients with nephropathy compared with five (9 %) of the patients without nephropathy had a parental history of Type II diabetes (p = 0.019). A parental history of Type II diabetes was associated with a three-fold risk [odds ratio 2.95 (95% confidence interval: 1.03 to 8.40), p = 0.043] of diabetic nephropathy after adjustment for sex, glycaemic control and family history of hypertension. Furthermore, there was an excess of risk factors for development of Type II diabetes (higher fasting plasma glucose concentrations, higher prevalence of hypertension, higher waist-hip ratio and a tendency towards more glucose intolerance) among previously non-diabetic parents of patients with nephropathy. CONCLUSION/INTERPRETATION: Genetic or environmental factors or both related to familial Type II diabetes increase susceptibility to diabetic nephropathy in patients with Type I diabetes.

Predisposition to essential hypertension and development of diabetic nephropathy in IDDM patients.

Conflicting results have been reported on the relationship between familial predisposition to hypertension and development of diabetic nephropathy in IDDM. In our case-control study, we assessed the prevalence of hypertension among parents of 73 IDDM patients with diabetic nephropathy (DN+; persistent albuminuria > 200 microg/min or > 300 mg/24 h) and 73 IDDM patients without diabetic nephropathy (DN-; urinary albumin excretion < 20 microg/min or < 30 mg/24 h). Arterial hypertension, defined as antihypertensive therapy or a 24-h ambulatory blood pressure (SpaceLabs 90207) > or = 135/85 mmHg, was present in 57% of parents of DN+ patients compared with 41% of parents of DN- patients (P = 0.034; difference 16% [95% CI 1.3-29.6%]). In addition, the cumulative incidence of hypertension was higher among parents of DN+ patients (log-rank test P < 0.001), with a shift toward younger age at onset of hypertension in this group. However, the difference in prevalence of parental hypertension was not evident using office blood pressure measurements (64 vs. 57%; NS; difference 7% [-5.8-20%). Furthermore, patients with DN+ and with antihypertensive therapy in both parents were themselves more frequently treated for hypertension than were patients with DN+ and without parental treatment for hypertension (100 vs. 61%; P = 0.034; difference 39% [21-57%]). In conclusion, familial predisposition to essential hypertension increases the risk of diabetic nephropathy and may also contribute to the development of systemic hypertension in patients with IDDM and diabetic nephropathy.

Urinary excretion of TGF-beta 1, PDGF-BB and fibronectin in insulin-dependent diabetes mellitus patients.

We studied the urinary excretion of transforming growth factor-beta 1 (TGF-beta 1), platelet-derived growth factor-BB (PDGF) and fibronectin (FN) in 104 patients (52 normoalbuminuric, 24 microalbuminuric, and 28 with overt diabetic nephropathy) with insulin-dependent diabetes mellitus (IDDM) of a long duration and in 30 non-diabetic controls. IDDM patients had higher urinary excretion of TGF-beta 1, PDGF and FN compared to controls. Urinary excretion of TGF-beta 1 and PDGF was elevated in all IDDM subgroups, while FN excretion was significantly increased only in patients with macroalbuminuria. Urinary excretion of TGF-beta 1 and FN did not differ between normoalbuminuric IDDM patients with long duration of diabetes, a group at low risk of ever developing diabetic nephropathy, and IDDM patients with incipient or overt diabetic nephropathy. Excretion of PDGF was significantly higher in patients with micro- and macroalbuminuria compared to normoalbuminuric patients, but there was a considerable overlap between the groups. In conclusion, although longitudinal follow-up studies are needed to further clarify the issue, our results in long-standing IDDM do not support a hypothesis of urinary excretion of TGF-beta 1, PDGF or FN to predict development of diabetic nephropathy.