Association of single nucleotide polymorphisms in the gene encoding GLUT1 and diabetic nephropathy in Brazilian patients with type 1 diabetes mellitus.

Mesangial cells subject to high extracellular glucose concentrations, as occur in hyperglycaemic states, are unable to down regulate glucose influx, resulting in intracellular activation of deleterious biochemical pathways. A high expression of GLUT1 participates in the development of diabetic glomerulopathy. Variants in the gene encoding GLUT1 (SLC2A1) have been associated to this diabetic complication. The aim of this study was to test whether polymorphisms in SLC2A1 confer susceptibility to diabetic nephropathy (DN) in Brazilian type 1 diabetes patients. Four polymorphisms (rs3820589, rs1385129, rs841847 and rs841848) were genotyped in a Brazilian cohort comprised of 452 patients. A prospective analysis was performed in 155 patients. Mean duration of follow-up was 5.6 ± 2.4 years and the incidence of renal events was 18.0%. The rs3820589 presented an inverse association with the prevalence of incipient DN (OR: 0.36, 95% CI: 0.16 - 0.80, p=0.01) and with progression to renal events (HR: 0.20; 95% CI: 0.03 - 0.70; p=0.009). AGGT and AGAC haplotypes were associated with the prevalence of incipient DN and the AGAC haplotype was also associated with the prevalence of established/advanced DN. In conclusion, rs3820589 in the SLC2A1 gene modulates the risk to DN in Brazilian patients with inadequate type 1 diabetes control.

Intake of soluble fibers has a protective role for the presence of metabolic syndrome in patients with type 2 diabetes.

BACKGROUND/OBJECTIVES: Dietary factors have been associated with metabolic syndrome (MS) in healthy individuals and specific ethnic groups. To evaluate possible associations of usual dietary factors with the presence of MS in patients with type 2 diabetes mellitus (DM). SUBJECTS/METHODS: In this cross-sectional study, 214 patients with type 2 DM without dietary counseling during previous 6 months were studied. After clinical and laboratory examinations, dietary intake was evaluated by 3-day weighed-diet records, whose reliability was confirmed by 24-h urinary nitrogen output. The presence of MS was defined according to International Diabetes Federation. RESULTS: Patients with MS (n=174) had a lower intake of total (16.7 +/- 6.2 vs 19.5 +/- 6.5 g day(-1); P=0.010) and soluble fibers (5.3 +/- 1.8 vs 6.0 +/- 2.7 g day(-1); P=0.011) than patients without MS. In multiple logistic regression models, adjusted for gender and DM duration, variables associated with MS were soluble fibers (OR=0.86; 95% CI=0.74-0.98; P=0.046), soluble fibers from whole-grain foods (OR=0.43; 95% CI=0.25-0.76; P=0.002) and soluble fibers from fruits (OR=0.76; 95% CI=0.62-0.95; P=0.017). Whole-grain and fruits were the foods negatively associated with MS. CONCLUSIONS: The intake of soluble fibers, particularly from whole-grain foods and fruits, may have a protective role for the presence of MS in this selected sample of patients with type 2 DM.

Glomerular filtration rate, urinary albumin excretion rate, and blood pressure changes in normoalbuminuric normotensive type 1 diabetic patients: an 8-year follow-up study.

OBJECTIVE: To analyze the changes in glomerular filtration rate (GFR), urinary albumin excretion rate (UAER), and blood pressure (BP) levels in a cohort of normoalbuminuric and normotensive type 1 diabetic patients. RESEARCH DESIGN AND METHODS: This is an 8.4+/-2.1-year prospective study of 33 normotensive normoalbuminuric (24-h UAER <20 microg/min) type 1 diabetic patients. UAER (radioimmunoassay), GFR (51Cr-EDTA single-injection technique), and GHb (ion-exchange chromatography) were measured at baseline and at 1- to 2-year intervals. RESULTS: The GFR decreased (137.6+/-16.5 to 116.4+/-21.3 ml x min(-1) x 1.73 m(-2) P < 0.05) during the follow-up period. GFR reduction (-0.20+/-0.29 ml x min(-1) x month(-1); P < 0.05) was associated with baseline GFR and mean GHb (R2 = 0.30; beta = 0.072; F = 6.54; P = 0.004). UAER was higher at the end of the study (3.7-7.1 microg/min; P = 0.017). Microalbuminuria was observed in two patients, while macroalbuminuria was observed in one. No changes in UAER were observed when these three patients were excluded from the analysis. Mean blood pressure (MBP) increased during the study (85.8+/-9.7 to 99.6+/-11.6 mmHg; P < 0.001). MBP at the end of the study was associated with age and GFR at baseline (R2 = 0.39; beta = 0.074; F = 9.64; P = 0.001). CONCLUSIONS: In this cohort of normoalbuminuric normotensive type 1 diabetic patients, GFR decreased and BP levels increased during the follow-up period. The predictors for the GFR change were baseline GFR level and metabolic control. For end-of-study MBP, the predictor was baseline GFR level.

Proteinuria is still useful for the screening and diagnosis of overt diabetic nephropathy.

OBJECTIVE: To assess the performance of urinary total protein measurements in timed 24-h urine collection (24-h UP) and in a diurnal random urine specimen (RUS) for the screening and diagnosis of overt diabetic nephropathy. RESEARCH DESIGN AND METHODS: A total of 167 diabetic patients (20 type 1 and 147 type 2 diabetic patients; 78 women and 89 men), aged 20-84 years, collected 217 timed 24-h urine specimens. Albumin was measured by immunoturbidimetry, total protein by sulfosalicylic acid technique, and creatinine by Jaffe's method. According to the timed 24-h urinary albumin excretion rate (UAER), samples were divided into three groups: normoalbuminuric (NORMO) (UAER < 20 micrograms/min; n = 84), microalbuminuric (MICRO) (UAER 20-200 micrograms/min; n = 78), and macroalbuminuric (MACRO) (UAER > or = 200 micrograms/min; n = 55). Eighty-six patients also collected 105 RUSs (NORMO, n = 47; MICRO, n = 37; MACRO, n = 21), and urinary protein concentration (UPC) and urinary protein-to-creatinine ratio (UPCR) were measured. The receiver operating characteristics (ROC) curve approach was used to analyze the performance of the diagnostic tests. RESULTS: Spearman's coefficient of correlation of 24-h UAER versus 24-h UP was 0.95 (P < 0.001), and of 24-h UAER versus UPC and UPCR were 0.77 and 0.72, respectively (P < 0.001). The calculated areas (+/- SEM) under the ROC curve for the diagnosis of over diabetic nephropathy were 0.9987 +/- 0.001 for 24-h UP, 0.9926 +/- 0.006 for UPC, and 0.9751 +/- 0.014 for UPCR. In the ROC curves, the first points with 100% sensitivity were 541 mg (95.7% specificity) for 24-h UP, 431 mg/l (92.9% specificity) for UPC, and 0.2 (76.2% specificity) for UPCR. CONCLUSIONS: Measurements of proteinuria presented almost perfect accuracy for the screening and diagnosis of overt diabetic nephropathy. Protein measurement in spot urine is a reliable and simple method for the screening and diagnosis of overt diabetic nephropathy.

Lack of effect of captopril on glomerular hyperfiltration in normoalbuminuric normotensive insulin-dependent diabetic patients.

The aim of the present study was to evaluate the effects of captopril on the glomerular filtration rate (GFR) and urinary albumin excretion rate (UAER) of normoalbuminuric normotensive insulin-dependent diabetes mellitus (IDDM) patients with and without glomerular hyperfiltration. Eleven normoalbuminuric (UAER < 30 micrograms/min) patients (age: 34.3 +/- 4.6 years: diabetes duration: 9.5 +/- 6.4 years) participated in the study. Six patients were considered to be hyperfiltering (GFR > or = 134 ml/min/ 1.73m2). GFR (51Cr-EDTA single injection technique), extracellular volume (ECV; distribution volume of 51Cr-EDTA), UAER (RIA) and metabolic and biochemical parameters were measured at baseline, after 6 weeks on captopril (25 mg p.o. twice daily) and after 6 weeks off captopril. Plasma renin activity (PRA; RIA), plasma aldosterone (RIA) and blood volume (51Cr red cell labeled) were measured at baseline and after 6 weeks on captopril. The baseline clinical and laboratory characteristics of hyperfiltering and normofiltering IDDM patients were similar. GFR did not change during the study (144.1 +/- 28.8; 139.7 +/- 21.8; 132.8 +/- 29.9 ml/min/1.73 m2) either in patients with hyperfiltration (164.6 +/- 20.7; 153.8 +/- 18.3; 148.6 +/- 31.0 ml/min/1.73 m2; n = 6) or without hyperfiltration (119.6 +/- 11.1; 123.2 +/- 11.9; 113.8 +/- 14.4 ml/min/1.73 m2; n = 5). Also, ECV (22.2 +/- 3.6; 21.5 +/- 4.3; 21.5 +/- 3.5 L/1.73 m2), UAER (3.9 [0.4-22.1]; 4.0 [0.2-11.4]; 3.7 [2.0-26.2] micrograms/min), systolic (112 +/- 13; 105 +/- 10; 111 +/- 11 mmHg) and diastolic (76 +/- 12; 72 +/- 9; 73 +/- 12 mmHg) blood pressure did not change. No difference in blood volume (60.8 +/- 10.4; 62.3 +/- 8.4 ml/kg) or plasma aldosterone (10.4 +/- 4.9; 7.7 +/- 3.8 ng/dl) was observed between baseline values and values after captopril use. PRA increased (2.4 [0.4-22.1]; 12.9 [2.2-41.1]ng/ml/h) at the end of 6 weeks on captopril (P = 0.002). Fasting plasma glucose, glycated hemoglobin, fructosamine, plasma cholesterol and potassium, 24 h urinary urea and sodium were similar during the study. These results were unchanged when patients with and without hyperfiltration were analyzed as separate groups. From baseline to the end of 6 weeks on captopril there was no correlation between change in GFR and change in glycated hemoglobin (r = 0.02, P = 0.96), systolic (r = 0.23; P = 0.49) and diastolic (r = -0.32, P = 0.32) blood pressure, urinary urea (r = 0.21; P = 0.53) and UAER (r = -0.16; P = 1.00). In conclusion, captopril has no effect on the GFR and UAER of normoalbuminuric normotensive IDDM patients irrespective of the presence of glomerular hyperfiltration.

Five-year prospective study of glomerular filtration rate and albumin excretion rate in normofiltering and hyperfiltering normoalbuminuric NIDDM patients.

OBJECTIVE: To evaluate the evolution of glomerular filtration rate (GFR) and albumin excretion rate (AER) of normofiltering (NF) and hyperfiltering (HF) normoalbuminuric NIDDM patients. RESEARCH DESIGN AND METHODS: A longitudinal study of 32 normoalbuminuric (AER < 20 micrograms/min) NIDDM patients and 20 age-, sex-, and BMI-matched normal individuals was done. Subjects had their GFR (51Cr-labeled EDTA single-injection method) measured at entry and after 40 and 60 months. At entry, 13 NIDDM patients had GFR values above the upper limit of the normal range in our laboratory (> 137 ml.min-1 x 1.73 m-2) and were considered as HF. In NIDDM patients, the 24-h AER (radioimmunoassay), HbA1c, urinary urea, and mean arterial blood pressure (MBP) were analyzed at entry and after 40 and 60 months. RESULTS: There was a significant decline of GFR in NIDDM patients and normal subjects at 60 months. The decline was significantly greater in HF patients (-0.61 ml.min-1.month-1; P = 0.001) than in NF (-0, 18) and control subjects (-0, 14); the rate of change in NF and control subjects was the same (P > 0.05). In stepwise multiple regression analysis, with GFR decline as the dependent variable and GFR and AER at baseline, age and change in MBP, change in urinary urea, change in HbA1c, and change in therapy as independent variables, only baseline GFR (R2 = 0.19, P = 0.002) and age (R2 = 0.31, P = 0.048) were significantly related to the outcome. At 60 months, AER raised > 20 micrograms/min in three HF and in four NF patients. In logistic regression analysis, only higher initial AER (although still in the normal range; P = 0.037) and an increase in urinary urea (P = 0.021) were significantly related to the later development of microalbuminuria. CONCLUSIONS: The GFR of normoalbuminuric NIDDM patients declines significantly over 60 months. This decline is associated to baseline GFR and age. HF NIDDM patients show a faster decline in GFR than NF patients, whose GFR falls at a rate that is compatible with the age-related change observed in normal control subjects. The development of microalbuminuria is related to higher baseline AER and to increases in urinary urea and is similar in NF (4 of 19) and HF (3 of 13) NIDDM patients (P > 0.05).

Abnormalities in gallbladder dynamics of type 1 (insulin-dependent) diabetic patients with autonomic neuropathy.

The aim of this study was to evaluate gallbladder dynamics in insulin-dependent diabetic patients with and without autonomic neuropathy. Gallbladder dynamics was studied by a scintigraphic method after a test meal in 26 insulin-dependent diabetic patients and 10 normal individuals. The presence and severity of autonomic neuropathy were defined according to the number of abnormal cardiovascular reflex tests: absent (no abnormal test), mild (1-3 abnormal tests), and severe (4-5 abnormal tests). The time from the moment when the patient started to take the test meal to the beginning of gallbladder emptying was longer (P = 0.01) in diabetic patients with mild (N = 11, 12.1 +/- 7.6 min) and severe neuropathy (N = 8, 11.0 +/- 10.6 min) than diabetic patients without autonomic neuropathy (N = 7, 3.9 +/- 4.4 min) and controls (N = 10, 4.8 +/- 4.2 min). The ejection rate was higher (P = 0.02) in the group with severe autonomic neuropathy (N = 8, 5.1 +/- 3.3%/min) than diabetic patients with mild (N = 11, 2.0 +/- 1.0%/min) or without autonomic neuropathy (N = 7, 1.8 +/- 0.8%/min) and controls (N = 10, 2.6 +/- 1%/min). Thirty-two percent of the diabetic patients with autonomic neuropathy presented increased perspiration, nausea and urgency to defecate after the ingestion of the test meal. A significant positive correlation of ejection rate with the presence of these symptoms (biserial point correlation test = 0.67, P < 0.01) was also observed. These data suggest that insulin-dependent diabetic patients with autonomic neuropathy present abnormalities of gallbladder emptying that could be related to specific gastrointestinal symptoms.

[Analysis of the factors associated with recurrence of post-thyroidectomy goiter]. / Análise de fatores associados à recorrência de bócio pós-tiroidectomia.

The factors associated with post-thyroidectomy goiter recurrence in benign thyroid disease are not clearly defined, especially prophylactic thyroxine treatment. PURPOSE--To determine the prevalence, characteristics and associated factors of recurrence of goiter post-thyroidectomy in patients submitted to surgery for benign disease. METHODS--Sixty-six patients, 53 female and 13 male (mean age = 51 yrs., range 20-82 yrs.), previously (5.6 +/- 6.1 yrs.) submitted to thyroidectomy (lobectomy, n = 50; nodulectomy, n = 5; subtotal thyroidectomy, n = 11) for benign thyroid disease were included. Measurements of T3, T4, TSH, thyroid microsomal autoantibody titers and thyroid ultrasonography were performed at the time of the study. Recurrence of goiter post-thyroidectomy was defined on ultrasonography as the presence of residual thyroid volume > 20mL and/or new nodules > 0.5mL not detected at surgery. RESULTS--Seven patients (10%) developed recurrence of goiter. The post-operative follow-up period was longer in the recurrence group and there was no difference between the two groups as to age, sex, familial history of thyropathy and preoperative goiter diagnosis. In multiple regression analysis only the following post-operative period was significantly associated to goiter recurrence (beta = 0.02; R2 = 0.16; p < 0.05) and influenced the goiter recurrence rate by 14%. Familial history of thyropathy, thyroxine treatment in non-supressible doses after thyroidectomy and seric T4 and TSH levels did not influence the recurrence. CONCLUSION--Recurrence of goiter post-thyroidectomy occurs in a small number of patients and is related to longer post-operative follow-up time. Thyroxine treatment in non-supressible doses after surgery is not related to goiter recurrence prevention.

Renin-aldosterone axis in normoalbuminuric insulin-dependent diabetes mellitus patients with glomerular hyperfiltration.

The renin-aldosterone axis was evaluated by captopril test in 22 normotensive normoalbuminuric insulin-dependent diabetes mellitus (IDDM) patients with and without glomerular hyperfiltration. Patients were divided into those with glomerular hyperfiltration (Hf-IDDM) and with normal glomerular filtration rate (GFR; Nf-IDDM) according to the upper limit of GFR (134.7 ml/min per 1.73 m2). Sixteen normal individuals were also studied. GFR was measured by the 51Cr-EDTA single injection method, extracellular fluid volume as the distribution volume of 51Cr-EDTA, and blood volume using 51Cr-sodium chromate-labelled red blood cells. Twenty-five mg of captopril were administered per os and plasma renin activity (PRA; RIA), plasma aldosterone (RIA) and blood pressure were measured at 0 and 120 min post-captopril. PRA at time zero (Hf-IDDM = 2.4 +/- 1.7; Nf-IDDM = 2.5 +/- 1.9; controls = 1.0 +/- 0.6 ng/ml/h) and at 120 min (Hf-IDDM = 9.9 +/- 8.3; Nf-IDDM = 11.2 +/- 8.9; controls = 5.4 +/- 5.7 ng/ml/h) was higher in IDDM patients than in controls (P = 0.01). The increase of PRA was similar in patients (Hf-IDDM = 7.5 +/- 7.3, and Nf-IDDM = 8.7 +/- 7.2 ng/ml/h) and controls (4.4 +/- 5.3 ng/ml/h). There was no difference in PRA levels between Hf-IDDM and Nf-IDDM patients. PRA did not correlate with GFR, aldosterone, blood pressure, blood volume, duration of diabetes, 24-h urinary sodium and metabolic control indexes. Plasma aldosterone and the magnitude of its decrease after captopril was similar among patients and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Chicken and fish diet reduces glomerular hyperfiltration in IDDM patients.

OBJECTIVE: To compare the effect of a normal protein diet (test diet) in which chicken and fish were substituted for red meat with a low-protein diet (LPD) on glomerular filtration rate (GFR) in normoalbuminuric insulin-dependent-diabetes mellitus (IDDM) patients. RESEARCH DESIGN AND METHODS: A crossover randomized clinical trial was performed in 15 normoalbuminuric IDDM patients, 9 normofiltering, and 6 hyperfiltering patients. They followed three diets for a 3-week period each: a usual diet (UD), an LPD (0.5 g.kg-1.day-1 of proteins, 7% calories as protein, 33% as fat, and 60% as carbohydrates), and a normoproteic isocaloric test diet in which white meat (chicken and fish) was substituted for red meat of the UD. At the end of each diet, a clinical evaluation and measurements of GFR (51Cr-ethylenediaminetetraacetate (EDTA) single injection technique), urinary albumin excretion (UAE), and plasma amino acids were performed. Dietary compliance was assessed by a 24-h urinary urea and weekly interviews with the dietitian. RESULTS: In all diabetic patients, GFR after the LPD (114.9 +/- 16.5 ml.min-1 x 1.73 m-2) and after the test diet (122.7 +/- 16.7 ml.min-1 x 1.73 m-2) was significantly lower than after the UD (132.0 +/- 27.7 ml.min-1 x 1.73 m-2) (P = 0.001). Similar results were found in the hyperfiltering group: after UD = 161.1 +/- 15.4 ml.min-1 x 1.73 m-2, after LPD = 129.8 +/- 9.0 ml.min-1 x 1.73 m-2, and after the test diet = 136.5 +/- 3.1 ml.min-1 x 1.73 m-2, (P < 0.001). In the normofiltering group, no significant changes in GFR were observed after the three diets. Metabolic control, nutritional indexes, blood pressure (BP), and UAE did not change after the three diets in all patients. CONCLUSIONS: A normoproteic diet with chicken and fish as the only meat protein source decreases the GFR in the hyperfiltering normoalbuminuric IDDM patients. The GFR reduction after this diet is similar to that observed after an LPD.

Risk factors for development of proteinuria by type II (non-insulin dependent) diabetic patients.

1. Renal involvement in non-insulin dependent diabetes mellitus patients is the single most important cause of renal failure. The aim of this study was to evaluate the clinical features and to assess the risk factors for the development of proteinuria by non-insulin dependent diabetic patients. 2. Risk factors (expressed as an odds ratio) were calculated by multiple logistic regression analysis taking into account age, sex, body mass index, known duration of diabetes, presence of arterial hypertension, fasting plasma glucose, cholesterol and triglycerides as independent variables and proteinuria as the dependent variable. Sixty-four normoalbuminuric (24-h albumin excretion rate < 30 micrograms/min, 27 females, mean age 53.7 years) and 53 proteinuric (24-h proteinuria > 0.5 g, 31 females, mean age 59.3 years) were studied. 3. Proteinuric patients were older, with a longer mean known duration of diabetes (12.4 vs 5.6 years), higher mean fasting plasma glucose (214 vs 168 mg/dl) and plasma creatinine (1.5 vs 1.1 mg/dl) and more frequently presented diabetic retinopathy (94% vs 23%), peripheral neuropathy (94% vs 23%) and arterial hypertension (73% vs 16%) than normoalbuminuric patients. Age > 50 years, body mass index > 28.6 kg/m2, known duration of diabetes > 10 years, presence of arterial hypertension, and fasting plasma glucose > 160 mg/dl were significantly and independently associated with development of proteinuria.

Is endogenous creatinine clearance still a reliable index of glomerular filtration rate in diabetic patients?

Three methods routinely used for estimation of renal function - plasma creatinine, endogenous creatinine clearance and estimation of endogenous creatinine clearance from plasma creatinine - are compared with the measurement of glomerular filtration rate based on a single injection of 51Cr-EDTA, a technique that was standardized for this study in 20 healthy volunteers. The different creatinine methods were compared with the 51Cr-EDTA method in 30 diabetic patients, resulting in 68 sets of data in which all four estimates were made simultaneously. Spearman's correlation values (rs) for comparing the three creatinine methods with that of 51Cr-EDTA were 0.74, 0.40 and 0.82 (P less than 0.05). It is suggested that the use of endogenous creatinine clearance to estimate the glomerular filtration rate (GFR) requires caution and the recognition of the limitations of the method, and that simpler techniques (serum creatinine or estimated endogenous creatinine clearance) are preferable in routine practice. GFR based on 51Cr-EDTA injection is the method of choice for monitoring renal function in special situations such as renal transplantation and progressive nephropathies.