Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients

Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes. To determine whether the TZD-induced improvement in glycemic control is associated with enhanced insulin receptor signaling in skeletal muscle, 20 type 2 diabetic patients received a 75-g oral glucose tolerance test (OGTT) and euglycemic insulin (80 mU x m(-2) x min(-1)) clamp with [3-(3)H]glucose/indirect calorimetry/vastus lateralis muscle biopsies before and after 16 weeks of rosiglitazone treatment. Six age-matched nondiabetic subjects served as control subjects. RSG improved fasting plasma glucose (185 +/- 8 to 139 +/- 5 mg/dl), mean plasma glucose during the OGTT (290 +/- 9 to 225 +/- 6 mg/dl), HbA(1c) (8.5 +/- 0.3 to 7.1 +/- 0.3%), insulin-mediated total-body glucose disposal (TGD) (6.9 +/- 0.7 to 9.2 +/- 0.8 mg x kg(-1) fat-free mass x min(-1)) (all P < 0.001), and decreased fasting plasma free fatty acid (FFA) (789 +/- 59 to 656 +/- 50 micro Eq/l) and mean FFA during the OGTT (644 +/- 41 to 471 +/- 35 micro Eq/l) (both P < 0.01). Before RSG treatment, insulin infusion did not significantly increase insulin receptor tyrosine phosphorylation (0.95 +/- 0.10 to 1.08 +/- 0.13 density units; NS) but had a small stimulatory effect on insulin receptor substrate (IRS)-1 tyrosine phosphorylation (1.05 +/- 0.10 to 1.21 +/- 0.12 density units; P < 0.01) and the association of p85 with IRS-1 (0.94 +/- 0.06 to 1.08 +/- 0.06 activity units; P < 0.01). RSG therapy had no effect on basal or insulin-stimulated insulin receptor tyrosine phosphorylation but increased insulin stimulation of IRS-1 tyrosine phosphorylation (1.13 +/- 0.11 to 1.56 +/- 0.17 density units; P < 0.01 vs. prerosiglitazone) and p85 association with IRS-1 (1.00 +/- 0.06 to 1.27 +/- 0.07 activity units; P < 0.05 vs. prerosiglitazone). In control and type 2 diabetic subjects, TGD/nonoxidative glucose disposal correlated positively with the insulin-stimulated increments in IRS-1 tyrosine phosphorylation (r = 0.52/r = 0.57, P < 0.01) and inversely with the plasma FFA concentration during the insulin clamp (r = -0.55/r = -0.53, P < 0.01). However, no significant association between plasma FFA concentrations during the insulin clamp and the increment in either IRS-1 tyrosine phosphorylation or the association of p85 with IRS-1 was observed. In conclusion, in type 2 diabetic patients, rosiglitazone treatment enhances downstream insulin receptor signaling in muscle and decreases plasma FFA concentration while improving glycemic control.     

Causes of albuminuria in patients with type 2 diabetes without diabetic retinopathy

BACKGROUND: The causes of albuminuria in patients with type 2 diabetes are heterogeneous and are scantily investigated, particularly if the patient has a lack of diabetic retinopathy. Therefore, we evaluated the structural background of albuminuria in a large consecutive group of Caucasian patients with type 2 diabetes without retinopathy. METHODS: Three hundred forty-seven consecutive patients with type 2 diabetes with persistent albuminuria (>300 mg/24 h) were recorded. Fundus photo (80%) and ophthalmoscopy were performed. Ninety-three (27%) had no retinopathy, and a kidney biopsy was performed in 52 (56%) of these patients. An insufficient tissue sample was obtained in one patient. The biopsies were evaluated by three masked nephropathologists. RESULTS: The biopsies revealed diabetic glomerulopathy in 69% of the patients (28 males and 7 females), while the remaining 31% (95% CI, 18 to 44) had either nondiabetic glomerulopathies such as glomerulonephritis (N = 7, 6 males and 1 female, 13%) or normal glomerular structure (N = 9, 7 males and 2 females, 18%). No significant differences in sex, age (56 +/- 8 vs. 53 +/- 10 years, mean SD), body mass index (30 +/- 4 vs. 31 +/- 8 kg/m2), known duration of diabetes (6 +/- 6 vs. 4 +/- 3 years), GFR (95 +/- 29 vs. 89 +/- 31 mL/min/1.73 m2), albuminuria (1304 +/- 169 to 4731 vs. 1050 +/- 181 to 5176 mg/24 hours), blood pressure (150/87 +/- 16/9 vs. 145/89 +/- 16/9 mm Hg), prevalence of hypertension (89 vs. 100%), hemoglobin A1c (8.2 +/- 1.6% vs. 9.0 +/- 2.5%), and serum total cholesterol (7.1 +/- 2.4 vs. 6.3 +/- 1.6 mmol/L) were found between patients with and without diabetic glomerulopathy. CONCLUSIONS: Albuminuric patients with type 2 diabetes without diabetic retinopathy have a prevalence of biopsies with normal glomerular structure or nondiabetic kidney diseases of approximately 30%. A separation between diabetic and nondiabetic glomerular lesions was not possible based on demographic, clinical, or laboratory data. Consequently, such patients may require further evaluation, including a kidney biopsy.     

Podocyte number in normotensive type 1 diabetic patients with albuminuria

We estimated glomerular cell number in 50 normotensive type 1 diabetic patients with raised albumin excretion rate (AER) and investigated any change after 3 years in a subgroup of 16 placebo-treated patients. Biopsies from 10 normal kidney donors were used as controls. Mesangial and endothelial cell number was increased in the 50 diabetic patients at the start of the study compared with control subjects. There was no difference in podocyte number. Glomerular volume was increased in diabetic patients, but surface area of glomerular basement membrane (GBM) underlying the podocytes did not differ between groups. AER correlated positively with mesangial cell number in microalbuminuric patients (r = 0.44, P = 0.012) and negatively with podocyte number in proteinuric patients (r = -0.48, P = 0.040). In the 16 placebo-treated patients, glomerular volume increased after 3 years owing to matrix accumulation and increased GBM surface area. Although overall cell number did not differ significantly from baseline, the decrease in podocyte number during follow-up correlated with AER at follow-up (r = -0.72, P = 0.002). In conclusion, cross-sectional analysis of podocyte number in type 1 diabetic patients with raised AER but normal blood pressure shows no significant reduction compared with nondiabetic control subjects. Longitudinal data provide evidence for an association between podocyte loss and AER, but whether cellular changes are a response to, a cause of, or concomitant with the progression of nephropathy remains uncertain.     

Serum uric acid level is positively related to albuminuria in type 2 diabetic patients

Objective To investigate association between serum uric acid (SUA), albuminuria and glomerular filtration rates (eGFR) in type 2 diabetic patients. Methods A total of 220 patients were enrolled in this cross-sectional study. According to urinary albumin excretion rates, patients were divided into 3 groups: normoalbuminuria (NAU) group, microalbuminuria (MAU) group, and macroalbumnuria group (MAAU). The first two groups were subdivided at SUA＞420 μmol/L (＞357 μmol/L, female) into normouricemia group and hyperuricemia group, at eGFR＞90 ml/min into high and low renal function groups. General information, blood biochemical results were collected to analyze the association between serum uric acid, eGFR, UAER and urine albumin quantification among different groups. Results The difference of SBP, duration of diabetes (DD), Scr, SUA and eGFR between every two groups were significant (P＜0.05). SBP, DD, Scr and SUA were highest in subjects with macroalbumnuria, second in microalbuminuria group, and lowest in normoalbuminuria group, while eGFR was lowest in macroalbumnuria group and highest in normoalbuminuria group. Prevalence of hyperuricemia in macroalbumnuria group (56.9%) and microalbuminuria group (51.2%) were also significantly higher than that in normoalbuminuria group (17.5%) (all P＜0.01). The difference of UAER in the subgroups of normouricemia and hyperuricemia was more significant in microalbuminuria group than in normoalbuminuria group. eGFR was significantly lower in hyperuricemia subgroups (P＜0.01). Age and SUA were significantlg higher in subjects with low renal function compared with high eGFR (P＜0.05). Linear regression analysis indicated SUA was negatively correlated with eGFR after adjusted age, DD and UAER (β＝-0.430, P＜0.01). Binary logistic regression analysis found that increased age, DD and SUA were risk factors of microalbuminuria [β＝1.092, 95％CI(1.025, 1.163), P＜0.01; β＝1.005, 95%CI(1.001, 1.009), P＜0.05; β＝1.407, 95％CI(1.052, 1.881), P＜0.05)] andSUA, age were risk factors of early renal function decline [β＝1.015, 95％CI(1.00, 1.023), P＜0.01; β＝1.098, 95％CI(1.006, 1.199), P＜0.05]. Conclusion SUA is independently associated with albumnuria and renal function decline in type 2 DM patients.     

Predictors of cardiovascular events in patients with type 2 diabetic nephropathy and hypertension: a case for albuminuria

Individuals with type 2 diabetes and nephropathy represent a particularly high-risk group for both adverse cardiac as well as renal events. Using the Irbesartan in Diabetic Nephropathy Trial (IDNT) cohort, our objective was to determine baseline characteristics of individuals with type 2 diabetic nephropathy and hypertension predictive for cardiac events. IDNT identified 1715 individuals with type 2 diabetic nephropathy and hypertension having serum creatinine of 1.0 to 3.0 mg/dL and urinary albumin excretion rates > or = 900 mg/day. A cardiovascular (CV) composite was used consisting of CV death, nonfatal MI, hospitalization for heart failure, stroke, amputation, and coronary and peripheral revascularization. Using multivariable Cox regression analysis, 41 baseline characteristics determined a priori were analyzed for their potential relationship to risk of experiencing a CV event. Of the 1715 individuals, 518 (30.2%) had at least one of the CV composite end points. Older age, male gender, longer duration of diabetes, history of cardiovascular disease, history of CHF, high urinary albumin:creatinine ratio, and low serum albumin were strong predictors for CV events; of these, prior history of CVD (RR 2.00, 95% CI 1.63-2.45; P < 0.0001) and high urinary albumin:creatinine ratio (RR 1.29 per natural log unit, 95% CI 1.13-1.48; P = 0.0002) at baseline were highly predictive for cardiovascular events. In conclusion, among individuals with hypertension and diabetic nephropathy, both the degree of albuminuria and lower serum albumin levels provide additional prognostic information concerning cardiovascular risk, in addition to traditional coronary risk factors.     

Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes

BACKGROUND: Although several important studies have been performed in hypertensive type 2 diabetic patients, it is not known whether lowering blood pressure in normotensive (BP <140/90 mm Hg) patients offers any beneficial results on vascular complications. The current study evaluated the effect of intensive versus moderate diastolic blood pressure (DBP) control on diabetic vascular complications in 480 normotensive type 2 diabetic patients. METHODS: The current study was a prospective, randomized controlled trial in normotensive type 2 diabetic subjects. The subjects were randomized to intensive (10 mm Hg below the baseline DBP) versus moderate (80 to 89 mm Hg) DBP control. Patients in the moderate therapy group were given placebo, while the patients randomized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication. The primary end point evaluated was the change in creatinine clearance with the secondary endpoints consisting of change in urinary albumin excretion, progression of retinopathy and neuropathy and the incidence of cardiovascular disease. RESULTS: The mean follow-up was 5.3 years. Mean BP in the intensive group was 128 +/- 0.8/75 +/- 0.3 mm Hg versus 137 +/- 0.7/81 +/- 0.3 mm Hg in the moderate group, P < 0.0001. Although no difference was demonstrated in creatinine clearance (P = 0.43), a lower percentage of patients in the intensive group progressed from normoalbuminuria to microalbuminuria (P = 0.012) and microalbuminuria to overt albuminuria (P = 0.028). The intensive BP control group also demonstrated less progression of diabetic retinopathy (P = 0.019) and a lower incidence of strokes (P = 0.03). The results were the same whether enalapril or nisoldipine was used as the initial antihypertensive agent. CONCLUSION: Over a five-year follow-up period, intensive (approximately 128/75 mm Hg) BP control in normotensive type 2 diabetic patients: (1) slowed the progression to incipient and overt diabetic nephropathy; (2) decreased the progression of diabetic retinopathy; and (3) diminished the incidence of stroke.     

Association of 276G>T adiponectin gene polymorphism to plasma adiponectin and albuminuria in type 2 diabetic patients

Purpose

The 276G>T polymorphism of the adiponectin (ADIPOQ) gene has been correlated with plasma adiponectin, type 2 diabetes (T2D) and its complications. Studies of the role of 276G>T polymorphism in the prevalence of T2D kidney disease are few and contradictory; ethnic differences might play a role. We aimed to assess the relationship of this polymorphism with albuminuria in a cohort of Caucasian T2D patients.

Methods

Consecutive T2D outclinic patients were screened and included upon informed consent; exclusion criteria were glomerular filtration rate (GFR) <30?ml/min, acute intercurrent illness and urinary tract infection. History, standard laboratory evaluation, total plasma adiponectin and genotyping for the 276 ADIPOQ locus were obtained.

Results

One hundred and three T2D patients were included. Forty-three (41.7%) of them had GG genotype, 50 (48.5%) had GT and 10 (9.7%) had TT genotype. Plasma adiponectin was significantly higher in TT-allele carriers (19.03?±?3.46???g/ml) than in GT (10.14?±?1.78???g/ml) and GG carriers (8.71?±?1.60???g/ml), P?=?0.003. Adiponectin was higher in albuminuric (13.97?±?2.07???g/ml) than in normoalbuminuric patients (6.91?±?0.88???g/ml), P?=?0.004. The prevalence of T allele was higher in normoalbuminuric patients [36 (69.2%) GT?+?TT carriers] than in albuminuric ones [24 (47.1%)], P?=?0.02. Logistic regression identified the following as predictors of albuminuria: GG genotype: P?=?0.003 (OR 4.2; CI 1.61?C10.96); low GFR: P?=?0.003 (OR 0.97; CI 0.95?C0.99); and high plasma adiponectin: P?=?0.012 (OR 1.07; CI 1.01?C1.14).

Conclusions

Our data suggest that 276G>T polymorphism of the ADIPOQ gene is associated with plasma adiponectin levels. By influencing adiponectinemia, 276G>T polymorphism might predict the presence of albuminuria in Caucasian T2D patients.     

Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes

Previous studies showed that low serum bilirubin concentrations are associated with increased risk of cardiovascular disease. To explore this further, we evaluated the relationships between serum bilirubin concentrations and the degree of urinary albumin excretion and other markers of subclinical atherosclerosis in 633 consecutive patients with type 2 diabetes. Multiple regression analysis showed that the serum bilirubin concentration was an independent determinant of and had a significant inverse correlation to the log urinary albumin excretion. Serum bilirubin concentrations were significantly lower in patients with than in those without cardiovascular disease. A significant inverse correlation was found between the serum bilirubin concentration and pulse wave velocity, while a significant positive correlation was found to the ankle-brachial index in a subgroup of 386 patients. Our study shows that the serum bilirubin level is associated with microalbuminuria and subclinical atherosclerosis in patients with type 2 diabetes.     

Aortic pulse wave velocity and albuminuria in patients with type 2 diabetes

Development of microalbuminuria increases the risk for cardiovascular disease (CVD) in type 2 diabetes. The nature of this relationship is unclear but may involve arterial stiffness, an independent risk marker for CVD mortality. Aortic pulse wave velocity (Ao-PWV) and albumin creatinine ratio (ACR) were measured in 134 consecutive patients with type 2 diabetes without overt renal impairment (serum creatinine <150 micromol/L). ACR ranged from 0.2 to 153 mg/mmol. Patients with raised ACR (>/=3 mg/mmol) had higher Ao-PWV, poorer diabetic control, and higher pulse pressure (PP) and systolic BP (SBP) (all P < 0.05) than those with normal ACR. The closest univariate associations of Ao-PWV were positively with age, duration of diabetes, SBP, PP, ACR, and insulin treatment and negatively with GFR and weight (all P < 0.01). In a multiple linear step-down regression analysis, the significant predictors of Ao-PWV were age, SBP or PP, duration of diabetes, gender, number of antihypertensive medications, and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which together explained 55% of the variance of Ao-PWV. When ACR was offered in place of arterial pressure to a separate model, ACR emerged as a significant predictor of Ao-PWV. After age adjustment, patients with lower, below median GFR had higher Ao-PWV than those with GFR above the median (P = 0.043). In patients with type 2 diabetes without overt renal impairment, raised ACR is associated with higher Ao-PWV, a relationship most likely mediated by raised BP. The association of Ao-PWV with reduced GFR suggests that even modest renal dysfunction may affect the viscoelastic properties of large arteries.     

Effect of suiphated glycosaminoglycans on albuminuria in patients with overt diabetic (type 1) nephropathy

Decreased expression of heparan sulphate has been shown in theglomerular basement membrane of patients with overt diabeticnephropathy. Low-molecular-weight heparin (LMWH) is a highlysulphated glycosaminoglycan with strong structural and functionalsimilarities to heparan sulphate. In a first study, we set outto assess if LMWH could decrease the urinary albumin excretionrate (AER) in diabetic patients with overt nephropathy. Sixpatients entered a randomized, double-blind, placebo-controlledcrossover study with treatment episodes of 1 month, separatedby a 1-month wash-out. Patients self-administered prefilledsyringes with either placebo or LMWH (enoxaparin 40 mg/0.4 ml)at bedtime. Baseline AER levels before either treatment periodwere similar. In contrast to placebo, AER significantly decreasedfrom 447 (181—1102) to 295 (100—873) µg/minafter 1 month treatment with LMWH (P<0.05). Compared to placebo,the effect of LMWH did not reach statistical significance inthese six patients after 1 month treatment (P=0.16). Haemodynamicvariables including glomerular filtration rate and filtrationfraction did not change during enoxaparin treatment. We observed a favourable effect on AER during LMWH treatmentin diabetic patients with overt nephropathy. These data suggestthat long-term treatment trials in a larger group of patientsmay potentially demonstrate a new therapeutic option for patientswith overt diabetic nephropathy.     

Bladder dysfunction in type 2 diabetic patients

AIMS: To reevaluate urodynamic findings of bladder dysfunction (BD) in type 2 diabetic patients with patient characteristics and concommittant chronic complications. METHODS: Patients (M/F:27/27) with lower urinary tract symptoms (LUTS) underwent a detailed urodynamic investigation. Urodynamic findings were classified as diabetic cystopathy [DC, characterized by impaired bladder sensation, increased post-void residual urine (PVR) and increased bladder capacity and decreased bladder contractility], detrusor overactivity, bladder outlet obstruction (BOO), urge and stress urinary incontinence or BD in which one of the alterations was included. Glycated hemoglobin (HbA1C), diabetic retinopathy, nephropathy, sensorimotor, and autonomic neuropathies were evaluated. RESULTS: BD was present in 74.07% of men (DC, 50%; BOO, 25%; detrusor overactivity, 25%) and in 59.26% of diabetic women (DC, 43.75%; detrusor overactivity, 31%; urge incontinence, 12.5%; stress urinary incontinence 12.5%). In men, age, duration of diabetes and HbA1C threshold values predicting BD were >64 years, >9 year, >7.9%, while in women, they were >56 years, >8 years, >7%, respectively. Prolongation of QTc, abnormal esophageal transit and gastric emptying times, diabetic retinopathy, and microalbuminuria were associated with an increased risk of PVR >or= 100 ml. CONCLUSIONS: DC was the most frequent finding in patients. Ageing, duration of diabetes, worse metabolic control, PVR 100 ml, cardiac, esophageal and gastric parasympathetic autonomic neuropathies, retinopathy, and microalbuminuria provided a means to predict BD in patients in order to investigate by urodynamics. The establishment of DC in at least 8-9 years after the diagnosis of type 2 DM was an important parameter to inform our diabetic patients.     

Severity of albuminuria as an early indicator for wound healing in type 2 diabetic foot ulcers

This study aimed to investigate the relationship between the severity of albuminuria and wound healing in type 2 diabetic foot ulcers. A total of 121 patients with diabetic foot ulcers were recruited from January 2015 to June 2017 and divided into nonproliferation and proliferation groups according to their healing status. Univariate and multivariate logistic regression were performed to assess the risk factors of wound proliferation. Skin biopsies were also taken from normal tissue near the wound in 54 participants. The microvessel density as well as the relationships among the microvessel density, albuminuria and wound proliferation were evaluated. Results showed that in a multiple linear regression model, factors including body‐mass index, microalbuminuria, and macroalbuminuria showed independently significant association with wound healing in patients. The receiver operating characteristic curve analysis indicated albuminuria as a predicator for wound healing with a cutoff value of 32 mg/g. Meanwhile, normoalbuminuric patients showed significantly higher level of skin microvessels density than microalbuminuria and macroalbuminuria patients, while microalbuminuria patients also had statistically more microvessels that macroalbuminuria patients. The microvessel density were statistically significantly higher in the proliferation group than that in the nonproliferation group. In summary, this study suggested that albuminuria can be used as an independent indicator for the healing of type 2 diabetic foot ulcers.     

Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients.

A prospective study of the prevalence and causes of persistent albuminuria (greater than 300 mg/24 hr) was conducted in non-insulin-dependent diabetic (NIDDM) patients, age less than 66 years, attending a diabetic clinic during 1987. All eligible patients (N = 370) were asked to collect at least one 24-hour urine sample for albumin analysis. Urine collection was obtained in 224 males and 139 females (98%). Fifty patients (7 women) suffered from persistent albuminuria (13.8%). The prevalence of albuminuria was significantly higher in males (19%) than in females (5%). A kidney biopsy was performed in 35 patients (70%). The kidney biopsies revealed diffuse and/or nodular diabetic glomerulosclerosis in 27 patients (77%), while the remaining eight patients (23%) had a variety of non-diabetic glomerulopathies, such as minimal lesion and mesangioproliferative glomerulonephritis. Diabetic retinopathy was present in 15 of 27 patients (56%) with diabetic glomerulosclerosis, while none of the eight patients with a non-diabetic glomerulopathy had retinopathy. Our cross sectional study has revealed a high prevalence of albuminuria and of non-diabetic glomerulopathy as a cause of this complication in NIDDM patients. Presence of diabetic retinopathy strongly suggests that a diabetic glomerulopathy is the cause of albuminuria. Albuminuric non-insulin-dependent diabetic patients without retinopathy require further evaluation, that is, kidney biopsy.     

Endocan and albuminuria in type 2 diabetes mellitus

Background: Endocan is a newly identified proteoglycan released from endothelium, stimulating angiogenesis and when increased, indicates endothelial activation (inflammation). Our aim was to examine the association between serum endocan levels and urine albumin–creatinine ratio (UACR).

Method: One hundred and thirty-seven patients with type 2 diabetes mellitus and normal serum creatinine who had no co-morbidities other than hypertension, diabetic nephropathy, retinopathy, or neuropathy were divided into normoalbuminuria (G1), microalbuminuria (G2), and macroalbuminuria (G3) groups and compared cross-sectionally regarding serum endocan levels.

Result: There were 55, 47, and 35 patients in G1, G2, and G3, respectively. The groups were comparable in terms of gender, age, duration of diabetes, diabetic neuropathy/retinopathy, fasting glucose, HbA1c, serum creatinine level, and eGFR. Patients in G3 had significantly higher blood pressure but lower serum albumin and endocan levels. UACR showed a negative bivariate correlation with serum endocan levels (r?=??.282, p?=?.001). There was bivariate positive correlation between endocan and systolic blood pressure (r=.185, p?=?.030). In linear regression analysis, UACR was negatively correlated with endocan while positively correlated with systolic blood pressure, duration of diabetes, and platelet distribution width.

Conclusion: Patients with macroalbuminuria had lower endocan levels, and increasing UACR was associated with decreasing serum endocan levels. Despite the occurrence of angiogenesis and glomerular hypertrophy in the early phase of diabetic nephropathy, ensuing significant renal injury over time may reduce the expression of endocan. Serum endocan levels may represent a novel marker for nephropathy progression.     

Effect of angiotensin-converting enzyme inhibition on renal function and albuminuria in normotensive type I diabetic patients.

Normotensive patients with insulin-dependent (type I) diabetes mellitus (n = 18) were given 25 mg captopril (b.i.d.) and placebo for 3 mo in a randomized double-blind crossover study. Patients had normal renal function, and none had retinopathy. Albuminuria was less than 20 micrograms/min in 12 patients and between 20 and 200 micrograms/min in the other 6. Patients were examined at the end of the placebo and captopril phases. Captopril caused little reduction in blood pressure obtained by 24-h ambulatory monitoring (systolic 126.0 +/- 2.7 to 123.9 +/- 2.4 mmHg, P less than 0.08; diastolic 74.2 +/- 1.9 to 72.1 +/- 1.9 mmHg, P less than 0.09). Captopril lowered glomerular filtration rate from 99.5 +/- 7.7 to 71.0 +/- 5.5 ml.min-1. 1.73 m-2 (P less than 0.01), whereas renal plasma flow (443.9 +/- 15.2 ml.min-1. 1.73 m-2) remained unchanged. Filtration fraction was reduced from 22.4 +/- 1.4 to 17.4 +/- 1.4% (P less than 0.01). Urinary albumin excretion was reduced from 59.1 +/- 0.15 to 27.7 +/- 13.9 micrograms/min (P less than 0.1). Reduction was related to the extent of initial albuminuria (r = 0.997, P less than 0.001), a relationship that remained significant after logarithmic transformation (r = 0.540, P less than 0.02). Dextran clearance was used to determine glomerular capillary function. Angiotensin inhibition caused reduction in effective glomerular pore size and also reduced flow via the nondiscriminatory shunt. Angiotensin inhibition in normotensive patients with type I diabetes was well tolerated. Reduction in albuminuria is mediated by a combination of hemodynamic changes and alterations in glomerular capillary function.     

Relationship between serum Dickkopf-1 and albuminuria in patients with type 2 diabetes

BACKGROUND Diabetic kidney disease is a microvascular complication of diabetes with complex pathogenesis. Wingless signaling-mediated renal fibrosis is associated with diabetic kidney disease. Dickkopf-1, a negative regulator of Wingless, has been proven to participate in renal fibrosis, glucose metabolism, and inflammation. However, whether serum Dickkopf-1 levels are associated with diabetic kidney disease remains unclear.AIM To assess the relationship between serum Dickkopf-1 levels and albuminuria in individuals with type 2 diabetes.METHODS Seventy-three type 2 diabetes patients and 24 healthy individuals were enrolled in this case-control study. Diabetic individuals were separated into normal albuminuria, microalbuminuria, and macroalbuminuria groups based on their urinary albumin/creatinine ratios(UACRs). Clinical characteristics and metabolic indices were recorded. Serum Dickkopf-1 levels were determined by enzymelinked immunosorbent assay.RESULTS No significant difference in serum Dickkopf-1 levels was found between healthy individuals and the normal albuminuria group. However, the levels in the microalbuminuria group were significantly lower than those in the normal albuminuria group(P = 0.017), and those in the macroalbuminuria group were the lowest. Bivariate analysis revealed that serum Dickkopf-1 levels were positively correlated with hemoglobin A1 c level(r = 0.368, P 0.01) and estimated glomerular filtration rate(r = 0.339, P 0.01), but negatively correlated with diabetes duration(r =-0.231, P = 0.050), systolic blood pressure(r =-0.369, P = 0.001), serum creatinine level(r =-0.325, P 0.01), and UACR(r =-0.459, P 0.01). Multiple and logistic regression showed that serum Dickkopf-1 levels were independently associated with UACR(odds ratio = 0.627, P = 0.021).CONCLUSION Serum Dickkopf-1 levels are negatively associated with UACR. Lower serum Dickkopf-1 levels could be a critical risk factor for albuminuria in diabetes.     

Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria.

BACKGROUND: Urinary albumin excretion frequently persists in diabetic patients who are treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Sulodexide, a glycosaminoglycan mixture of 80% heparan sulfate and 20% dermatan sulfate, has been hypothesized to reduce persistent albuminuria. We have conducted a multi-center randomized double-blind pilot study in order to determine the effect of 6 months' therapy with sulodexide on urinary albumin excretion and to address logistical issues for a full-scale trial. METHODS: A total of 149 patients with type 2 diabetes and an albumin:creatinine ratio (ACR) between 20 and 300 mg/g were randomized with equal allocation to either placebo, 200 mg of sulodexide or 400 mg of sulodexide. The primary endpoint was the achievement, at 6 months, of either 3(1) return to normoalbuminuria (ACR < 20 mg/g with a decrease of at least 25%) or (2) a decrease in ACR of at least 50% from the baseline value. All patients used a maximum tolerated recommended FDA approved dose of an ACEI or ARB for at least 60 days and had stable blood pressure prior to randomization. RESULTS: The primary efficacy endpoint was achieved in 25.3% of the patients in the two sulodexide groups combined versus 15.4% of the placebo-treated patients (P = 0.26). The primary endpoint was achieved in 33.3% (P = 0.075 for the comparison to placebo) in the sulodexide 200 mg group and 18.4% (P = 0.781) in the sulodexide 400 mg group. (No consistent patterns of side effects were observed. CONCLUSION: Based on the experience gained in this pilot study, one full-scale trial is currently being conducted to evaluate the effects of sulodexide on change in ACR in patients with persistent microalbuminuria, and a longer-term trial is underway to evaluate the effects of sulodexide on long-term renal disease progression in patients with overt proteinuria.     

Progression of nephropathy in type 2 diabetic patients

BACKGROUND: Nephropathy in type 2 diabetes is the single most common cause of end-stage renal disease (ESRD), but the decline in kidney function varies considerably between individuals, and determinants of renal function loss, early in the course of renal disease, have not been clearly identified. METHODS: In a prospective observational study, we followed 227 (60 female) Caucasian type 2 diabetic patients with nephropathy for 6.5 (range 3 to 17) years from a baseline glomerular filtration rate (GFR) of 83 (SD30) mL/min/1.73m(2) with 7 (range 3 to 22) measurements of GFR ((51)Cr-EDTA) per patient. We evaluated determinants of (1) rate of decline in GFR, (2) risk of doubling in serum creatinine or ESRD, and (3) mortality using potential risk factors at baseline and during follow-up. RESULTS: The mean (SD) rate of decline in GFR was 5.2 (4.1) mL/min/year. In multivariate regression analysis, higher baseline albuminuria, systolic blood pressure (SBP), hemoglobin A1c, GFR, age, and degree of diabetic retinopathy were significantly associated with increased rate of decline in GFR (R(2) (adj) 0.24). During follow-up, elevated mean albuminuria, SBP, hemoglobin A1c, and lower hemoglobin, heavy smoking, and presence of diabetic retinopathy were significantly associated with increased decline in GFR (R(2) (adj) 0.26). During follow-up, 63 patients had a doubling in serum creatinine or developed ESRD, and 79 patients died, primarily due to cardiovascular disease. In Cox regression analysis, higher baseline albuminuria, hemoglobin A1c, and SBP, together with lower GFR and hemoglobin, were significantly associated with shorter time to doubling of serum creatinine or ESRD. Higher baseline albuminuria, hemoglobin A1c, SBP, and age were significantly associated with increased mortality. CONCLUSION: Our long-term prospective study of type 2 diabetic patients with nephropathy has revealed several modifiable risk factors of enhanced progression in kidney disease and increased mortality.     

Familial clustering of diabetic nephropathy in Brazilian type 2 diabetic patients

There is evidence for genetic predisposition to diabetic nephropathy in type 1 diabetic patients. However, there are few studies on type 2 diabetic patients, and most of those have been conducted on ethnic minorities or Caucasian individuals. The aim of this study was to ascertain the presence of an inherited predisposition to diabetic nephropathy in a sample of Brazilian type 2 diabetic patients. Families with two or more type 2 diabetic siblings were identified. Subjects with the longest duration of known diabetes were considered probands. Some 90 probands and their 107 diabetic siblings were studied. Urinary albumin excretion rate was measured in a sterile 24-h urine sample on at least three different occasions. Probands and siblings were classified according to urinary albumin excretion rate as normo- (<20 microg/min), micro- (20-200 microg/min), or macroalbuminuric (>200 microg/min). Patients with end-stage renal disease were included in the macroalbuminuric group. Macroalbuminuria was identified in 5.2% of the siblings of normoalbuminuric probands and in 24.1% of the siblings of macroalbuminuric probands (P = 0.024). In multiple logistic regression, the presence of diabetic nephropathy in probands (micro- or macroalbuminuria and end-stage renal disease) was significantly associated with the presence of sibling diabetic nephropathy (odds ratio = 3.75, 95% CI = 1.36-10.40, P = 0.011) adjusted for proband fasting plasma glucose and diabetes duration. Interpretation of these results should take into account the possibility that the families including siblings with diabetic nephropathy may have been overcounted and, on the other hand, that the siblings without diabetic nephropathy may have been undercounted. In conclusion, there is a familial aggregation of diabetic nephropathy in this sample of type 2 diabetic patients.     

Captopril acutely lowers albuminuria in normotensive patients with diabetic nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors decrease albuminuria in patients with diabetic nephropathy. To study the change in albuminuria in relation to changes in systemic and renal hemodynamics, nine normotensive patients with type 1 (insulin-dependent) diabetes mellitus and persistent proteinuria were given a single oral dose of 25 mg of the ACE inhibitor captopril. Blood pressure, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and albumin excretion rate (AER) were measured in two periods of 40 minutes before and in four periods of 40 minutes after administration of captopril. A constant water diuresis was maintained. Blood pressure did not decrease significantly (130/79 +/- 4/3 v 124/74 +/- 4/3 mm Hg; mean +/- SEM), median AER decreased from 403 (interquartile range [IQR], 812) micrograms/min to 333 (707) micrograms/min (P < 0.01). GFR did not change (123 +/- 13 v 117 +/- 14 mL/min), but ERPF increased significantly from 609 +/- 56 to 714 +/- 55 mL/min (P < 0.01). Consequently, the filtration fraction (FF; quotient of GFR and ERPF) decreased from 0.20 +/- 0.014 to 0.17 +/- 0.014 (P < 0.01). A strong correlation was found between the decrease of AER and the decrease of FF (rs = 0.75; P < 0.02). No correlation was found between the decrease in AER and changes in GFR or blood pressure. In the normotensive patient with diabetic nephropathy, captopril causes an acute reduction of AER, which is probably mediated by a lowering of the intraglomerular pressure.