Associations of Bone Mineral Density and Bone Metabolism Indices with Urine Albumin to Creatinine Ratio in Chinese Patients with Type 2 Diabetes.

OBJECTIVE: To identify correlations of bone mineral density (BMD) and bone metabolism indices with the urine albumin to creatinine ratio (ACR) as an indicator of nephropathy in Chinese patients with type 2 diabetes (T2D). METHODS: In this retrospective analysis, 297 patients with T2D were divided into 3 groups according to the urine ACR. Patients' data were analyzed to identify associations of general conditions, blood glucose level, lipid levels, and uric acid level with BMD and bone metabolism indices. RESULTS: BMD at every location tested (femoral neck, trochanter, inside hip, Ward's triangle, total hip, and lumbar vertebrae) was negatively correlated with the urine ACR (all p<0.05). Osteocalcin, beta-C-terminal telopeptide (ß-CTX), and procollagen type 1 N- peptide (P1NP) were positively correlated with urine ACR (all p<0.05). Finally, 25-hydroxyvitamin D [25(OH)D] was negatively correlated with urine ACR (p<0.05). Multiple regression analysis with adjustment for age, body mass index, disease duration, and other clinical measurements revealed no significant correlation between urine ACR and BMD measurements or ß-CTX (p>0.05). However, significant correlations remained between urine ACR and osteocalcin, P1NP, and 25(OH)D (p<0.05). The same results were obtained for postmenopausal women specifically, with the exception of a significant correlation between the ACR and ß-CTX (p<0.05). CONCLUSION: In the early stage of diabetic nephropathy, BMD changes and bone transformation acceleration may occur, and the acceleration of bone transformation may occur before the change in BMD. Therefore, it is important to monitor bone metabolism indices in the early stage of diabetic nephropathy in T2D patients.

Can both normal and mildly abnormal albuminuria and glomerular filtration rate be a danger signal for diabetic peripheral neuropathy in type 2 diabetes mellitus?

We aimed to investigate the potential association between urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) and diabetic peripheral neuropathy (DPN). We were especially interested in the relationship between normal or mildly abnormal UACR and eGFR with DPN. A retrospective study was performed in 1059 patients with type 2 diabetes patients from Fuzhou, China, who were seen between 2010 and 2015. The DPN population demonstrated higher UACR and lower eGFR than the non-DPN population. Nerve conduction velocities (NCVs) were negatively correlated with UACR and were positively correlated with eGFR. UACR and eGFR were associated with the risk of DPN. Even in the UACR < 30 mg/g and eGFR ≥ 60 ml/min/1.73 m2 groups, the relationship above still existed and patients in the highest tertiles of UACR and lowest tertiles of eGFR demonstrated a greater risk of DPN (OR = 2.456, 95% CI 1.461-4.127; OR = 2.021, 95% CI 1.276-3.203). Receiver operating characteristic (ROC) analysis revealed that the area under curve (AUC) of UACR, eGFR, and joints indicates that DPN was 0.749, 0.662, and 0.731, respectively. Lower eGFR and higher UACR may be associated with the risk of DPN, even though normal or mildly abnormal UACR and eGFR have already been found to be predictive factors of DPN. Further, UACR is more sensitive than eGFR. Separately, UACR was a moderate indication of DPN, and combining it with eGFR did not increase its effect of indication to DPN.

Serum albumin is associated with peripheral nerve function in patients with type 2 diabetes.

The aim of this study is to investigate the association between serum albumin concentrations and nerve conduction (NC) parameters in Chinese patients with type 2 diabetes (T2DM). A total of 409 T2DM patients were enrolled between October 2010 and April 2014. All participants underwent nerve conduction studies. The composite Z scores for NC parameters including conduction velocity (CV), amplitude, and latency were calculated as well. Serum albumin was measured by Bromcresol Green dye-binding method. The composite Z scores of CV and amplitude increased with the increasing albumin tertiles (test for trend, both P < 0.001), while the composite Z score of latency decreased with increasing albumin tertiles (test for trend, P < 0.001). After adjusting for age, sex, duration, and HbA1c, higher serum albumin concentrations were associated with higher composite Z scores of CV (ß = 0.314, P < 0.001), amplitude (ß = 0.279, P < 0.001), and lower composite Z score of latency (ß = -0.279, P < 0.001). When participants were stratified into albuminuria and normoalbuminuria group, we found the associations of serum albumin with composite Z scores of NC parameters remained significant only in the albuminuria group (CV Z score: ß = 0.253, P = 0.002; amplitude Z score: ß = 0.233, P = 0.006; latency Z score: ß = -0.217 P = 0.013) after further adjustment for urinary albumin to creatinine ratio. The optimal cutoff point of serum albumin to indicate abnormal peripheral nerve function was 36.75 g/L in T2DM patients with albuminuria, with a sensitivity of 65.6 % and a specificity of 78.0 %. Serum albumin was independently associated with peripheral nerve function in T2DM patients, especially in those with albuminuria. Serum albumin could be a potential biomarker for diabetic peripheral neuropathy.

Retinal nerve fiber layer loss is associated with urinary albumin excretion in patients with type 2 diabetes.

OBJECTIVES: To identify the factors associated with retinal nerve fiber layer (RNFL) loss in patients with type 2 diabetes. DESIGN: Cross-sectional study. PARTICIPANTS: Ninety-six nonglaucomatous patients with type 2 diabetes without renal impairment (estimated glomerular filtration rate, ≥60 ml/minute per 1.73 m(2)). METHODS: Eyes were divided into 2 groups based on the presence or absence of RNFL defects detected by red-free retinal fundus photography. All participants underwent an eye fundus examination, and the urinary albumin-to-creatinine ratio (ACR) was determined. A cardiovascular autonomic function test was performed using the following heart rate variability parameters: expiration-to-inspiration ratio, response to the Valsalva maneuver, and standing. Multiple logistic regression analyses were performed to determine potential risk factors related to the presence of RNFL defects in these patients. MAIN OUTCOMES AND MEASURES: The association between RNFL defects and diabetic complications. RESULTS: Among the patients, 43 (44.8%) had localized RNFL defects (group 1), whereas the others (55.2%) did not (group 2). The RNFL defects occurred more frequently on the superior side (75.6% and 71.0% in right and left eyes, respectively) compared with the inferior side (13.8% and 0.0% in right and left eyes, respectively). Patients with RNFL defects (group 1) had significantly higher rates of diabetic retinopathy (60.5%) compared with those without RNFL defects (group 2; 32.1%; P = 0.007). The urinary ACR was significantly higher in patients with RNFL defects than in those without defects (45.3±72.1 µg/mg vs. 15.4±17.3 µg/mg creatinine, respectively; P = 0.015), whereas autonomic function test grading was similar between the groups. The urinary ACR was the only factor related to visual field defect location in both univariate (P = 0.021) and multivariate (P = 0.036) logistic regression analyses after adjusting for age; gender; presence of diabetic retinopathy; diabetes duration; smoking; statin use; and antiplatelet, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment. CONCLUSIONS: Urinary albumin excretion was associated with nerve fiber layer loss in patients with type 2 diabetes. Careful examination of the optic nerve head may be necessary, particularly in patients with type 2 diabetes exhibiting albuminuria.

Atherogenic lipids and vascular complications in a selected diabetic population with normal urinary albumin/creatinine ratios.

OBJECTIVE: To test the hypothesis that at different urinary albumin/creatinine ratios within the normal ranges, diabetics have low but similar prevalence of metabolic and micro vascular disease. METHODS: The study sample consisted of normotensive diabetics not taking any medications known to effect blood pressure and lipids. The data were collected from the Diabetes Register. The diabetics were subgrouped according to the urinary albumin/creatinine ratios. MA is defined as present if the albumin/creatinine ratio (ACR) is more than 2 mg/mmol. RESULTS: MA was present in 16% of the 152 diabetics. Total cholesterol, systolic BP, and triglycerides were significantly high in diabetics with ACR≥1<2 compared with <1. The prevalence rates for retinopathy and neuropathy in the MA group were also significantly high. However, a large number of diabetics without MA had had established complications (37% retinopathy, 40% neuropathy, and 16% peripheral vascular disease). Because these results were based on single early morning urine samples, we looked at their MA in the past year. After exclusion of regressed and progressed groups, the complications rate remained the same. CONCLUSION: The high prevalence of metabolic and vascular complications seen even in absence of MA indicates an early intervention and those diabetics should not wait unitl CVD risk scores raise to receive preventive treatment.

Urinary methylmalonic acid as an indicator of early vitamin B12 deficiency and its role in polyneuropathy in type 2 diabetes.

The rising incidence of diabetes and its negative impact on quality of life highlights the urgent need to develop biomarkers of early nerve damage. Measurement of total vitamin B12 has some limitations. We want to determine the levels of urinary methylmalonic acid and its relationships with serum vitamin B12 and polyneuropathy. The 176 Chinese patients with Type 2 diabetes mellitus were divided into 3 groups according to the levels of vitamin B12. A gas chromatography mass spectrometric technique was used to determine blood methylmalonic acid and urinary methylmalonic acid. The diagnosis of distal diabetic polyneuropathy was based on the determination of bilateral limb sensory and motor nerve conduction velocity and amplitude with electromyogram. Multiple regression analysis revealed that urinary methylmalonic acid/creatinine, blood methylmalonic acid, and so forth were variables that influenced diabetic polyneuropathy significantly. Nerve sensory conduction velocity and nerve amplitude in the group of urinary methylmalonic acid/creatinine >3.5 mmol/mol decreased significantly. Superficial peroneal nerve sensory and motor conduction velocity and ulnar nerve compound motor active potential amplitude were inversely correlated with urinary methylmalonic acid/creatinine. Urinary methylmalonic acid correlates with serum vitamin B12 levels in person with diabetes and is a sensitive marker of early polyneuropathy.

The co-occurrence of myocardial dysfunction and peripheral insensate neuropathy in a streptozotocin-induced rat model of diabetes.

BACKGROUND: Cardiomyopathy and distal symmetrical polyneuropathy (DSPN), including sensory and autonomic dysfunction, often co-occur in diabetic mellitus (DM) patients. However, the temporal relationship and progression between these two complications has not been investigated. Using a streptozotocin DM animal model that develops insensate neuropathy, our aim was to examine in parallel the development of DSPN and DM-associated changes in cardiac structure and function as well as potential mechanisms, such as autonomic dysfunction, evaluated by changes in urinary and myocardial norepinephrine content and myocardial neuronal markers. METHODS: Sensory neuropathy was measured by behavioral tests using Von Frey filaments and Hargreaves methods. Echocardiography was used to evaluate myocardial structure and function. Autonomic function was evaluated by measuring urinary and myocardial norepinephrine (NE) levels by enzyme-linked immunosorbent assay and high-performance liquid chromatography/mass spectrometry. Quantitative immunohistochemistry was used to measure the myocardial neuronal markers, calcitonin gene-related peptide (CGRP) and general neuronal protein gene product 9.5 (PGP 9.5). RESULTS: The DM group developed tactile and thermal insensate neuropathy 4-5 weeks after DM onset. Cardiovascular changes were found between 4 and 12 weeks after DM onset and included bradycardia, diastolic and systolic dysfunction and cardiac dilation. There was a 2.5-fold reduction in myocardial NE levels and a 5-fold increase in urinary NE levels in the DM group. Finally, there was a 2.3-fold increase in myocardial CGRP levels in the DM group and no change in PGP9.5 levels. CONCLUSIONS: Cardiovascular structural and functional changes developed early in the course of DM and in combination with insensate neuropathy. In parallel, signs of cardiac autonomic dysfunction were also found and included decreased myocardial NE levels and altered CGRP levels. These results may indicate the need for early cardiovascular evaluation in DM patients with insensate neuropathy.

A microarray analysis of urinary microRNAs in renal diseases.

BACKGROUND: MicroRNAs (miRNAs), a family of endogenous small non-coding RNAs, are associated with the development of renal diseases. To clarify whether urinary miRNAs (UmiRNAs) can be used for the evaluation of renal disease, we examined the profiles of UmiRNAs in various renal diseases. METHODS: We extracted miRNAs from urine specimens of 5 healthy controls and 71 patients with renal diseases, and we examined the correlation between clinical and histological parameters and the profile of UmiRNAs by microarray analysis. RESULTS: The urinary concentration of miRNAs increased in patients with renal disease compared with healthy controls, and the levels correlated with urinary protein and the degree of glomerular sclerosis. The microarray analysis detected 83-137 distinct UmiRNAs. We observed 80-99 % of the miRNAs in both the healthy controls and the renal disease patients. The majority of UmiRNAs displayed higher signal intensity in renal disease patients than in healthy controls, including 39 miRNAs exhibiting signal intensities 100 times greater than in healthy controls. A different pattern of UmiRNAs was observed in each type of renal disease. A comparison of renal tissue and UmiRNAs revealed that the sample profiles were similar and that their signal intensity was significantly correlated. CONCLUSION: This study demonstrated that UmiRNAs are correlated with renal pathological changes and that the profile of UmiRNAs presented different patterns corresponding to the type of renal disease. These results suggest that UmiRNAs can potentially be used as novel biomarkers for renal diseases.

Urinary n-acetyl-beta-d-glucosaminidase excretion: an indicator of neuropathy in type 2 diabetes.

The established marker for tubular damage, urinary n-acetyl-beta-d-glucosaminidase is significantly increased in type 1 and 2 diabetes patients and is related to albuminuria and other diabetic complications. In this cross sectional study of type 2 diabetes patients with a history of albuminuria, we studied the relationship between excretion of n-acetyl-beta-d-glucosaminidase in urine and diabetic neuropathy.160 type 2 diabetes patients were screened for diabetic peripheral neuropathy and cardiovascular autonomic neuropathy. N-acetyl-beta-d-glucosaminidase excretion was detected in 24 h urine samples.Urinary excretion of n-acetyl-beta-d-glucosaminidase correlated significantly with -glucose control (fasting glucose r=0.18; p=0.04; HbA1c r=0.20; p=0.02) and urine albumin excretion (r=0.22; p=0.01). Binary regression analyses showed that increased urinary n-acetyl-beta-d-glucosaminidase concentration is an independent predictor for presence of clinical symptoms of peripheral neuropathy (OR 1.8 [95%CI 1.2-2.74] and vibration deficiency [OR 1.7; 95% CI 1.2-2.66]. There was also a significant negative association between urinary n-acetyl-beta-d-glucosaminidase and E/I-Ratio (r=-0.21, p<0.02) as well as the 30:15-Ratio (r=-0.24; p<0.01) of heart rate variability. Furthermore, increased n-acetyl-beta-d-glucosaminidase excretion independently predicted cardiovascular autonomic diabetic neuropathy with an OR for decreased E/I-Ratio of 1.7 [95%CI 1.1-2.75]; (p<0.02) and 30:15-Ratio:OR 2.4 [95% CI 1.26-4.45]; (p<0.01).Urinary n-acetyl-beta-d-glucosami-nidase excretion is an independent marker for diabetic peripheral and cardiovascular autonomic neuropathy in type 2 diabetic patients.

Impact of diabetic polyneuropathy and cardiovascular autonomic neuropathy on the excretion of urinary 8-epi-PGF2alpha and its metabolites (2, 3-dinor and 2, 3-dinor-5, 6-dihydro).

The objective of this study was to establish if diabetes in the presence of polyneuropathy (PN) and/or cardiovascular autonomic neuropathy (CAN) is associated with alterations in the amounts of 8-epi-PGF2alpha (IP) and its metabolites including 2, 3-dinor-8-epi-PGF2alpha (dinor-IP) and 2, 3-dinor-5, 6 dihydro-8-epi-PGF2alpha (dinor-dihydro-IP) in urine. Mass spectrometric separation showed that excretion of IP was similar in the PN + /CAN- and PN+/CAN+ groups but higher than in the PN-/CAN- group (n = 103, 22 and 60, respectively; P < 0.05). By contrast, excretion of dinor-IP or dinor-dihydro-IP were similar in the PN-/CAN- and PN+/CAN- groups but higher than in PN+/CAN+ group. Correlations were obtained between IP and dinor-IP or dinor-dihydro-IP (r = 0.30; P < 0.001 and r = 0.31; P < 0.001, respectively). A significant association was also observed between dinor-IP and dinor-dihydro-IP (r = 0.48; P < 0.001). In conclusion, these biomarkers should prove useful in studies evaluating the impact of therapeutic drugs or antioxidant interventions aimed at delaying the onset of diabetic complications.

Duloxetine vs. placebo in patients with painful diabetic neuropathy.

The aim of this study was to examine the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain. Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/d (20 mg QD), 60 mg/d (60 mg QD), 120 mg/d (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score, which was rated on an 11-point (0-10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits. Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo on the 24-h Average Pain Score, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h Average Pain Score compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events. Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain.

Urinary concentration of transforming growth factor-beta-inducible gene-h3(beta ig-h3) in patients with Type 2 diabetes mellitus.

AIMS: The expression of TGF beta-inducible gene h3(beta ig-h3) has been used to assess the biological activity of TGF beta in the kidney. In this study, we investigated whether the urinary concentration of beta ig-h3 is associated with diabetic nephropathy in patients with Type 2 diabetes mellitus. We also evaluated the relationship between the urinary concentration of beta ig-3 and proteinuria and microalbuminuria (AER) in a normal healthy population and in Type 2 diabetes patients. METHODS: Four hundred and seventy-nine Type 2 diabetic patients without non-diabetic kidney diseases and 528 healthy control subjects were enrolled. The study subjects were divided into five groups: a non-diabetic healthy control group with normal ACR (n = 443), a non-diabetic healthy control group with microalbuminuria (n = 85), a normoalbuminuric diabetic group (n = 198), a microalbuminuric diabetic group (n = 155) and an overt proteinuria group (n = 126). Urinary levels of beta ig-h3 were measured by enzyme-linked immunosorbent assay. RESULTS: (i) Urinary excretion of beta ig-h3 was significantly higher in the diabetic groups than in the controls, even in the normoalbuminuric stage (25.02 +/- 8.84 vs. 18.67 +/- 6.56, P = 0.03). In diabetic patients, urinary beta ig-h3 levels increased significantly as diabetic nephropathy advanced (25.02 +/- 8.84 vs. 34.06 +/- 24.55 vs. 169.63 +/- 57.33, P < 0.001). (ii) Proteinuria was found to be significantly correlated with urinary beta ig-h3 (healthy control; r = 0.137, P = 0.019, diabetic patients; r = 0.604, P < 0.001). ACR was also found to be significantly related with urinary beta ig-h3 in diabetic patients (r = 0.383, P = 0.006). (iii) In diabetic patients, urinary beta ig-h3 was significantly related with systolic and diastolic blood pressure (systolic blood pressure: r = 0.436, P = 0.024; diastolic blood pressure, r = 0.365, P = 0.042), total cholesterol and HbA(1c) (cholesterol: r = 0.169, P = 0.03, HbA(1c); r = 0.387, P = 0.044). Logistic regression analyses showed that urinary beta ig-h3 was associated with a significant increase in the risk of microalbuminuria and proteinuria in diabetic patients. CONCLUSIONS: Longitudinal monitoring of urinary beta ig-h3 may improve the likelihood of detecting diabetic nephropathy at an earlier stage and beta ig-h3 could be a sensitive marker of diabetic kidney disease progression.

Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy.

In the early stage of diabetic nephropathy (one of the major microvascular complications of diabetes) glomerular hyperfiltration and hypertrophy are observed. It is clinically important to regulate glomerular hypertrophy for preventing glomerulosclerosis. The number of glomerular endothelial cells is known to be increased in diabetic nephropathy associated with enlarged glomerular tufts, suggesting that the mechanism is similar to that of angiogenesis. Tumstatin peptide is an angiogenesis inhibitor derived from type IV collagen and inhibits in vivo neovascularization induced by vascular endothelial growth factor (VEGF), one of the mediators of glomerular hypertrophy in diabetic nephropathy. Here, we show the effect of tumstatin peptide in inhibiting alterations in early diabetic nephropathy. Glomerular hypertrophy, hyperfiltration, and albuminuria were suppressed by tumstatin peptide (1 mg/kg) in streptozotocin-induced diabetic mice. Glomerular matrix expansion, the increase of total glomerular cell number and glomerular endothelial cells (CD31 positive), and monocyte/macrophage accumulation was inhibited by tumstatin peptide. Increase in renal expression of VEGF, flk-1, and angiopoietin-2, an antagonist of angiopoietin-1, was inhibited by tumstatin treatment in diabetic mice. Alteration of glomerular nephrin expression, a podocyte protein crucial for maintaining glomerular filtration barrier, was recovered by tumstatin in diabetic mice. Taken together, these results demonstrate the potential use of antiangiogenic tumstatin peptide as a novel therapeutic agent in early diabetic nephropathy.

Cardiovascular autonomic neuropathy is associated with microalbuminuria in older patients with type 2 diabetes.

OBJECTIVE: Cardiovascular autonomic neuropathy is associated with microalbuminuria in young and middle-aged patients with type 2 diabetes. We examined this relationship and the potential mediating role of blood pressure in older patients. RESEARCH DESIGN AND METHODS: At least two of three components of cardiovascular autonomic testing were completed by 132 patients (mean age 70 +/- 5.6 years). Relative rankings on each of the components were averaged to create a summary heart rate variability (HRV) measure. The urine microalbumin-to-creatinine ratio (milligrams albumin/grams creatinine) was calculated. Blood pressure was measured at rest and by 24-h ambulatory recording. RESULTS: Urine microalbumin-to-creatinine ratio was higher in those with lower HRV (mean urine microalbumin-to-creatinine ratio 28, 56, and 191 mg/g from the highest to lowest tertile of HRV; P < 0.0001). Resting and ambulatory blood pressure levels were negatively correlated with HRV and positively correlated with urine microalbumin-to-creatinine ratio. In multivariate analysis adjusting for age, duration of diabetes, HbA(1c), and HDL cholesterol, HRV and blood pressure were both independently associated with urine microalbumin-to-creatinine ratio, with no evidence that either mediates the effect of the other. CONCLUSIONS: Cardiovascular autonomic neuropathy and blood pressure are independently associated with microalbuminuria in older patients with type 2 diabetes.

Absolute level and rate of change of albuminuria over 1 year independently predict mortality and cardiovascular events in patients with diabetic nephropathy.

AIMS: To determine the nature of the association between baseline albuminuria and risk of all-cause mortality and cardiovascular disease, and to determine if the rate of change of albuminuria from baseline over 1 year predicts these endpoints in patients with diabetic nephropathy. METHODS: Cohort study of 427 patients (161 Type 1 and 266 Type 2) with diabetic nephropathy defined as urinary albumin excretion (UAE) > or = 30 mg/24 h at baseline (mean age 53.4 years). Patients were recruited at the time of referral to a diabetic nephropathy clinic and followed up annually for an average of 5 years. UAE rate was re-measured at 1 year and the rate of change from baseline calculated. RESULTS: All-cause mortality and cardiovascular disease increased significantly and continuously across quintiles of baseline UAE (P for linear trend < 0.001 in both outcomes). The rate of change of albuminuria over 1 year (log10) independently predicted all-cause mortality (hazard ratio (95% confidence interval) 1.76 (1.39, 3.11)) and cardiovascular mortality (1.57 (1.13, 5.22)). Taken as a categorical variable, a rate of change of albuminuria > or = 30% independently predicted mortality and cardiovascular events (2.07 (1.5, 4.30) and 1.89 (1.33, 4.06), respectively). CONCLUSIONS: The rate of change of albuminuria over 1 year independently predicts mortality and cardiovascular disease in diabetic nephropathy and may have clinical utility as a risk marker in identifying a subgroup of patients at particular risk. The risk of these outcomes is continuous across the range of baseline albuminuria in patients with diabetic nephropathy.

Dietary glutathione protects rats from diabetic nephropathy and neuropathy.

Recently, much attention has focused on the role of oxidative stress in the various forms of tissue damage in patients with diabetes. The aim of this study was to examine the involvement of oxidative stress in the progression of kidney dysfunction and neuropathy in diabetes and to evaluate the potential usefulness of glutathione (GSH) in diabetes. We examined the effect that treatment of streptozotocin (STZ)-induced diabetic rats with GSH has on the renal and neural functions. Diabetic rats were treated with 1 g/100 g GSH as a dietary supplement. GSH significantly suppressed the diabetes-induced increase in urinary 8-hydroxy-2'-deoxyguanosine, one of the markers of oxidative stress. It also prevented the diabetes-induced increases in albumin and creatinine in urine. The diabetes-induced increase in the tail flick reaction time to thermal stimuli also was normalized by treatment with dietary GSH. In conclusion, GSH treatment can beneficially affect STZ-induced diabetic rats, with preservation of in vivo renal and neural function. This suggests a potential usefulness of dietary GSH treatment to reduce diabetic complications.

Relationship between thromboxane/prostacyclin ratio and diabetic vascular complications.

To elucidate the relationship between the thromboxane A2/prostacyclin (TXA2/PGI2) ratio and diabetic complications, the levels of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1alpha, the urinary metabolites of thromboxane A2 and prostacyclin, were measured in diabetics by gas chromatography/selected ion monitoring. We compared the TXA2/PGI2 ratio in healthy volunteers and diabetics. The TXA2/PGI2 ratio of diabetics was significantly higher than that of healthy volunteers and we could reconfirm the hypercoagulable condition in diabetics. We also investigated the difference of TXA2/PGI2 levels in diabetics with retinopathy and neuropathy. The TXA2/PGI2 ratio of diabetics with retinopathy showed significantly higher level than without retinopathy. However, the TXA2/PGI2 ratio of diabetics with neuropathy was the same as without neuropathy. These results suggest that the TXA2/PGI2 ratio reflects the pathological conditions of diabetes, especially the change of vasculature. The monitoring and improvement of TXA2/PGI2 ratio could be useful for the prevention of diabetic vascular complications.

Clinical usefulness of measuring urinary polyol excretion by gas-chromatography/mass-spectrometry in type 2 diabetes to assess polyol pathway activity.

INTRODUCTION: Decreased myo-inositol levels and increased activity of the polyol pathway have been proposed to play a role in causing diabetic microvascular complications. There are few clinical methods for examining the activity of the polyol pathway in diabetic patients. We assessed the effect of changes in glycemic control on polyol pathway activity by measuring urinary polyol excretion. MATERIALS AND METHODS: Gas-chromatography/mass-spectrometry (GC/MS) was used to assess the urinary excretion of glucose and polyols (myo-inositol, sorbitol, and fructose) in 50 patients who had type 2 diabetes without nephropathy and 20 healthy subjects. RESULTS: In the diabetic patients with poor glycemic control, urinary sorbitol levels were significantly increased and urinary myo-inositol excretion was approximately 6.5-fold higher than in healthy controls (33.0+/-6.5 vs 221.7+/-45.9 mg/day, mean+/-SE, P<0.01). During strict glycemic control, some patients (Group A) showed simultaneous disappearance of glucosuria and normalization of the urinary excretion of myo-inositol (<50 mg/day) and, while others (Group B) showed delayed normalization of urinary myo-inositol excretion. Group B showed significantly higher urinary myo-inositol, sorbitol, and fructose excretion than Group A at the time of disappearance of glucosuria. These findings suggest that patients in Group B may have increased polyol pathway activity. CONCLUSION: Even though short-term strict glycemic regulations were established in long-standing hyperglycemic diabetic patients, to normalize the once-exaggerated polyol pathway activities, it was essential to maintain glucosuria-free conditions for some period. Quantitation of urinary polyols using GC/MS appears to be a clinically useful method for assessing polyol pathway activity.

[Autonomic neuropathy in patients with type 2 diabetes and microalbuminuria]. / Autonomní neuropatie u nemocných s diabetem 2. typu a mikroalbuminurií.

BACKGROUND: Microalbuminuria (MAU) represents in patients with type 2 diabetes a risk factor for total and cardiovascular mortality and morbidity, whose principal pathogenic mechanism is the development of atherosclerosis. Other factors may also participate, e.g., cardiovascular vegetative neuropathy, which is supposed to be an independent risk factor. The aim of the study was the analysis of the cardiovascular autonomic regulations in patients with type 2 diabetes and microalbuminuria. METHODS AND RESULTS: 16 patients with type 2 diabetes and microalbuminuria and 23 healthy controls were included in the study. Heart rate variability was tested (during short-term recording at rest, deep breathing, orthostasis and Valsalva manoeuvre) and spectral analysis of telemetric records of heart rate in three positions (lying--standing--lying) was employed. In the group of patients with type 2 diabetes and MAU, in comparison with patients without MAU and controls, significant differences in heart rate variability during deep breathing were found. In comparison to controls, differences were found also during the Valsalve manoeuvre. In parameters of reaction of the heart rate to orthostasis, both groups of diabetic patients differed from controls. When comparing patients with MAU and controls significant differences were also found in spectral analysis of the heart rate variability, namely in total spectral power and the power of the low frequency band in both recumbent positions. In the same parameters, significant differences were found also between patients with and without MAU. The later were not different from the controls. CONCLUSIONS: The presented results indicate the existence of a significant impairment of the autonomic nervous system in patients with type 2 diabetes and microalbuminuria. This fact may contribute to the higher cardiovascular risk in this group of diabetic patients.

Elevated serum leptin concentrations in type 2 diabetic patients with microalbuminuria and macroalbuminuria.

Leptin levels are elevated in end-stage renal disease, suggesting an impairment of renal leptin degradation. The present study aimed to determine whether leptin levels are also elevated in patients with earlier stages of renal disease, ie, microalbuminuric and macroalbuminuric nephropathy. A total of 60 subjects were assigned to two study groups. Group A contained 10 type 2 diabetics with macroalbuminuria, 10 type 2 diabetics with normoalbuminuria, and 10 healthy control subjects. Group B contained 10 type 2 diabetics with microalbuminuria, 10 type 2 diabetics with normoalbuminuria, and 10 healthy controls. The subgroups of both study groups were matched for sex and body fatness. In group A, macroalbuminuric diabetic patients had higher serum leptin levels than the normoalbuminuric diabetics (11.90 +/- 2.98 v 4.13 +/- 0.92 ng/mL, P < .002) and control subjects (4.78 +/- 1.37 ng/mL, P < .006). In group B, microalbuminuric diabetics had higher serum leptin levels than the normoalbuminuric diabetics (21.16 +/- 5.80 v8.74 +/- 1.89 ng/mL, P < .04) and control subjects (10.06 + 3.00 ng/mL, P < .06). In both groups A and B, creatinine clearance was inversely correlated with the serum leptin level after adjusting for body fat. In conclusion, serum leptin levels are elevated in type 2 diabetic patients with microalbuminuria and macroalbuminuria, suggesting that renal leptin degradation is already impaired in the early stages of renal disease.