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Query: UMLS:C0011849 (diabetes)
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A radioimmunoassay has been developed for the measurement in urine of retinol-binding protein (alpha 2-microglobulin) and used as an index of renal tubular function in adult Type 1 (insulin-dependent) diabetics and to define reference ranges in non-diabetic controls. There was a significantly greater excretion (P less than 0.001) of retinol-binding protein in the diabetic group compared to the controls in both overnight and daytime samples. There was a weak positive correlation with albumin excretion (r = 0.33; P less than 0.01) but no correlation with HbA1, duration of diabetes or arterial blood pressure. The results indicate that retinol-binding protein excretion may be increased in diabetic subjects without increased albumin excretion. The possibility therefore exists that renal tubular damage may occur early in diabetic nephropathy without apparent glomerular dysfunction.
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PMID:Retinol binding protein as a small molecular weight marker of renal tubular function in diabetes mellitus. 366 97

Although the protein leak of early diabetic nephropathy is said to be purely a glomerular lesion, there is still controversy as to the existence of a tubular component. We have, therefore, assessed the urine of insulin-dependent diabetics for tubular proteinuria as a feature of early diabetic nephropathy. The urine of 25 patients with increased albumin excretion rate was analyzed by sodium dodecyl polyacrylamide gel electrophoresis. One patient showed high molecular weight proteinuria, 2 showed low molecular weight proteinuria and 2 patients showed both low and high molecular weight proteinuria. The urine was also analyzed for 3 tubular proteins by single radial immunodiffusion. No patient showed elevated beta-2-microglobulin, but alpha-1-microglobulin (A1M) (corrected for creatinine excretion) was elevated in 3 out of 25 patients including 2 of the 4 patients with a low molecular weight pattern. One of the patients with raised A1M also had raised retinol-binding protein concentration. We conclude that, in early diabetic nephropathy, proteinuria can have a proximal tubular, as well as a glomerular, component.
Diabetes Res 1986 May
PMID:Low molecular weight proteinuria in insulin-dependent diabetes. 374 42

The authors evaluated serum retinol, retinol-binding protein (RBP), and beta-carotene levels to elucidate the retinoid metabolism in non-insulin-dependent diabetes mellitus (NIDDM). The mean retinol levels by gender (1.83 mumol/L for females and 2.24 mumol/L for males) in diabetics were higher than those (1.31 mumol/L for females and 1.82 mumol/L for males) in control subjects (P < 0.0001, P < 0.01, respectively). The mean retinol/RBP ratios (0.95 for females and 0.97 for males) of diabetics were higher than those of the control subjects (0.60 for females and 0.64 for males) and of male patients having impaired glucose tolerance (0.55) (P < 0.0001). Lipid-lowering medication significantly decreased retinol, with decreasing apolipoprotein C-II but without a commensurate decrease in RBP. The retinol levels had a positive correlation with apolipoprotein C-II in all or normolipidemic patients with diabetes and control subjects. The high retinol/RBP ratio implies that an excessive or free retinol possibly exists in NIDDM. An alternative metabolism of retinol is inferred to underlie NIDDM without direct influences of cholesterol or triglyceride themselves.
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PMID:High retinol/retinol-binding protein ratio in noninsulin-dependent diabetes mellitus. 748 20

Urine albumin, alpha 1- and beta 2-microglobulins, retinol-binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG) were measured in early morning urine samples from 99 non-insulin-dependent diabetic (NIDDM) patients receiving ambulatory care at a primary health care polyclinic. Elevated NAG levels were found in 90% of diabetics regardless of the duration of their disease. Almost half (43.4%) of the subjects had microalbuminuria. Over a third of the subjects without albuminuria had elevated alpha 1-microglobulin levels in their urine. The proportion of subjects with elevated alpha 1 levels increased significantly with the presence of albumin, poor glycaemic control and increased duration of disease. These findings suggest that proximal tubular as well glomerular dysfunction coexist in the NIDDM patients studied.
Diabetes Res Clin Pract 1993 Jun
PMID:Proteinuria and enzymuria in non-insulin-dependent diabetics. 769 91

We performed a cross-sectional study on the urinary excretion profiles of albumin (a marker of glomerular dysfunction) and retinol-binding protein (a low molecular mass protein marker of renal proximal tubular dysfunction) in non-insulin dependent (Type II) diabetics, with or without retinopathy. The urinary excretion of both proteins, in particular retinol-binding protein, was significantly higher in patients with background/proliferative retinopathy compared to patients without retinopathy. The degree of retinopathy correlated to the urinary excretion of albumin (P < 0.005) and retinol-binding protein (P < 0.0001). Retinopathy occurred at a higher frequency in patients with above-normal urinary excretion of retinol-binding protein, both in the absence or presence of micro/macroalbuminuria. The frequency of retinopathy among micro/macroalbuminuric patients with a normal urinary excretion of retinol-binding protein did not differ significantly from that observed in patients with a normal urinary excretion of both proteins. We cannot explain the association between retinopathy and proximal tubular dysfunction in Type II diabetes. However, it is possible that both phenomena are related to a common pathogenetic factor.
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PMID:Retinopathy in type II diabetes mellitus associated with above-normal urinary excretion of RBP. 786 57

Two groups of patients with insulin-dependent diabetes mellitus of > 10 years duration and either persistent normoalbuminuria (group 1, n = 49; albumin excretion < 30 mg/day) or microalbuminuria (group 2, n = 33; albumin excretion 30-300 mg/day) were investigated for evidence of free oxygen radical activity (erythrocytic superoxide dismutase and glutathione peroxidase) and oxidant injury (serum malondialdehyde). Glomerular proteinuria (albuminuria, transferrinuria), tubular proteinuria (retinol-binding protein) and tubular enzymuria (N-acetyl-glucosaminidase and leucine aminopeptidase) were also measured. Healthy controls (n = 38) were matched for age and sex. Groups 1 and 2 were similar in terms of age, sex, duration of diabetes and recent glycaemic control. Serum cholesterol and creatinine were similar in all three groups. Free-radical activity and oxidant injury were significantly higher in groups 1 and 2 than in controls (p < 0.001). Glomerular proteinuria, tubular proteinuria and enzymuria were significantly higher in group 2 than in group 1 and controls (p < 0.01). Group 1 had significantly higher transferrinuria, tubular enzymuria and tubular proteinuria than controls. However, groups 1 and 2 were similar in degree of free oxygen radical generation and oxidant injury. In diabetic nephropathy, oxidant injury and renal tubular damage accompany and may even precede microalbuminuria. The presence of these abnormalities in the absence of glomerular proteinuria favours the hypothesis that alterations first occur in the peritubular microcirculation, which by causing oxidant injury and tubular damage, may initiate diabetic nephropathy.
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PMID:Evidence of oxidant injury and tubular damage in early diabetic nephropathy. 798 55

Seventy-two diabetic (38 males) and 86 normal (41 males) children provided timed overnight urine collections. Fourteen of the diabetic and 33 of the normal children had concurrent overnight plasma insulin profiles. Urinary insulin clearance in the diabetic subjects was compared with excretion of albumin, growth hormone, retinol-binding protein, and N-acetyl-beta-D-glucosaminidase. In the normal subjects, urinary insulin excretion correlated with mean overnight plasma levels in the boys (r = 0.82, p < 0.001) but not in the girls (r = 0.32), and varied with puberty stage in the boys. Insulin clearance was greater in boys than girls during puberty, and fell in both sexes with advancing puberty. Insulin excretion was greater in diabetic than normal children in both sexes at all puberty stages. Insulin clearance was also greater in diabetic than normal subjects (1.05 +/- 0.1 ml min-1 1.73 m-2 vs 0.48 +/- 0.05 ml min-1 1.73 m-2, p < 0.001). Insulin excretion as a percentage of the filtered load was also greater in diabetic than normal subjects (1.9 +/- 0.27% vs 0.85 +/- 0.09%, p < 0.01). In the diabetic children, there was a correlation between urinary insulin and growth hormone excretion (r = 0.52, p < 0.02), and retinol-binding protein in those (n = 10) with higher retinol binding protein excretion (r = 0.76, p = 0.01). The value of urinary insulin excretion as a measure of free plasma insulin levels in normal and diabetic children may be limited by sex differences in renal insulin clearance, and by proximal renal tubular dysfunction in children with diabetes.
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PMID:Urinary excretion and clearance of insulin in diabetic and normal children and adolescents. 826 51

1. Diabetic nephropathy is a serious microvascular complication in patients with insulin-dependent diabetes mellitus, resulting in end-stage renal disease in 30-45% of such patients. Despite intensive investigation, the pathophysiology of diabetic renal disease has not been fully elucidated. However, several clinical and experimental studies have suggested that endothelial dysfunction and free-radical activity may be important factors. 2. Forty normotensive patients with insulin-dependent diabetes mellitus of between 10 and 20 years duration with persistent normoalbuminuria (albumin excretion < 30 mg/day) and normal renal function were investigated for markers of endothelial dysfunction (plasma von Willebrand factor, soluble thrombomodulin and angiotensin-converting enzyme activity), free oxygen radical generation (erythrocytic superoxide dismutase and glutathione peroxidase) and oxidant injury (serum malondialdehyde). Glomerular proteinuria (albuminuria, transferrinuria), tubular proteinuria (retinol-binding protein) and tubular enzymuria (N-acetyl glucosaminidase and leucine aminopeptidase) were also measured. 3. Patients were divided into two groups. Group 1 comprised 21 patients with elevated markers of endothelial dysfunction, and group 2 comprised 19 patients with normal levels of plasma von Willebrand factor, soluble thrombomodulin and angiotensin-converting enzyme activity. Thirty-eight healthy subjects matched for age and sex acted as controls. 4. Groups 1 and 2 were similar in age, sex, body weight, duration of diabetes mellitus and recent glycaemic control. Serum cholesterol, serum creatinine and glomerular proteinuria were similar in the three groups. Group 1 patients had significantly increased oxidant injury, tubular enzymuria and proteinuria compared with group 2 patients and control subjects (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relationship between markers of endothelial dysfunction, oxidant injury and tubular damage in patients with insulin-dependent diabetes mellitus. 828 43

To define the mechanism of vitamin A action at the beta-cell level, we tested for the presence of messenger RNA for retinoic acid receptors alpha, beta, and gamma; cytosolic retinol-binding protein; and cytosolic retinoic acid-binding protein in RINm5F cells, an insulin-secreting cell line, and determined whether cytosolic retinol-binding protein and cytosolic retinoic acid-binding protein are present in isolated purified normal rat beta-cells. Northern blot analyses showed two transcripts of retinoic acid receptor alpha messenger RNA (3.8 and 2.4 kb), one transcript of retinoic acid receptor messenger RNA (3.8 kb), and one transcript of cytosolic retinol-binding protein (0.9 kb) in RINm5F cells. Ribonuclease protection assays also showed the presence of cytosolic retinol-binding protein and cytosolic retinoic acid-binding protein in RINm5F cells. Quantitatively, cytosolic retinol-binding protein levels were 0.10 +/- 0.02 pg/micrograms total RNA. Using specific radioimmunoassays, normal isolated purified rat beta-cells contained CRBP (19.2 +/- 2.38) and cytosolic retinoic acid-binding protein (16 +/- 0.53 ng/10(6) cells). The presence of message for retinoic acid receptors alpha and gamma, cytosolic retinol-binding protein, cytosolic retinoic acid-binding protein, and the gene products of cytosolic retinol-binding protein and cytosolic retinoic acid-binding protein in insulin-secreting cells support a mechanism of vitamin A action and role for cytosolic and nuclear receptors at the beta-cell level similar to that suggested in nonendocrine cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Aug
PMID:Retinoic acid receptor, cytosolic retinol-binding and retinoic acid-binding protein mRNA transcripts and proteins in rat insulin-secreting cells. 839 9

Early tubular alterations were studied in 53 children with insulin-dependent diabetes mellitus (IDDM), 32 of whom were followed at regular 6-monthly intervals for 3 years. The urinary levels of retinol-binding protein (RBP), beta 2-microglobulin and brush border antigens (BBA) (determined by monoclonal enzyme immunoassay) were taken as indices of functional and cellular tubular alterations; urinary albumin was considered an early marker of glomerular alterations. All indices of tubular alterations were higher in IDDM children than in 368 normal children, while albuminuria was unchanged. Urinary levels of BBA, however, varied widely during follow-up, with 25 of the 32 IDDM patients who were followed at regular intervals having pathological values for BBA on at least one occasion, followed by normalization. Metabolic alteration was found to be the main cause of this variability, since a high statistical correlation was found between urinary BBA and fructosamine (P < 0.001) and between RBP and the stable fraction of glycosylated haemoglobin (P < 0.001). The data confirm that transient tubular proteinuria occurs in diabetic children before any other marker of renal involvement such as microalbuminuria. The maintenance of good metabolic control is essential to normalize this early abnormality that can be considered a reversible sign of functional renal involvement.
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PMID:Reversible tubular proteinuria precedes microalbuminuria and correlates with the metabolic status in diabetic children. 843 75


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