Role of angiotensin and aldosterone in the pathogenesis of hypertension in insulin-dependent diabetes mellitus?
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Aldosterone↗
Biomedical subjects
B Feldt-Rasmussen
Publications and source records attributed to B Feldt-Rasmussen.
Micro-ELISA for the quantitation of human urinary and serum retinol-binding protein.
A highly sensitive enzyme linked immunoadsorbent assay for determining retinol-binding protein in urine and serum is described. Commercially available reagents are used. The standard curve ranges from 1.2-24 micrograms/l, recovery of retinol-binding protein added to urine was 99-102% (n = 10) and dilution of urine was linear. The within-assay coefficient of variation ranged from 1.2-3.1% and the day-to-day coefficient of variation from 9.2-10.5% depending on concentration. The correlation with urinary retinol-binding protein determined by radioimmunoassay was good (n = 90, r = 0.95). In vitro experiments show that retinol-binding protein is stable in urine with pH 5.2.
Enzyme-Linked Immunosorbent Assay↗
Impaired aerobic work capacity in insulin dependent diabetics with increased urinary albumin excretion.
To assess whether decreased aerobic work capacity was associated with albuminuria in insulin dependent diabetics aerobic capacity was measured in three groups of 10 patients matched for age, sex, duration of diabetes, and degree of physical activity. Group 1 comprised 10 patients with normal urinary albumin excretion (less than 30 mg/24 h), group 2 comprised 10 with incipient diabetic nephropathy (urinary albumin excretion 30-300 mg/24 h, and group 3 comprised 10 with clinical diabetic nephropathy (urinary albumin excretion greater than 300 mg/24 h). Ten non-diabetic subjects matched for sex, age, and physical activity served as controls. Oxygen uptake was similar in the four groups at rest and during a 75 W workload. Maximal oxygen uptake was also similar in the control subjects and group 1 (median 41.7, (range 29.1-53.0) ml/kg/min v 38.5 (26.6-59.2) ml/kg/min, respectively), but was significantly lower in group 2 (27.7 (13.9-44.3) ml/kg/min) and group 3 (22.6-36.7) ml/kg/min). The difference in maximal oxygen uptake between groups 1 and 2 was 10.8 ml/kg/min (95% confidence interval 3.6 to 23.4 ml/kg/min) and between groups 1 and 3, 11.7 ml/kg/min (4.9 to 22.5 ml/kg/min). These differences were not explained by differences in metabolic control or the degree of autonomic neuropathy. Thus the insulin dependent diabetics with only slightly increased urinary albumin excretion had an appreciably impaired aerobic work capacity which could not be explained by autonomic neuropathy or the duration of diabetes. Whether the reduced capacity is due to widespread microangiopathy or another pathological process affecting the myocardium remains to be established.
Adolescent↗
Improved metabolic control does not alter the charge-dependent glomerular filtration of albumin in uncomplicated type 1 (insulin-dependent) diabetes.
The selectivity index, i.e. clearance of non glycated albumin/clearance of glycated albumin was studied in fourteen patients with Type 1 (insulin-dependent) diabetes and normal urinary albumin excretion. The index was increased above one in all patients, and correlated significantly to HbA1c. It was, however, unaffected by 12 weeks of improved metabolic control with a mean decline in HbA1c of 1.9% in seven patients. We conclude that the increased electronegative charge of the glomerular filtration barrier observed in uncomplicated diabetes is related to long term metabolic control but not reversible during twelve weeks of strict metabolic control. This indicates a slow turnover of the components responsible for the increased charge selectivity in uncomplicated diabetes.
Adult↗
Glomerular size and charge selectivity in insulin-dependent diabetes mellitus.
The pathogenesis of clinical nephropathy in Type 1 (insulin-dependent) diabetes was investigated by measuring renal fractional clearances of albumin, total IgG, IgG4 and beta 2-microglobulin, four plasma proteins which differ in size and charge. Seventy patients and eleven control subjects were studied. In diabetic patients with normal urinary albumin excretion (less than 30 mg/24 hr), fractional IgG clearance was two to three times higher than in control subjects, whereas fractional clearance of the anionic plasma proteins IgG4 and albumin was similar to that of control subjects. These alterations indicate an increase in anionic pore charge within the glomerular basement membrane concomitant with an increase in either pore size or impairment of tubular reabsorption. Diabetic patients, whose urinary albumin excretion has started to rise (30 to 100 mg/24 hr), had unchanged fractional IgG compared to patients with normal albumin excretion, while fractional IgG4 and albumin clearances were increased three- to fourfold; indicating unchanged glomerular pore size, but a decrease in anionic pore charge. In patients demonstrating urinary albumin excretion of greater than 100 mg/24 hr fractional IgG clearance increased to the same extent as fractional albumin clearance, indicating an increase in large pore area. Fractional beta 2-microglobulin clearances were similar to that of control subjects in the different patient groups indicating unchanged tubular reabsorption of proteins. Thus, the increase in large pore area seen in patients with clinical nephropathy is preceded by loss of anionic charge in the glomerular basement membrane. It is likely that this loss of anionic charge is due to loss of heparan sulphate-proteoglycan.
Adult↗
Myocardial infarction before the age of 20 is rare.
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Adolescent↗
Central role for sodium in the pathogenesis of blood pressure changes independent of angiotensin, aldosterone and catecholamines in type 1 (insulin-dependent) diabetes mellitus.
We studied 73 Type 1 (insulin-dependent) diabetic patients, 18 to 50 years of age, with a diabetes duration of more than five years. Group 1: normal urinary albumin excretion below 30 mg per 24 h (n = 19); group 2: microalbuminuria, 30-300 mg per 24 h (n = 36); and group 3: diabetic nephropathy, above 300 mg per 24 h (n = 18). Fifteen nondiabetic persons matched for sex and age served as control subjects. The sodium intake evaluated on the basis of 24-h urine sodium excretion was similar in patients and control subjects. Blood pressure in groups 1 and 2 and control subjects was below 160/95 mmHg. The blood pressure was increased in group 3 as compared with the other groups (systolic/diastolic 161 +/- 22/101 +/- 9 mmHg vs 131 +/- 13/84 +/- 10, mean +/- SD, p less than 0.0001). Exchangeable sodium was increased in patients (p less than 0.01) and correlated to the mean blood pressure (n = 70, r = 0.41, p less than 0.01). Extracellular volume was increased in patients (p less than 0.05), whereas plasma volume was normal. Supine serum angiotensin II was suppressed in the patients (p less than 0.001). A negative correlation was found between mean blood pressure and supine serum aldosterone (n = 68, r = -0.24, p less than 0.05), and exchangeable sodium and aldosterone (n = 66, r = -0.36, p less than 0.002) in all patients. The catecholamine levels were also suppressed or normal in the patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Transcapillary escape rate and relative metabolic clearance of glycated and non-glycated albumin in type 1 (insulin-dependent) diabetes mellitus.
The transcapillary escape rate and relative plasma disappearance of glycated and non-glycated albumin were measured in 25 male Type 1 (insulin-dependent) diabetic patients using a double tracer technique. The patients were divided into three groups on the basis of their urinary albumin excretion: group 1, normal albumin excretion (less than 30 mg/24 h) (n = 8); group 2, microalbuminuria (30-300 mg/24 h) (n = 9); and group 3, clinical nephropathy (greater than 300 mg/24 h) (n = 8). Six male age-matched non-diabetic persons served as control subjects. The transcapillary escape rate of glycated albumin was similar in group 1 and control subjects (4.7 +/- 2.1 versus 5.1 +/- 1.7%), but significantly increased in group 2 (7.0 +/- 1.7%, p less than 0.05) and in group 3 (7.9 +/- 3.1%, p less than 0.05). The transcapillary escape rate of glycated albumin was slightly lower than that of non-glycated albumin in all groups, but significant only in normal control subjects. No difference in the catabolic rate of glycated and non-glycated albumin was found. We conclude that the in vivo effects of glycation on the clearance and transcapillary passage of albumin are small and not likely to play any significant role in the development of late diabetic microvascular complications.
Capillary Permeability↗
Kinetics of insulin disappearance from plasma in cortisone-treated normal subjects.
The effect of glucocorticoid excess on insulin disappearance from plasma was examined in eight normal men during cortisone treatment (50 mg orally twice daily for 4 d) and in the absence of any medication (control) in random order. Constant infusion of insulin (1-5 mU/kg/min) was used to achieve different levels of steady state plasma insulin concentrations; normoglycaemia was preserved by a glucose clamp technique. The experimentally determined data were compared using a previously validated model of saturation kinetics. The amount of glucose required to maintain normoglycaemia during the insulin infusions was significantly less in the cortisone study than in the control study, while the parameter estimates for the kinetics of insulin disappearance from plasma were unaffected by cortisone. Thus, insulin action and insulin kinetics in the steady state are dissociated in normal subjects rendered insulin resistant by short-term cortisone treatment.
Adult↗
Kinetic models for insulin disappearance from plasma in type I diabetic patients.
We have tested whether our previous finding in normal subjects that the disappearance of insulin from plasma obeys saturation kinetics alone also applies to type I diabetic patients. In six long-term diabetic patients steady state plasma insulin concentrations resulting from constant insulin infusion at different rates were compared with the predictions of three models for the kinetics of insulin in plasma. The models allowed the existence of non-saturable (first order equation) or saturable (Michaëlis-Menten equation) mechanisms, or both. The minimal acceptable model included saturation kinetics alone in four subjects and first order kinetics alone in two subjects. The clearance of insulin in diabetic patients, calculated from the best fitting model, was 18.0 (median, range 10.0-23.7) ml X kg-1 X min.-1 versus 25.0 (18.6-47.1) ml X kg-1 X min.-1 in six normal subjects (2p = 0.008). Insulin thus disappears from plasma at a lower rate in diabetic patients than in normal subjects at physiological plasma concentrations.
Adult↗
Micro-ELISA for the quantitation of human urinary IgG.
When investigating glomerular changes in the early stages of diabetic renal disease, it is important to be able to estimate low concentrations of urinary immunoglobulins, as well as the albumin/immunoglobulin ratio. For this reason there is a need for highly sensitive and specific routine assays for urinary immunoglobulins. A 'sandwich' enzyme-linked immunoadsorbent assay (ELISA) for the quantitation of urinary immunoglobulin G is described, in which microtest plates are used as the solid phase. The assay is specific, sensitive and simple, and only used commercially available reagents. The assay range was 5-200 micrograms/l. The relative standard deviations within and between assays were 5 and 9%, respectively. Recovery of IgG added to urine was 100-102% (n = 12), and dilution of urine was linear. The assay range allowed for the quantitation of IgG in human urine samples, covering the clinical range from physiological to raised pathological values.
Enzyme-Linked Immunosorbent Assay↗
Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes.
36 patients with insulin-dependent diabetes mellitus who had 'Albustix'-negative urine but raised urinary albumin excretion (30 to 300 mg/24 h) were randomly assigned to either remaining on conventional insulin treatment or continuous subcutaneous insulin infusion and followed up for 2 years. The insulin-infusion group showed a significant, sustained improvement in metabolic control, with a median glycosylated haemoglobin of 7.2% (range 5.9-8.8), but there was no change in the conventional-treatment group (median 8.6%, range 7.2-13.4) (p less than 0.001). Clinical diabetic nephropathy (a urinary albumin excretion rate above 300 mg/24 h in at least two of three 24 h urine collections) developed in 5 patients in the conventional-treatment group, but not in the insulin-infusion group (p less than 0.05, two-tailed). Fractional albumin clearance (mean and range X 10(7] increased in the conventional-treatment group from 160 (35-468) to 360 (29-1580) and was unchanged in the insulin-infusion group (170 [31-608] before to 160 [26-460] after) (p less than 0.05). Insulin infusion had an overall beneficial effect on the annual increase in urinary albumin excretion (p less than 0.05), and the mean glycosylated haemoglobin values correlated positively with annual change in albumin excretion (r = 0.57, p less than 0.0001). The diastolic blood pressure rose significantly in the conventional-treatment group (p less than 0.001), and annual change in mean blood pressure correlated with change in urinary albumin excretion (r = 0.49, p less than 0.001).
Adolescent↗
Kidney function during 12 months of strict metabolic control in insulin-dependent diabetic patients with incipient nephropathy.
Thirty-six patients with insulin-dependent diabetes mellitus who had Albustix-negative urine but elevated urinary albumin excretion (30 to 300 mg per 24 hours) were matched in pairs according to their urinary albumin level, blood glycosylated hemoglobin level, and sex and assigned randomly to either unchanged conventional treatment or continuous insulin infusion. During the next 12 months a significant improvement in glycemic control was observed in the insulin-infusion group, with a reduction in the mean glycosylated hemoglobin level from 9.5 to 7.3 percent. There was no change in the control group (9.3 to 9.2 percent). No significant change in albumin excretion was observed in either group. The mean blood pressure increased slightly in both groups (from 98 to 101 mm Hg in the insulin-infusion group and from 98 to 103 mm Hg in the control group). Kidney size was significantly reduced in all patients during insulin infusion, but no consistent change was observed in the control group. No significant change was observed in the glomerular filtration rate. Our data suggest that the pathologic processes causing microalbuminuria in early renal disease are not reversed during 12 months of strict metabolic control.
Adolescent↗
Increased transcapillary escape rate of albumin in type 1 (insulin-dependent) diabetic patients with microalbuminuria.
The transcapillary escape rate, intravascular mass and outflux of albumin were measured in 75 Type 1 (insulin-dependent) diabetic patients. The groups were defined as: group 1: normal urinary albumin excretion, less than 30 mg/24 h (n = 21); group 2: microalbuminuria, 30-300 mg/24 h (n = 36); group 3: diabetic nephropathy, less than 300 mg/24 h (n = 18). Fifteen sex- and age-matched non-diabetic persons served as control subjects. The diabetes duration was: group 1: 20 +/- 9 years, group 2: 17 +/- 5 years, group 3: 19 +/- 7 years. The transcapillary escape rate of albumin was similar in controls and group 1 (5.0 +/- 1.8 versus 5.2 +/- 1.5%) and was significantly higher in the microalbuminuric group 2 and group 3 (8.1 +/- 2.2 versus 8.1 +/- 2.3%). The differences were not explained by differences in metabolic control or blood pressure at the time of investigation. The outflux of albumin was also higher in group 2 than in group 1 and controls (7.1 +/- 2.0 versus 5.3 +/- 1.5 and 5.1 +/- 2.0 g/h X 1.73 m2). It was indistinguishable from controls in group 3 (5.8 +/- 1.5 g/h X 1.73 m2) because of a reduced intravascular mass of albumin (p less than 0.01) in group 3. In conclusion, a universal vascular leakage of albumin is an early event in the development of diabetic nephropathy, with the leakage of albumin being fully developed in the microalbuminuric patient. In contrast, long-term diabetic patients with normal urinary albumin excretion have a normal transcapillary escape rate of albumin.
Adolescent↗
Evidence of changes in renal charge selectivity in patients with type 1 (insulin-dependent) diabetes mellitus.
Altered filtration of macromolecules due to decreased electrical charge of the glomerular basement membrane might be the initial step in the development of albuminuria in patients with Type 1 (insulin-dependent) diabetes mellitus. We therefore investigated the selectivity index, i.e. renal clearance of non-glycated plasma albumin/clearance of glycated plasma albumin in 38 patients with Type 1 diabetes mellitus. The two albumin molecules differed slightly in charge, non-enzymatic glycated albumin being more anionic at physiological pH compared with unmodified plasma albumin. Glycated albumin in plasma and urine was determined by a specific, sensitive and highly reproducible chromatographic procedure. In diabetic patients with normal urinary albumin excretion, the selectivity index was increased three-fold compared with that of non-diabetic subjects (2 p less than 0.01). A significant correlation (r = 0.53, 2 p less than 0.01) between haemoglobin A1c and selectivity index was demonstrated in these patients, indicating a change in charge-dependent renal filtration could possibly be attributed to non-enzymatic glycation of components in the glomerular basement membrane and tubuli. Diabetic patients with increased albumin excretion rate had a significantly lower selectivity index compared with patients with normal albumin excretion (2 p less than 0.01). A significant negative correlation (r = 0.85, 2 p less than 0.001, exponential curve fit) was seen between urinary albumin excretion and selectivity index in the diabetic patients, indicating that the capability of differentiating between macromolecules of different charges is again lost with increasing urinary albumin excretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Diabetic control and microvascular complications: the near-normoglycaemic experience.
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Blood Glucose↗
Beta 2-microglobulin in urine and serum determined by a micro-ELISA technique.
An enzyme-linked immunoadsorbent assay for the determination of beta 2-microglobulin in serum and urine using microtest plates as solid phase is described. All reagents are commercially available. The assay has a high capacity and it is inexpensive using only 3% of the amounts of antibodies required in a previously described ELISA based on tubes as solid phase.
Diabetes Mellitus, Type 1↗