Antihypertensive drugs and diabetes mellitus.
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Antihypertensive Agents↗
Biomedical subjects
H H Parving
Publications and source records attributed to H H Parving.
Effect of captopril on kidney function in insulin-dependent diabetic patients with nephropathy.
The influence of angiotensin II on kidney function in diabetic nephropathy was assessed by studying the effect of 12 weeks' monotherapy with captopril (25-50 mg twice a day) in 16 hypertensive insulin dependent diabetic patients with persistent albuminuria. In an initial one week randomised single blind trial of captopril versus placebo, captopril (for nine patients) reduced arterial blood pressure from 148/94 (SD11/6) to 135/88 (8/7) mm Hg (p less than 0.05) and albuminuria from 1549 (range 352-2238) to 1170 (297-2198) micrograms/min (p less than 0.05), while glomerular filtration rate remained stable. No significant changes occurred in seven patients treated with placebo. During the 12 weeks of captopril treatment arterial blood pressure in all patients fell from 147/94 (11/6) to 135/86 (13/7) mm Hg (p less than 0.01), albuminuria fell from 1589 (range 168-2588) to 1075 (35-2647) micrograms/min (p less than 0.01), and glomerular filtration rate fell from 99 (SD19) to 93 (25) ml/min/1.73 m2 (p less than 0.01). The renin-angiotensin system showed suppressed plasma concentrations of angiotensin II and increased concentrations of angiotensin I and renin. The study showed that glomerular filtration rate is not dependent on angiotensin II, that captopril reduces albuminuria, probably by lowering glomerular hypertension, and that captopril represents a valuable new drug for treating hypertension in diabetics dependent on insulin with nephropathy.
Adult↗
Acute reduction of arterial blood pressure reduces urinary albumin excretion in type 1 (insulin-dependent) diabetic patients with incipient nephropathy.
The effect of an acute reduction in arterial blood pressure upon kidney function was studied in 12 patients with Type 1 (insulin-dependent) diabetes and incipient nephropathy (persistent microalbuminuria). Renal function was assessed by measurement of the glomerular filtration rate (single bolus 51Cr-EDTA technique) and by the urinary albumin excretion rate (radioimmunoassay). The study was performed twice within 2 weeks, with the patients receiving a slow intravenous injection of either clonidine (225 micrograms) or saline (154 mmol/l) in random order. Clonidine reduced arterial blood pressure from 125/79 +/- 13/8 to 104/68 +/- 9/7 mmHg (p less than 0.01), urinary albumin excretion rate from 68 (31-369) to 46 (6-200) micrograms/min (median and range) (p less than 0.01), and fractional clearance of albumin in all patients (median 29%) (p less than 0.01). Glomerular filtration rate was 110 +/- 11 before and 106 +/- 13 ml/min/1.73 m2 after clonidine injection. The blood glucose concentration was 15 +/- 4 mmol/l before and 14 +/- 5 mmol/l after clonidine injection. In agreement with findings in animal studies, our results suggest that microalbuminuria is to a large extent pressure-dependent, probably because of glomerular hypertension, and that autoregulation of glomerular filtration rate is normal in most patients with incipient diabetic nephropathy.
Adult↗
Prevalence of microalbuminuria in children with type 1 (insulin-dependent) diabetes mellitus.
The prevalence of microalbuminuria was determined in children aged 7 to 18 years with Type 1 (insulin-dependent) diabetes of more than 2 years' duration. All patients (n = 102) attending 2 diabetes clinics were asked to collect 2 overnight timed urine samples for albumin analysis by radioimmunoassay. Complete urine collection was obtained in 97 patients (95%). Overnight urinary albumin excretion rates were also measured in 36 healthy children matched for age and sex. Nineteen of the 97 patients (20%) had microalbuminuria, i.e. overnight urinary albumin excretion rates above the upper normal level (14 micrograms/min) in both urine collections. Microalbuminuria was only demonstrated in patients aged greater than or equal to 15 years, prevalence 37% (19/52 patients). Arterial blood pressure was elevated, mean 122/84 +/- 11/9mmHg, in the microalbuminuric group (19 patients) compared to the age-matched normoalbuminuric diabetic group (33 patients), mean 117/74 +/- 10/10mm Hg, p less than 0.001. The prevalence of simplex retinopathy was identical in these two groups, i.e. 25%. Glycosylated haemoglobin was slightly higher in the microalbuminuric patients, p less than 0.10. Our cross-sectional study reveals a high prevalence (37%) of persistent microalbuminuria, a stage highly predictive of later development of diabetic nephropathy, in Type 1 diabetic children aged greater than or equal to 15 years.
Adolescent↗
Effects of indomethacin on glomerular hemodynamics in experimental diabetes.
The glomerular hemodynamics were studied in streptozotocin diabetic rats 3 months after the induction and in age-matched normal animals. Indomethacin infusion failed to cause changes in glomerular hemodynamics in normal rats but produced striking effects in the diabetic rats: The afferent arteriolar hydraulic resistance increased substantially while the efferent resistance rose moderately causing large reductions in single nephron blood flow and in the hydraulic pressure in the glomerular capillaries. Consequently, single nephron glomerular filtration rate (SNGFR) was reduced significantly below normal. The ultrafiltration coefficient of the glomerular membrane was significantly lower in the diabetic than in the normal animals (2.8 versus 5.0 nl min-1 mm Hg-1) and remained unchanged during indomethacin infusion. Our results suggest that the prostaglandin system compensates for the changes in the glomerular hemodynamics induced by diabetes by reducing the arteriolar resistances to increase the glomerular capillary pressure making it possible to maintain normal values of SNGFR and nephron blood flow.
Animals↗
Effect of ganglionic blockade on endogenous circulating pancreatic polypeptide, vasoactive intestinal polypeptide, substance P, neurotensin and noradrenaline in healthy controls and long-term insulin-dependent diabetic patients.
Plasma pancreatic polypeptide (PP), vasoactive intestinal polypeptide (VIP), substance P (SP), neurotensin (NT) and noradrenaline (NA) were measured in eight healthy subjects and 12 long-term insulin-dependent diabetic patients with and without autonomic neuropathy, before and after intravenous infusion of the ganglionic blocking agent trimethaphan camsylate, in order to determine the influence of the autonomic nervous system on the baseline values of the substances. The basal levels of the measured substances were not significantly different in healthy subjects and patients with or without diabetic autonomic neuropathy. In healthy subjects, the ganglionic blockade induced a significant decrease in PP (80%) (P less than 0.02), NA (58%) (P less than 0.05), NT (27%) (P less than 0.05) and a significant increase in SP (30%) (P less than 0.05), while the VIP concentration remained unchanged. The diabetic patients had nearly the same significant decrease in PP (68%) (P less than 0.01), NA (50%) (P less than 0.01), NT (22%) (P less than 0.02), VIP (21%) (P less than 0.05) and increase in SP (73%) (P less than 0.01). No relationship was found between the autonomic neuropathy and changes of the substances during ganglionic blockade. The results indicate that the postganglionic part of the autonomic nervous system participates in the maintenance of a normal baseline level of PP, NT and NA, but not of VIP. The regulation of VIP may be disturbed in long-term diabetic subjects.
Adult↗
Prevalence of hyperglycaemia and undiagnosed diabetes mellitus in patients with acute myocardial infarction.
The prevalence of hyperglycaemia and undiagnosed diabetes mellitus was assessed in 214 consecutive patients admitted to the coronary care units with acute myocardial infarction (AMI). On admission, 16 patients (7.5%) had known diabetes, and 19 patients, not previously known to be diabetic, had blood glucose concentrations of greater than or equal to 9 mmol/l. Fifteen patients survived for 2 months at which time a 75 g oral glucose tolerance test showed diabetes in 9 (60%) and impaired glucose tolerance in 4 (27%). Ten of these 13 patients (77%) with abnormal glucose tolerance had elevated glycosylated haemoglobin (HbA1c) on admission, indicating pre-existing glucose intolerance or diabetes. The prevalence of undiagnosed diabetes was 4.5% (9/198). However, we may have overlooked undiagnosed diabetes in a small number of patients on admission, since only a random blood glucose less than 8 mmol/l rules out diabetes, WHO criteria. Elevated blood glucose in patients with AMI is more likely to reflect a stationary pre-existing abnormal glucose tolerance than a temporary stress-induced phenomenon.
Adult↗
HLA associations in insulin-dependent diabetes: search for heterogeneity in different groups of patients from a homogeneous population.
A total of 317 unrelated Danish patients with insulin-dependent diabetes mellitus (IDDM) have been HLA-DR typed and the antigen and phenotype frequencies compared with those in 1177 unrelated Danish controls. The strong positive associations with DR3 and 4 and the strong negative one with DR2 were confirmed, and the remaining antigens showed a hierarchy from weakly positive to strongly negative associations: DRw9, w8, 1, 5, w6, 7. The study population included various special groups of patients selected in order to study heterogeneity: very early (less than 5 years) and very late (greater than 40 years) onset IDDM, pregnancy-induced IDDM, IDDM nephropathy, and long-term (greater than 40 years) survivors without complications. When comparing these groups, the following minor differences were seen: the DR3,4 phenotype is significantly (p = .02) more frequent in IDDM with onset before age 20 (35%) than in other cases (24%), and in familial IDDM (48%) than in other cases (28%); the frequency of the DR4 antigen was significantly (p = .008) more frequent in long-term survivors (86%) than in other patients (69%), while it was significantly (p = .02) less frequent in IDDM nephropathy (63%) than in long-term survivors. However, apart from the age-at-onset heterogeneity, which was suspected a priori, these differences may be due to chance, and the main conclusion of this study is that the HLA-DR associations in IDDM are indeed extraordinarily homogeneous irrespective of the clinical characteristics at onset and course of the disease.
Age Factors↗
Impaired autoregulation of cerebral blood flow in long-term type I (insulin-dependent) diabetic patients with nephropathy and retinopathy.
Autoregulation of cerebral blood flow, i.e., the maintenance of cerebral blood flow within narrow limits during changes in arterial perfusion pressure, was studied in nine healthy control subjects and in 12 long-term Type I (insulin-dependent) diabetic patients with clinical microangiopathy. Cerebral blood flow was measured by the intravenous 133Xenon method. Mean arterial blood pressure was elevated approximately 30 mmHg by intravenous infusion of angiotensin amide II and lowered about 10 mmHg by intravenous infusion of trimethaphan camsylate. In the control subjects the flow/pressure curve was horizontal indicating perfect autoregulation. In the diabetic patients the flow/pressure curve showed a significant slope with a 1.9% change in CBF per 10 mmHg change in mean arterial blood pressure as compared to a slope value of -0.4% in the control subjects (P less than 0.05). Our results confirm the previous findings suggesting that autoregulation of cerebral blood flow is impaired in some long-term Type I diabetic patients with clinical microangiopathy (arteriolar hyalinosis).
Adult↗
The effect of l-thyroxine treatment on skin accumulation of acid glycosaminoglycans in primary myxoedema.
We assessed skin accumulation of acid glycosaminoglycans in ten patients with primary myxoedema (median age 70 years) before and during l-thyroxine treatment (median 7 months). Eight subjects matched for sex and age served as controls. Acid glycosaminoglycans were determined biochemically on small skin biopsies. Hyaluronic acid was elevated in untreated myxoedema, median 0.60, range 0.39-0.90 microgram hexosamine/mg dried defatted tissue compared to a median control value of 0.52, range 0.43-0.65 microgram hexosamine/mg dried defatted tissue, P less than 0.02. Chondroitin-4,6-sulphate and dermatan sulphate showed no elevation, while heparan sulphate was actually reduced in myxoedema, P less than 0.01. l-thyroxine treatment induced a significant reduction in hyaluronic acid, median 0.41, range 0.24-0.71 microgram hexosamine/mg dried defatted tissue, while no consistent changes occurred in the remaining three acid glycosamine glycans. The accumulation of hyaluronic acid might contribute to the peculiar non-pitting oedema of the skin in myxoedema, due to the strong water-binding capacity of the substance.
Adult↗
Transcapillary escape rates.
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Capillary Permeability↗
Impaired autoregulation of blood flow in subcutaneous tissue of long-term type 1 (insulin-dependent) diabetic patients with microangiopathy: an index of arteriolar dysfunction.
Autoregulation of blood flow in subcutaneous tissue was studied at the level of the lateral malleolus in eight long-term Type 1 (insulin-dependent) diabetic patients with clinical microangiopathy, eight short-term Type 1 diabetic patients without clinical microangiopathy and seven healthy control subjects. Blood flow was measured by the local 133Xenon washout technique. Mean arterial blood pressure was reduced by a maximum of 23 mmHg by elevating the limb above heart level and elevating to a maximum of 70 mmHg by head-up tilt; in the latter position venous pressure was kept constant and low by activation of the leg muscle vein pump (heel raising). Mean arterial blood pressure was thus varied between 60 and 160 mmHg. In normal and short-term diabetic subjects blood flow remained within 10% of control values during the changes in arterial blood pressure. In six of the eight Type 1 diabetic patients with clinical microangiopathy, autoregulation of blood flow was impaired, blood flow changing approximately 20% per 10 mmHg change in arterial blood pressure; the slope of the autoregulation curves was significantly higher compared with the two control groups (p less than 0.02). Resting mean arterial blood pressure was significantly elevated in long-term diabetic patients (median: 107 mmHg) compared with short-term diabetic (median: 85 mmHg) and control subjects (median: 91 mmHg) (p less than 0.01 and p less than 0.02, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Reduced transcapillary escape of albumin during acute blood pressure-lowering in type 1 (insulin-dependent) diabetic patients with nephropathy.
The effect of acute arterial blood pressure lowering upon albumin extravasation was studied in 10 patients with nephropathy and retinopathy due to long-standing Type 1 (insulin-dependent) diabetes. The following variables were measured: transcapillary escape rate of albumin (initial disappearance of intravenously injected 125I-labelled human serum albumin), and urinary albumin excretion rate (radial immunodiffusion). The study was performed twice within 2 weeks, with the patients receiving an intravenous injection of either clonidine (225 micrograms) or saline (0.154 mmol/l). The clonidine injection induced the following changes: arterial blood pressure decreased from 134/87 to 107/73 mmHg (p less than 0.01), transcapillary escape rate of albumin declined from 8.1 to 6.7% of the intravascular mass of albumin/h (p less than 0.01), albuminuria diminished from 1434 to 815 micrograms/min (p less than 0.01), and plasma volume raised slightly from 2916 to 2995 ml (p less than 0.05). Our findings demonstrate that the enhanced albumin passage through the wall of the microvasculature characteristically found in long-term Type 1 diabetic patients with clinical microangiopathy is pressure-dependent to a large extent. This may be due to elevated hydrostatic pressure in the microcirculation.
Adult↗
Changes in plasma volume, in transcapillary escape rate of albumin and in subcutaneous blood flow during hypoglycaemia in man.
Hypoglycaemia was induced by insulin injected intravenously (0.15 i.u./kg body weight) in seven healthy young males. Plasma volume was measured before and during hypoglycaemia by intravenous injection of 125I before hypoglycaemia and of 131I during hypoglycaemia. Plasma volume decreased and transcapillary escape rate increased significantly during hypoglycaemia. Skin temperature and local subcutaneous adipose tissue blood flow were measured in four different regions. Both tended to decrease during hypoglycaemia and decreased significantly 2 h after hypoglycaemia. There was no correlation between changes in the two measurements, suggesting that there is no simple relationship between subcutaneous blood flow and skin temperature during hypoglycaemia.
Adult↗
Short-term inhibition of prostaglandin synthesis has no effect on the elevated glomerular filtration rate of early insulin-dependent diabetes.
Glomerular filtration rate and renal plasma flow (constant infusion technique using 125I-iothalamate and 131I-hippuran) were measured twice within a 1-week interval in nine young males with insulin-dependent diabetes of short duration (2-5 years). The study was performed in a randomized double-blind design, with the patients receiving either indomethacin (150 mg/day) or placebo for 3 days before the study. Measures of metabolic control did not change. No differences were found in glomerular filtration rate (144 +/- 9 versus 144 +/- 9 ml/min X 1.73 m2, mean +/- S.E.M.) or renal plasma flow (579 +/- 43 versus 560 +/- 52 ml/min X 1.73 m2), when measured during placebo or indomethacin treatment, respectively. It is concluded that the steady-state enhancement of glomerular filtration rate and renal plasma flow found in early insulin-dependent diabetes is not due to an excessive activity of the prostaglandin system.
Adult↗
The blood-retinal barrier permeability to fluorescein in juvenile diabetics treated with continuous subcutaneous insulin infusion.
To determine possible quantitative changes of the blood-retinal barrier permeability in juvenile diabetics treated with continuous subcutaneous insulin infusion (CSII), we studied seven patients (three females and four males, mean age 36 years) with a mean duration of the disease of 19 years. The pump treatment was continued for seven to eight days and during the treatment mean blood glucose level decreased to near-normal values (before 13.7 mmol per liter - during 6.2 mmol per liter). There was no changes in retinal appearance during treatment. Determination of the blood-retinal barrier permeability showed no quantitative changes during the one week treatment with CSII (mean permeability before 7.6 10 divided by 7 cm/sec - mean permeability during 7.8 10 divided by 7 cm/sec). In order to quantitate possible long-term reversibility of break-down of the blood-retinal barrier we have design to extend the treatment period.
Adult↗
The effect of metabolic control on hemodynamics in short-term insulin-dependent diabetic patients.
Hemodynamics variables (heart rate, arterial blood pressure, cardiac output, hepato-splanchnic blood flow, forearm blood flow, and plasma catecholamines) were measured during good (median blood glucose 4.7 mmol/L) and poor (median blood glucose 16.3 mmol/L) metabolic control in eight young, short-term, insulin-dependent diabetic patients. The measurements were performed twice within 2 wk, in random order. Continuous subcutaneous insulin infusion (CSII) was applied for 1 wk in order to obtain good control. All eight patients had elevated cardiac output (median 9%) and forearm blood flow (median 34%) during poor compared with good metabolic control, P less than 0.01. In contrast, hepato-splanchnic blood flow was lower (median 12%) during poor compared with good metabolic control, P less than 0.05. Heart rate remained unchanged, while mean arterial blood pressure was slightly higher during poor control, P less than 0.05. Five of six patients had elevated plasma noradrenaline concentration during poor metabolic control. Due to the small number of patients investigated, no valid conclusion regarding the activity of the sympathoadrenal system can be drawn. Our study suggests that both increased cardiac output and reduced hepato-splanchnic blood flow (redistribution) contribute to the elevated blood flow previously demonstrated in various other organs and tissues in diabetic patients during poor metabolic control.
Adult↗
Monitoring progression of diabetic nephropathy.
Glomerular filtration rate (GFR, single bolus 51Cr-EDTA technique), serum creatinine and serum beta 2-microglobulin concentrations were measured simultaneously in 49 insulin-dependent diabetics with diabetic nephropathy. GFR ranged from 148 to 23 ml/min/1.73 m2. Inverse serum concentrations of creatinine and beta 2-microglobulin showed a significant correlation with GFR over the whole range of values, r = 0.87 and r = 0.90, respectively (p less than 0.001). In the 31 patients with a GFR less than 80 ml/min/1.73 m2, serum concentration of creatinine and beta 2-microglobulin were within the normal range in 12 and 9 patients, respectively. With GFR below 60 ml/min/1.73 m2, all patients had elevated serum beta 2-microglobulin concentrations, while 24% of the patients still had normal creatinine concentration. Linear regression analysis between log GFR and log serum beta 2-microglobulin showed a better relationship than between log GFR and log serum creatinine, slope -0.90 and -0.57, respectively, p less than 0.01. A prospective study for up to 70 months was performed in 18 of the patients. The study showed a closer relationship between the individual rate of decline in log GFR and log serum beta 2-microglobulin compared to log GFR versus log serum creatinine, p less than 0.01. Neither serum creatinine nor serum beta 2-microglobulin can be used as methods for screening of early impairment of renal function (GFR less than 80 ml/min/1.73 m2 in diabetic nephropathy. Our study suggests that serum beta 2-microglobulin is more ideal endogenous marker for GFR estimation than serum creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗