Normotensive Diabetic Patients Research Articles

A Six‐year Follow‐up of the Relationship Between N‐Acetyl‐β‐glucosaminidase and Albuminuria in Relation to Retinopathy

Fifty patients with Type 1 diabetes mellitus were observed over 6 years. Serum and urinary N-acetyl-beta-glucosaminidase (NAG) activity, and albuminuria were measured in groups of patients subdivided according to ophthalmological findings. Significantly higher mean serum NAG activity was found at the beginning of the study in patients who later developed diabetic retinopathy in comparison with those who did not (geometric mean (2SD range) 19.7 (12.4-31.2) vs 14.4 (9.5-22.7) U l-1, p less than 0.01). Urinary NAG activity was significantly higher in all groups of diabetic patients than in healthy control subjects (p less than 0.05). A significant increase in albumin:creatinine ratio during the study was found in patients with newly developed diabetic retinopathy compared with patients who did not (at 6 years 1.33 (0.40-4.43) vs 0.75 (0.24-2.31) g mol-1, p less than 0.01). No differences in either biochemical variable were found between hypertensive and normotensive diabetic patients at the end of the study. The results suggest that both serum NAG activity and albuminuria may serve as early functional indicators of diabetic retinopathy.

Elevated endogenous digitalis-like substance in hypertensive diabetic patients with a family history of hypertension

Endogenous digital-like substance (DLS) is increased in patients with essential hypertension and is hypothesized to play a role in the pathogenesis of high blood pressure. Whether an increase in DLS in diabetic patients with hypertension is associated with a family history of hypertension or diabetic nephropathy was investigated. Plasma DLS was measured as Na(+)-K(+)-ATPase inhibitory activity (ATPI) in 100 Type 2 diabetic patients. Ouabain was used as a standard of Na-K-ATPase inhibition. Diabetic patients with hypertension demonstrated a greater ATPI level than normotensive diabetic patients (p less than 0.05). In patients with hypertension groups, the positive family history group had a higher ATPI level than the negative family history group (p less than 0.01). Microalbuminuria was not correlated with the ATPI level in diabetic patients. These results suggest that ATPI might play a role in the pathogenesis of hereditary hypertension associated with diabetes mellitus, but not have etiologic significance in diabetic nephropathy.

Comparison between perindopril and nifedipine in hypertensive and normotensive diabetic patients with microalbuminuria. Melbourne Diabetic Nephropathy Study Group.

To compare the efficacy of angiotensin converting enzyme inhibition with calcium antagonism in diabetic patients with microalbuminuria. Randomised study of diabetic patients with microalbuminuria treated with perindopril or nifedipine for 12 months and monitored for one or three months after stopping treatment depending on whether they were hypertensive or normotensive. Patients were randomised separately according to whether they were hypertensive or normotensive. Diabetic clinics in three university teaching hospitals. 50 diabetic patients with persistent microalbuminuria. In all, 43 completed the study: 30 were normotensive and 13 hypertensive; 19 had type I diabetes and 24 had type II diabetes. For 12 months 20 patients were given perindopril 2-8 mg daily and 23 were given nifedipine 20-80 mg daily. Albumin excretion rate, blood pressure, and glomerular filtration rate. Both perindopril and nifedipine significantly reduced mean blood pressure. During treatment there was no significant difference between those treated with perindopril and those treated with nifedipine with respect to albuminuria or mean blood pressure. Stopping treatment with both drugs was associated with a sustained increase in albuminuria and mean blood pressure. There was a significant correlation between mean blood pressure and albuminuria and also between the reduction in mean blood pressure and the decrease in albuminuria during treatment with both drugs. In hypertensive patients both drugs caused significant decreases in mean blood pressure and albuminuria. In normotensive patients there was no significant reduction in albuminuria with either regimen. In diabetic patients with microalbuminuria blood pressure seems to be an important determinant of urinary albumin excretion. Perindopril and nifedipine have similar effects on urinary albumin excretion, both preventing increases in albuminuria in normotensive patients and decreasing albuminuria in hypertensive patients.

Short-Term Administration of Captopril and Nifedipine and Exercise-Induced Albuminuria in Normotensive Diabetic Patients With Early-Stage Nephropathy

Recent studies have demonstrated that short-term angiotensin converting enzyme (ACE) inhibition with captopril can reduce urinary albumin excretion rate (UAER) after exercise in normotensive diabetic patients with early-stage nephropathy. The aim of this study was to investigate whether this effect of ACE inhibition was due to a systemic hypotensive action or a specific action at the intrarenal level. Thus, we compared the acute effects of captopril and the Ca2(+)-channel blocker nifedipine on exercise-induced UAER in normotensive (blood pressure less than 165/95 mmHg) diabetic patients who were normoalbuminuric or microalbuminuric at rest (stage 2 or 3 of diabetic nephropathy). Twenty-five stage 2 diabetic nephropathy patients, 39 stage 3 diabetic nephropathy patients, and 12 nondiabetic subjects performed five submaximal cycloergometric exercises (90% of theoretical heart rate) on nonconsecutive days. The first two exercises were performed in basal conditions; the next three exercises were performed 24 h after administration of captopril (25 mg twice daily) or nifedipine AR (20 mg twice daily) or placebo (1 tablet twice daily) according to a randomized double-blind crossover trial. After placebo, blood pressure and UAER did not change at rest or 1 h after exercise. After captopril, blood pressure at rest and during exercise was similar to that observed after placebo. UAER at rest was not modified, whereas 1 h after exercise, it was significantly decreased both in stage 2 and stage 3 diabetic nephropathy patients (P less than 0.001). After nifedipine, blood pressure decreased significantly at rest and during exercise in respect to placebo and captopril. UAER at rest did not change significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term administration of captopril and nifedipine and exercise-induced albuminuria in normotensive diabetic patients with early-stage nephropathy

Short-term administration of captopril and nifedipine and exercise-induced albuminuria in normotensive diabetic patients with early-stage nephropathy

Preeclampsia in diabetic pregnancies

Diabetic pregnancies complicated by preeclampsia are of concern because of poor perinatal outcome. However, with improved maternal and fetal surveillance the impact of preeclampsia in diabetic pregnancies is declining. This prospective controlled study compared the incidence of preeclampsia and maternal-fetal outcome in 334 diabetic pregnancies and 16,534 nondiabetic pregnancies. The incidence of preeclampsia was 9.9% (33/334) in diabetic pregnancies compared with 4.3% (716/16,534) in nondiabetic controls. The incidence of preeclampsia rose with increasing severity of diabetes by White classification, but was still 8.9% after exclusion of diabetic patients with nephropathy or chronic hypertension. The perinatal mortality rate per 1000 births was 60 for preeclamptic diabetic patients compared with 3.3 for normotensive diabetic patients. Parity, maternal age, and blood glucose control were similar in preeclamptic diabetic patients compared with normotensive diabetic patients. We conclude that preeclampsia is twice as common in diabetic pregnancies compared with normal controls.

Acute Effects of a Somatostatin Analogue on Kidney Function in Type 1 Diabetic Patients

Suppression of growth hormone by means of somatostatin has been suggested as a possible adjunct therapy in Type 1 diabetes. To assess the acute effect of the somatostatin analogue SMS 201-995 on kidney function in uncomplicated Type 1 diabetes, 13 normoalbuminuric, normotensive diabetic patients were investigated before and during IV infusion of SMS 201-995 (8 micrograms h-1). A control experiment with infusion of carrier only was also performed. The SMS infusion induced a reduction in the glomerular filtration rate (clearance of 125I-iothalamate) and renal plasma flow (131I-hippuran) from 140 +/- 15 (mean +/- SD) and 550 +/- 69 to 131 +/- 14 (2p less than 0.005) and 492 +/- 73 ml min-1 1.73-m-2 (2p less than 0.001), while filtration fraction and total renal resistance rose (both 2p less than 0.001). Urinary albumin excretion rate, blood pressure, and blood glucose concentration were unchanged. Plasma growth hormone and glucagon were significantly suppressed. The reduction in glomerular filtration rate and renal plasma flow correlated with the fall in glucagon concentration (r = 0.57, 2p = 0.04, and r = 0.63, 2p = 0.02). The urinary flow rate was markedly reduced, urine osmolality increased, and fractional excretion of sodium, calcium, and phosphate were reduced. Arginine vasopressin, atrial natriuretic peptide, angiotensin II, and aldosterone were unchanged by the SMS infusion. Thus SMS 201-995 acutely reduces glomerular filtration rate and renal plasma flow in uncomplicated Type 1 diabetes and has an antidiuretic effect. The effects may be related to suppression of glucagon secretion.

Increased Proximal Tubular Sodium Reabsorption in Hypertensive Patients with Type 2 Diabetes

Hyperinsulinaemia and sodium retention have been studied in 22 Type 2 diabetic patients (10 normotensive, 12 hypertensive) and 10 normal control subjects matched for age, sex, and body mass index. Exchangeable sodium was similar in the three groups. Plasma renin activity and plasma angiotensin II were lower in both groups of diabetic patients than in the normal control subjects (p less than 0.01). Plasma atrial natriuretic peptide was increased in the hypertensive patients (7.3 +/- 1.1 vs normotensive 4.7 +/- 1.1 pmol l-1 and control 4.0 +/- 0.2 pmol l-1, p less than 0.01). Fractional lithium clearance, a measure of sodium clearance from the proximal tubule, was decreased (18.5 +/- 1.4, p less than 0.01) and fractional excretion of sodium in the distal tubule was increased (6.66 +/- 0.66, p less than 0.01) in untreated hypertensive diabetic patients compared with both normotensive diabetic patients (25.3 +/- 1.6 and 3.96 +/- 0.52 respectively) and normal control subjects (25.2 +/- 2.9 and 3.31 +/- 0.38, respectively). Fasting serum insulin was higher in hypertensive than in normotensive diabetic patients (18.5 +/- 3.0 vs 10.7 +/- 1.1 mU l-1, p less than 0.01) and higher in both groups than in normal control subjects (5.6 +/- 0.1 mU l-1, both p less than 0.01). Creatinine clearance was higher in both groups of diabetic patients than in normal control subjects (p less than 0.05). Thus there appears to be increased proximal renal tubular sodium reabsorption in these hypertensive Type 2 diabetic patients, matched by a reduction in distal sodium reabsorption so that net sodium excretion was maintained. This was associated with fasting hyperinsulinaemia.

Noninvasive assessment of cardiomyopathy in normotensive diabetic patients between 20 and 50 years old

To further the understanding of diabetic heart disease, we tested the hypothesis that an asymptomatic group of normotensive diabetic patients between 20 and 50 years old had a restrictive cardiomyopathy independent of clinically significant coronary artery disease. Quantitative two-dimensional echocardiography and stress myocardial perfusion scintigraphy were performed to detect and characterize the cardiac abnormalities in this study group comprising 88 patients with rigorously classified diabetes and 65 volunteer control subjects. Diabetic patients were shown to have a mildly reduced left ventricular end-diastolic volume index: 50.1 +/- 8.2 and 52.1 +/- 14.7 mL/m2 for patients with type I and type II diabetes, respectively, versus 58.9 +/- 11.7 mL/m2 for control subjects. The left ventricular diastolic filling was also impaired in diabetic patients as reflected by a lower atrial emptying index: 0.73 +/- 0.24 and 0.76 +/- 0.3 for type I and type II diabetics, respectively, compared with 1.14 +/- 0.24 for control subjects. Exercise tolerance was normal in subjects with type I diabetes and slightly reduced in subjects with type II diabetes. Only one patient developed regional ischemia on thallium exercise testing. Using a comprehensive, noninvasive approach, we have shown that asymptomatic normotensive patients with type I or type II diabetes who were between 20 and 50 years old had a restrictive cardiomyopathy characterized by mildly reduced left ventricular end-diastolic volume and altered left ventricular compliance independent of critical coronary artery disease.

Short term effect of captopril on microalbuminuria induced by exercise in normotensive diabetics.

To investigate whether captopril has any effect on microalbuminuria induced by exercise in normotensive diabetic patients with early stage nephropathy. Randomised, double blind, crossover trial. Outpatient department. 22 diabetics with stage II nephropathy (urinary albumin excretion rate less than 20 micrograms/min; 15 with type I diabetes and seven with type II), 32 patients with stage III nephropathy (urinary albumin excretion rate 20-200 micrograms/min; 14 with type I diabetes and 18 with type II), and 10 normal subjects. Four exercise tests on a cycle ergometer: the first two under basal conditions and the third and fourth after subjects had received captopril (two 25 mg doses in 24 hours) or placebo (two tablets in 24 hours). Exercised until 90% of maximum heart rate achieved. Mean urinary excretion one hour after the first two exercise tests was 21 micrograms/min in normal subjects, 101 micrograms/min in diabetic patients with stage II nephropathy, and 333 micrograms/min in those with stage III nephropathy. Similar results were obtained after placebo. After captopril the urinary excretion rate one hour after exercise was significantly decreased in diabetics with stage II (36 micrograms/min) and stage III (107 micrograms/min) disease compared with placebo but not in normal subjects. Systolic and diastolic pressures were similar in the three groups after placebo and captopril had been given. Captopril significantly reduces microalbuminuria induced by exercise in normotensive diabetics without affecting systemic blood pressure. Captopril may reduce renal intracapillary pressure.

Noninvasive assessment of cardiomyopathy in normotensive diabetic patients between 20 and 50 years old☆

Noninvasive assessment of cardiomyopathy in normotensive diabetic patients between 20 and 50 years old☆

Association of hypertension with blood viscosity in diabetes.

Plasma and whole blood viscosity and its determinants were measured in 86 diabetic patients (29 hypertensive and 57 normotensive) and compared with 52 non-diabetic control subjects to assess whether hypertension has an additive and adverse effect on blood viscosity. Whole blood viscosity (corrected for haematocrit), at high and low shear rates (95 and 0.95 s-1), was significantly higher in both Type 1 (5.1 +/- 0.5 (+/- SD), 19.8 +/- 2.9) and Type 2 (5.2 +/- 0.3, 21.1 +/- 2.0) diabetic patients compared with control subjects (4.9 +/- 0.6, 17.4 +/- 2.6 mPa s, p less than 0.01). Corrected whole blood viscosity at high shear rate was significantly higher in hypertensive than in normotensive Type 2 diabetic patients (5.5 +/- 0.4 vs 5.2 +/- 0.3 mPa s, p less than 0.01). Plasma viscosity was significantly higher in diabetic patients compared with control subjects (1.4 +/- 0.1 vs 1.3 +/- 0.1 mPa s, p less than 0.01), but there was no difference between hypertensive and normotensive diabetic patients (1.4 +/- 0.1 vs 1.4 +/- 0.2 mPa s). Fibrinogen levels were similar in all the groups.

Hemodynamic factors in the pathogenesis of diabetic nephropathy.

The pathogenesis of the diabetic glomerular lesion is unknown. However, cumulative indirect evidence favors hemodynamic factors associated with the abnormal endocrine environment as the cause of diabetic angiopathy. Experimental evidence suggests that the increased hydrostatic pressures in capillary beds, a hallmark of the early stages of insulin-dependent diabetes, are associated with macromolecular leakage leading to the typical thickening of glomerular capillary basement membrane and increased glomerular mesangial matrix even prior to the occurrence of systemic hypertension. Patients with renal or carotid artery stenosis seem to be protected against diabetic nephropathy and retinopathy on the stenosed side. The first signal of diabetic nephropathy even before deterioration of the renal function is microalbuminuria detected by sensitive methods such as radioimmunoassay. Not only in hypertensive, but even in normotensive diabetic patients with microalbuminuria antihypertensive therapy has been shown to reduce albumin excretion rate and to slow the progression of diabetic nephropathy. Once overt diabetic nephropathy has been established, hypertension is a constant accompaniment of the disease. Thus, hypertension may be a cause as well as a result of diabetic nephropathy. Tight control of blood sugar in close association with antihypertensive treatment reducing blood pressure to a lower normal limit, possibly with agents that specifically decrease glomerular capillary hydraulic pressure are the corner stone in protection against progression of the diabetic angiopathy.

HYPERTENSION AND HYPERINSULINAEMIA: A RELATION IN DIABETES BUT NOT ESSENTIAL HYPERTENSION

To investigate the hypothesis that insulin resistance is concerned in the pathogenesis of essential hypertension fasting glucose/insulin and fasting insulin/C-peptide ratios were measured in non-obese normotensive and hypertensive diabetic and non-diabetic subjects. Patients with essential hypertension had normal fasting serum insulin values and normal fasting glucose/ insulin ratios; by contrast, the hypertensive non-insulin-dependent diabetic subjects had higher fasting serum insulin and lower glucose/insulin ratios than either normotensive diabetic or non-diabetic patients. Both hypertensive and normotensive diabetic subjects had higher fasting C-peptide values than those without diabetes. Hypertensive diabetic patients had the highest insulin/C-peptide ratios, indicating low hepatic insulin extraction rates. These findings suggest that hyperinsulinaemia is not causally related to essential hypertension but that it may contribute to the hypertension of non-insulin-dependent diabetes in association with low hepatic insulin clearance.

Plasma renin and prorenin (inactive renin) in diabetes mellitus: effects of intravenous furosemide.

PRA, active renin, and prorenin were measured in 32 normotensive diabetic patients and 14 normal subjects of similar ages before and after iv injection of 40 mg furosemide. The majority of the diabetic patients had normal PRA and active renin levels before and after furosemide, but in 4 normal subjects and 5 diabetic patients PRA did not rise after furosemide treatment to at least 0.25 ng angiotensin I/(L.s) as previously found in 90% of normal subjects. Two thirds of the diabetic patients had higher plasma prorenin levels than the normal subjects. Four of the 5 diabetic patients whose PRA failed to rise to the usual level after furosemide treatment attained a plasma prorenin level higher than any normal subject, suggesting that furosemide stimulated synthesis and secretion of prorenin, but that conversion of prorenin to active renin was impaired. These 5 diabetic patients also had higher plasma creatinine and potassium levels as well as an increased frequency of albuminuria compared with the other diabetic patients. In contrast, the 4 normal subjects whose PRA failed to reach the usual level after furosemide treatment had low unresponsive prorenin levels, indicating that furosemide did not evoke the expected increase in prorenin or renin synthesis. We conclude that the inability of some diabetic patients to increase PRA after furosemide treatment is not dependent on failure of renin synthesis, but reflects an impairment of the normal processing of prorenin, leading to high levels of prorenin in plasma.

MORE ON LOWERING BLOOD PRESSURE IN DIABETES.

A randomized, placebo-controlled, double-blind study investigated the effect of reducing blood pressure on persistent microalbuminuria in normotensive diabetic patients. Two matched groups of 10 patients were randomly …

Renal kallikrein in diabetic patients with hypertension accompanied by nephropathy.

We measured the 24-h excretion of urinary kallikrein in 27 patients with Type 2 (non-insulin-dependent) diabetes and in 10 normal control subjects. Mean (+/- SD) kallikrein excretion in diabetic patients with nephropathy (6.2 +/- 2.4 naphthyl units (NU)/day, n = 13) was significantly lower than in control subjects (12.8 +/- 3.4 NU/day, p less than 0.01) and in diabetic patients without nephropathy (9.4 +/- 3.4 NU/day, n = 14, p less than 0.05). Kallikrein excretion in hypertensive diabetic patients with nephropathy (5.1 +/- 1.6 NU/day, n = 8) was significantly lower (p less than 0.05) than in normotensive patients with nephropathy (8.3 +/- 2.1 NU/day, n = 5). There were no significant differences in kallikrein excretion rate (24-h excretion of urinary kallikrein/24-h creatinine clearance) among control subjects (9.9 +/- 4.3 NU/ml), diabetic patients with (9.0 +/- 3.2 NU/ml) and without (9.3 +/- 3.5 NU/ml) nephropathy. However, kallikrein excretion rate in hypertensive diabetic patients with nephropathy (7.7 +/- 3.3 NU/ml) was significantly lower (p less than 0.05) than in normotensive diabetic patients with nephropathy (11.8 +/- 2.0 NU/ml, n = 10). Respective basal and post-stimulated (with intravenous furosemide 40 mg plus 60 min ambulation) plasma aldosterone concentrations measured in control subjects and in hypertensive diabetic patients with nephropathy were similar and increased to the same extent in the 2 groups (5.5 +/- 3.2 versus 5.3 +/- 3.2 and 9.3 +/- 2.6 versus 10.5 +/- 3.4 ng/ml), although the respective plasma renin activity tended to be lower in diabetic patients than in control subjects (0.7 +/- 0.6 versus 1.3 +/- 0.9 and 1.8 +/- 1.8 versus 3.0 +/- 2.6 ng-1 . ml-1 . h-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum angiotensin-converting enzyme in diabetes mellitus: a negative report.

Serum angiotensin-converting enzyme (ACE) was measured by a direct photometric method in 78 normotensive diabetic patients and in 34 controls. For comparison, ACE was also assayed in 24 subjects by a radiometric procedure. We found no ACE elevations in diabetics and no significant difference in mean ACE levels between diabetics and normals. Within the diabetic group, enzyme levels were not affected by duration of disease, degree of metabolic control, or presence or not of microangiopathy. Only type I subjects had mean ACE significantly (p less than 0.05) higher than type II, very likely due to their younger age. Serum ACE data from photometric and radiometric methods significantly correlated. ACE measurement seems to be of scarce significance in diabetes mellitus.

Blood pressure may be sodium-dependent in diabetic patients without overt nephropathy.

We studied 29 normotensive diabetic patients free of long-term complications (13 insulin requiring and 16 noninsulin requiring), and 54 normotensive control subjects. No diabetic patient had overt nephropathy (in all 24 h urinary albumin excretion was <0.5G and Albustix was negative), but 24 h urinary albumin excretion was significantly higher than in control subjects in both insulin requiring and non-insulin requiring patients.

Blood pressure and metabolic control as risk factors for nephropathy in type 1 (insulin-dependent) diabetes.

The respective rôles of arterial blood pressure and metabolic control in different stages of diabetic nephropathy were analyzed retrospectively in 52 sequentially-followed Type 1 (insulin-dependent) diabetic patients. A negative correlation was found between median post-prandial blood glucose and median duration of diabetes until onset of persistent proteinuria (p less than 0.01). Systolic blood pressure was higher in patients who subsequently developed persistent proteinuria than those who did not (140 versus 121 mmHg; p less than 0.05), but duration of the interval until onset of persistent proteinuria was not related to blood pressure. After onset of persistent proteinuria, hypertensive diabetic patients developed elevated serum creatinine concentrations more frequently than normotensive diabetic patients (67% versus 14%, p less than 0.05). In these patients, the delay until elevation of serum creatinine concentration was negatively correlated with blood glucose (p less than 0.01). Once serum creatinine was raised, decay of renal function occurred faster in patients with persistent than intermittent hypertension (p less than 0.05). No effect of metabolic control was demonstrable at this stage of nephropathy. It is concluded that metabolic control determines the early course of diabetic nephropathy, whereas blood pressure is more important in advanced stages of nephropathy.