Increased urinary free cortisol: a potential intermediate phenotype of essential hypertension

We evaluated urinary cortisol excretion as a potential intermediate phenotype of essential hypertension in 153 white patients with essential hypertension and 18 normotensive white control subjects. Analyses were controlled for dietary sodium and gender to adjust for potential confounding effects of these variables on cortisol excretion. Urinary cortisol excretion measured on both high- and low-salt diets was significantly related to hypertension by repeated measures ANCOVA (P=.02). Additional determinants of urinary free cortisol included dietary sodium intake and gender; cortisol excretion was significantly higher in men (P=.0006) and during a high-sodium diet (P=.0001). Maximum likelihood analysis showed urinary cortisol to have a bimodal distribution on both 200-mmol (P<.01) and 10-mmol (P<.002) sodium diets in hypertensive subjects. On the low-salt diet, the mean urinary cortisol in normotensive subjects (108.7+/-44.7 nmol/d) was similar to the mean of hypertensive subjects in the low mode (127.2+/-43.0 nmol/d). The high mode comprised 31.2% of the hypertensive population and had a mean urinary cortisol of 224.3+/-93.8 nmol/d. Subjects with the highest urinary free cortisol showed the least sensitivity of blood pressure to dietary sodium loading (P<.05). These data suggest that there is an association between salt-resistant hypertension and high urine cortisol levels. This association may have a genetic basis.     

Enhanced coronary vasoconstriction in the Syrian myopathic hamster supports the microvascular spasm hypothesis

This study examines the relation between blood pressure and insulin resistance in obese, sedentary middle-aged and older men. Eleven hypertensive and 17 normotensive subjects of comparable age (58.6 +/- 1.0 years, mean +/- SEM), percent body fat (27.7 +/- 0.7%), and maximal aerobic capacity (30.2 +/- 0.9 mL.kg-1.min-1) participated in this study. Glucose disposal (M, milligrams per kilogram of fat-free mass per minute) determined during a three-dose hyperinsulinemic euglycemic clamp was lower in the hypertensive than normotensive subjects at the low (M at 120 pmol/m2.min: 2.3 +/- 0.2 versus 3.2 +/- 0.3, P = .06), intermediate (M at 600 pmol/m2.min: 8.0 +/- 0.6 versus 10.4 +/- 0.6, P = .02), and high (M at 3000 pmol/m2.min: 13.5 +/- 0.5 versus 15.5 +/- 0.7, P = .04) insulin infusion rates. The calculated insulin concentration necessary for a half-maximal effect (EC50) was greater in the hypertensive than normotensive subjects (1164 +/- 168 versus 864 +/- 66 pmol/L, P = .03). In this population of normotensive and hypertensive men, systolic, diastolic, and mean arterial blood pressures were related to glucose disposal at these insulin infusion rates (r = -.35 to -.46, P < .05) as well as the EC50 (r = .42 to .44, P < .05). Thus, hypertensive obese, sedentary older men have a reduction in both sensitivity and maximal responsiveness to insulin that is directly related to the severity of hypertension independent of obesity and physical fitness.     

Coexistence of both oleosin isoforms on the surface of seed oil bodies and their individual stabilization to the organelles

Increased urine albumin is associated with atherosclerotic disease and predicts cardiovascular morbidity and mortality in nondiabetic populations. This finding is frequently postulated to reflect the impact of atherosclerotic damage on glomerular and systemic capillary permeability, an interesting but as yet untested hypothesis. The transcapillary escape rate of albumin (TERalb, the 1-hour decline rate of intravenous 125I-albumin, a measure of capillary macromolecular permeability), albuminuria, lipid levels, echocardiographic wall thickness, and insulin responses to oral glucose were measured in 30 untreated dipstick-negative lean men and clinically stable atherosclerotic peripheral vascular disease; tolerance to oral glucose was a requirement for inclusion in the study. Because hypertension per se might influence TERalb, the sample included either normotensive (n=18, 118+/-6/72+/-7 mm Hg) or hypertensive (n=12, 141+/-7/84+/-6 mmHg by 24-hour blood pressure monitoring) arteriopathic patients; 11 normal age- and gender-matched subjects (121+/-7/76+/-5 mmHg) were used as control subjects. TERalb was higher in patients (10.7+/-3.2 versus 7.4+/-1.7%/h, P<0.013), a difference that persisted after postload glucose, insulin, and lipid levels were accounted for by covariance analysis; atherosclerosis and hypertension together did not further impair vascular permeation to albumin. In contrast with TERalb, albuminuria was elevated only in the hypertensive subgroup; the 2 variables showed no relationship, even when the data were analyzed separately in normotensive and hypertensive subgroups. Urine albumin correlated positively with 24-hour blood pressure and wall thickness. Thus, systemic capillary permeability is altered in nondiabetic atherosclerotic patients independently from blood pressure levels, but this abnormality is not reflected by proportionate changes in albuminuria.     

Urinary excretion and clearance of insulin in diabetic and normal children and adolescents

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.     

Monosodium glutamate (MSG)-obese rats develop glucose intolerance and insulin resistance to peripheral glucose uptake

Different levels of insulin sensitivity have been described in several animal models of obesity as well as in humans. Monosodium glutamate (MSG)-obese mice were considered not to be insulin resistant from data obtained in oral glucose tolerance tests. To reevaluate insulin resistance by the intravenous glucose tolerance test (IVGTT) and by the clamp technique, newborn male Wistar rats (N = 20) were injected 5 times, every other day, with 4 g/kg MSG (N = 10) or saline (control; N = 10) during the first 10 days of age. At 3 months, the IVGTT was performed by injecting glucose (0.75 g/kg) through the jugular vein into freely moving rats. During euglycemic clamping plasma insulin levels were increased by infusing 3 mU.kg-1.min-1 of regular insulin until a steady-state plateau was achieved. The basal blood glucose concentration did not differ between the two experimental groups. After the glucose load, increased values of glycemia (P < 0.001) in MSG-obese rats occurred at minute 4 and from minute 16 to minute 32. These results indicate impaired glucose tolerance. Basal plasma insulin levels were 39.9 +/- 4 microU/ml in control and 66.4 +/- 5.3 microU/ml in MSG-obese rats. The mean post-glucose area increase of insulin was 111% higher in MSG-obese than in control rats. When insulinemia was clamped at 102 or 133 microU/ml in control and MSG rats, respectively, the corresponding glucose infusion rate necessary to maintain euglycemia was 17.3 +/- 0.8 mg.kg-1.min-1 for control rats while 2.1 +/- 0.3 mg.kg-1.min-1 was sufficient for MSG-obese rats. The 2-h integrated area for total glucose metabolized, in mg.min.dl-1, was 13.7 +/- 2.3 vs 3.3 +/- 0.5 for control and MSG rats, respectively. These data demonstrate that MSG-obese rats develop insulin resistance to peripheral glucose uptake.     

Depletion of NOS activity in the rat dentate gyrus neurons by DSP-4 and protection by deprenyl

Insulin resistance and hyperinsulinemia have been linked with essential hypertension. Age-associated increases in glucose intolerance and hypertension are also well established. To clarify the influence of aging on the insulin sensitivity, euglycemic hyperinsulinemic glucose clamp technique was carried out in 41 normotensive subjects and 42 patients with essential hypertension. The subjects of these groups were divided into two subgroups: young (< 40 years old) and middle-elderly (> or = 40 years old). Insulin sensitivity was assessed as M-value, the rate at which glucose must be infused to maintain a basal blood glucose level. In normotensive subjects, the young subgroup had a significantly higher M-value than did the middle-elderly subgroup. There was a significant negative correlation between age and M-value in normotensive subjects. On the other hand, there was no significant difference in M-value between the young and middle-elderly subgroups in the patients with essential hypertension. The age did not correlate with M-value in the hypertensive group. The normotensive subjects showed a significantly lower M-value than the hypertensive patients in the young group, but not in the middle-elderly group. These results indicate that 1) insulin sensitivity declines with age in normotensive subjects and that 2) insulin sensitivity is already diminished in the early stage of hypertension, and no further decrease in insulin sensitivity occurs with aging in essential hypertensive patients.     

Insulin resistance and essential hypertension in Vietnamese subjects

Several epidemiological and experimental studies suggest that essential arterial hypertension is associated with hyperinsulinism and insulin resistance in obese subjects and also in subjects with normal body weight. Undernutrition remains frequent in adult Vietnamese people and mean body mass index is around 18.5 kg/m2 in Vietnam. The aim of this study was to look for insulin resistance in hypertensive Vietnamese subjects, despite a markedly lower BMI in Vietnam than in occidental countries. One hundred and eight hypertensive patients (51 men and 57 women) over 40 years (mean = 65.4 years) were compared with 36 healthy subjects (23 men and 13 women) over 40 years (mean = 63.8 years). Hypertensive patients had significantly higher BMI (20.5 +/- 0.3 (SEM) kg/m2 vs 18.4 +/- 0.4 kg/m2; p < 0.01), thicker triceps skinfold (1.26 +/- 0.07 cm vs 0.71 +/- 0.07 cm; p < 0.001) and not significantly different waist/hip ratio (0.88 +/- 0.01 vs 0.85 +/- 0.01). Blood glucose at fasting and 2 hours after 75 g glucose taken orally were similar in hypertensive and normotensive subjects. Plasma insulin at fasting and 2 hours after glucose were significantly higher in hypertensive patients (44.4 +/- 5.1 pmol/L vs 21.6 +/- 3.2 pmol/L; p < 0.05 and 271.1 +/- 21.6 pmol/L vs 139.1 +/- 15.2 pmol/L; p < 0.001). Thus, despite under-nutrition, hypertensive Vietnamese patients have a moderate but significant increase in BMI and fat mass without predominant abdominal localization, and a state of insulin-resistance, compared with normotensive healthy subjects.     

Effect of argatroban on microthrombi formation and brain damage in the rat middle cerebral artery thrombosis model

BACKGROUND: The role of the kidney in the development of essential hypertension is subject of debate. METHODS: We compared the renin, kallikrein and prostaglandin renal systems in two groups of normotensive boys, aged 7-16 years, with different degrees of risk for future hypertension: 27 had parents with essential hypertension and 12 had normotensive parents. Supine, standing and post-exercise plasma renin activity as well as levels of urinary kallikrein and prostaglandin E2 before and after exercise were measured. RESULTS: The ratio of post-exercise plasma renin activity (ng/ml/h) to 24 h urinary sodium excretion (mEq/kg/day) was lower in children with hypertensive parents (mean +/- SEM 1.86 +/- 0.24 compared with 3.62 +/- 0.94, P = 0.02). The boys with hypertensive parents had a lower ratio of urinary kallikrein to creatinine before (0.70 +/- 0.13 compared with 1.54 +/- 0.36, P = 0.01) and after exercise (0.80 +/- 0.13 compared with 1.35 +/- 0.23, P = 0.03). The ratio of urinary prostaglandin E2 to creatinine levels did not differ between the groups before or after exercise. CONCLUSION: The plasma renin activity response to exercise and urinary kallikrein excretion were decreased in boys at increased risk of future essential hypertension. These early abnormalities in the renin and kallikrein renal systems may be associated with the development of essential hypertension.     

Lack of association of higher insulin levels with diffuse atherosclerotic coronary artery disease in nondiabetics

Since there is experimental evidence that insulin promotes atherosclerosis, we tested the hypothesis that insulin levels are higher in patients with diffuse atherosclerotic coronary artery disease by measuring insulin levels in 46 nondiabetic patients with angiographically defined diffuse coronary artery disease and 46 normal controls with angiographically normal coronary arteries. Fasting insulin levels were similar in both groups of patients: 7.70 +/- 5.77 microU/mL in those with diffuse coronary disease versus 7.39 +/- 5.01 microU/mL in controls. Also, insulin levels drawn 1 and 2 h after oral glucose challenge were not significantly different in patients with diffuse disease (48.78 +/- 32.46 microU/mL and 42.26 +/- 32.38 microU/mL, respectively) compared with patients with normal coronary arteries (51.03 +/- 28.01 microU/mL and 43.79 +/- 31.62 microU/mL, respectively). We conclude that insulin probably does not promote clinical atherosclerosis in nondiabetics.     

Increased nonoxidative glucose metabolism in idiopathic reactive hypoglycemia

Idiopathic reactive hypoglycemia (IRH) is responsible for postprandial hypoglycemia. Normal insulin secretion and reduced response of glucagon to acute hypoglycemia, but mostly increased insulin sensitivity, represent the metabolic features of this syndrome- The present study has two aims: first, to investigate the fate of glucose utilization inside the cells to assess whether increased glucose disposal in IRH is due to the oxidative and/or nonoxidative pathway; and second, to evaluate glucagon response to prolonged insulin-induced hypoglycemia. In eight patients with IRH and eight normal (N) subjects, we performed two studies on different days: (1) 120-minute euglycemic-hyperinsulinemic (1.0 mU . kg-1 . min-1 regular human insulin) clamp associated with indirect calorimetry; and (2) 180-minute hypoglycemic (2.22 to 2.49 mmo/L achieved through 0.85 mU . kg-1 . min-1 intravenous [IV] regular human insulin) clamp. The results showed an increased insulin-mediated glucose uptake in IRH (9.10 +/- 0.19 v 6.78 +/- 0.18 mg kg-1 . min-1, P < .005). Glucose oxidation was similar in IRH subjects and controls both in basal conditions (1.39 +/- 0.16 v 1.42 +/- 0.15 mg . kg-1 . min-1 and during the clamp studies (2.57 +/- 0.21 v 2.78 +/- 0.26 mg . kg-1 . min-1. In contrast, nonoxidative glucose disposal was significantly higher in IRH than in N subjects (6.53 +/- 0.30 v 4.00 +/- 0.21 mg . kg-1 . min-1, P < .001). During insulinization, fat oxidation was reduced slightly more in IRH than in control subjects. During the hypoglycemic clamp, a significant (P < .01) increase in plasma glucagon concentrations was observed in normal subjects as compared with baseline, whereas no change occurred in IRH patients. In conclusion, in IRH: (1) increased insulin-mediated glucose disposal is due to the increase of nonoxidative glucose metabolism; and (2) glucagon secretion has been confirmed to be inadequate. The increase of insulin sensitivity associated with a deficiency in glucagon secretion can widely explain the occurrence of hypoglycemia in the late postprandial phase.     

NIDDM in the elderly

OBJECTIVE: We conducted this study to assess the metabolic alterations in elderly patients with NIDDM. RESEARCH DESIGN AND METHODS: Healthy, lean (n = 15; age, 73 +/- 1 years; BMI, 23.8 +/- 0.5 kg/m2), and obese (n = 10; age, 71 +/- 1 years; BMI, 28.9 +/- 1.2 kg/m2) control subjects and lean (n = 10; age, 75 +/- 2 years; BMI, 24.0 +/- 0.5 kg/m2) and obese (n = 23; age, 73 +/- 1 years; BMI, 29.9 +/- 0.7 kg/m2) NIDDM patients underwent a 3-h glucose tolerance test, a 2-h hyperglycemic glucose clamp study, and a 3-h euglycemic glucose clamp study with tritiated glucose methodology to measure glucose production and disposal rates. RESULTS: Waist-to-hip ratio (WHR) was greater in both lean and obese NIDDM patients than in control subjects. Insulin responses during the oral glucose tolerance test were similar in obese subjects (control subjects: 417 +/- 64 pmol/l; NIDDM patients: 392 +/- 47 pmol/l) but were reduced in lean NIDDM patients (control subjects: 374 +/- 34 pmol/l; NIDDM patients: 217 +/- 20 pmol/l, P < 0.01). Lean and obese NIDDM patients had absent first-phase insulin responses during the hyperglycemic clamp. Second-phase insulin responses were reduced in lean (P < 0.01 vs. control subjects by analysis of variance) but not obese NIDDM patients. Hepatic glucose output was not increased in lean or obese NIDDM patients. Steady-state (150-180 min) glucose disposal rates were 16% less in lean NIDDM patients (control subjects: 8.93 +/- 0.37 mg.kg LBM (lean body mass)-1.min-1; NIDDM patients: 7.50 +/- 0.28 mg.kg LBM-1.min-1, P < 0.05) and 37% less in obese NIDDM patients (control subjects: 8.17 +/- 0.38 mg.kg LBM-1.min-1; NIDDM patients: 5.03 +/- 0.36 mg.kg LBM-1.min-1, P < 0.001). CONCLUSIONS: Lean elderly NIDDM patients have a profound impairment in glucose-induced insulin release but mild resistance to insulin-mediated glucose disposal. Obese elderly NIDDM patients have adequate circulating insulin, but marked resistance to insulin-mediated glucose disposal. Hepatic glucose output is not increased in elderly NIDDM patients.     

Determining residual urine volumes using a portable ultrasonographic device

To evaluate the effects of long-term treatment antihypertensive with the dihydropyridine calcium antagonist amlodipine on insulin sensitivity, plasma insulin, and lipoprotein metabolism in obese hypertensive patients. We measured the insulin sensitivity index (SI), determined by the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure in 20 obese, non-diabetic patients with essential hypertension before and after 6 weeks of placebo and again after 6 months of amlodipine. Ten patients [mean body mass index (BMI) 30.2 kg.m-2] had been on prior treatment with a thiazide diuretic in low dosage and/or a beta-adrenoceptor blocker (group A), and 10 matched patients [BMI 31.8 kg.m-2] had been previously untreated (group B). Amlodipine was started in a dose of 5 mg and was increased to 10 mg once daily in 14 patients who were hypertensive after 8 weeks on the lower dosage. At entry (before placebo), SI was slightly but not significantly lower in group A than B [2.7 vs. 3.6 x 10(-4) ml.microU-4.min-1]; fasting plasma insulin was 13.6 vs. 12.9 microU.ml-1. After 6 weeks on placebo, S1 averaged 3.7 in group A and 4.4 x 10(-4) microU.ml-1.min-1 in group B; fasting plasma insulin was 14.6 vs. 15.1 microU.ml-1, and glucose 5.5 vs. 5.5 mmol.l-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low urinary dopamine excretion associated to low sodium excretion in normotensive Piaroa Amazonian ethnia compared to urban subjects

The objective of this work was to compare urinary dopamine, noradrenaline, adrenaline, sodium and potassium excretion in a group of normotensive Piaroa Amazonic ethnia who do not use salt in their regular food intake, against a group of urban normotensive citizens known to have a high salt intake in their regular meals. Twenty adult normotensive Piaroa subjects living in the Amazonas forest, 11 men and 9 women, 23-72 years old, and 33 normotensive urban citizens, 25-70 years old, 17 men and 17 women, were included in the study. After a 10 min. rest, an average of three supine systolic (SBP) and diastolic (DBP) blood pressure recordings was obtained. Piaroas subjects SBP and DBP were 111.3 +/- 2.9 mmHg and 62.7 +/- 1.9 mmHg respectively; urban subjects SBP and DBP were 111.8 +/- 2.2 mmHg and 70.3 +/- 1.6 mmHg respectively. Supine heart rate was lower in Piaroas (58.0 +/- 1.8 beats/min) than in urban subjects (76.5 +/- 1.9 beats/min), p < 0.05. Sodium urinary excretion was much lower in Piaroas (12.6 +/- 5.2 mmol/24 h) when compared to urban subjects (210.7 +/- 24.5 mmol/24 h), p < 0.01. No difference was found in daily urinary potassium excretion between Piaroas and urban subjects (50.4 +/- 7.2 mmol/24 h vs 45.1 +/- 7.4 mmol/24 h). Urinary dopamine excretion was lower in Piaroas (314.7 +/- 40.1 micrograms/24 h) in comparison to urban subjects (800.4 +/- 59.2 micrograms/24 h), p < 0.05. Daily urinary noradrenaline and adrenaline excretion were 67.9% and 85.4% respectively lower in Piaroas than in urban subjects. In conclusion, lower amounts of sodium daily intake are associated to lower kidney dopamine production in Piaroas as compared to urban subjects. Apparently indigenous tribes might require less kidney dopamine synthesis to excrete the very small amounts of salt they consume in their regular food intake. The opposite was found in urban subjects; more kidney dopamine synthesis would be required for larger amounts of urinary sodium excretion. In this population, essential hypertension has been associated to a failure of the natriuretic mechanism triggered by dopamine onkidney tubules.     

Renal glomerular and tubular function following acute insulin deprivation in juvenile diabetes mellitus

The effects of acute deprivation of insulin on renal glomerular and tubular functions were studied in 10 children with juvenile diabetes mellitus. Serum glucose concentrations were similar when insulin was administered (251 +/- 112 mg/dl) and when it was withheld (306 +/- 130 mg/dl; 0.5 greater than 0.2). Acute insulin deprivation was associated with a significant reduction in glomerular filtration rate, from 151 +/- 48 ml/min/1.73 m2 to 114 +/- 41 ml/min/1.73 m2 (p less than 0.01). The fractional excretion of sodium rose from 0.45 +/- 0.43 to 0.85 +/- 0.54% (p less than 0.05) and was associated with an enhanced natriuresis; the urinary excretion of sodium increased from 1.67 +/- 1.23 to 2.43 +/- 1.72 microEq/min/kg body weight (p less than 0.05), whereas the urinary excretion of phosphate was not significantly altered from control values. During insulin deprivation a drop occurred in the serum concentration of calcium from 10.37 +/- 0.52 to 9.73 +/- 0.61 mg/dl (p less than 0.01) as well as in its urinary excretion from 0.34 +/- 0.24 to 0.24 +/- 0.20 microgram/min/kg body weight (p less than 0.01). The serum concentration of potassium rose from 4.44 +/- 0.41 to 4.96 +/- 0.51 mEq/l, but its urinary excretion was not significantly different from control values. These data suggest that in juvenile diabetes mellitus the acute deprivation of insulin, dissociated from fluctuations in serum glucose concentration, is associated with a fall in glomerular filtration rate, an increased natriuresis, and a modified calcium and potassium homeostasis.     

Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus

BACKGROUND: Insulin resistance has been associated with hypertension and with renal complications in patients with type 1 diabetes mellitus. Causal relationships have not been fully explained. METHODS: We investigated whether insulin resistance precedes microalbuminuria by measuring insulin resistance with a euglycaemic clamp in combination with indirect calorimetry in 16 uncomplicated type 1 diabetic patients and in six healthy control subjects. The patients had over 10 year duration of diabetes, and were expected to experience either a complication-free or complicated disease course within the next few years. They have thereafter been followed for the development of microalbuminuria for 3 years. RESULTS: In a euglycaemic insulin clamp glucose disposal was lower in diabetic patients compared with control subjects (7.5 +/- 2.9 and 12.6 +/- 2.0 mg/kg LBM/min; P<0.002), mainly due to impaired glucose storage (4.3 +/- 2.3 vs 8.6 +/- 1.6 mg/kg LBM/min; P<0.001). Three years later seven IDDM patients had albumin excretion rate over 30 mg/24 h; glucose disposal (5.5 +/- 2.1 vs 9.0 +/- 2.2 mg/kg LBM/min; P<0.01) had been lower in patients who developed microalbuminuria compared with those who remained normoalbuminuric. CONCLUSIONS: Insulin resistance predicts the increment in urinary albumin excretion. Insulin resistance depends mainly on impaired glucose storage in uncomplicated IDDM.     

Unusual accumulation of glycogen in liver parenchymal cells in a patient with anorexia nervosa

Raised plasma concentrations of atrial natriuretic peptide (ANP) have been reported in patients with Type 1 (insulin dependent) diabetes mellitus (DM) who have poor glycaemic control and are associated with the presence of microalbuminuria. To test the hypothesis that elevations in plasma ANP concentration increase urinary albumin excretion in Type 1 DM, we have studied the effects of intravenous infusions of ANP in eight such subjects with established microalbuminuria. Blood glucose was maintained between 4 and 7 mmol l-1 in all subjects for the duration of studies; after euglycaemia had been established, a standard oral water load (20 ml kg-1 plus replacement of urinary losses) was given. Once steady state diuresis was attained, subjects received intravenous infusion of either placebo (0.9% saline), low dose (2.5 pmol kg-1 min-1) or high dose (5.0 pmol kg-1 kg min-1) ANP solution in a randomized, double-blind protocol. Infusion of ANP caused a dose-dependent increase in urinary albumin excretion rate (placebo, 11.3 (SD 8.9) to 8.7 (SD 6.8) micrograms min-1; low dose ANP, 12.4 (SD 9.9) to 26.5 (SD 27.5) micrograms min-1, p < 0.01; high dose ANP 10.3 (SD 7.3) to 36.6 (SD 28.5) micrograms min-1, p < 0.001, ANOVA). Only high dose ANP caused an increase in urine flow. Blood glucose remained unchanged in all studies. We conclude that intravenous infusions of ANP cause a dose-dependent increase in urinary albumin excretion rate in Type 1 DM subjects with microalbuminuria. These data support the hypothesis that ANP has albuminuric actions which may contribute to microalbuminuria in Type 1 DM.     

Intralymphocyte free magnesium in a group of subjects with essential hypertension

Despite the importance of magnesium in essential hypertension, few data are available on the ionized intracellular concentration of this ion. We therefore studied intralymphocyte free intracellular magnesium (Mgi) in 32 untreated essential hypertensive subjects and 27 normotensive control subjects by means of a fluorimetric technique based on the use of the new magnesium-sensitive dye furaptra. We also measured intralymphocyte ionized calcium (Cai) with fura 2. No statistically significant differences were found in Mgi in hypertensive compared with normotensive subjects (essential hypertensive, 0.291 +/- 0.053 mmol/L; normotensive, 0.293 +/- 0.043 [mean +/- SD]). A statistically significant inverse correlation was established between Mgi and plasma triglycerides in essential hypertensive subjects (r = -.521, P = .002). The hypertensive group was arbitrarily divided into two subgroups according to plasma triglyceride levels (> 2 [n = 10] or < 2 mmol/L [n = 22]), and Mgi proved to be significantly lower in the subgroup with high plasma triglyceride levels compared with either the subgroup with normal triglycerides (P = .009; 95% confidence interval, 0.013-0.088) or the normotensive control group as a whole (P = .03; 95% confidence interval, 0.003-0.069) (high-triglyceride hypertensive subgroup, Mgi = 0.256 +/- 0.045 mmol/L; normal-triglyceride hypertensive subgroup, Mgi = 0.307 +/- 0.049). No statistically significant differences were found in Cai in hypertensive compared with normotensive subjects (hypertensive, 53 +/- 12 nmol/L; normotensive, 54 +/- 14). We did not find statistically significant correlations between Cai and plasma triglycerides, nor did we find any differences in Cai between the subgroup of hypertensive subjects with high plasma triglyceride levels and either the subgroup of hypertensive subjects with normal triglycerides or the normotensive control group as a whole. The discrepancies between our results in lymphocytes and data relating to either erythrocytes or platelets emphasize the need for caution before the results are extrapolated from one tissue to the other. The decreased Mgi levels in the subgroup of high-triglyceride hypertensive subjects may suggest a role for magnesium in plurimetabolic syndrome.     

Glucose and amino acid turnover in untreated gestational diabetes

OBJECTIVE: Although gestational diabetes affects as many as 3% of all pregnant women, specific aspects of glucose and protein metabolism in this population have not been clearly delineated. We tested the hypothesis that gestational diabetes mellitus (GDM) results in increased glucose production and proteolysis during fasting. RESEARCH DESIGN AND METHODS: Using tracer isotope infusions, the rate of appearance (Ra) of glucose, leucine, phenylalanine and tyrosine, phenylalanine hydroxylation, leucine oxidation, and urea nitrogen excretion were determined after an overnight fast in 10 GDM subjects, within 2 weeks of diagnosis and before initiation of treatment, and in a matched control group of nine healthy nondiabetic pregnant women. RESULTS: Fasting glucose Ra was similar in GDM patients and control subjects (GDM, 12.8 +/- 1.1 vs. control subjects, 12.8 +/- 0.9 mumol . kg-1 . min-1). Leucine and phenylalanine Ra (reflecting proteolysis) also were not different between GDM patients and control subjects (GDM leucine Ra, 128 +/- 14 vs. control subjects, 124 +/- 5; phenylalanine Ra GDM, 35 +/- 4 vs. control subjects, 40 +/- 2 mumol . kg-1 . h-1). Furthermore, leucine oxidation and phenylalanine hydroxylation were not increased in GDM subjects, urea nitrogen excretion was actually lower in GDM patients. However, fasting insulin concentrations were significantly elevated in GDM subjects (GDM, 165 +/- 35 vs. control subjects, 30 +/- 5 pmol/l; P < 0.01). CONCLUSIONS: Hepatic glucose release and whole-body proteolysis in GDM patients were remarkably similar to matched pregnant control subjects. This was achieved with insulin concentrations three- to fivefold higher than normal, suggesting significant insulin resistance for both glucose and protein metabolism in GDM.     

Defective L-arginine-nitric oxide pathway in offspring of essential hypertensive patients

BACKGROUND: Essential hypertension is characterized by impaired endothelium-dependent vasodilation. The present study was designed to investigate whether this abnormality is a primary defect or a consequence of blood pressure increases. METHODS AND RESULTS: In offspring of essential hypertensive patients (n = 34) and normotensive subjects (n = 30), we evaluated forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 micrograms.100 mL-1.min-1), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 micrograms.100 mL-1.min-1), an endothelium-independent vasodilator. Minimal forearm vascular resistances also were calculated as the ratio between mean intra-arterial pressure and maximal forearm blood flow induced by forearm ischemia and hand exercise. Vasodilation to acetylcholine was significantly (P < .01) blunted in offspring of hypertensive patients compared with offspring of normotensive subjects, whereas the responses to sodium nitroprusside and minimal forearm vascular resistances were similar. In two subgroups of 14 offspring of essential hypertensive patients but not in 10 offspring of normotensive subjects, vasodilation to acetylcholine was increased by intra-brachial L-arginine (1 mumol.100 mL-1.min-1), the substrate for nitric oxide synthesis, whereas in the other 10 and 8 offspring of essential hypertensive patients and normotensive subjects, respectively, cyclooxygenase blockade by intra-brachial indomethacin (50 micrograms.100 mL-1.min-1) was ineffective. CONCLUSIONS: Offspring of essential hypertensive patients are characterized by a reduced response to acetylcholine linked to a defect in the nitric oxide pathway, suggesting that an impairment in nitric oxide production precedes the onset of essential hypertension.     

Effect of reduced dietary sodium on blood pressure: a meta-analysis of randomized controlled trials

OBJECTIVE:- To ascertain whether restriction of dietary sodium lowers blood pressure in hypertensive and normotensive individuals. DATA SOURCES:- An English-language computerized literature search, restricted to human studies with Medical Subject Heading terms, "hypertension," "blood pressure," "vascular resistance," "sodium and dietary," "diet and sodium restricted," "sodium chloride," "clinical trial," "randomized controlled trial," and "prospective studies," was conducted. Bibliographies of review articles and personal files were also searched. TRIAL SELECTION:- Trials that had randomized allocation to control and dietary sodium intervention groups, monitored by timed sodium excretion, with outcome measures of both systolic and diastolic blood pressure were selected by blinded review of the methods section. DATA EXTRACTION:- Two observers extracted data independently, using purpose-designed forms, and discrepancies were resolved by discussion. DATA SYNTHESIS:- The 56 trials that met our inclusion criteria showed significant heterogeneity. Publication bias was also evident. The mean reduction (95% confidence interval) in daily urinary sodium excretion, a proxy measure of dietary sodium intake, was 95 mmol/d (71-119 mmol/d) in 28 trials with 1131 hypertensive subjects and 125 mmol/d (95-156 mmol/d) in 28 trials with 2374 normotensive subjects. After adjustment for measurement error of urinary sodium excretion, the decrease in blood pressure for a 100-mmol/d reduction in daily sodium excretion was 3.7 mm Hg (2.35-5.05 mm Hg) for systolic (P<.001) and 0.9 mm Hg (-0.13 to 1.85 mm Hg) for diastolic (P=.09) in the hypertensive trials, and 1.0 mm Hg (0.51-1.56 mm Hg) for systolic (P<.001) and 0.1 mm Hg (-0.32 to 0.51 mm Hg) for diastolic (P=.64) in the normotensive trials. Decreases in blood pressure were larger in trials of older hypertensive individuals and small and nonsignificant in trials of normotensive individuals whose meals were prepared and who lived outside the institutional setting. CONCLUSION:- Dietary sodium restriction for older hypertensive individuals might be considered, but the evidence in the normotensive population does not support current recommendations for universal dietary sodium restriction.