Insulin resistance and hyperinsulinemia: No independent relation to left ventricular mass in humans.

BACKGROUND: Hyperinsulinemia and insulin resistance may contribute to the development of cardiac hypertrophy. In humans, however, the evidence is inconclusive. METHODS AND RESULTS: We studied 50 nondiabetic subjects covering a wide range of age (20 to 65 years), body mass index (BMI, 19 to 40 kg x m(-2)), and mean blood pressure (72 to 132 mm Hg). Plasma insulin concentrations and secretory rates were measured at baseline and during an oral glucose tolerance test; insulin sensitivity was measured by the insulin clamp technique. Left ventricular mass (LVM) (by 2D M-mode echocardiography) was distributed normally and was higher in obese (BMI >/=27 kg x m(-2), n=16) or hypertensive patients (blood pressure >140/90 mm Hg, n=21) (50+/-8 and 55+/-10 g x m(-2.7), respectively) than in 13 nonobese, normotensive subjects (40+/-8 g x m(-2.7), P:=0.0004). In a multivariate model adjusting for sex, age, BMI, and blood pressure, neither insulin concentrations (fasting or postglucose) nor insulin sensitivity or secretory rates were significant correlates of LVM. Systolic blood pressure (P:=0.003) and BMI (P:=0.01) were the only independent correlates of LVM. From the regression, the impact of hypertension (as a systolic pressure of 180 versus 140 mm Hg=+20%) was twice as large as that of obesity (as a BMI of 35 versus 25 kg x m(-2)=+11%), the two factors being additive. CONCLUSIONS: When adequate account is taken of body mass and blood pressure, insulin, as concentration, secretion, or action, is not an independent determinant of LVM in nondiabetic subjects.

Insulin: new roles for an ancient hormone.

Recent research has greatly expanded the domain of insulin action. The classical action of insulin is the control of glucose metabolism through the dual feedback loop linking plasma insulin with plasma glucose concentrations. This canon has been revised to incorporate the impact of insulin resistance or insulin deficiency, both of which alter glucose homeostasis through maladaptive responses (namely, chronic hyperinsulinaemia and glucose toxicity). A large body of knowledge is available on the physiology, cellular biology and molecular genetics of insulin action on glucose production and uptake. More recently, a number of newer actions of insulin have been delineated from in vitro and in vivo studies. In sensitive individuals, insulin inhibits lipolysis and platelet aggregation. In the presence of insulin resistance, dyslipidaemia, hyper-aggregation and anti-fibrinolysis may create a pro-thrombotic milieu. Preliminary evidence indicates that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo. Insulin plays a role in mediating diet-induced thermogenesis, and insulin resistance may therefore be implicated in the defective thermogenesis of diabetes. In the kidney, insulin spares sodium and uric acid from excretion; in chronic hyperinsulinaemic states, these effects may contribute to high blood pressure and hyperuricaemia. Insulin hyperpolarises the plasma membranes of both excitable and non-excitable tissues, with consequences ranging from baroreceptor desensitisation to cardiac refractoriness (prolongation of QT interval). Under some circumstances insulin is vasodilatory-the mechanism involving both the sodium-potassium pump and intracellular calcium transients. Finally, by crossing the blood-brain barrier insulin exerts a host a central effects (sympatho-excitation, vagal withdrawal, stimulation of corticotropin releasing factor), collectively resembling a stress reaction. Description and understanding of these new roles, their interactions, the interplay between insulin resistance and hyperinsulinaemia, and their implications for cardiovascular disease have only begun.

Effects of acute alpha 2-blockade on insulin action and secretion in humans.

We tested whether acute alpha 2-blockade affects insulin secretion, glucose and fat metabolism, thermogenesis, and hemodynamics in humans. During a 5-h epinephrine infusion (50 ng.min-1.kg-1) in five volunteers, deriglidole, a selective alpha 2-receptor inhibitor, led to a more sustained rise in plasma insulin and C-peptide levels (+59 +/- 14 vs. +28 +/- 6, and +273 +/- 18 vs. +53 +/- 14 pM, P < 0.01 vs. placebo) despite a smaller rise in plasma glucose (+0.90 +/- 0.4 vs. +1.5 +/- 0.3 mM, P < 0.01). Another 10 subjects were studied in the postabsorptive state and during a 4-h hyperglycemic (+4 mM) clamp, coupled with the ingestion of 75 g of glucose at 2 h. In the postabsorptive state, hepatic glucose production, resting energy expenditure, and plasma insulin, free fatty acid (FFA), and potassium concentrations were not affected by acute alpha 2-blockade. Hyperglycemia elicited a biphasic rise in plasma insulin (to a peak of 140 +/- 24 pM), C-peptide levels (1,520 +/- 344 pM), and insulin secretion (to 410 +/- 22 pmol/min); superimposed glucose ingestion elicited a further twofold rise in insulin and C-peptide levels, and insulin secretion. However, alpha 2-blockade failed to change these secretory responses. Fasting blood beta-hydroxybutyrate and glycerol and plasma FFA and potassium concentrations all declined with hyperglycemia; time course and extent of these changes were not affected by alpha 2-blockade. Resting energy expenditure (+25 vs. +16%, P < 0.01) and external cardiac work (+28% vs. +19%, P < 0.01) showed larger increments after alpha 2-blockade. We conclude that acute alpha 2-blockade in humans 1) prevents epinephrine-induced inhibition of insulin secretion, 2) does not potentiate basal or intravenous- or oral glucose-induced insulin release, 3) enhances thermogenesis, and 4) increases cardiac work.

Metabolic and cardiovascular assessment in moderate obesity: effect of weight loss.

Metabolic and hemodynamic abnormalities have been separately described in obesity, and weight reduction is known to lead to some improvement in each. Our aim was to simultaneously assess metabolic and cardiovascular function in normotensive, normotolerant patients with moderate obesity (body mass index = 32.6 +/- 1.1 kg/m2) before and after weight loss. The obese were insulin resistant [37.4 +/- 4.8 mumol/min.kg FFM; P < 0.02 vs. 12 lean controls (50.6 +/- 2.6), on a euglycemic insulin clamp], secreted more insulin both in the fasting state and after oral glucose (70 +/- 10 vs. 48 +/- 6 nmol/mmol.L plasma glucose; P < 0.05), and had higher resting energy expenditure (4.62 +/- 0.18 vs. 4.00 +/- 0.23 kJ/min), systolic and mean blood pressure, stroke volume (87 +/- 8 vs. 67 +/- 4 mL/min; P = 0.05), and cardiac output. There was, however, no relationship between the metabolic and hemodynamic abnormalities. After a weight loss of 11 +/- 1 kg (approximately 15%), insulin sensitivity improved in proportion to the weight reduction, whereas insulin hypersecretion and high energy expenditure persisted. In contrast, all hemodynamic changes reverted to normal. We conclude that in moderate obesity, the metabolic and cardiovascular abnormalities are largely independent of one another; accordingly, weight loss affects them differentially. Partial weight normalization may provide sufficient cardiovascular protection.

In vivo effect of insulin on intracellular calcium concentrations: relation to insulin resistance.

Elevated intracellular calcium concentrations ([Ca2+]i) have been described in essential hypertension and other insulin-resistant states. Our aim was to explore the relationship between insulin resistance and abnormal Ca2+ metabolism. In 50 nondiabetic subjects, half of whom had untreated essential hypertension, we simultaneously measured the in vivo effect of insulin on glucose metabolism (by the insulin clamp technique) and on platelet [Ca2+]i (by the Fura-2 method). In each subject, [Ca2+]i measurements (both in Ca(2+)-free medium and, sequentially, following in vitro Ca2+ loading) were obtained in the fasting state and after 2 hours of euglycemic hyperinsulinemia. In the fasting state, no association was found between any measure of [Ca2+]i and gender, age, body mass index (BMI), blood pressure, or insulin sensitivity. In contrast, following in vivo insulin, platelet [Ca2+]i increased significantly (from 23 +/- 1 to 28 +/- 1 nmol/L in Ca(2+)-free medium, P < .01) in the whole group, and an insulin-induced increase in [Ca2+]i was associated with insulin resistance (r = .35, P = .01) but not with hypertension (r = .2, P = .17) and with impaired glucose storage (as determined by indirect calorimetry, r = .39, P = .01) but not with glucose oxidation. Thus, the 12 most insulin-resistant subjects were characterized by a cluster of abnormalities (mild overweight, higher blood pressure and prevalence of hypertension, higher serum triglycerides and insulin response to oral glucose, and reduced glucose storage) that included an insulin-induced increase in [Ca2+]i (9 +/- 2 nmol/L, P < .001 v basal). We conclude that insulin resistance, rather than hypertension, is associated with an abnormal in vivo effect of insulin on platelet [Ca2+]i.

Effect of a reduced-fat diet with or without pravastatin on glucose tolerance and insulin sensitivity in patients with primary hypercholesterolemia.

Pharmacological treatment of hyperlipidemia may be associated with deterioration of glucose tolerance. We randomized 20 nonobese patients with primary familial hypercholesterolemia (serum total cholesterol 7.8 +/- 0.4 mM, triglycerides 1.4 +/- 0.2 mM) to an isocaloric, reduced fat (< 30%) low-cholesterol (200 mg/day) diet with placebo or pravastatin (40 mg/day). Oral glucose tolerance, endogenous insulin response to glucose, insulin sensitivity (determined by the euglycemic insulin clamp technique), hepatic glucose production (by the tritiated glucose technique), and substrate utilization (by indirect calorimetry) were measured at baseline and after 8 weeks of treatment. Ten normocholesterolemic healthy subjects, matched to the patients by age, sex, and body weight, served as the control group. Diet alone (with no change in body weight) was associated with a significant 15% decrease in both serum low density lipoprotein (LDL)-cholesterol and triglycerides (p < 0.001 for both), and a slight decrease in high density lipoprotein (HDL)-cholesterol concentrations, paralleled by reductions in Apo B, C2, C3, and E levels (p < 0.05 or less). The addition of pravastatin led to a significantly larger reduction in LDL-cholesterol (30%, p < 0.05) and an 8% increase (p < 0.02) in total HDL-cholesterol concentrations. Accordingly, the ratio of LDL:HDL cholesterol (which was 60% higher than in controls at baseline) remained unchanged in the placebo-diet group whereas it was restored to normal in the pravastatin-diet group. Glucose tolerance, insulin response, insulin-induced inhibition of hepatic glucose production and lipolysis, and insulin-mediated glucose uptake and oxidation were all slightly but not significantly improved after treatment, with no significant differences between pravastatin and placebo. In nonobese patients with primary hypercholesterolemia, pravastatin treatment in combination with an isocaloric, reduced-fat diet leads to a marked reduction in LDL-cholesterol and triglycerides levels and a normalization of the LDL:HDL ratio without affecting glucose tolerance or insulin sensitivity.

Effect of insulin on renal sodium and uric acid handling in essential hypertension.

In normal subjects, insulin decreases the urinary excretion of sodium, potassium, and uric acid. We tested whether these renal effects of insulin are altered in insulin resistant hypertension. In 37 patients with essential hypertension, we measured the changes in urinary excretion of sodium, potassium, and uric acid in response to physiological euglycemic hyperinsulinemia (by using the insulin clamp technique at an insulin infusion rate of 6 pmol/min/kg). Glucose disposal rate averaged 26.6 +/- 1.5 mumol/min/kg, i.e., 20% lower than in normotensive controls (33.1 +/- 2.1 mumol/min/kg, P = .015) In the basal state, fasting plasma uric acid concentrations were higher in men than women (P < .001), were positively related to body mass index (r = 0.38, P = .02), waist/hip ratio (r = 0.35, P < .05), and serum triglyceride levels (r = 0.59, P = .0001), and negatively related to HDL cholesterol concentrations (r = -0.59, P = .0001) and glucose disposal rate (r = 0.42, P < .01). Uric acid clearance, on the other hand, was inversely related to body mass index (r = 0.41, P = .01), plasma uric acid (r = 0.65, P < .0001) and triglyceride concentrations (r = 0.39, P < .02), and directly related to HDL cholesterol levels (r = 0.52, P < .001). During insulin infusion, blood pressure, plasma uric acid and sodium concentration, and creatinine clearance did not change. In contrast, hyperinsulinemia caused a significant decrease in the urinary excretion of uric acid (2.67 +/- 0.12 to 1.86 +/- .14 mumol/min/1.73 m2, P = .0001), sodium (184 +/- 12 to 137 +/- 14 mumol/min/1.73 m2, P = .0001), and potassium (81 +/- 7 to 48 +/- 4 mumol/ min/1.73 m2, P = .0001). Both in absolute terms (clearance and fractional excretion rates) and percentagewise, these changes were similar to those found in normotensive subjects. Insulin-induced changes in urate excretion were coupled (r = 0.55, P < .0001) to the respective changes in sodium excretion. In hypertensive patients, higher uric acid levels and lower renal urate clearance rates cluster with insulin resistance and dyslipidemia. Despite insulin resistance of glucose metabolism, acute physiological hyperinsulinemia causes normal antinatriuresis, antikaliuresis, and antiuricosuria in these patients.

Insulin decreases circulating vitamin E levels in humans.

Both hyperinsulinemia and free oxygen radicals have been implicated in the pathogenesis of atherosclerosis, but the relationship between insulin levels or insulin action and the oxidant/antioxidant balance has not been explored. We measured the effect of physiologic hyperinsulinemia on plasma concentrations of vitamin E, a major free radical scavenger molecule. Isoglycemic clamps (at an insulin infusion rate of 6 pmol . min-1 . kg-1) were performed in four groups of subjects: (1) 12 non-insulin-dependent diabetic (NIDDM) patients, (2) eight patients with essential hypertension, (3) 11 nondiabetic obese individuals, and (4) 12 healthy subjects. In 10 healthy volunteers, a time-control experiment was performed by replacing the insulin infusion with normal saline. Vitamin E and plasma lipid levels were determined at baseline and after 2 hours of insulin/saline infusion. Insulin sensitivity was reduced in diabetic, obese, and hypertensive groups in comparison to healthy controls, but fasting plasma vitamin E concentrations were similar in all groups. A consistent decrement in plasma vitamin E concentrations (averaging 12% of baseline, P < .0001) was observed in all subjects receiving insulin regardless of the level of insulin sensitivity, whereas no significant changes in plasma vitamin E were seen in subjects receiving saline infusion (P < .001 v insulin infusion groups). The insulin-induced decrement persisted in all study groups when plasma vitamin E concentrations were corrected for total serum cholesterol levels (-8.9% +/- 1.2% v -0.4 +/- 2.3% of saline controls, P = .0004) or serum low-density lipoprotein (LDL(-10.0% +/- 1.2% v -0.4% +/- 2.2%, P = .0002). We conclude that insulin infusion acutely depletes vitamin E in circulating lipids regardless of insulin resistance. This effect may represent a physiologic means of transferring vitamin E into cell membranes; alternatively, it might reflect a pro-oxidant action of insulin in vivo.

Insulin resistance and vasodilation in essential hypertension. Studies with adenosine.

Insulin-mediated vasodilation has been proposed as a determinant of in vivo insulin sensitivity. We tested whether sustained vasodilation with adenosine could overcome the muscle insulin resistance present in mildly overweight patients with essential hypertension. Using the forearm technique, we measured the response to a 40-min local intraarterial infusion of adenosine given under fasting conditions (n = 6) or superimposed on a euglycemic insulin clamp (n = 8). In the fasting state, adenosine-induced vasodilation (forearm blood flow from 2.6 +/- 0.6 to 6.0 +/- 1.2 ml min-1dl-1, P < 0.001) was associated with a 45% rise in muscle oxygen consumption (5.9 +/- 1.0 vs 8.6 +/- 1.7 mumol min-1dl-1, P < 0.05), and a doubling of forearm glucose uptake (0.47 +/- 0.15 to 1.01 +/- 0.28 mumol min-1dl-1, P < 0.05). The latter effect remained significant also when expressed as a ratio to concomitant oxygen balance (0.08 +/- 0.03 vs 0.13 +/- 0.04 mumol mumol-1, P < 0.05), whereas for all other metabolites (lactate, pyruvate, FFA, glycerol, citrate, and beta-hydroxybutyrate) this ratio remained unchanged. During euglycemic hyperinsulinemia, whole-body glucose disposal was stimulated (to 19 +/- 3 mumol min-1kg-1), but forearm blood flow did not increase significantly above baseline (2.9 +/- 0.2 vs 3.1 +/- 0.2 ml min-1dl-1, P = NS). Forearm oxygen balance increased (by 30%, P < 0.05) and forearm glucose uptake rose fourfold (from 0.5 to 2.3 mumol min-1dl-1, P < 0.05). Superimposing an adenosine infusion into one forearm resulted in a 100% increase in blood flow (from 2.9 +/- 0.2 to 6.1 +/- 0.9 ml min-1dl-1, P < 0.001); there was, however, no further stimulation of oxygen or glucose uptake compared with the control forearm. During the clamp, the ratio of glucose to oxygen uptake was similar in the control and in the infused forearms (0.27 +/- 0.11 and 0.23 +/- 0.09, respectively), and was not altered by adenosine (0.31 +/- 0.9 and 0.29 +/- 0.10). We conclude that in insulin-re15-76sistant patients with hypertension, adenosine-induced vasodilation recruits oxidative muscle tissues and exerts a modest, direct metabolic effect to promote muscle glucose uptake in the fasting state. Despite these effects, however, adenosine does not overcome muscle insulin resistance.

Insulin sensitivity in familial hypercholesterolemia.

Insulin resistance is found in association with obesity, non-insulin-dependent diabetes mellitus, and essential hypertension, which are all risk factors for atherosclerotic cardiovascular disease. Furthermore, hyperinsulinemia has been reported in familial combined hyperlipoproteinemia and endogenous hypertriglyceridemia. Finally, relatively high serum triglyceride and low high-density lipoprotein (HDL) cholesterol concentrations invariably accompany hyperinsulinemia. Whether insulin sensitivity is affected by the isolated presence of high levels of serum low-density lipoprotein (LDL) cholesterol has not been clearly established. We studied 13 subjects with heterozygous familial hypercholesterolemia (FHC) and 15 normocholesterolemic subjects selected to be free of any other known cause of insulin resistance. Thus FHC patients and controls had normal body weight and fat distribution, glucose tolerance, blood pressure, and serum triglyceride and HDL cholesterol concentrations, but were completely separated on plasma LDL cholesterol concentrations (6.05 +/- 0.38 v 3.27 +/- 0.15 mmol/L, P < .0001). Fasting plasma levels of glucose, insulin, free fatty acids (FFA), and potassium and fasting rates of net carbohydrate and lipid oxidation were superimposable in the two study groups. During a 2-hour euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 340 pmol/L) clamp, whole-body glucose disposal rates averaged 30.4 +/- 2.3 and 31.1 +/- 3.0 mumol.kg-1 x min-1 in FHC and control subjects, respectively (P = 0.88). The ability of exogenous hyperinsulinemia to stimulate carbohydrate oxidation and energy expenditure and suppress lipid oxidation and plasma FFA and potassium levels was equivalent in FHC and control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Some metabolic aspects of essential hypertension and its treatment.

We tested whether patients with essential hypertension (EH) have metabolic evidence of increased adrenergic activity, and if a relationship exists between carbohydrate metabolism and the blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibition. Study 1 included 59 subjects who underwent resting ambulatory BP, heart rate, and resting energy expenditure (REE) measurement (by indirect calorimetry). REE was directly related to lean body mass (LBM) (r = 0.56, p < 0.0001) and to fasting plasma insulin levels (p < 0.03), after adjusting for LBM and age) but not to BP. The 38 subjects with EH had significantly higher fasting plasma insulin levels (54 +/- 4 vs 42 +/- 4 pM; p < 0.05) than the 21 normotensive subjects. When normalized by the LBM, the hypertensive patients had significantly higher REE values than the normotensive subjects (89 +/- 2 vs 78 +/- 3 J min-1.kg-1; p < 0.005). No differences in the other measured variables were found between the two groups. Thus, in this group of lean patients with stable EH, relative hyperinsulinemia is associated with a small increase in REE, the significance of which remains to be determined. In study 2, 20 patients with EH received an oral glucose tolerance test and a euglycemic insulin clamp before and after 3 months of treatment with cilazapril. Glucose-induced insulin response, but not insulin sensitivity, was improved by treatment in the whole group. Before therapy, the 12 responders (diastolic BP < 95 mm Hg) had similar glucose tolerance and insulin sensitivity to the eight nonresponders. Responders, however, had lower fractional potassium excretion than nonresponders both during fasting (9.6 +/- 1 vs 16.0 +/- 2.4%; p < 0.02) and during the glucose load (9.1 +/- 1.4 vs 13.1 +/- 1.1%; p < 0.04). In the responders, fasting potassium levels at baseline were directly related to the decrease in BP (p < 0.01) and to the improvement of glucose-induced insulin response (p < 0.04) achieved after treatment. Thus, the therapeutic effect of ACE inhibition is in part related to fractional potassium excretion, which, in turn, affects glucose tolerance through the influence of potassium levels on glucose-induced insulin release.

Potassium as a link between insulin and the renin-angiotensin-aldosterone system.

PURPOSE: To focus on the interactions between insulin secretion, glucose tolerance and insulin sensitivity on the one hand and the renin-angiotensin-aldosterone system on the other. EFFECTS ON INSULIN: Insulin is a potent stimulus for hypokalaemia, sparing body potassium from urinary excretion by transporting it into cells. Potassium also appears to play a key role in the antinatriuretic effect of insulin. Insulin-induced hypokalaemia increases plasma renin and angiotensin II levels while decreasing the serum aldosterone concentration. In turn, the renin-angiotensin-aldosterone system affects glucose tolerance by modulating plasma potassium levels, which act as a stimulus for glucose-induced insulin release. EFFECTS OF ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITION: Interference with the renin-angiotensin-aldosterone system by ACE inhibition blunts the hypokalaemic response to insulin, thereby improving glucose-induced insulin release and oral glucose tolerance. ACE inhibition, however, does not cause major changes in insulin sensitivity. POTASSIUM AND BLOOD PRESSURE: Plasma potassium levels are inversely related to blood pressure, both in population surveys and in intervention studies. In addition, in patients with essential hypertension, the level of plasma potassium appears to predict the blood pressure response to ACE inhibition. SUMMARY: Potassium metabolism is an important link between carbohydrate metabolism and the renin-angiotensin-aldosterone system by way of a double-feedback mechanism. Through the potential effects on blood pressure control, plasma levels of potassium represent a link between insulin and blood pressure in humans.

Impact of associated conditions on glycemic control of NIDDM patients.

OBJECTIVE: To assess the impact of associated conditions (obesity, dyslipidemia, and hypertension) on the glycemic control of non-insulin-dependent diabetes mellitus (NIDDM) patients under home-life conditions. RESEARCH DESIGN AND METHODS: We analyzed the metabolic data of 271 NIDDM patients (89% Mexican American) screened in a population-based survey (the San Antonio Heart Study). RESULTS: Obesity was present in 77% of the patients, hypertension in 23%, hypertriglyceridemia (serum triglycerides greater than 2.9 mM) in 23%, and hypercholesterolemia (serum total cholesterol greater than 6.5 mM) in 14%. Forty percent of the patients had two or more comorbid conditions. With the use of a multiple linear regression model, which was adjusted for age, sex, ethnicity, distribution of body fat (waist-hip ratio), plasma insulin, and treatment (of both diabetes and hypertension), we found that the presence of higher serum triglyceride concentrations was associated with significantly higher plasma glucose levels both in the fasting state (1.4 mM, P less than 0.001) and 2 h after an oral glucose load (1.2 mM, P = 0.003). The presence of obesity, hypertension, or high serum cholesterol levels was not associated with significant changes in glycemic control. When the entire group was stratified by diabetes treatment (untreated n = 89, diet n = 75, oral agents n = 82, insulin n = 25) and after adjusting for age, sex, ethnicity, and waist-hip ratio, only fasting and 2-h plasma glucose and insulin concentrations were significantly different across treatment groups, with diet and oral agents being associated with higher fasting (P less than 0.001) and postglucose (P less than 0.005) plasma glucose levels and lower plasma insulin concentrations (P less than 0.005) compared with newly diagnosed patients. Neither serum lipids nor blood pressure differed across treatment. CONCLUSIONS: In NIDDM patients under home-life conditions, higher serum triglycerides are associated with higher fasting and postglucose hyperglycemia regardless of antidiabetic treatment. The presence of obesity, hypertension, or high serum cholesterol levels is not associated with significant changes in glycemic control.