Brunella Capaldo

Insulin Resistance, Hyperinsulinemia, and Blood Pressure: Role of Age and Obesity

In population surveys, blood pressure and plasma insulin concentration are related variables, but the association is confounded by age and obesity. Whether insulin resistance is independently associated with higher blood pressure in normal subjects is debated. We analyzed the database of the European Group for the Study of Insulin Resistance, made up of nondiabetic men and women from 20 centers, in whom insulin sensitivity was measured by the euglycemic insulin clamp. After excluding subjects aged > or =70 years, those with severe obesity (body mass index [BMI] >40 kg x m[-2]), and those with abnormal blood pressure values (> or =140/90 mm Hg), 333 cases (ages 18 to 70 years; BMI, 18.4 to 39.8 kg x m[-2]) were available for analysis. In univariate analysis, both systolic and diastolic blood pressures were inversely related to insulin sensitivity, with r values of 0.18 (P<.005) and 0.34 (P<.0001), respectively. In a multivariate model simultaneously accounting for sex, age, BMI, and fasting insulin, systolic and diastolic blood pressures were still inversely related to insulin sensitivity (partial r, 0.15 and 0.19; P<.01 for both). In this model, age was positively related to blood pressure levels independently of insulin sensitivity, whereas BMI was not. The predicted impact on blood pressure of a decrease in insulin sensitivity of 10 micromol x min(-1) x kg(-1) was +1.4 mm Hg, similar to that associated with a 10-year difference in age. Although insulin levels and insulin action were reciprocally interrelated, diastolic blood pressure varied as a simultaneous function of both. In normotensive, nondiabetic Europeans, insulin sensitivity and age are significant, mutually independent correlates of blood pressure, whereas body mass is not. The relation of blood pressure to both insulin action and circulating insulin levels is compatible with distinct influences on blood pressure by insulin resistance and compensatory hyperinsulinemia.

Abnormal sympathetic overactivity evoked by insulin in the skeletal muscle of patients with essential hypertension.

The reason why hyperinsulinemia is associated with essential hypertension is not known. To test the hypothesis of a pathophysiologic link mediated by the sympathetic nervous system, we measured the changes in forearm norepinephrine release, by using the forearm perfusion technique in conjunction with the infusion of tritiated NE, in patients with essential hypertension and in normal subjects receiving insulin intravenously (1 mU/kg per min) while maintaining euglycemia. Hyperinsulinemia (50-60 microU/ml in the deep forearm vein) evoked a significant increase in forearm NE release in both groups of subjects. However, the response of hypertensives was threefold greater compared to that of normotensives (2.28 +/- 45 ng.liter-1.min-1 in hypertensives and 0.80 +/- 0.27 ng.liter-1 in normals; P less than 0.01). Forearm glucose uptake rose to 5.1 +/- .7 mg.liter-1.min-1 in response to insulin in hypertensives and to 7.9 +/- 1.3 mg.liter-1.min-1 in normotensives (P less than 0.05). To clarify whether insulin action was due to a direct effect on muscle NE metabolism, in another set of experiments insulin was infused locally into the brachial artery to expose only the forearm tissues to the same insulin levels as in the systemic studies. During local hyperinsulinemia, forearm NE release remained virtually unchanged both in hypertensive and in normal subjects. Furthermore, forearm glucose disposal was activated to a similar extent in both groups (5.0 +/- 0.6 and 5.2 +/- 1.1 mg.liter-1.min-1 in hypertensives and in normals, respectively). These data demonstrate that: (a) insulin evokes an abnormal muscle sympathetic overactivity in essential hypertension which is mediated by mechanisms involving the central nervous system; and (b) insulin resistance associated with hypertension is demonstrable in the skeletal muscle tissue only with systemic insulin administration which produces muscle sympathetic overactivity. The data fit the hypothesis that the sympathetic system mediates the pathophysiologic link between hyperinsulinemia and essential hypertension.

A high-monounsaturated-fat/low-carbohydrate diet improves peripheral insulin sensitivity in non-insulin-dependent diabetic patients☆

It is commonly believed that high-carbohydrate (CHO) diets improve peripheral insulin sensitivity; however, this concept is based on anecdotal evidence. Furthermore, it has been demonstrated that in non-insulin-dependent diabetic patients treated with insulin, a high-monounsaturated-fat (MUFA) diet is more effective than a high-complex-CHO diet in reducing blood glucose levels. The aim of our study was to compare the effect of a high-MUFA diet and a high-CHO diet on peripheral insulin sensitivity and metabolic control in non-insulin-dependent diabetic patients. Ten non-insulin-dependent diabetic patients aged 52 +/- 8 years with a body mass index (BMI) of 26.7 +/- 3.5 kg/m2 who were being treated with diet alone (n = 5) or with diet plus glibenclamide (n = 5) were randomly assigned to a 15-day period of either a high-MUFA/low-CHO diet (CHO, 40%; fat, 40%; protein, 20%; fiber, 24g) or a low-MUFA/high-CHO diet (CHO, 60%; fat, 20%; protein, 20%; fiber, 24g) and were then crossed-over to the other diet. Diets were similar in their content of monosaccharides, disaccharides, and saturated fats, and were administered to the patients in a metabolic ward. The dosage of hypoglycemic drugs was maintained at a constant level throughout the study. With the high-MUFA/low-CHO diet, a decrease in both postprandial glucose (8.76 +/- 2.12 v 10.08 +/- 2.76 mmol/L; P < .05) and plasma insulin (195.0 +/- 86.4 v 224.4 +/- 75.6 pmol/L; P < .02) levels was observed. Furthermore, fasting plasma triglyceride levels were reduced after the high-MUFA fat/low-CHO diet (1.16 +/- 0.59 v 1.37 +/- 0.59 mmol/L; P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Early detection of diabetic cardiomyopathy: usefulness of tissue Doppler imaging

Objective  The aim of the study was to evaluate whether tissue Doppler imaging (TDI) detects a pre‐clinical impairment of diastolic function in subjects with Type 2 diabetes with short duration of disease and normal cardiac function with conventional echocardiography (CE), and whether echocardiographic parameters are related to metabolic abnormalities.

Diastolic Dysfunction in Patients with Non-insulin-dependent Diabetes Mellitus of Short Duration

To determine whether abnormal left ventricular diastolic function is present at an early stage of non‐insulin‐dependent diabetes mellitus (NIDDM), left ventricular diastolic filling was evaluated by pulsed doppler echocardiography in 16 normotensive patients with NIDDM of short duration (1.8 ± 1 years, mean ± SD) and no evidence of microangiopathy, and in 16 healthy volunteers comparable for age, body mass index, and sex distribution. All patients showed normal systolic function. The interventricular septum thickness, left atrial diameter, and left ventricular mass index were increased in the diabetic as compared with the control group (p < 0.01, p < 0.01, and p < 0.02, respectively). Isovolumic relaxation time and atrial peak filling velocity were greater in diabetic patients (p < 0.001, and p < 0.01, respectively), whereas early to atrial peak filling velocity ratio was significantly reduced (p < 0.05). This study demonstrates that an impairment of left ventricular diastolic function occurs early in the natural history of NIDDM, and that this abnormality is unlikely to be related to clinical evidence of microangiopathic complications.

A controlled study on the effects of n-3 fatty acids on lipid and glucose metabolism in non-insulin-dependent diabetic patients.

Eight male non-insulin-dependent diabetic patients participated in a double-blind randomized cross-over study (2 weeks for each period) evaluating the effects of 10 g/day fish oil dietary supplementation on glucose and lipid metabolism. Fasting serum triglyceride concentrations were decreased by fish oil because of a reduction in VLDL (1.4 +/- 0.2 vs. 1.9 +/- 0.2 mmol/l, P less than 0.025). LDL cholesterol concentration was instead increased (3.4 +/- 0.3 vs. 2.8 +/- 0.3 mmol/l, P less than 0.025) and net changes in VLDL triglyceride and in LDL cholesterol were inversely correlated (r = -0.86, P less than 0.01). Plasma free fatty acids concentrations and turnover rate [( 3H]palmitate method) were similar after fish oil and placebo. Fish oil supplement did not induce significant changes in fasting blood glucose (8.1 +/- 1.1 vs. 8.5 +/- 1.2 mmol/l) and average daily blood glucose (BG) (9.4 +/- 3.2 vs. 9.3 +/- 3.5 mmol/l). Glucose stimulated plasma insulin response during a hyperglycemic clamp was not significantly influenced by fish oil both in the early phase and during steady state. Insulin sensitivity (M/I index) was also unchanged. In conclusion, this study shows that a dietary supplement of fish oil decreases plasma triglyceride levels in non-insulin-dependent diabetic patients, an increased conversion rate of VLDL to LDL playing a role in this change. With this dosage of fish oil no relevant variations in glycemic control, insulin secretion and insulin sensitivity occurred.

Skeletal muscle is a primary site of insulin resistance in essential hypertension

To determine the contribution of skeletal muscle to the insulin resistance of essential hypertension, insulin-stimulated forearm glucose uptake was quantitated in 12 control (age, 32 +/- 3 years) and 12 hypertensive subjects (age, 36 +/- 2 years) using the forearm perfusion technique. Peripheral insulin levels were raised acutely (approximately 60 microU/mL), while blood glucose concentration was clamped at its basal value (90 mg/dL) by a variable glucose infusion. During insulin stimulation, whole body glucose uptake was lower in hypertensive (4.5 +/- .3 mg.kg-1.min-1) than in normal subjects (5.8 +/- .4 mg.kg-1.min-1, P less than .05). Similarly, the amount of glucose taken up by the forearm was markedly reduced in the hypertensive (5.3 +/- .91 mg.L-1.min-1) compared with the control group (8.7 +/- 1.1 mg.L-1.min-1). No appreciable difference was observed as to forearm blood flow (39 +/- 4 mL.L-1.min-1 and 37 +/- 5 mL.L-1.min-1) in hypertensive patients. These results indicate that skeletal muscle is a major site of insulin resistance in essential hypertension and that this defect is independent of muscle perfusion.

Usefulness of the High Triglyceride-to-HDL Cholesterol Ratio to Identify Cardiometabolic Risk Factors and Preclinical Signs of Organ Damage in Outpatient Children

OBJECTIVE To evaluate whether the high triglyceride-to-HDL cholesterol (TG-to-HDL-C) ratio is associated with cardiometabolic risk (CMR) factors and preclinical signs of organ damage in an outpatient population of white children and adolescents. RESEARCH DESIGN AND METHODS The study population included 884 subjects (aged 6–16 years), of whom 206 (23%) were normal weight, 135 (15%) were overweight, and 543 (61%) were obese. Biochemical variables were analyzed in the whole sample, whereas homocysteine and left ventricular (LV) geometry and function were evaluated in 536 and 258 children, respectively. RESULTS The percentage of pubertal children (P < 0.001), as well as measurements of BMI, waist circumference, homeostasis model assessment of insulin resistance, white blood cell count, alanine aminotransferase (ALT), systolic blood pressure (P < 0.0001, for all), creatinine (P < 0.001), and diastolic blood pressure (P < 0.02), increased from the lowest to the highest tertile of the TG-to-HDL-C ratio. Age, sex, homocysteine, and glomerular filtration rate did not change. Moreover, interventricular septum thickness, relative wall thickness, and LV mass index (P = 0.01 to P < 0.0001) increased across tertiles of the TG-to-HDL-C ratio. Children with a TG-to-HDL-C ratio ≥2.0 showed a two- to threefold higher risk of elevated ALT levels and concentric LV hypertrophy than those with a TG-to-HDL-C ratio <2.0, independent of confounding factors. CONCLUSIONS The high TG-to-HDL-C ratio is associated with several CMR factors and preclinical signs of liver and cardiac abnormalities in the outpatient, white pediatric population. Thus, a TG-to-HDL-C ratio ≥2.0 may be useful in clinical practice to detect children with a worsened CMR profile who need monitoring to prevent cardiovascular disease in adulthood.

Abnormal Vascular Reactivity in Growth Hormone Deficiency

Background —The reason why patients with growth hormone (GH) deficiency (GHD) are at increased risk for premature cardiovascular death is still unclear. Although a variety of vascular risk factors have been identified in GHD, little is known regarding vascular reactivity and its contribution to premature arteriosclerosis. Methods and Results —We assessed vascular function in 7 childhood-onset, GH-deficient nontreated patients (age 22±3 years, body mass index [BMI] 25±1 kg/m2) and 10 healthy subjects (age 24±0.4 years, BMI 22±1 kg/m2) by using strain gauge plethysmography to measure forearm blood flow in response to vasodilatory agents. The increase in forearm blood flow to intrabrachial infusion of the endothelium-dependent vasodilator acetylcholine was significantly lower in GH-deficient nontreated patients than in control subjects (P <0.05). Likewise, forearm release of nitrite and cGMP during acetylcholine stimulation was reduced in GH-deficient nontreated patients (P <0.05 and P <0.002 versus controls). The response to the endothelium-independent vasodilator sodium nitroprusside was also markedly blunted in GH-deficient patients compared with control subjects (P <0.005). To confirm that abnormal vascular reactivity was due to GHD, we also studied 8 patients with childhood-onset GHD (age 31±2 years, BMI 24±1 kg/m2) who were receiving stable GH replacement therapy. In these patients, the response to both endothelium-dependent and -independent vasodilators, as well as forearm nitrite and cGMP, release was not different from that observed in normal subjects. Peak hyperemic response to 5-minute forearm ischemia was significantly reduced in GH-deficient nontreated patients (17.2±2.6 mL · dL−1 · min−1, P <0.01) but not in GH-treated patients (24.8±3.3 mL · dL−1 · min−1) compared with normal subjects (29.5±3.2 mL · dL−1 · min−1). Conclusions —The data support the concept that GH plays an important role in the maintenance of a normal vascular function in humans.

Carnitine improves peripheral glucose disposal in non-insulin-dependent diabetic patients

To investigate the effects of carnitine on insulin sensitivity in non-insulin-dependent diabetes, insulin-mediated glucose disposal was measured in nine diabetic patients (age 54 +/- 3 years, BMI 27 +/- 1 kg/mq) during a primed (3 mmol) constant (1.7 mumol/min) intravenous infusion of carnitine. In control experiments, the same patients received saline instead of carnitine. Plasma glucose concentration was maintained constant at the level of 100 mg/dl during both studies while plasma insulin was raised to a plateau of 60 microU/ml. Despite similar insulin levels, whole-body glucose utilization was higher with carnitine (4.05 +/- 0.37 mg/kg/min) than saline infusion (3.52 +/- 0.36). Blood lactate concentrations were similar in the basal state and decreased significantly during carnitine infusion (P less than 0.05-0.005), whereas it remained substantially unchanged during saline infusion. Plasma FFA decreased to a similar level (0.1 mmol/l) in both studies. We conclude that an acute carnitine administration is able to improve insulin sensitivity in NIDDM patients. The lactate data suggest that this effect may at least in part be mediated by carnitine activation of pyruvate dehydrogenase.