Maria Rosaria Tagliamonte

Advancing age and insulin resistance: role of plasma tumor necrosis factor-α

In 70 healthy subjects with a large age range, the relationships between plasma tumor necrosis factor-alpha (TNF-alpha) and body composition, insulin action, and substrate oxidation were investigated. In the cross-sectional study (n = 70), advancing age correlated with plasma TNF-alpha concentration (r = 0.64, P < 0.001) and whole body glucose disposal (WBGD; r= -0.38, P < 0.01). The correlation between plasma TNF-alpha and age was independent of sex and body fat (BF; r = 0.31, P < 0.01). Independent of age and sex, a significant relationship between plasma TNF-alpha and leptin concentration (r = 0.29, P < 0.02) was also found. After control for age, sex, BF, and waist-to-hip ratio (WHR), plasma TNF-alpha was still correlated with WBGD (r = -0.33, P < 0.007). Further correction for plasma free fatty acid (FFA) concentration made the latter correlation no more significant. In a multivariate analysis, a model made by age, sex, BF, fat- free mass, WHR, and plasma TNF-alpha concentrations explained 69% of WBGD variability with age (P < 0.009), BF (P < 0.006), fat-free mass (P < 0.005), and plasma TNF-alpha (P < 0.05) significantly and independently associated with WBGD. In the longitudinal study, made with subjects at the highest tertiles of plasma TNF-alpha concentration (n = 50), plasma TNF-alpha concentration predicted a decline in WBGD independent of age, sex, BF, WHR [relative risk (RR) = 2.0; 95% confidence intervals (CI) = 1.2-2.4]. After further adjustment for plasma fasting FFA concentration, the predictive role of fasting plasma TNF-alpha concentration on WBGD (RR = 1.2; CI = 0.8-1.5) was no more significant. In conclusion, our study demonstrates that plasma TNF-alpha concentration is significantly associated with advancing age and that it predicts the impairment in insulin action with advancing age.

Plasma Leptin Level Is Associated With Myocardial Wall Thickness in Hypertensive Insulin-Resistant Men

Leptin, the product of the ob gene, has been shown to increase heart rate and blood pressure through a stimulation of cardiac sympathetic nervous system activity, a phenomenon also involved in the pathogenesis of left ventricular hypertrophy in hypertensives. Thus, we hypothesize that plasma leptin concentration is associated with left ventricular hypertrophy. Forty hypertensive males and 15 healthy male subjects underwent anthropometric and echocardiographic evaluations, assessment of insulin sensitivity through euglycemic glucose clamp combined with indirect calorimetry, and determination of fasting plasma leptin concentration. Fasting plasma leptin levels were higher in hypertensives than in controls (6.48+/-2.9 versus 4. 62+/-1.5 ng/mL, P<0.05); these results were unchanged after adjustment for body mass index (P<0.05). In the whole group of patients (n=55), fasting plasma leptin concentration was correlated with body mass index (r=0.46, P<0.001) and waist/hip ratio (r=0.50, P<0.001); independent of body mass index and waist/hip ratio, fasting plasma leptin concentration was correlated (n=55) with whole-body glucose disposal (r=-0.27, P<0.04), interventricular septum thickness (r=0.34, P<0.001), posterior wall thickness (r=0.38, P<0.003), and the sum of wall thicknesses (r=0.68, P<0.001). In a multivariate analysis (n=55), age, body mass index, fasting plasma leptin concentration, plasma Na(+) concentration, whole-body glucose disposal, and diastolic blood pressure explained 68% of the variability of the sum of wall thicknesses with fasting plasma leptin concentration (P<0.03), whole body glucose disposal (P<0.002), and diastolic blood pressure (P<0.001), which were significantly and independently associated with the sum of wall thicknesses. In conclusion, our study demonstrates that fasting plasma leptin levels are associated with increased myocardial wall thickness independent of body composition and blood pressure levels in hypertensives.

Effect of metformin on food intake in obese subjects

It has been hypothesized that metformin inhibits food intake, but in humans such effect needs to be demonstrated. Our study aims at investigating the effect of metformin administration on food intake in obese, non‐diabetic, normotensive patients.

Oxidative Stress and Advancing Age: Results in Healthy Centenarians

OBJECTIVE: Our study aims at investigating the degree of oxidative stress in centenarians

Effects of Vitamin E and Glutathione on Glucose Metabolism: Role of Magnesium

Vitamin E is an antioxidant that has been demonstrated to improve insulin action. Glutathione, another natural antioxidant, may also be important in blood pressure and glucose homeostasis, consistent with the involvement of free radicals in both essential hypertension and diabetes mellitus. Our group has recently suggested that the effects of reduced glutathione on glucose metabolism may be mediated, at least in part, by intracellular magnesium levels (Mg([i])). Recent evidence suggests that vitamin E enhances glutathione levels and may play a protective role in magnesium deficiency-induced cardiac lesions. To directly investigate the effects of vitamin E supplementation on insulin sensitivity in hypertension, in relation to the effects on circulating levels of reduced (GSH) and oxidized (GSSG) glutathione and on Mg([i]), we performed a 4-week, double-blind, randomized study of vitamin E administration (600 mg/d) versus placebo in 24 hypertensive patients and measured whole-body glucose disposal (WBGD) by euglycemic glucose clamp, GSH/GSSG ratios, and Mg([i]) before and after intervention. The relationships among WBGD, GSH/GSSG, and Mg([i]) in both groups were evaluated. In hypertensive subjects, vitamin E administration significantly increased WBGD (25.56+/-0.61 to 31.75+/-0.53 micromol/kg of fat-free mass per minute; P<0.01), GSH/GSSG ratio (1.10+/-0.07 to 1.65+/-0.11; P<0.01), and Mg([i]) (1.71+/-0.042 to 1.99+/-0.049 mmol/L; P<0.01). In basal conditions, WBGD was significantly related to both GSH/GSSG ratios (r=0.58, P=0.047) and Mg([i]) (r=0.78, P=0.003). These data show a clinical link between vitamin E administration, cellular magnesium, GSH/GSSG ratio, and tissue glucose metabolism. Further studies are needed to explore the cellular mechanism(s) of this association.

Lowering fatty acids potentiates acute insulin response in first degree relatives of people with Type II diabetes

Summary Studies have shown that a high plasma non-esterified fatty acid concentration may inhibit glucose induced insulin secretion in vitro and in vivo. The effect of lowering the fatty acid concentration on the acute insulin response was investigated in first degree relatives of people with Type II diabetes in a double-blind, randomised, placebo-controlled trial. Fifty first degree relatives of people with Type II diabetes volunteered for the study. Twenty five were given acipimox (250 mg/day, four times daily) and 25 placebo. The group treated with acipimox had a lower 2-h plasma glucose concentration (6.1 ± 0.2 vs 7.7 ± 0.3 vs mmol/l, p < 0.01); better insulin-mediated glucose uptake (35.4 ± 0.5 vs 28.3 ± 0.4 μmol/kg fat free mass per min, p < 0.01), acute insulin response (68 ± 4.4 vs 46 ± 7.3 mU/l, p < 0.01) and respiratory quotient (0.81 ± 0.02 vs 0.77 ± 0.03, p < 0.05); and a rise in the plasma glucagon (164 ± 63 vs 134 ± 72 ng/l, p < 0.05), growth hormone (1.31 ± 0.13 vs 0.97 ± 0.21 μg/l, p < 0.03) and cortisol (325 ± 41 vs 284 ± 139 nmol/l, p < 0.05) concentrations. The difference in the acute insulin response persisted, even after adjustment for the 2-h plasma glucose concentration, insulin-mediated glucose uptake, the fasting plasma glucagon concentration and the growth hormone concentration (p < 0.05). In a subgroup of eight patients acipimox was compared with acipimox plus intralipid. The acute insulin response (44 ± 5.1 vs 71 ± 5.3 mU/l, p < 0.01) and the insulin-mediated glucose uptake (27.4 ± 0.4 vs 36.7 ± 0.5 μmol/kg fat free mass per min, p < 0.003) were lower with acipimox plus intralipid treatment than with acipimox alone. It is concluded that long term acipimox treatment lowers the plasma fasting free fatty acid concentration and improves the acute insulin response and the insulin mediated glucose uptake. [Diabetologia (1998) 41: 1127–1132]

Plasma sex hormones are significantly associated with plasma leptin concentration in healthy subjects

In humans a sexual dimorphism of plasma leptin concentration has been demonstrated but its significance remains to be established. Sex hormones may have a role.

Losartan mediated improvement in insulin action is mainly due to an increase in non-oxidative glucose metabolism and blood flow in insulin-resistant hypertensive patients

We investigated the possible role of losartan on insulin-mediated glucose uptake, substrate oxidation and blood flow in insulin-resistant hypertensive patients. Sixteen newly diagnosed patients with mild-to-moderate hypertension were studied. The study design was a single-blind, randomised, placebo-controlled trial. After a 1 week run-in period, each patient was randomly assigned to placebo (n = 7) and losartan (n = 9). Both treatment periods lasted 4 weeks. At baseline, and at the end of the placebo and losartan treatment periods, euglycaemic hyperinsulinaemic glucose clamp and indirect calorimetry were performed. Before and along each glucose clamp, blood flow was also determined in the femoral artery by image-directed duplex ultrasonography combining B-mode imaging and pulse Doppler beams. Losartan vs placebo lowered systolic blood pressure by 163 ± 3.5 and 147 ± 4.1 mm Hg (P < 0.001), and diastolic blood pressure by 95 ± 3.2 and 85 ± 3.2 mm hg (P < 0.001). losartan enhanced glucose metabolic clearance rate by 5.1 ± 0.3 and 6.3 ± 0.4 mg/kg × min (P < 0.05), and whole body glucose disposal (wbgd) by 29.2 ± 0.5 and 38.1 ± 0.4 μ mol/kg free fatty mass (FFM) × min (P < 0.01) but did not affect heart rate. insulin-mediated change in blood flow was greater after losartan than placebo administration (111 ± 4 vs 84 ± 3%, P < 0.01). per cent change in insulin-mediated stimulation of blood flow and wbgd were also correlated (r = 0.76, P < 0.01). analysis of substrate oxidation revealed that losartan adminstration improved insulin action and non-oxidative glucose metabolism (nogm) (30.8 ± 2.2 vs 22.8 ± 2.8 μmol/kg FFM × min, P < 0.05). in conclusion losartan improves insulin-mediated glucose uptake through an increase in nogm and blood flow in hypertensive patients.

Myocardial Wall Thickness and Left Ventricular Geometry in Hypertensives: Relationship With Insulin

In hypertensive patients the presence of left ventricular (LV) hypertrophy has been associated with a more severe degree of insulin resistance. Whether myocardial wall thickness or LV geometry are associated with a different degree of insulin resistance is still unknown in essential hypertensives. For this reason 26 men with new diagnosed essential hypertension were enrolled. All patients underwent echocardiographic examination and euglycemic hyperinsulinemic glucose clamp combined with indirect calorimetry. According to LV mass and relative wall thickness data, all patients were categorized in four groups: 1) patients with a normal geometric LV pattern (n = 8) (PAT = 0); 2) patients with concentric remodeling LV mass (n = 8) (PAT = 1); 3) patients with eccentric LV hypertrophy (n = 3) (PAT = 2); and 4) patients with concentric LV hypertrophy (n = 7) (PAT = 3). All groups were similar for anthropometric characteristics. Patients with normal echocardiographic LV pattern (PAT = 0) had higher whole body glucose disposal (WBGD), oxidative and nonoxidative glucose metabolism, and lower lipid oxidation than patients with abnormal echocardiographic LV patterns (PAT = 1 to 3). Nevertheless, no significant differences among the groups with abnormal echocardiographic patterns were found. After controlling for age, body mass index (BMI), waist/hip ratio (WHR), and mean arterial blood pressure, only sum of the wall thickness was significantly correlated with fasting plasma insulin (r = -0.38, P < .05), WBGD (r = - 0.50, P < .009), and NOGM (r = - 0.48, P < .02). In multivariate analysis, a model made by age, BMI, WHR, systolic and diastolic blood pressure, and WBGD explained 38% of the echocardiographic pattern variability. In this model, WBGD (P < .02) was significantly and independently associated with echocardiographic patterns explaining 19% of the echocardiographic pattern variability. In conclusion, our data demonstrate that in arterial hypertension hyperinsulinemia/insulin resistance mainly affects myocardial wall thickness, whereas only a trivial association with LV geometry occurs.

Is insulin action a determinant of left ventricular relaxation in uncomplicated essential hypertension

Objective To examine the relation of insulin action and left ventricular diastolic function in uncomplicated essential hypertension. Methods Doppler echocardiography and glucose clamping combined with indirect calorimetry were performed in 29, newly diagnosed, hypertensive men, free from cardiac and metabolic drugs. They were divided into two groups according to the clamp-derived whole-body glucose disposal level: 20 with insulin resistance (whole-body glucose disposal < 33 μmol/kg per min) and nine with normal insulin sensitivity. Results The two groups were comparable in age, body mass index, heart rate and blood pressure. No difference in diastolic function was found except for the isovolumic relaxation time, which was prolonged for patients with insulin resistance (P = 0.02). For the population as a whole, the relaxation time had univariate relations with the left ventricular mass index (r = 0.57, P < 0.001), whole-body glucose disposal (r = −0.56, P < 0.001) and non-oxidative glucose metabolism (r = −0.54, P = 0.002). In a multivariate model including age, body mass index, heart rate, diastolic blood pressure, left ventricular mass index and whole-body glucose disposal as potential determinants, only the left ventricular mass index (β = 0.39, P = 0.02) and whole-body glucose disposal (β = −0.38, P = 0.03) were independent predictors of the relaxation time (R2 = 0.43, P < 0.001). Conclusions In uncomplicated essential hypertension the insulin resistance is a determinant of abnormalities in isovolumic relaxation, independently from the influence exerted by increased blood pressure levels, being overweight and left ventricular hypertrophy.