Independent association of plasma leptin levels and left ventricular isovolumic relaxation in uncomplicated hypertension.

BACKGROUND: On the basis of evidence of plasma leptin (LE) effects on cardiovascular system, we assessed possible association of LE and Doppler-derived left ventricular (LV) diastolic function in arterial hypertension. METHODS: Doppler echocardiography, blood sample for fasting plasma LE levels, and euglycemic hyperinsulinemic glucose clamp were performed on 15 healthy insulin-sensitive men and 40 newly diagnosed hypertensive men, who were divided into two groups according to insulin sensitivity degree: 15 insulin sensitive (IS) and 25 insulin resistant (IR) individuals (whole body glucose disposal >33.3 and <33.3 micromol/kg, respectively). RESULTS: The IR hypertensives had significantly higher body mass index (BMI), waist/hip ratio, LE and LV mass index than the other two groups. IR hypertensives had lower LE (even after adjusting for BMI and waist/hip ratio) and among LV diastolic indexes, lower E peak velocity (P < .05) and longer isovolumic relaxation time (IVRT) (P < .001) in comparison to IR hypertensives. IR hypertensives had the lowest E/A ratio (0.88 +/- 0.2) compared to IS patients (1.03 +/- 0.1 P < .05) and controls (1.31 +/- 10.2 P < .001). By multiple linear regression analyses performed both in the overall population and hypertensives, LV mass index and LE were independently associated to IVRT (R2 = 0.41 in overall population, R2 = 0.42 in hypertensives, both P < .0001), whereas age, heart rate, diastolic and systolic blood pressure (BP), BMI, waist/hip ratio, and insulin action were not significant. CONCLUSIONS: Our study underscores an independent association of increased plasma LE and lengthening of isovolumic relaxation in uncomplicated hypertension. Further studies will need to understand the conditions underlying both these phenomena.

ACE gene polymorphism and insulin action in older subjects and healthy centenarians.

OBJECTIVES: To evaluate the possible relationship between angiotensin-converting enzyme (ACE) insertion-deletion (ID) genotype and insulin resistance in a population of healthy older Italian subjects. DESIGN: Prospective recruitment of a convenience sample. PARTICIPANTS: One hundred twenty-five subjects age 62 to 105 in good health and not taking any drug known to interfere with glucose metabolism. RESULTS: In the sample population, the relative frequencies of the ACE genotypes deletion-deletion (DD) (0.424), ID (0.400), and insertion-insertion (II) (0.176) were not significantly different from values predicted by Hardy-Weinberg equilibrium. The genotype distribution was similar in men and women. Subjects carrying the II genotype had a higher FPG (P <.001) and FPI (P <.001) than did subjects with DD or ID genotype. Subjects with II genotype also had a significantly higher HOMA index than did subjects with DD or ID genotype (P for trend <.002). In a multivariate stepwise regression analysis, the ACE ID polymorphism was significantly and independently associated with the HOMA index (P <.001). The same result was confirmed performing multivariate analysis in the younger group and centenarians separately. CONCLUSIONS: In an older population, the presence of II ACE genotype is associated with a high degree of insulin resistance independent of other anthropometric variables known to interfere with insulin action; this association is significant in both the younger subjects and the centenarians.

Plasma leptin concentration, insulin sensitivity, and 24-hour ambulatory blood pressure and left ventricular geometry.

Left ventricular (LV) hypertrophy is an important predictor of cardiovascular morbidity and mortality. Hemodynamic factors, such as 24-h blood pressure (BP) values, are responsible for left ventricular hypertrophy in hypertensives. On the other hand, some metabolic factors have also been suggested to affect LV mass and geometry. In particular, plasma leptin concentrations have been found associated to LV myocardial growth. Because chronic leptin infusion stimulates sympathetic nervous system activity and increases BP levels, the role of 24-h BP values on leptin-related changes in myocardial wall geometry cannot be ruled out. Thus, the aim of our study was to evaluate whether the relationship between plasma leptin levels and LV wall thickness is mediated by 24-h BP values in hypertensive male patients. Thirty-six newly diagnosed hypertensive patients underwent Doppler echocardiographic examination, 24-h ambulatory BP recording, and metabolic (euglycemic hyperinsulinemic glucose clamp and fasting plasma leptin levels) measurements. Left ventricular mass correlated positively only with ambulatory diastolic BP (DBP) values, whereas the indices of myocardial wall growth such as interventricular septum thickness and sum of wall thickness (ie, septal + posterior wall thickness) correlated either with 24 h, daytime, or nighttime DBP, as well as with fasting plasma glucose, fasting plasma leptin, and insulin action after adjustment for age, body mass index (BMI), and waist/hip ratio (WHR). In contrast, plasma leptin concentration did not correlate with clinical and ambulatory BP values. A multiple linear regression analysis allowed to investigate the independent role of main anthropometric and cardiovascular covariates on the sum of wall thickness variability. A model that includes age, BMI, WHR, fasting plasma leptin concentration, plasma Na+ concentration, insulin action, and nighttime DBP explained 68% of the sum of wall thickness variability. In such a model, plasma leptin concentration (P < .001), insulin action (P < .029), and nighttime DBP (P < .002) were significantly and independently associated with myocardial wall thickness. In conclusion, our study demonstrates that in hypertensive men fasting plasma leptin levels are determinant of myocardial wall thickness independently of 24-h BP values.

The BB-paraoxonase genotype is associated with impaired brachial reactivity after acute hypertriglyceridemia in healthy subjects.

The possible relationship between paraoxonase (PON) gene polymorphism and brachial reactivity in healthy adult subjects in the presence of acute hypertriglyceridemia (HT), as a prooxidant factor, was investigated. In 101 healthy subjects the response to flow- induced vasodilatation was measured before and after Intralipid infusion. In the same subjects the A/B PON polymorphism was detected. The frequency was 0.545 for AA genotype, 0.356 for the AB genotype, and 0.099 for the BB genotype. At baseline all genotype groups had a similar increase in brachial artery diameter and flow. After Intralipid infusion, subjects sharing the BB genotype had a significant decrease vs. baseline values in changes in brachial artery diameter (P for trend < 0.001 vs. the other genotypes), but not in flow. In a subgroup of 55 subjects distributed among the 3 PON genotypes the same study protocol was repeated by buccal nitroglycerine administration to study the endothelium-independent vasodilatation. Again, subjects with the BB genotype had the worse vasodilation (P for trend < 0.001). Furthermore, subjects sharing the BB genotype had the lowest endothelium-independent and -dependent changes in diameter (P for trend < 0.001 vs. the other genotypes) independently of gender ratio, basal plasma triglycerides concentrations, and changes in plasma triglycerides concentrations. In conclusion, our study demonstrates that transient HT decreases vascular reactivity more in subjects with the PON BB genotype than in those with the other PON genotypes.

Hemodynamic effects of acute hyperglycemia in type 2 diabetic patients.

OBJECTIVE: The aim of the present study was to evaluate the hemodynamic effects of acute hyperglycemia in type 2 diabetic patients and to see whether these effects are related to changes in nitric oxide (NO) availability. RESEARCH DESIGN AND METHODS: Twenty newly diagnosed complication-free diet-treated type 2 diabetic patients participated in the study. All patients underwent 3 hyperglycemic glucose clamps in random order: 1) the control study was performed with plasma glucose clamped at 18 mmol/l for 2 h; 2) the octreotide study with plasma insulin blocked at basal levels during the clamp; and 3) the L-arginine study with L-arginine (1 g/min) infused during the last 30 min of the clamp. A group of 8 patients also underwent a glutathione infusion (600 mg as an intravenous bolus followed by 5 mg/min infusion) during the clamp. RESULTS: During hyperglycemia, there were significant increments of systolic (sBP) (from 115.5 +/- 9.1 to 120.3 +/- 8.2 mmHg, P < 0.01) and diastolic (dBP) (from 70.3 +/- 7.8 to 79.7 +/- 5.3 mmHg, P < 0.01) blood pressure, as well as heart rate (from 75.2 +/- 7.8 to 80.8 +/- 5.4 beats/min, P < 0.01) and plasma catecholamines (P < 0.05). Squatting ratios, a measure of the baroreflex activity, significantly deteriorated after hyperglycemia (P < 0.01). The infusion of octreotide, used to avoid the possible confounding influence of insulin, did not change the hemodynamic effects of hyperglycemia. Glutathione, a free radical scavenger, completely prevented the vascular effects of hyperglycemia. L-Arginine produced a fall in sBP and dBP to baseline values and normalized squatting ratios. CONCLUSIONS: Acute hyperglycemia in newly diagnosed type 2 diabetic patients causes significant hemodynamic changes that are independent of endogenous insulin and are prevented by glutatione and reversed by L-arginine, suggesting an interference with endogenous NO availability. These observations could help explain the adverse cardiovascular effects of hyperglycemic spikes.

Chronic vitamin E administration improves brachial reactivity and increases intracellular magnesium concentration in type II diabetic patients.

Vascular disease accounts for the majority of the clinical complications in diabetes mellitus. As an exaggerated oxidative stress degree has been postulated as the link between diabetes mellitus and endothelial function, a possible positive effect of plasma vitamin E (Vit.E) administration on brachial reactivity could be postulated. Our study aims at investigating the possible effect of chronic Vit.E administration on brachial reactivity, oxidative stress indexes, and intracellular magnesium and calcium content in type II diabetic patients free of diabetic complications. Forty adult, type II diabetic patients were enrolled in the study, which was deigned as a double blind, randomized vs. placebo trial. At baseline all patients underwent the following tests: 1) anthropometric and metabolic examinations, 2) evaluation of oxidative stress indexes, 3) intracellular magnesium and calcium measurements, and 4) determination of arterial compliance and distensibility. Then, all patients were randomly assigned to Vit.E treatment at a dose of 600 mg/day (Evion Forte; n = 20) or placebo (n = 20) over 8 weeks. At the end of this treatment period, a complete reevaluation of the patients was made. Vit.E treatment was associated with a significant improvement in the percent change in brachial artery diameter (P<0.03) and oxidative stress indexes (P< 0.005). In the Vit.E group, the percent change in brachial artery diameter correlated positively with the percent change in oxidative stress indexes (oxidized/reduced glutathione, Trolox-equivalent antioxidant capacity, thiobarbituric acid reaction products, lipid peroxides) and intracellular cation content (magnesium and calcium). After adjustment for age, sex, body mass index, and wait/hip ratio, all of these correlations remained significant (P<0.03 for all). Furthermore, adjusting for glycosylated hemoglobin, plasma total cholesterol, and homeostatic model index, brachial artery diameter was still correlated with the percent change in oxidative stress indexes (P<0.04 for all). Nevertheless, the relationship between the percent change in brachial artery diameter and oxidative stress indexes was no longer significant after adjustment for intracellular Mg and Ca2+. In conclusion, our study demonstrates that chronic administration of Vit.E improves brachial artery reactivity in patients with type II diabetes mellitus. Such an effect seems mediated by a reduction in oxidative stress and a regulation of intracellular calcium and magnesium contents.

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.

Low plasma insulin-like growth factor-1 concentrations predict worsening of insulin-mediated glucose uptake in older people.

OBJECTIVE: The relationship among insulin action, advancing age, and insulin like growth factor-1 (IGF-1) is poorly understood. To gain further insight, the predictive role that low plasma IGF-1 concentration may have on insulin- mediated glucose uptake in older persons was investigated. DESIGN: The study was designed as a longitudinal, observational trial. PARTICIPANTS: Fifty-eight healthy aged (73.1+/-9.4 years) subjects (31 males/27 females) were followed up for 12 months. MEASUREMENTS: At baseline and at the end of the follow-up, insulin-mediated glucose uptake was assessed by euglycemic glucose clamp and plasma total IGF-1 and IGF-binding protein 3 (IGF-BP-3) in each subject, and concentrations were determined. RESULTS: At baseline, plasma IGF-1 concentrations correlated with whole body glucose uptake (WBGD) (r = 0.39, P < .003), insulin-stimulated glucose oxidation (GOX) (r = 0.35, P < .009), and non-oxidative glucose metabolism (r = 0.37, P < .007). Such correlations were also independent of age, sex, body fat, and waist/hip ratio. Fasting plasma total IGF-1 concentrations (84+/-56 vs 63+/-44 microg/L, P < .040), plasma IGF-1/IGF-BP3 molar ratio (0.13+/-0.05 vs 0.10+/-0.03 P < .050), and WBGD (34.8+/-5.0 vs 23.1+/-4.6 micromol/kg x min, P < .010) were more elevated at baseline than at the end of the follow-up. Low baseline fasting plasma IGF-1 concentration (RR = 1.5, 95%CI = 1.3-1.7) and plasma IGF-1/IGFBP-3 molar ratio (RR = 1.4, 95% CI = 1.3-1.8) predicted a decline in WBGD. The predictive role of plasma IGF-1 on age-related decline in WBGD was independent of age, sex, body fat, waist/hip ratio, and degree of physical activity (model 1), or of fasting plasma free fatty acid and triglyceride concentrations, LDL/HDL ratio, and basal adjusted respiratory quotient (model 2). Finally, low plasma IGF-1 concentration predicts a decline in WBGD independent of body fat, free fatty acids, waist/hip ratio, and basal adjusted respiratory quotient (model 3). CONCLUSION: Our study demonstrates that fasting plasma IGF-1 concentration may have a modulatory role on insulin action in older people. This finding might prompt an evaluation of the direct effect of IGF-1 administration on insulin sensitivity in older adults.

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.

Advancing age and insulin resistance: new facts about an ancient history.

The relationship between advancing age and insulin resistance is widely known, but the cause(s) of such association are less well understood. Age-related changes in anthropometric characteristics and environmental factors (changes in diet habits and decline in physical activity) have been hypothesized as being among the main causes. More recently, the role of plasma insulin-like growth factor I (IGF-I), dehydroepiandrosterone sulphate (DHEAS) and tumour necrosis factor alpha (TNF-alpha) concentrations as well as the degree of oxidative stress have also been evaluated. As far as the anthropometric changes are concerned, a decline in fat-free mass and a relative or absolute increase in fat mass are common findings in aged subjects. Such changes are combined with a decline in plasma DHEAS and IGF-I concentration and a rise in plasma TNF-alpha concentrations and oxidative stress, which, in turn, may interact with the anthropometric changes determining the worsening in insulin-mediated glucose uptake. Finally, age-related environmental factors (changes in diet quality and decline in the degree of physical activity) might be a common factor allowing anthropometric factors and age-related remodelling to accelerate their negative impact on insulin action.

Effects of glutathione on red blood cell intracellular magnesium: relation to glucose metabolism.

Recent evidence suggests that the endogenous antioxidant glutathione may play a protective role in cardiovascular disease. To directly investigate the role of glutathione in the regulation of glucose metabolism in hypertension, we studied the acute effects of in vivo infusions of this antioxidant (alone or in combination with insulin) on whole body glucose disposal (WBGD) using euglycemic glucose clamp and the effects on total red blood cell intracellular magnesium (RBC-Mg) in hypertensive (n=20) and normotensive (n=30) subjects. The relationships among WBGD, circulating reduced/oxidized glutathione (GSH/GSSG) levels, and RBC-Mg in both groups were evaluated. The in vitro effects of glutathione (100 micromol/L) on RBC free cytosolic magnesium (Mg(i)) were also studied. In vivo infusions of glutathione (15 mg/minx120 minutes) increased RBC-Mg in both normotensives and hypertensives (1.99+/-0.02 to 2.13+/-0.03 mmol/L, P<0.01, and 1.69+/-0.03 to 1.81+/-0.03 mmol/L, P<0.01, respectively). In vitro GSH but not GSSG increased Mg(i) (179+/-3 to 214+/-5 micromol/L, P<0.01). In basal conditions, RBC-Mg values were related to GSH/GSSG ratios (r=0.84, P<0.0001), and WBGD was directly, significantly, and independently related to both GSH/GSSG ratios (r=0.79, P<0.0001) and RBC-Mg (r=0.89, P<0.0001). This was also true when hypertensive and control groups were analyzed separately. On multivariate analysis, basal RBC-Mg (t=6.81, P<0.001), GSH/GSSG (t=3. 67, P<0.02), and blood pressure (t=2.89, P<0.05) were each independent determinants of WBGD, with RBC-Mg explaining 31% of the variability of WBGD. These data demonstrate a direct action of glutathione both in vivo and in vitro to enhance intracellular magnesium and a clinical linkage between cellular magnesium, GSH/GSSG ratios, and tissue glucose metabolism.

Lack of association between changes in plasma leptin concentration and in food intake during the menstrual cycle.

BACKGROUND: Changes in plasma leptin concentration and food intake occur during the menstrual cycle; because leptin regulates food intake, one could hypothesize that changes in plasma leptin concentration and in food intake are associated throughout the menstrual cycle. However, no data have ever been provided to support such a relationship. The aim of our study was to investigate, during the different phases of the menstrual cycle, (a) the changes in plasma leptin concentration and, if such changes were demonstrated, (b) the potential relationship between the changes in plasma leptin concentration and food intake. DESIGN: The study was designed as an observational study. The plasma leptin concentration was determined in 16 healthy, young women during different phases of the menstrual cycle. At the same time, the basal metabolic rate (BMR), respiratory quotient (RQ) and food intake (FI) were also determined. RESULTS: The plasma leptin concentration increased throughout the menstrual cycle (P < 0.01 for trend) and was significantly correlated with plasma progesterone concentration (r = 0.55, P < 0.007, for follicular phase, r = 0.58, P < 0.02, for the periovulatory period and r = 0.57, P < 0.02, for the luteal phase). No significant differences in BMR and fasting RQ throughout the different phases of the menstrual cycle were found. In contrast, FI significantly declined in the periovulatory phase. No significant correlations between BMR, RQ and FI values and fasting plasma leptin concentration at all menstrual phases were found. CONCLUSION: Changes in plasma leptin concentration and in food intake were found at different phases of the menstrual cycle. Nevertheless, no correlation among those parameters at any phase of the menstrual cycle was observed.

Effects of different insulin infusion rates on heart rate variability in lean and obese subjects.

The low-frequency to high-frequency ratio (LF/HF ratio) is an index of cardiac sympathovagal balance. We hypothesized that insulin might also stimulate the LF/HF ratio. Thus, 15 lean and 15 obese subjects were studied. Each subject underwent sequential hyperinsulinemic clamps (insulin infusion rate 0.50, 1, and 2 mU/kg x min) while the heart rate was recorded by the Holter technique continuously. Indirect calorimetry allowed determination of the respiratory quotient (Rq) and substrate oxidation. The leg blood flow (LBF), leg vascular resistance (LVR), and plasma norepinephrine concentration were also measured. In seven lean subjects, hyperinsulinemic clamps were repeated along with propranolol infusion (0.1 mg x kg(-1) as an intravenous bolus dose followed by continuous intravenous infusion of 0.5 mg x kg(-1) x min(-1) throughout the study). Lean subjects had better insulin action than obese subjects. Insulin infusion was associated with an increase of the deltaLF/HF ratio in both lean (P < .001 for time-dependent changes) and obese (P < .02 for time-dependent changes) subjects; however, the extent of insulin-mediated stimulation of the LF/HF ratio was greater in lean versus obese subjects. Insulin infusion did not significantly affect HF values in both groups. Independently of gender, body fat, changes in the plasma norepinephrine concentration, LBF, and LVR, the deltaLF/HF ratio at the end of the fastest insulin infusion (0.8 +/- 0.2 v 0.3 +/- 0.2, P < .04) was still greater in lean versus obese subjects. The deltaLF/HF ratio was also more stimulated during insulin versus insulin + propranolol infusion in lean subjects. In conclusion, insulin stimulates the LF/HF ratio in both lean and obese subjects and thus produces a shift in the cardiac autonomic nervous system activity toward sympathetic predominance.

Prognostic importance of insulin-mediated glucose uptake in aged patients with congestive heart failure secondary to mitral and/or aortic valve disease.

Previous studies have demonstrated that insulin resistance is a common feature of congestive heart failure (CHF), but the clinical significance of such insulin resistance is still debated. We tested the hypothesis that insulin-mediated glucose uptake (IMGU) is a prognostic factor in CHF in aged patients. For this purpose 174 aged patients with CHF participated in a cross-sectional and a longitudinal study of 24 months' duration. In this latter study survival analysis was calculated comparing subjects at the first and second tertile of IMGU with those at third tertile. All subjects underwent anthropometric (body mass index, waist/hip ratio), cardiovascular (arterial blood pressure, 24-hour Holter monitoring, peak VO2, left ventricular ejection fraction, echocardiography), and metabolic (determination of fasting plasma glucose, insulin, catecholamine, free fatty acids, tumor necrosis factor-alpha concentrations, and assessment of IMGU by euglycemic hyperinsulinemic glucose clamp) investigations. In the cross-sectional study, IMGU correlated with age (r = -0.33, p <0.001), body mass index (r = -0.46 p <0.001), ventricular premature complexes (r = -0.78, p <0.001), left ventricular ejection fraction (r = -0.15, p <0.05), fasting plasma norepinephrine (r = -0.75, p <0.001), tumor necrosis factor-alpha (r = -0.45, p <0.001), free fatty acids (r = -0.54, p <0.001), and peak VO2 (r = 0.67, p <0.001). In the longitudinal study patients at the first and second tertile of IMGU had a lower probability of survival than patients at the third tertile (p <0.03). Cox regression analysis showed IMGU to be a prognostic factor independent of fasting plasma norepinephrine, tumor necrosis factor-alpha, free fatty acid concentration, New York Heart Association class, peak VO2, and left ventricle ejection fraction (relative risk 1.1, 95% confidence intervals 1.0 to 2.1). In conclusion, our study demonstrates that insulin resistance is a common feature of CHF most likely due to elevated plasma norepinephrine and tumor necrosis factor-alpha concentrations, and that IMGU is an independent prognostic factor in CHF.

Mean arterial blood pressure and serum levels of the molar ratio of insulin-like growth factor-1 to its binding protein-3 in healthy centenarians.

OBJECTIVE: Healthy centenarians have a greater molar ratio of plasma insulin-like growth factor-1 to insulin-like growth factor binding protein-3 than that of aged subjects. We investigated the question of whether differences in mean arterial pressure and in this plasma ratio were related in healthy centenarians. SUBJECTS AND METHODS: We studied 52 subjects in total, 30 aged subjects (70-99 years) and 22 healthy centenarians (> 100 years) to determine differences in mean arterial pressure, endothelial function and intracellular cation levels. RESULTS: In the healthy centenarians, the molar ratio of fasting plasma insulin-like growth factor-1 to its binding protein-3 was significantly correlated with mean arterial pressure (r = -0.66, P < 0.001). Baseline (19.3 +/- 1.5 versus 27.6 +/- 2.2 mumol/l, P < 0.05) and L-arginine-stimulated percentage increases in the plasma total nitrate: nitrite ratio (67 +/- 3.4 versus 48 +/- 4.5%, P < 0.03) were greater in the healthy centenarians than in the aged subjects. An L-arginine bolus elicited an increase in forearm blood flow which was correlated with the percentage increase in the plasma total nitrate: nitrite ratio (r = 0.79, P < 0.001) and with the fasting erythrocyte magnesium concentration (r = 0.80, P < 0.001) in healthy centenarians. Both correlations remained significant (P < 0.01) after adjustment for sex, body mass index and the waist: hip ratio. Moreover, the fasting plasma molar ratio of insulin-like growth factor-1 to its binding protein-3 was correlated with the percentage increase in forearm blood flow (r = 0.59, P < 0.005) and with the percentage increase in the plasma total nitrate: nitrite ratio (r = 0.54, P < 0.009) in healthy centenarians. The centenarians had higher baseline total erythrocyte magnesium and lower calcium concentrations than the aged subjects. The addition of insulin growth factor-1 to the incubation medium increased the total intracellular erythrocyte magnesium content and decreased the calcium content in both groups of subjects. Nevertheless, the percentage increase in total erythrocyte magnesium (33 +/- 3.8 versus 12 +/- 3.4%, P < 0.03) and decline in intracellular calcium (17 +/- 2.8 versus 8 +/- 3.1%, P < 0.02) concentrations were greater in the healthy centenarians than the aged subjects. CONCLUSION: In healthy centenarians, insulin-like growth factor-1 may preserve endothelial function and modulate the intracellular cation content, thus contributing to a lower mean arterial pressure than that in aged subjects.

Intralipid infusion combined with propranolol administration has favorable metabolic effects in elderly malnourished cancer patients.

Previous studies have shown that an elevated basal metabolic rate (BMR) is present in elderly malnourished cancer patients. A possible dysfunction of the autonomic nervous system needs to be demonstrated. In aged weight-losing cancer patients (n = 40), aged non-weight-losing cancer patients (n = 30), and aged weight-losing noncancer patients (n = 18), the baseline BMR and heart rate variability were studied. Aged weight-losing cancer patients (n = 40) underwent bioimpedance analysis, ambulatory electrocardiographic monitoring with analysis of heart rate variability, and determination of the BMR. Then, the patients received infusion of Intralipid (Pharmacia, Uppsala, Sweden) without and with propranolol (6 days of 40 mg twice daily) administration. At baseline, a simple correlation between the BMR and the low-frequency component (LF) (r = .42, P < .006) and LF to high-frequency (HF) ratio (r = .51, P < .001) was found. After propranolol administration, the percent decline in the BMR was significantly correlated with the percent decline in the LF (r = .39, P < .01) and LF/HF ratio (r = .53, P < .001). The percent decline in the BMR was not correlated with the HF (r = .13, P < .34) or the plasma noradrenaline concentration (r = .21, P < .20) at any time. With regard to the BMR and substrate oxidation, 6-day propranolol administration plus Intralipid infusion produced the strongest decline in the BMR. This study demonstrates that autonomic nervous system dysfunction occurs and is responsible for the elevated BMR in elderly cancer patients, propranolol administration rectifies the autonomic dysfunction, and Intralipid infusion combined with propranolol administration is useful for enhancing the daily caloric intake without a strong increase in energy expenditure.

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

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 mumol/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/1, p < 0.05), growth hormone (1.31 +/- 0.13 vs 0.97 +/- 0.21 microgram/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 mumol/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.

Effect of metformin on food intake in obese subjects.

BACKGROUND: 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. METHODS: Thirty patients underwent a double-blind, randomized study. Placebo (P; n = 15) and metformin (M; n = 15) were both given for 15 days, and food intake (FI) was recorded at baseline and in the last 4 days of each treatment period. RESULTS: M administration allowed a stronger decline in body weight (BW) (-2.8 +/- 1.6 vs. -0.3 +/- 0.4 kg P < 0.01), body fat (BF) (-1.4 +/- 1.2 vs. -0.3 +/- 1.1 kg P < 0.01), plasma leptin concentration (-5.2 +/- 8.9 vs. -1.8 +/- 10.4 ng mL-1 P < 0.05) and FI (-642 +/- 491 vs.-70 +/- 1165 kJ per 24 h P < 0.01) than P. In M-treated subjects, changes in FI significantly correlated with those in BW (r = 0.63, P < 0.007) and BF (r = 0.74, P < 0.001). Independently of sex and change in BF, the changes in FI and in fasting plasma leptin concentration (r = 0.58, P < 0.01) were still correlated. CONCLUSION: Our study suggests that metformin administration is useful to inhibit FI and to lower BW and BF in obese non-diabetic patients.

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

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.