Drugs and toxins associated with myopathies

BACKGROUND: The sympathetic nervous system has long been believed to be involved in the pathogenesis of panic disorder, but studies to date, most using peripheral venous catecholamine measurements, have yielded conflicting and equivocal results. We tested sympathetic nervous function in patients with panic disorder by using more sensitive methods. METHODS: Sympathetic nervous and adrenal medullary function was measured by using direct nerve recording (clinical microneurography) and whole-body and cardiac catecholamine kinetics in 13 patients with panic disorder as defined by the DSM-IV, and 14 healthy control subjects. Measurements were made at rest, during laboratory stress (forced mental arithmetic), and, for 4 patients, during panic attacks occurring spontaneously in the laboratory setting. RESULTS: Muscle sympathetic activity, arterial plasma concentration of norepinephrine, and the total and cardiac norepinephrine spillover rates to plasma were similar in patients and control subjects at rest, as was whole-body epinephrine secretion. Epinephrine spillover from the heart was elevated in patients with panic disorder (P=.01). Responses to laboratory mental stress were almost identical in patient and control groups. During panic attacks, there were marked increases in epinephrine secretion and large increases in the sympathetic activity in muscle in 2 patients but smaller changes in the total norepinephrine spillover to plasma. CONCLUSIONS: Whole-body and regional sympathetic nervous activity are not elevated at rest in patients with panic disorder. Epinephrine is released from the heart at rest in patients with panic disorder, possibly due to loading of cardiac neuronal stores by uptake from plasma during surges of epinephrine secretion in panic attacks. Contrary to popular belief, the sympathetic nervous system is not globally activated during panic attacks.     

Norepinephrine release in the human forearm: effects of epinephrine

It has been postulated that delayed facilitation of norepinephrine release by epinephrine is causally related to the development of hypertension. It has been proposed that a brief increase in epinephrine concentrations results in the uptake of epinephrine into the sympathetic nerve terminal. Subsequent rerelease of epinephrine stimulates presynaptic beta-adrenergic receptors, resulting in a prolonged increase in plasma norepinephrine (NE) concentrations, with amplified sympathetic responses and vasoconstriction. To determine whether such epinephrine-induced, delayed facilitation of NE release occurs in a vascular bed draining resistance vessels and, if it occurs, whether that facilitation differs in hypertension, we used a radioisotope dilution method to measure unstimulated and isoproterenol-stimulated forearm NE spillover before, during, and after a 50 ng/min infusion of epinephrine for 30 minutes directly into the brachial artery. No delayed facilitatory effects of epinephrine on forearm NE spillover were observed in either 6 normotensive (NT) or 8 borderline hypertensive (BHT) subjects (NT unstimulated forearm NE spillover preepinephrine 1.79+/-0.41 ng/min versus postepinephrine 2.36+/-0.65 ng/min, P=.38; BHT preepinephrine 2.24+/-0.70 ng/min versus postepinephrine 1.93+/-0.46 ng/min, P=.51; NT isoproterenol-stimulated forearm NE spillover preepinephrine 4.61+/-1.01 ng/min versus postepinephrine 4.4+/-0.98 ng/min, P=.9; BHT preepinephrine 4.04+/-1.36 ng/min versus postepinephrine 4.69+/-1.49 ng/min P=.5). We conclude that the short-term local infusion of epinephrine does not have a delayed facilitatory effect on forearm NE spillover in NT or BHT subjects. Therefore, the prolonged increase in NE concentrations after epinephrine infusion previously shown systemically, and not seen locally in the forearm, suggests that the delayed facilitatory response to epinephrine may occur in other organs.     

Oral tolerance induction with altered forms of ovalbumin

The mechanism of insulin resistance in obesity was examined in ten obese (BMI 33 +/- 1 kg/m2) and nine lean (BMI 22 +/- 1 kg/m2) Caucasian women during a hyperglycemic-hyperinsulinemic clamp using 13C and 31P nuclear magnetic resonance (NMR) spectroscopy to measure rates of muscle glycogen synthesis and intramuscular glucose-6-phosphate (G-6-P) concentrations. Under similar steady-state plasma concentrations of glucose (approximately 11 mmol/l) and insulin (approximately 340 pmol/l), rates of muscle glycogen synthesis were reduced approximately 70% in the obese subjects (52 +/- 8 micromol/[l muscle-min]) as compared with the rates in the lean subjects (176 +/- 22 micromol/[l muscle-min]; P < 0.0001). Basal concentrations of intramuscular G-6-P were similar in the obese and lean subjects; but during the clamp, G-6-P failed to increase in the obese group (deltaG-6-P obese 0.044 +/- 0.011 vs. lean 0.117 +/- 0.011 mmol/l muscle; P < 0.001), reflecting decreased muscle glucose transport and/or phosphorylation activity. We conclude that insulin resistance in obesity can be mostly attributed to impairment of insulin-stimulated muscle glycogen synthesis due to a defect in glucose transport and/or phosphorylation activity.     

Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover

The afferent signals that evoke changes in energy intake with regard to body weight regulation are presumed to arise partly from body stores, with the most likely candidate being adipose tissue depots. However, clinical investigation of the neuronal circuitry involved in the central nervous system's processing of such satiety signals remains largely unexplored. Using percutaneously placed catheters in either the right or left internal jugular veins, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters in 64 weight-stable male subjects with varying degrees of adiposity. Veno-arterial plasma concentration differences and internal jugular blood or plasma flow were used, according to the Fick Principle, to quantify the amount of neurotransmitter stemming from the brain. By combining this technique with a noradrenaline and adrenaline isotope dilution method for examining neuronal transmitter release, we were able to examine the association between central nervous system neurotransmitters and efferent sympathetic nervous outflow and adrenomedullary function in human obesity. We found that brain 5-hydroxytryptamine (serotonin) turnover is chronically elevated in proportion to adiposity and is increased postprandially to a similar degree in lean and obese individuals. There was no difference in the degree of sympathetic nervous activity or rate of adrenaline secretion in the subjects examined. It therefore seems that in human obesity, in the face of a chronic elevation in peripheral satiety signals, brain serotonergic processes are switched on accordingly, but the subsequent physiological response involving a reduction in food intake, increased thermogenesis and sympathetic activity is in some way impeded.     

Attenuated cardiac sympathetic responsiveness during dynamic exercise in patients with heart failure

BACKGROUND: Cardiac norepinephrine (NE) spillover is increased in patients with chronic heart failure. This elevation is partly due to augmented NE release but also to reduced capacity for cardiac NE removal processes. In patients with mild to moderate heart failure, it is not known whether the described alteration in cardiac sympathetic function also affects cardiac NE spillover during intense sympathetic activation and whether other organs respond in proportion to the heart. METHODS AND RESULTS: Twenty-two patients with heart failure and 15 age-matched healthy subjects were studied. Whole-body and regional (NE) spillovers from the heart and kidneys were assessed at baseline and during supine cycling exercise (10 minutes) with the use of steady-state infusions of tritiated NE (isotope dilution). Cardiac performance was evaluated by means of catheterization of the right side of the heart. Cardiac NE spillover was higher (P < .05) at baseline in the patient group than in healthy subjects, whereas renal and whole-body NE spillovers were similar between the study groups. During exercise, cardiac NE spillover increased 13-fold (P < .05) in healthy subjects but only 5-fold (P < .05) in the cardiac failure group, the latter reaching a lower peak value (P < .05). In contrast, there was no difference between the study groups in either renal or whole-body NE spillover responsiveness to exercise. CONCLUSIONS: Patients with mild to moderate heart failure demonstrated a selective attenuation of cardiac sympathetic responsiveness during dynamic exercise. This attenuation may convey reduced inotropic and chronotropic support to the failing heart.     

Reduced cardiac contractile responsiveness to isoproterenol in obese rabbits

Although obesity is characterized by increased sympathetic nervous system activity, there is often a paradoxical reduction in cardiovascular end-organ response to sympathetic stimulation. Mechanisms involved in reduced sympathetic responsiveness in obesity have not been well characterized. Therefore, we determined cardiac contractile responsiveness to beta-stimulation in the obese rabbit model using both isolated heart (IH) and isolated papillary muscle (IPM) preparations. Female New Zealand White rabbits were fed control (IH: n=9; IPM: n=6) or 10% fat diets (IH: n=9; IPM: n=7) for 12 weeks. Contractile responsiveness in the IH was determined using a modified Langendorff preparation to evaluate the dose-response relationship between isoproterenol and 1) peak developed pressure/g of left ventricular wet weight and 2) maximal rate of pressure development (+dP/dt/P). Contractile responsiveness in the IPM was determined using right ventricular papillary muscles to evaluate the dose-response relationship between isoproterenol and (1) peak developed tension (T)/mm2 cross-sectional area (CSA) and (2) maximal rate of tension development (dT/dt/CSA). In the IH, baseline and maximum developed pressure/g were reduced in obese rabbits by 37% and 31%, respectively (P< or =.05). In the IPM, baseline and maximum T/CSA responses were reduced in obese rabbits by 59% and 33%, respectively (P< or =.05). Potency of isoproterenol as reflected by the EC50 did not differ between lean and obese animals in either preparation. These results demonstrate that left ventricular contractility in obesity is reduced at baseline and in response to stimulation with isoproterenol and suggest that decreased responsiveness to beta-stimulation may be a factor in the obesity-related systolic dysfunction.     

Managed care and outcomes of hospitalization among elderly patients with congestive heart failure

123I-radiolabeled metaiodobenzylguanidine (123I-MIBG) cardiac imaging has been used to evaluate the distribution of sympathetic nervous system (SNS) in the heart. Different heart diseases have shown impaired cardiac SNS distribution as reflected by MIBG activity. The aim of this study was to assess the cardiac distribution of SNS in normal subjects, using MIBG imaging. Ten normal subjects (1 male and 9 females, mean age 46 +/- 9 years) with no cardiac abnormalities underwent myocardial 123I-MIBG scintigraphy, Tc-99m methoxyisobutylisonitrile (MIBI) cardiac perfusion imaging and equilibrium radionuclide angiography (RNA). Regional myocardial MIBG and MIBI activities were quantitatively evaluated using a region of interest analysis. For this purpose, the left ventricle was divided into 6 myocardial regions as anterior, apical, inferior, septum, lateral and posterolateral. In particular, myocardial MIBG and MIBI activities were measured as myocardium to mediastinum ratio. Regional left ventricular function was assessed by RNA. Myocardial MIBG uptake was homogeneous in anterior (2.2 +/- 0.5), inferior (2.5 +/- 0.7), septal (2.4 +/- 0.4), lateral (2.3 +/- 0.4), and posterolateral (2.3 +/- 0.4) regions. Conversely, MIBG uptake was significantly lower in the apical region (1.9 +/- 0.3) compared to all other left ventricular segments (p < 0.05). Regional myocardial perfusion, as measured by MIBI uptake, was homogeneous in all regions. No regional left ventricular wall motion abnormalities were observed by RNA. In conclusion, our data suggest that a decreased MIBG uptake may be observed in the left ventricular apical region of normal subjects reflecting reduced sympathetic innervation of the apex. This finding is not related to myocardial perfusion or wall motion abnormalities. The knowledge of cardiac sympathetic innervation in normal subjects may be helpful to assess SNS abnormalities in heart disease.     

Prevalance of obesity and overweight in northeastern peninsular Malaysia and their relationship with cardiovascular risk factors

Height and body weight were measured in 2,284 subjects over 20 years old. The subjects were chosen by cluster sampling in 9 districts of Kelantan. Blood was drawn after an overnight fast for measurement of cholesterol (chol), triglyceride (TG), VLDL and HDL-Chol. Oral glucose tolerance test was performed with 75 g glucose. The overall prevalence of overweight [BMI (kg/m2) > or = 25-< or = 30] and obesity (BMI > 30) was 21.3% and 4.5% respectively. The overweight and obese were significantly younger than the lean subjects. The prevalence of hypercholesterolemia (chol > 5.2 mmol/l) in lean, overweight and obese subjects was 65.3%, 70.2% and 74.7%, respectively. Impaired glucose tolerance was found in 16.6% of the lean, 21.6% of the overweight and 32.0% of the obese subjects. Diabetes mellitus was found in 7.9% of the lean, 10.5% of the overweight and 6.7 of the obese subjects. 10.1% of lean, 13.2% of overweight and 23.3% of obese individuals were hypertensive. In conclusion, the high prevalence of overweight and obesity in Malaysia was associated with adverse lipid and glucose metabolism as well as poor blood pressure control.     

Prevalence of obesity and ischaemic heart disease in hypertensive subjects

In the present study the prevalence of obesity and its association with ischemic heart disease, recognized according to clinical criteria (chest pain or previous infarction) and/or instrumental data, were described in 8,847 normotensive subjects and in 867 hypertensive subjects, hospitalized during a ten years period (1983-1992), through a cross-sectional study. In view of this all the subjects were considered as lean or obese according to their body mass index (BMI) and to sex specific cut-off values reported in the Italian Consensus Conference on Obesity. In particular, according to BMI values, the subjects were grouped as lean, overweight, moderate and severe obese subjects. Our results indicated that 3,982 normotensive subjects (45%) could be considered lean, whereas 2,654 of them (30%) were overweight, 1,769 of them (20%) were moderate obese and 442 of them (5%) were severe obese. On the contrary only 206 hypertensives (23.7%) might be considered lean, whereas 313 (36.1%) were overweight, 302 (34.8%) were moderate obese and 46 (5.3%) were severe obese. According to age subgrouping (lower than or equal to 65 years or higher than 65 years) the distribution of hypertensives within the lean, overweight, moderate and severe obese groups did not change significantly, but, according to sex subgrouping, the distribution of hypertensives within the BMI groups was significantly different (chi 2, p < 0.001). When we considered the degree of hypertension, distribution of hypertensives was significantly different according to c2 test (p < 0.004), suggesting that the percentage of the subjects with severe hypertension increased only in subjects with severe obesity. Concomitant ischaemic heart disease (IHD) was also documented in 350 normotensives (4%) and in 119 hypertensives (13.8%). The prevalence of IHD was not significantly different in lean, overweight, moderate and severe obese hypertensives, also when sex and smoking habits were considered. Our data indicated a strong association between obesity and hypertension. In addition they may be consistent with the suggestion that obese hypertensives were not characterized by a lower risk of ischaemic heart disease (IHD), than lean hypertensives.     

Cholesterol transport between cells and high density lipoprotein subfractions from obese and lean subjects

We studied the pathway of cholesterol efflux from fibroblasts by testing plasma samples from obese and lean subjects. Plasma samples were incubated with [3H]cholesterol-labeled human skin fibroblasts for 1 h to ensure uniform labeling of all of the high density lipoprotein (HDL) subfractions. Supernatants were then transferred to unlabeled cells and the displacement of labeled cholesterol within HDL subfractions by unlabeled cellular cholesterol was analyzed in short-term experiments. Plasma samples of obese subjects were characterized by a lower content of total apolipoprotein A-I (apoA-I) and alpha1-HDL and a lower overall capacity to take up labeled cholesterol. In plasma of lean subjects, pre beta2-HDL and alpha1-HDL appeared to be the most active particles in the initial uptake of unlabeled cellular cholesterol. By contrast, in plasmas of obese subjects, the pre beta1-HDL appeared to be most active in taking up unlabeled cellular cholesterol and transferring [3H]cholesterol. There were negative correlations between body mass index (BMI) and apoA-I and alpha1-HDL concentrations, and with the apparent increments of cellular cholesterol uptake within pre beta2-HDL and alpha1-HDL, as well as with the overall capacity to promote cholesterol efflux. By contrast, BMI was positively correlated with the apparent increment in cellular cholesterol within pre beta1-HDL. While cholesterol efflux was correlated with total plasma apoA-1, there were no such correlations with the concentration of any individual HDL subfraction. We conclude that the pattern of cholesterol transfer between fibroblasts and high density lipoprotein particles is influenced by body fatness and may be a factor in the abnormal metabolism of HDL in obesity.     

Autonomic control of heart rate during physical exercise and fractal dimension of heart rate variability

The objectives of the present study were to investigate autonomic nervous system influence on heart rate during physical exercise and to examine the relationship between the fractal component in heart rate variability (HRV) and the system's response. Ten subjects performed incremental exercise on a cycle ergometer, consisting of a 5-min warm-up period followed by a ramp protocol, with work rate increasing at a rate of 2.0 W/min until exhaustion. During exercise, alveolar gas exchange, plasma norepinephrine (NE) and epinephrine (E) responses, and beat-to-beat HRV were monitored. HRV data were analyzed by "coarse-graining spectral analysis" (Y. Yamamoto and R. L. Hughson. J. Appl. Physiol. 71: 1143-1150, 1991) to break down their total power (Pt) into harmonic and nonharmonic (fractal) components. The harmonic component was further divided into low-frequency (0.0-0.15 Hz) and high-frequency (0.15-0.8 Hz) components, from which low-frequency and high-frequency power (Pl and Ph, respectively) were calculated. Parasympathetic (PNS) and sympathetic (SNS) nervous system activity indicators were evaluated by Ph/Pt and Pl/Ph, respectively. From the fractal component, the fractal dimension (DF) and the spectral exponent (beta) were calculated. The PNS indicator decreased significantly (P < 0.05) when exercise intensity exceeded 50% of peak oxygen uptake (VO2 peak). Conversely, the SNS indicator initially increased at 50-60% VO2peak (P < 0.05) and further increased significantly (P < 0.05) at > 60% VO2peak when there were also more pronounced increases in NE and E.(ABSTRACT TRUNCATED AT 250 WORDS)     

Recent progress in research on plant polyphenol oxidase

The study objective was to determine circulating levels of the appetite-controlling neuropeptides, neuropeptide Y (NPY), galanin, and leptin, in subjects with eating disorders. The study group consisted of 48 obese women aged 19 to 45 years, 15 women with anorexia nervosa aged 18 to 23 years, and 19 lean healthy women aged 18 to 42 years (control group). The obese women were divided into four groups: (A) body mass index (BMI) = 25 to 30 kg/m2, n = 9 (overweight); (B) BMI = 31 to 40 kg/m2, n = 23 (moderate obesity); (C) BMI greater than 40 kg/m2, n = 9 (severe obesity); and (D) BMI = 31 to 40 kg/m2, n = 7 (moderate obesity + non-insulin-dependent diabetes mellitus [NIDDM]). Plasma NPY, galanin, and leptin concentrations were measured in peripheral blood samples with radioimmunoassay methods. Plasma NPY levels in obese women (groups A, B, C, and D) were significantly higher as compared with the control group (P < .01, P < .001, P < .001, and P < .001, respectively). The highest plasma NPY concentrations were observed in obese women with NIDDM. Plasma galanin levels were significantly higher in groups B, C, and D (P < .001, P < .001, and P < .001, respectively). Plasma leptin concentrations were significantly higher in groups C and D as compared with the control group (P < .001 and P < .001, respectively). Plasma NPY and galanin concentrations in women with anorexia nervosa did not differ from the levels in the control group. However, plasma leptin concentrations were significantly lower in anorectic women than in the control group (P < .01). Our results indicate that inappropriate plasma concentrations of NPY, galanin, and leptin in obese women may be a consequence of their weight status, or could be one of many factors involved in the pathogenesis of obesity.     

Prolonged inhibition of presynaptic catecholamine synthesis does not alter leptin secretion in normal-weight men and women

Leptin has been called a hormone of reproduction, and seems to link fat and fertility. It has been speculated that the neurotransmitter norepinephrine (NE) (noradrenaline), possibly via the sympathetic nervous system, may represent the afferent signal which modulates leptin release from adipocytes. The purpose of this study was to produce a state of decreased sympathetic output by using the catecholamine synthesis inhibitor alpha-methyl-para-tyrosine (AMPT), in order to study the effect of this compound on the secretion of leptin from fat cells. Ten subjects (five women and five men) received a total of 5 x 1 g doses of AMPT or 5 x 50 mg promethazine (active placebo) over a 26 h period, separated by 4-6 weeks using a randomized, double-blind, placebo-controlled, cross-over design. Blood samples for hormone measurements were obtained over 24 h (18 time points) on day 2 of each experiment. Urinary measurement of the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) on study day 2 served as a marker of the effectiveness of AMPT as an inhibitor of NE synthesis. The daily excretion of this metabolite decreased from 1.56 +/- 0.22 mg in the placebo experiment to 0.53 +/- 0.1 mg in the active experiment (P < 0.05). Plasma leptin concentrations measured in the control group in women and men were similar to those reported previously in lean subjects with a body mass index < 27.5 kg/m2. Leptin concentrations in women were 3-fold higher than in men. Leptin is secreted in a circadian rhythm in both sexes with an increase of nocturnal concentrations by approximately 50%. Two-way analysis of variance reveals no significant difference in leptin secretion between the control and active groups in women and men. In summary, preliminary results do not support the hypothesis that NE represents the afferent signal from the central nervous system which modulates leptin release from adipocytes in the human. Further studies are needed to define the role of the sympathetic nervous system as well as NE in the regulation of leptin secretion and its involvement in obesity and reproduction.     

Overweight and leanness in adulthood: prospective study of male participants in the Normative Aging Study

OBJECTIVE: Our objective was to examine the stability of body habitus over 15 years in Boston area adult males enrolled in the Normative Aging Study (NAS) and to examine stability as a function of initial leanness or obesity, age and reported body habitus at age 18. DESIGN: Prospective observational study of anthropometric/clinical measures initiated in 1961-1970, follow-up examinations at regular three and five year intervals. Subjects with complete data at entry, 5, 10 and 15 years. SUBJECTS: The 2280 Boston area subjects were aged 21-80 years (mean = 42 y) at entry. A subset (n = 350) with complete data for weight (WT) and height (HT) at four points over 15 years provided estimates of body habitus continuity. The prevalence of obesity and age of those studied were comparable to the complete sample of enrolled men (n = 1403) with any missing follow-up measures. MEASUREMENTS: Obesity was defined as body mass index (BMI) (weight in kg/height in m2) > or = 27.8 and leanness as BMI < 24.0. Three age categories at baseline (young = 25-39 y; middle = 40-49 y and old = 50-74 y) were used to examine secular and longitudinal changes. Obesity prevalence rates during late adolescence, based on self-reported weights at age 18, were compared with measured prevalence rates at entry and follow-up. Individual changes in BMI over time for each subject were estimated by linear regression and were combined to measure change in age and BMI groups. RESULTS: Weights and BMI at entry were highly correlated with 18 year values and 15 year follow-up values. New cases of obesity, defined on the basis of BMI, increased over time while the numbers of subjects classified as lean and intermediate decreased. Among oldest subjects both the lean and obese had slight but significant decreases in mean BMI. Among the lean, only the young showed consistent increments. DISCUSSION: Our results suggest consistency in body habitus among young and middle-aged obese subjects. There was little evidence of long-term reduction. In agreement with previous observations, the current findings of long-term duration in obesity suggest that preventive efforts should be focused on early years.     

Attenuated GLP-1 secretion in obesity: cause or consequence?

BACKGROUND: Hypersecretion of insulinotropic factors such as glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(7-36)amide (GLP-1) have been postulated to account for the hyperinsulinaemia of obesity. AIMS: To examine the role of GLP-1 and GIP in obese women and matched controls. SUBJECTS: Six lean and six obese women subjects matched for age. METHODS: The gut hormone, plasma glucose, and serum triglyceride responses were studied over 180 minutes after oral carbohydrate and fat meals. Heparin (10,000 units) was given intravenously at 120 minutes. RESULTS: There was pronounced attenuation of plasma GLP-1 secretion to oral carbohydrate in the obese compared with lean subjects but no such difference in response to oral fat load. There were no differences in the plasma GIP responses to carbohydrate or fat feeding. There was an apparent fall in plasma GLP-1 values in all subjects after administration of heparin. CONCLUSION: Postprandial GLP-1 secretion in response to oral carbohydrate is considerably attenuated in obese subjects. The cause of this attenuation of GLP-1 secretion is not known although we suggest that both this fall and the overall reduction in GLP-1 values in obese subjects may be related to an increase in plasma non-esterified fatty acids.     

Fasting hyperinsulinemia and cardiovascular disease risk factors in nondiabetic adults: stronger associations in lean versus obese subjects. Atherosclerosis Risk in Communities Study Investigators

The association between hyperinsulinemia and atherogenic risk factors has not been well studied in blacks and may be different for obese versus lean individuals. To investigate this possibility and to confirm the associations of hyperinsulinemia with cardiovascular disease risk factors in blacks and whites, we analyzed the joint associations of fasting serum insulin and obesity with risk factors in the Atherosclerosis Risk in Communities (ARIC) Study (1,293 black men, 4,797 white men, 2,033 black women, and 5,445 white women). Insulin values > or = 90th percentile (> or = 21 microU/mL) constituted hyperinsulinemia; body mass index (BMI) values > or = 27.3 kg/m2 for women and > or = 27.8 for men constituted obesity. Participants with hyperinsulinemia in all four race-sex groups had more atherogenic levels of most risk factors studied than those with normoinsulinemia. Among black men and women, mean levels of triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein (apo) B, glucose, and fibrinogen (men only) were higher in hyperinsulinemic lean participants as compared with the normoinsulinemic obese group. Furthermore, most associations between insulin level and risk factors were stronger among lean versus obese subjects. For example, among lean black men, the difference in mean triglyceride concentration between those with hyperinsulinemia and those with normoinsulinemia was 147 - 99 = 48 mg/dL; among obese black men, the difference was 155 - 121 = 34 mg/dL (P < .05 for the interaction). Generally, similar negative interactions between BMI and insulin concentration were also observed among whites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma PAF acetylhydrolase in non-insulin dependent diabetes mellitus and obesity: effect of hyperinsulinemia and lovastatin treatment

Insulin resistance is characterized principally by impaired insulin-mediated glucose uptake which provokes a compensatory increase in pancreatic beta-cell secretory activity. For a time this may produce well-controlled plasma glucose levels but as the insulin resistance worsens the augmented insulin production becomes inadequate to keep plasma glucose at euglycemia leading to the development of non-insulin dependent diabetes mellitus (NIDDM), accompanied by hyperinsulinemia and hyperglycemia. A number of metabolic defects are associated with NIDDM including obesity, hypercoagulability, cardiovascular disease risk factors such as hypertension and dyslipidemia and these constitute the insulin resistance syndrome. The identity of the biochemical factor that might link all these defects is not yet known. We have hypothesized that platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) may be such a link. In this study, we measured plasma acetylhydrolase (EC.1.1.48), which degrades PAF to the inactive metabolise lyso-PAF, as a surrogate for PAF activity in three groups of hypercholesterolemic subjects: lean controls (n = 9), non-diabetic obese (n = 6) and NIDDM subjects (n = 6). The ages and body mass indices of the subjects were 46 +/- 3.1 and 24.2 +/- 2.2 for the lean controls, 52 +/- 2.5 and 28.7 +/- 0.9 for the NIDDM subjects and 60 +/- 2 and 27.6 +/- 2.1 for the obese, non-diabetic subjects (mean +/- S.E.M.). The measurements were made before and after therapy with the cholesterol-lowering drug lovastatin, a 3-hydroxy 3 methylglutaryl (HMG) coenzyme. A reductase inhibitor (40 mg/day) for 3 months. Fasting plasma glucose (FPG) levels were 91 +/- 11, 96 +/- 3 and 146 +/- 11 mg/dl, for the lean, obese and NIDDM subjects, respectively, before therapy began. Lovastatin did not affect FPG in any of the three subject groups. Before treatment, the fasting plasma insulin (FPI) levels were 6.1 +/- 0.92, 10.83 +/- 2.03 and 14.68 +/- 3.64 mU/l for the lean, non-diabetic obese and NIDDM subjects, respectively. After lovastatin therapy only the obese group exhibited a significant change in FPI (15.35 +/- 2.47 mU/l) (P < 0.05). Total cholesterol levels were similar in all three groups both before and after lovastatin therapy but within each group lovastatin therapy significantly reduced the total cholesterol by 32, 29 and 34% in the lean, obese and NIDDM subject groups respectively (P < 0.0001). Lovastatin therapy reduced LDL-cholesterol levels by 40, 32 and 46% in the lean, obese and NIDDM subjects, respectively, but produced no significant effect on HDL or triglyceride levels. Before therapy, the plasma acetylyhydrolase activities were 104 +/- 7, 164 +/- 7 and 179 +/- 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Lovastatin therapy reduced plasma acetylhydrolase levels to 70 +/- 7, 87 +/- 6 and 86 +/- 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Plasma acetylhydrolase activity was predominantly (> 80%) associated with LDL cholesterol both before and after lovastatin treatment. Also, plasma acetylhydrolase activity significantly correlated with fasting plasma insulin levels before lovastatin therapy but not after. Taken together, this study clearly implicates PAF metabolism in three defects associated with the insulin resistance syndrome: hypercholesterolemia, obesity and NIDDM. Additionally, we conclude that chronic hyperinsulinemia may play a significant role in the production of plasma acetylhydrolase.     

Pharmacokinetics of ifosfamide administered according to three different schedules in metastatic soft tissue and bone sarcomas

We investigated whether an association exists between genetic variants of the human obesity (OB or leptin) gene and body mass index (BMI) or weight in subjects with Prader Willi syndrome (PWS) and in age- and gender-matched lean and obese subjects without PWS. The study included 51 subjects with PWS (mean age = 17.7 +/- 9.5 years, BMI = 29.7 +/- 8.3 kg/m2); 50 non-PWS obese subjects (mean age = 18.2 +/- 10.8 years, BMI = 33.3 +/- 9.5 kg/m2); and 53 non-PWS lean subjects (mean age = 17.8 +/- 9.5 years, BMI = 19.5 +/- 2.9 kg/m2). Allele sizes were determined via standard polymerase chain reaction of the D7S1875 locus, a dinucleotide repeat polymorphism close to the OB gene and classified as trichotomous (homozygous < 208 bp, heterozygous < 208/ > or = 208 bp, homozygous > or = 208 bp) or dichotomous (homozygous < 208 bp or not). Non-PWS males showed a marked decrease in weight with larger alleles while females did not (interaction effect, p < 0.05). Comparable effects were not observed among the PWS subjects. Associations between BMI and genotype were statistically significant (r = 0.22, one-tailed p < 0.05) and comparable to previous research among the non-PWS subjects < 18 years, but not the adults (r = 0.05, one-tailed p = 0.38). Correlations were not statistically significant among either the adult or non-adult PWS subjects.     

Insulin sensitivity, insulin action, and fibrinolysis activity in nondiabetic and diabetic obese subjects

Because inconsistencies occur with regard to the relative contribution of insulin to the hypofibrinolysis characteristic of obesity and diabetes, we explored the relationship between insulin and fibrinolysis, assessing both insulin sensitivity and insulin action. Seventeen markedly obese subjects (body mass index [BMI], 34.0+/-1.6 kg/m2; 12 nondiabetic and five diabetic) were studied using the three-step euglycemic-hyperinsulinemic clamp technique. Since the circadian rhythm of the fibrinolytic system may obscure a true effect of insulin, variations in fibrinolysis parameters observed during the glucose clamp were compared with those occurring spontaneously because of the circadian rhythm. Compared with six normal-weight subjects (BMI, 21.0+/-0.9 kg/m2), all obese subjects exhibited basal hyperinsulinism (fasting plasma insulin, 16.0+/-1.4 v 9.8+/-1.3 microU/microL, P < .001; fasting plasma C-peptide, 1.4+/-0.2 v 0.5+/-0.2 ng/mL, P < .001), hypofibrinolysis (euglobulin lysis time [ELT], 378+/-29 v 222+/-31 minutes, P=.01; tissue plasminogen activator [tPA] antigen, 7.8+/-0.9 v 4.2+/-0.5 ng/mL, P=.04; plasminogen activator inhibitor type 1 [PAI-1] activity, 22.2+/-2.5 v3.9+/-0.6 AU/mL, P=.004), and marked insulin resistance (M value, ie, the maximal glucose disposal rate, 9.1+/-0.6 v 18.6+/-0.8 mg/(kg x min), P < .001). The M value correlated inversely with tPA antigen (r=-.46, P=.05). During insulin infusion, values for fibrinolysis parameters decreased, but were not different compared with variations due to the circadian rhythm. In conclusion, our findings together with previously reported data reinforce the idea that chronic hyperinsulinism is linked to hypofibrinolysis, but insulin does not seem to acutely regulate the fibrinolysis system.