Insulin resistance in patients with polycystic ovaries: its relationship to body weight and androgen levels

Using a combined infusion of somatostatin, insulin and glucose, insulin resistance was assessed in vivo in two groups of females with polycystic ovaries (PCO), obese (PB-PCO) and normal weight (NO-PCO) and in two groups of matched (for age, sex and body mass index) controls (OB and NO). A steady state plasma glucose (SSPG) and insulin (SSPI) was attained after 90 min. OB-PCO and NO-PCO showed higher SSPG with respect to matched controls. The SSPG levels were related to body mass index (r = 0.69; P less than 0.001). The SSPG values were significantly correlated with the fasting insulin levels (r = 0.47; P less than 0.003). Gonadotrophin and steroid peripheral blood concentrations were also evaluated in the PCO females. A significant correlation was found between the SSPG values and the dehydroepiandrosterone sulphate levels (r = 0.46; P less than 0.05) and between the fasting insulin levels and the androstenedione concentrations (r = 0.64; P less than 0.01). Moreover, significant correlation coefficients were found between the glucose to insulin ratio and the A (r = -0.59; P less than 0.01) and the DHEA-S (r = -0.50; P less than 0.05) plasma levels. Finally, no relationship between body mass index and A or DHEA-S levels was found in PCO females considered as a group. We conclude that insulin resistance is present in females with PCO and it is mainly due to the presence of obesity, but other factors such as androgen levels, probably of adrenal sources, must be considered as a cause.     

Associations between regional body fat distribution, fasting plasma free fatty acid levels and glucose tolerance in premenopausal women

The associations between total adiposity, body fat distribution measured by computed tomography (CT) and estimated by the waist-to-hip ratio (WHR), regional fat cell morphology, fasting plasma free fatty acid (FFA) levels and glucose tolerance were studied in a sample of 37 premenopausal women aged 35.3 +/- 4.6 years (mean +/- s.d.). Body fat mass, CT-derived abdominal and femoral fat areas, as well as the abdominal fat cell weight were all significantly associated with fasting plasma FFA levels (0.34 less than r less than 0.49, 0.005 less than P less than 0.05), and with the glucose and insulin areas during the oral glucose tolerance test (OGTT) (0.36 less than r less than 0.70, 0.0001 less than P less than 0.05). No associations were found between the WHR, the femoral fat cell weight and fasting plasma FFA levels or glucose area during the OGTT. However, the WHR and the femoral fat cell weight were positively associated with insulin area. Plasma FFA levels were positively correlated with the glucose area during the OGTT, whereas no association was found between plasma FFA levels and the insulin area. Covariance analysis indicated that this effect of plasma FFA levels on the magnitude of glucose response to OGTT was independent from that of total adiposity or regional body fat distribution variables. These results emphasize the importance of plasma FFA levels as a correlate of glucose tolerance and suggest that the associations previously reported between obesity, regional body fat distribution, fat cell size and glucose tolerance are, at least partly, mediated by variations in plasma FFA levels.     

A study in the relationships between leptin, insulin, and body fat in Asian subjects

OBJECTIVE: To study the relationship of leptin concentrations with indices of obesity, fasting insulin, insulin resistance and lipid profiles (total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)- cholesterol and triglyceride) in an Asian cohort. DESIGN: Cross sectional study. SUBJECTS: A total of 133 healthy volunteers were enrolled (64 female: age: 25-61 y, body mass index (BMI): 18.7-45.1 kg/m2 and 69 male: age: 25-61 y, BMI: 19.3-35.0 kg/m2). MEASUREMENTS: Weight, height, waist and hip circumferences, blood pressure, lean body mass (by bioelectric impedence analysis (BIA)), plasma leptin and lipid profiles were taken after a 10 h fast. RESULTS: Percentage of body fat measured by bioelectric impedance was the strongest determinant of plasma leptin (r = 0.844, P < 0.0001). Females had higher leptin concentrations than males for the same fat mass. In a multiple linear regression model, body fat percentage, (percentage body fat* gender), hip circumference and fasting insulin were significant determinants of leptin concentration (r = 0.882, P < 0.0001). CONCLUSION: Leptin concentration correlated closely with percentage body fat in Asian subjects. Hip circumference as a corollary for peripheral obesity, was better associated with leptin than waist circumference or waist-to-hip ratio (WHR). Distribution of fat in females tended to be peripheral and may partly explain the gender difference. Fasting insulin level and central obesity were correlated with HDL-cholesterol, triglyceride and blood pressure, while fasting leptin had little correlation with these metabolic parameters. Therefore, insulin resistance was a better guide to cardiovascular risk assessment than plasma leptin.     

Effects of body composition and exercise capacity on glucose tolerance, insulin, and lipoprotein lipids in healthy older men: A cross-sectional and longitudinal intervention study

The relationships of age, body composition, and physical conditioning status to glucose tolerance, insulin, and lipoprotein levels were examined in 77 healthy, nonsmoking white male volunteers, aged 46 to 73 years with no evidence of coronary artery or endocrine-metabolic disease. The men had a wide range of body fat (13% to 39%), indexed as waist-to-hip ratio (WHR, 0.84 to 1.08), and maximal aerobic capacity (VO2max, 17 to 48 mL/kg.min). Multiple regression analysis with age, VO2max, WHR, and percent body fat as independent variables demonstrated that fasting plasma insulin, triglyceride (TG), and high density lipoprotein cholesterol (HDL-C) levels were independently related to both percent body fat and WHR. In contrast, fasting plasma glucose levels and insulin responses during oral glucose tolerance tests (OGTT) correlated independently with percent body fat, and glucose responses to OGTT correlated only with WHR. Although fasting plasma TG and HDL-C correlated with glucose and insulin levels, in multiple regression analyses only percent body fat and WHR were the significant independent variables. Fasting total and low density lipoprotein cholesterol values were not related to these variables. To test the effects of weight loss and exercise training on these relationships, 20 obese men of comparable age, percent body fat, WHR, and VO2max were randomly assigned to weight loss or aerobic exercise training programs. A 12% +/- 3% loss in body weight (P less than .01, mean +/- SD) resulted in a 19% +/- 9% decline in body fat (P less than .01) with no change in fat free mass, WHR, or VO2max.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of obesity on circulating intermediary metabolite concentrations in the absence of impaired glucose tolerance.

The published literature on the influence of obesity on intermediary metabolite concentrations does not adequately address the potential confounding effects of the increased prevalence of impaired glucose tolerance in obese subjects. In order to remove this, we studied 109 subjects with proven normal glucose tolerance ranging from underweight to grossly obese (range 15.3-80.9 body mass index). All had blood intermediary metabolites, plasma insulin and C-peptide measured after an overnight fast. Thirty-six (18 from each end of the range of body mass index) received a 3-hour oral glucose tolerance test for metabolites and insulin. Fasting plasma insulin was highly significantly associated with body mass index (r = 0.72; P less than 0.001). Concentrations of lipid intermediaries were better associated with body mass index than with fasting plasma insulin: non-esterified fatty acids (r = 0.36; P less than 0.001), glycerol (r = 0.47; P less than 0.001) and ketone bodies (r = 0.45; P less than 0.001). Fasting concentrations of carbohydrate intermediaries were, however, better correlated with fasting plasma insulin: lactate (r = 0.29; P less than 0.01), pyruvate (r = 0.24; P less than 0.01) and alanine (r = 0.36; P less than 0.001). Glucose concentrations were associated with both to a similar degree (r = 0.33, r = 0.32, respectively; P less than 0.001). After oral glucose, exaggerated rises in plasma insulin and blood glucose were observed in obese subjects but a lesser rise was seen for lactate. Non-esterified fatty acids and ketones, although having higher fasting concentrations in obese subjects, fell to similar concentrations in the two groups after glucose whereas blood glycerol did not fall so far in the obese subjects. The results suggest, even if those subjects with impaired glucose tolerance are excluded, insensitivity to insulin in several aspects of intermediary metabolism in obesity the degree of which may vary in different metabolic pathways or tissues.     

The associations between plasma adiponectin, ghrelin levels and cardiovascular risk factors

OBJECTIVE: Ghrelin is a recently discovered peptide, which is produced primarily in the stomach. This orexigenic peptide participates not only in the induction of mealtime hunger but also in long-term body weight regulation and energy homeostasis. Adiponectin is a protein secreted by adipocytes, and has been proposed to mediate obesity-related insulin resistance. Moreover, concentrations of adiponectin are reduced in individuals with obesity, insulin resistance and cardiovascular disease. However, human data are sparse about the direct relationship between adiponectin, ghrelin and cardiovascular risk factors including insulin resistance. DESIGN: Three hundred and thirty-eight elderly Korean women (mean age+/-s.d., 72.3+/-5.5 years) were included in the present study. METHODS: Plasma ghrelin and adiponectin levels were measured by RIA. Anthropometric measurements were taken and a 75 g oral glucose tolerance test performed. Fasting insulin and lipid profile were measured and insulin resistance was determined using the homeostasis model assessment insulin resistance index (HOMA-R) and the quantitative insulin sensitivity check index. RESULTS: Plasma adiponectin levels were negatively correlated with central obesity indices such as waist circumference (r=-0.27, P<0.001) and waist-to-hip ratio (WHR) (r=-0.32, P<0.001), and with insulin resistance indices such as fasting insulin (r=-0.17, P=0.004) and HOMA-R (r=-0.13, P=0.035). Plasma ghrelin levels were negatively correlated with WHR (r=-0.12, P=0.03), but plasma adiponectin and ghrelin levels were not correlated (r=0.03, P=0.66). Multiple regression analysis showed that adiponectin was associated with WHR, fasting insulin and fasting glucose levels. When ghrelin was used as a dependent variable, only WHR remained in the final fitted model. CONCLUSION: Fasting plasma adiponectin and ghrelin levels were found to be associated with central obesity or insulin resistance. However, plasma adiponectin and ghrelin concentrations were not associated with each other in elderly Korean women.     

Relationship of androgenic activity to splanchnic insulin metabolism and peripheral glucose utilization in premenopausal women

The importance of androgenic activity in mediating the effects of obesity and body fat topography on splanchnic insulin metabolism and peripheral insulin sensitivity was studied in 19 nonhirsute premenopausal women with a wide range of ideal body weight [percent ideal body weight (% IBW), 78-202%] and body fat distribution pattern [waist to hip girth ratio (WHR), 0.67-0.91]. Turnover kinetics of peripheral plasma C-peptide and insulin were measured, and estimates of pancreatic insulin production (PIP) and the hepatic extraction fraction (HEF) were calculated. The peripheral insulin sensitivity index (M/I) was determined during an euglycemic insulin clamp study. Androgenic activity was assessed by estimating the plasma level of sex hormone-binding globulin (SHBG) and percentage of free testosterone (% FT). After iv glucose stimulation, PIP ranged from 40-254 mU/min X m2 and correlated highly with % IBW (r = 0.78; P less than 0.01). Insulin HEF ranged from 5-69% of the pancreatic production and was inversely proportional to WHR (r = -0.60; P less than 0.01). Increasing WHR also correlated with the diminution in M/I (r = -0.47; P less than 0.05), which, in turn, correlated with the decline in the HEF of insulin (r = 0.60; P less than 0.01). Since PIP, HEF, and M/I correlated with SHBG and % FT, and since the degree of androgenic activity correlated with % IBW and WHR, partial regression analysis was performed. After adjusting for the effects of SHBG and % FT, the relationship between % IBW and PIP remained unaltered, whereas the correlation between WHR and HEF or M/I and their relationship to each other were either markedly reduced or became insignificant. Thus, in premenopausal women, the increase in pancreatic insulin production with increasing weight is independent of the degree of androgenic activity. On the other hand, the decline in hepatic insulin extraction and diminution in peripheral insulin sensitivity with upper body fat localization are in part mediated by increased androgenic activity. This association may account for the pronounced hyperinsulinemia and insulin resistance characteristic of this form of obesity.     

High plasma leptin concentrations in hypertensive men but not in hypertensive women.

OBJECTIVE: Previous studies on humans have reported higher leptin levels in women than in men, independent of body fat, and leptin has been correlated with insulin resistance in men but not in women. Since insulin resistance is thought to play a role in raising blood pressure, we investigated sex differences in leptin concentrations between hypertensive and normotensive individuals. METHODS: Ninety-two nondiabetic hypertensive patients (48 men and 44 women) and 92 age, body mass index (BMI)-matched normotensive control individuals were studied. Fasting plasma glucose, insulin, leptin and lipoprotein concentrations, glucose and insulin responses to 75 g oral glucose tolerance test (OGTT) and insulin suppression tests were determined. RESULTS: Fasting plasma leptin concentrations were higher in hypertensive men than in normotensive men (5.1 +/- 0.5 versus 3.9 +/- 0.4 ng/ml, P = 0.015). However, fasting plasma leptin concentrations were not significantly different between hypertensive and normotensive women (11.8 +/- 1.0 versus 10.9 +/- 1.0 ng/ml, P = 0.440). Fasting plasma leptin concentrations showed good correlation with BMI, body fat, fasting plasma insulin concentrations, and insulin area to OGTT in both men and women (all P < 0.001). However, fasting plasma leptin concentrations were related to steady-state plasma glucose (SSPG) concentrations, a measure of insulin sensitivity by insulin suppression test, in men only (P < 0.001). After adjustment for body fat amount, age and duration of hypertension, fasting plasma leptin levels still correlated significantly with SSPG concentrations in men. These four variables together accounted for a 67.9% variation in fasting plasma leptin levels in men. In women, body fat amount was the only significant determinant for plasma leptin levels. These four variables accounted for a 78.2% variation in plasma leptin levels in women. CONCLUSIONS: Our study confirmed a sex difference in leptin levels both in hypertensive and normotensive subjects. Higher plasma leptin concentrations in hypertensive men but not in hypertensive women when compared with normotensive control individuals was also demonstrated. These observations are consistent with the findings that plasma leptin is correlated with insulin sensitivity in men but not in women. Further studies are needed to understand the causes and consequences of sex effects on leptin in blood pressure regulation.     

Glucose-to-insulin ratio rather than sex hormone-binding globulin and adiponectin levels is the best predictor of insulin resistance in nonobese women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS), the main androgen disorder in women, has been suggested to be associated with a high risk of developing cardiovascular disease and type 2 diabetes. In many PCOS patients, overweight or central obesity is generally associated with increases in fasting insulin levels, insulin resistance, and glucose intolerance, and has been identified as a target for new therapeutic strategy, including early change in lifestyle. Early biochemical marker(s) for identifying at-risk patients will be useful for prevention studies. The main goal of the present study was to search for such tool(s). We investigated 16 nonobese PCOS women by performing euglycemic hyperinsulinemic clamp and measuring insulin levels during fasting and oral glucose tolerance test, as well as the serum concentrations of SHBG, leptin, and adiponectin, the newly identified adipose factors. Eight of the 16 patients had a steady-state glucose disposal rate less than 8.5 mg/kg.min, the lowest normal value for nonobese control women. These insulin-resistant patients had significant higher body mass index (BMI) and waist-to-hip ratio (WHR), and lower high-density lipoprotein cholesterol and SHBG levels. As expected, glucose disposal correlated negatively with BMI (P = 0.01), WHR (P = 0.01), and fasting insulin level (P = 0.003). On stepwise regression analysis, however, the glucose-to-insulin ratio (GIR) emerged as the strongest independent parameter to appraise insulin resistance (R(2) = 0.61). SHBG level correlated positively with GIR (P < 0.001) and negatively with BMI (P = 0.003) but did not correlate with either insulin response during the glucose tolerance test or plasma leptin and/or adiponectin levels. In contrast, BMI was the only independent predictive parameter of SHBG (P = 0.003, R(2) = 0.73). Interestingly, plasma adiponectin levels were positively associated with glucose disposal rate (P = 0.043) and negatively with WHR (P = 0.024), waist circumference being the best predictor of adiponectin level (P < 0.01). Leptin level correlated only with BMI (r = 0.62, P = 0.01). This study confirmed that insulin resistance, despite the lack of obesity as such, is clearly present in many PCOS women, and demonstrated that GIR is the best predictor for insulin resistance. It was also shown that adiponectin level is a good indicator of abdominal fat mass and is associated to insulin resistance. Finally, low SHBG levels in PCOS are intimately associated with BMI, suggesting that some signal(s) from the adipose tissue, independent of adiponectin and leptin, may regulate liver production of SHBG.     

Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity

The casual relationship between intraabdominal visceral fat accumulation and metabolic disorders was analyzed in 46 obese subjects (15 males, 31 females) having 34.1 +/- 5.5 of body mass index (BMI). The distribution of fat was determined by our CT scanning technique (Int J Obesity 7:437, 1983). The total cross-cut area, subcutaneous fat area, and intra-abdominal fat area was measured at the umbilical level. The fasting plasma glucose level, area under the plasma glucose concentration curve after oral glucose loading (plasma glucose area), fasting serum triglyceride level, and serum total cholesterol level were all significantly higher or otherwise greater in the group with intraabdominal visceral fat to subcutaneous fat ratio (V/S ratio) of not less than 0.4 than in the group with a lower V/S ratio, when either all or sex-matched obese subjects were examined, though BMI or the duration of obesity was not different between the two groups. The V/S ratio was significantly correlated with the level of plasma glucose area (r = 0.45, P less than .001) under the curve of 75 g oral glucose tolerance test and also with the serum triglyceride (r = 0.65, P less than .001) and total cholesterol levels (r = 0.61, P less than .001). These relationships were also observed when examined in each sex separately and found to be significant after adjustment for BMI and age by multiple regression analyses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Demonstration of a relationship between white blood cell count, insulin resistance, and several risk factors for coronary heart disease in women.

In order to evaluate the relationship between peripheral white blood cell (WBC) count, insulin-mediated glucose uptake, and several risk factors for coronary heart disease (CHD), WBC, plasma glucose and insulin responses to a 75-g oral glucose challenge, fasting plasma cholesterol, high-density-lipoprotein (HDL)-cholesterol, and triglyceride concentration, and systolic and diastolic blood pressure were determined in 63 consecutive female volunteers with normal glucose tolerance. The results demonstrated the presence of statistically significant correlation coefficients between WBC count and both insulin-mediated glucose disposal (r = 0.50, P less than 0.001) and insulin response to oral glucose (r = 0.50, P less than 0.001). Furthermore, WBC count correlated with plasma glucose response to oral glucose (r = 0.48, P less than 0.001), fasting plasma triglyceride (r = 0.37, P less than 0.005) and HDL-cholesterol concentrations (r = -0.38, P less than 0.005), and systolic (r = 0.22, P less than 0.1) and diastolic (r = 0.27, P less than 0.05) blood pressure. However, the only two variables significantly correlated with WBC count in multivariate regression analysis were insulin resistance (r = 0.49, P less than 0.01) and insulin response (r = 0.35, P less than 0.05). These data indicate that WBC count is significantly correlated with changes in carbohydrate and lipoprotein metabolism and blood pressure that increase the risk of CHD. However, it appears that these relationships are secondary to resistance to insulin-mediated glucose uptake and hyperinsulinaemia.     

Evidence for an independent relationship between insulin resistance and fasting plasma HDL-cholesterol, triglyceride and insulin concentrations.

Elevated plasma insulin and triglyceride (TG) and decreased high-density-lipoprotein (HDL)-cholesterol concentrations have been shown to be risk factors for coronary heart disease (CHD). It has been suggested that these metabolic abnormalities are all secondary to resistance to insulin-stimulated glucose uptake. To examine this in more detail, we divided 18 non-diabetic, moderately overweight, sedentary men aged 25-50 years into three groups on the basis of their steady-state plasma glucose levels (SSPG): a low group, (n = 7; SSPG less than 8.3 mmol l-1), a middle group, (n = 6; SSPG 8.3-11.1 mmol l-1), and a high group (n = 5; SSPG greater than 11.1 mmol l-1). The high group had significantly higher fasting (P less than 0.05) and post-oral glucose challenge (P less than 0.01) insulin concentrations, higher fasting TG (P less than 0.05) and lower fasting HDL-cholesterol (P less than 0.05) concentrations than the other two groups. However, there were no statistically significant differences between the groups with regard to body mass index, waist-to-hip ratio or physical endurance capacity as determined by maximal oxygen consumption during a treadmill test. The data suggest that insulin resistance has an effect on the modulation of plasma insulin, TG and HDL-cholesterol concentrations, independent of generalized, abdominal or physical endurance capacity.     

Contribution of glucose tolerance and plasma insulin levels to the relationships between body fat distribution and plasma lipoprotein levels in women.

Numerous interrelated metabolic and morphological variables such as plasma insulin levels, glucose tolerance and abdominal obesity are associated with changes in plasma lipoprotein levels. The present study was undertaken to differentiate, using a multivariate approach, the respective contributions of plasma glucose and insulin levels, obesity and regional adipose tissue distribution to the variance in plasma lipoproteins. The study group was composed of 69 healthy premenopausal women (age 35.4 +/- 5.0 years (mean +/- s.d.); percent body fat 40.7 +/- 10.1). Indices of carbohydrate metabolism showed significant univariate correlations with triglyceride (TG) and/or cholesterol (CHOL) content of plasma VLDL, LDL and HDL (P less than 0.05). Multivariate analyses indicated that the explained variance in plasma VLDL-TG (R2 x 100 = 44 percent, P less than 0.05) and LDL-apoprotein (apo) B levels (R2 x 100 = 33.1 percent, P less than 0.08) was entirely accounted for by indices of carbohydrate metabolism and body fat distribution, whereas total body fatness added no significant contribution to these models. Multivariate analyses also revealed that the best possible regression model to predict the variation in plasma HDL2-CHOL levels only included computed tomography-derived deep abdominal adipose tissue area (P less than 0.0001). All other variables were unable to further improve the explained variance in plasma HDL2-CHOL levels. In partial correlation analyses, indices of carbohydrate metabolism and the waist-to-hip circumference ratio (WHR) remained significantly correlated with plasma VLDL-TG and LDL-apo B levels after adjustment of VLDL-TG and LDL-apo B for either insulin and glucose levels, or for the WHR (P less than 0.08). After correcting for deep abdominal fat accumulation, no significant correlation was observed between indices of carbohydrate metabolism and plasma HDL2-CHOL levels whereas deep abdominal fat showed significant correlations with HDL2-CHOL levels (P less than 0.05) after correction for indices of carbohydrate metabolism. These results suggest that both disturbances in glucose-insulin homeostasis and abdominal obesity are significantly associated with changes in plasma VLDL-TG and LDL-apo B levels and that these associations are partly independent from each other. These results also indicate that mechanisms other than disturbances in glucose homeostasis and hyperinsulinemia are responsible for the association between the level of deep abdominal fat and plasma HDL2-CHOL levels.     

Exacerbation of insulin resistance and postprandial triglyceride response in newly diagnosed hypertensive patients with hypertriglyceridaemia

The purpose of the study is to examine the differences in insulin resistance and postprandial triglyceride (TG) response between hypertensive patients with or without hypertriglyceridaemia. The study is a comparative cohort study with matching. Thirty-one newly diagnosed hypertensive patients without any medication were recruited from a health survey. The participants were further divided into two groups: those with fasting TG <2.26 mmol/L, and those with TG between 2.26 and 5.65 mmol/L. Both groups were matched in age, sex, body mass index and waist circumference. Each patient received a 75-g oral glucose tolerance test, an insulin suppression test, and a 1000 kcal high fat mixed meal test. The hypertriglyceridaemic hypertensive patients had significantly higher fasting insulin, 2-h plasma glucose, 2-h insulin, and steady-state plasma glucose (SSPG) (13.16 +/- 1.87 vs 9.76 +/- 3.18 mmol/L). They also had a greater postprandial TG response to the challenge of mixed meal (DeltaAUC 20.76 +/- 10.06 vs 7.97 +/- 3.18 mmol 8 h/L). The postprandial TG response was closely correlated (r = 0.72-0.95, P < 0.0001) with fasting TG in all hypertensive patients. Both fasting TG levels and postprandial TG response were significantly (P < 0.05) correlated with SSPG. In conclusion, the hypertensive patients with hypertriglyceridaemia were more insulin resistant than those without it. Exacerbation of postprandial hypertriglyceridaemia was identified in these patients. The TG response to the challenge of high fat meal was significantly correlated with fasting TG and insulin resistant in them. The results provide a rationale for the alleviation of insulin resistance and hypertriglyceridaemia in these atherosclerosis-prone hypertensive patients.     

Plasma levels of agouti-related protein are increased in obese men

To investigate the relationship between peripheral blood levels of agouti-related protein (AGRP) and various parameters of obesity, we measured the plasma level of AGRP in 15 obese and 15 nonobese men and evaluated its relationship with body mass index (BMI), body fat weight, and visceral, sc, and total fat areas measured by computed tomography, fasting insulin levels, glucose infusion rate during an euglycemic hyperinsulinemic clamp study, serum leptin, and plasma alpha-MSH. Obese men had significantly higher plasma concentrations of AGRP than nonobese men (P < 0.01). Univariate analysis showed that the plasma levels of AGRP are proportionally correlated with BMI, body fat weight, and sc fat area in obese men (BMI: r = 0.732, P < 0.01; body fat weight: r = 0.603, P < 0.02; sc fat area: r = 0.668, P < 0.01) and in all men (BMI: r = 0.839, P < 0.0001; body fat weight: r = 0.818, P < 0.0001; sc fat area: r = 0.728, P < 0.0001). In all men, the plasma levels of AGRP were significantly correlated with the visceral fat area (r = 0.478, P < 0.01), total fat area (r = 0.655, P < 0.0001), fasting insulin level (r = 0.488, P < 0.01), glucose infusion rate (r = -0.564, P < 0.01), serum level of leptin (r = 0.661, P < 0.0001), and the plasma level of alpha-MSH (r = 0.556, P < 0.01). In all subjects, multiple regression analysis showed that the plasma levels of AGRP are significantly (F = 15.522, r = 0.801, P < 0.03) correlated with the plasma levels of alpha-MSH, independently from the total fat area. However, the correlation between plasma levels of AGRP and serum levels of leptin was found to be dependent on the total fat area. In brief, these findings showed that the circulating levels of AGRP are increased in obese men and that they are correlated with various parameters of obesity. Although correlation does not prove causation, the results of this study suggest that peripheral AGRP may play a role in the pathogenesis of obesity.     

Plasma homocysteine concentrations in healthy volunteers are not related to differences in insulin-mediated glucose disposal.

This study was initiated to test the hypothesis that plasma homocysteine concentrations are increased in insulin resistant individuals. For this purpose, the relationship between insulin resistance, as assessed by the steady-state plasma glucose (SSPG) concentration during the insulin suppression test, and fasting plasma homocysteine concentration was defined in 55 healthy volunteers. The results indicated that homocysteine concentrations did not vary as a function of SSPG concentrations (r = 0.02, P = 0.88). Furthermore, mean (+/- S.E.M.) plasma homocysteine concentrations were similar (8.2+/-0.4 vs. 8.7+/-0.7 micromol/l) in individuals classified as being either insulin sensitive (SSPG <100 mg/dl) or insulin resistant (SSPG >180 mg/dl). On the other hand, SSPG concentration was significantly correlated with fasting plasma insulin (r = 0.58, P<0.001), triglycerides (r = 0.34, P<0.05), and HDL-cholesterol (r = -0.36, P = 0.04) concentrations. These data strongly suggest that the increased risk of atherosclerosis associated with increased plasma homocysteine concentrations is unrelated to insulin resistance and/or the metabolic abnormalities associated with it.     

Gender differences in relation to leptin concentration and insulin sensitivity in nondiabetic Chinese subjects.

OBJECTIVE: To investigate the relationship between fasting plasma leptin concentrations and insulin resistance in Chinese men and women. DESIGN: Cross-sectional study design. SUBJECTS: Ninety-six nondiabetic Chinese (51 men and 45 women) with body mass index (BMI) between 18.4-35.8 kg/m2 were studied. MEASUREMENTS: Plasma glucose and insulin concentrations were measured every 30 min for 2 h after a 75 g oral glucose load. The degree of insulin resistance was assessed using a modified insulin suppression test. Plasma leptin values were determined by radioimmunoassay. RESULTS: Fasting plasma glucose, glucose areas, fasting insulin, insulin areas, most of the lipoprotein concentrations and steady state plasma glucose (SSPG) concentrations were relatively similar between men and women. Despite the fact that men had higher BMI values (26.1 +/- 0.5 vs 24.7 +/- 0.5 kg/m2, P < 0.05), fasting plasma leptin concentrations were significantly lower in men than in women (4.9 +/- 0.5 vs 9.0 +/- 0.8 ng/ml, P < 0.001). Fasting leptin values were positively related to SSPG concentrations by simple correlation analysis in both sexes. However, this relationship persisted in men (r = 0.513, P < 0.01) but not in women (r = 0.119, P = NS) after adjustment for BMI. Multiple regression analysis showed that SSPG concentrations, BMI, glucose and insulin responses together accounted for 62.5% and 52.2% of the variation in plasma leptin concentrations in Chinese men and women respectively. CONCLUSION: Fasting plasma leptin concentrations were lower in Chinese men than in Chinese women despite the higher BMI observed in men. After adjustment for BMI, plasma leptin values correlated with the degree of insulin resistance in men but not in women.     

Body fat topography in women with androgen excess

The relationship between body fat distribution and androgen excess was determined in 168 premenopausal women of varying degrees of androgen excess. In 84 women with the polycystic ovary syndrome or idiopathic hirsutism, the waist:hips girth ratio (WHR) was 0.81 +/- 0.01 (mean +/- s.e.m.) and was significantly greater (P less than 0.001) than in an age- and weight-matched group of 84 non-hirsute women (0.77 +/- 0.01), indicating upper body fat predominance in the hirsute subjects. Plasma testosterone was directly correlated with the WHR (r = 0.55, P less than 0.001) and this relationship was independent of obesity level, supporting the hypothesis that plasma androgens are an important determinant of body fat topography in premenopausal women.     

Microcirculatory damage of common carotid artery wall in obese and non obese subjects

The objective of the present study was to determine whether the intima-media thickness (IMT) is independently related with obesity, and central fat accumulation in healthy subjects. Common carotid artery IMT, parameters of body fat accumulation and distribution (body mass index, waist circumference, waist-to-hip ratio), blood pressure levels, and circulating fasting insulin, glucose, and lipid (cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol) levels were determined in a population of non-diabetic normal weight and obese subjects. Smoking habits (packs-years) were also taken into account. 239 healthy subjects (143 women and 96 men), with age ranging between 18 and 45 years, were enrolled into the study. They were divided indo two groups according to the body mass index (BMI), obese (132 subjects, 77 woman and 55 men, with BMI greater than 27.0) and controls (107 subjects: 66 women and 41 men, with BMI lower than 27.0). Common carotid artery intima-media thickness was measured by B-mode ultrasound imaging. Fasting plasma metabolic parameters (glucose and lipids) and insulin levels were determined by enzymatic and radioimmunological assays, respectively. Insulin sensitivity was estimated by insulin tolerance test (ITT) and the rate constant for plasma glucose disappearance (KITT) during the 3- to 15-min period following the regular insulin injection was taken as a measure of in vivo insulin action. Obese patients showed higher IMT than controls, and IMT was significantly associated with BMI in the whole population (r = 0.316, p < 0.001). Age (r = 0.327, p < 0.001), KITT (r = -0.201, p < 0.01), fasting blood glucose (r = 0.187, p < 0.01), LDL-chol (r = 0.201, p < 0.01), smoking (r = 0.147, p < 0.05), MBP levels (r = 0.154, p < 0.05), cholesterol (r = 0.152, p < 0.05) and HDL-chol (r = -0.159, p < 0.05) were also significantly associated with IMT. Age (r = 0.330, p < 0.05), BMI (r = 0.299, p < 0.01), waist (r = 0.312, p < 0.001), WHR (r = 0.266, p < 0.001) and KITT (r = -0.259, p < 0.01) were the parameters most strongly correlated with IMT in women, and age (r = 0.324, p < 0.001), BMI (r = 0.338, p < 0.001) waist (r = 0.325, p < 0.001) and LDL-chol (r = 0.283, p < 0.01) where the parameters most strongly correlated with IMT in men. When a stepwise multiple regression analysis was performed for the whole population, only age (p < 0.001) and BMI (p < 0.001) maintained a significant positive relationship with IMT. When a stepwise multiple regression analysis was performed separately for men and women, BMI or waist circumference or WHR were alternatively entered into the model; interestingly, only age, BMI and waist were still significantly correlated with IMT, whereas WHR did not maintain a significant correlation with IMT. In conclusion, BMI and waist circumference, but not WHR, are strongly and independently associated with the IMT of common carotid artery. These results suggests that central fat accumulation may accelerate the development of earlier clinically silent stages of atherosclerosis, thus possibly explaining the higher prevalence of cardiovascular diseases in patients with abdominal obesity.     

Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia

Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.