Comparison of fasting plasma leptin concentrations in healthy subjects with high and low plasma insulin

This study was initiated to evaluate the role of hyperinsulinemia in the regulation of fasting plasma leptin. We measured plasma leptin and insulin concentrations in 404 healthy nondiabetic subjects. For analytical purposes, the population was divided into quartiles on the basis of the lowest (quartile 1) and highest (quartile 4) plasma insulin response to oral glucose, and fasting plasma leptin values in these 2 dichotomous groups were compared. The total plasma integrated insulin response was 4-fold greater in quartile 4, associated with significantly higher (P < .001) fasting plasma leptin (12.60+/-0.85 v8.53+/-0.56 ng/mL). Fasting plasma leptin concentrations remained significantly higher in the hyperinsulinemic quartile when comparisons were made after subdividing the population on the basis of gender, body mass index (BMI), or waist to hip ratio (WHR). These results demonstrate that fasting plasma leptin concentrations are significantly higher in hyperinsulinemic individuals, and this difference is independent of either overall or central obesity.     

Plasma plasminogen activator inhibitor-I is associated with plasma leptin irrespective of body mass index, body fat mass, and plasma insulin and metabolic parameters in premenopausal women.

Leptin, the satiety hormone expressed almost exclusively in adipose tissue, is a marker of body fat accumulation in humans. Recent studies have shown that plasminogen activator inhibitor-1 (PAI-1), a prothrombotic factor associated with atherosclerosis complications, is also produced in adipose tissue. The objective of the present study was to determine whether PAI-1 antigen plasma concentrations are associated with leptin plasma levels or the body fat mass (FM) independently of the variables known to influence PAI-1 production. Sixty-one nondiabetic women aged 18 to 45 years with a wide range of values for the body mass index ([BMI] 18.1 to 37.7 kg/m2) were evaluated for (1) body FM and fasting plasma levels of (2) PAI-1 antigen, (3) PAI-1 activity, (4) leptin, (5) insulin, (6) blood glucose, and (7) lipids (cholesterol, high-density lipoprotein [HDL]-cholesterol, and triglycerides [TG]). Body FM and fat-free mass (FFM) were estimated during fasting conditions by the bioimpedance analysis (BIA) method using a tetrapolar device. Body fat distribution was evaluated by the waist circumference and the waist to hip ratio (WHR). FM was directly associated with both PAI-1 antigen (r = .585, P < .001) and PAI-1 activity (r = .339, P < .001). Seemingly, leptin was positively related to both PAI-1 antigen (r = .630, P < .001) and PAI-1 activity (r = .497, P < .001). Moreover, both PAI-I antigen and PAI-1 activity were directly correlated with FFM (r = .285, P < .05, and r = .336, P < .01, respectively), BMI (r = .594, P < .001, and r = .458, P < .001, respectively), and WHR (r = .510, P < .001, and r = .391, P < .005, respectively). Insulin was directly related to PAI-1 antigen (r = .540, P < .001), PAI-1 activity (r = .259, P < .05), leptin (r = .447, P < .001), and FM (r = .435, P < .001). The association between PAI-1 antigen (dependent variable) and leptin or FM was tested by a stepwise regression model simultaneously including leptin, FM, BMI, WHR, age, FFM, and fasting insulin, blood glucose, TG, cholesterol, and HDL-cholesterol as independent variables. PAI-1 antigen maintained a significant positive independent relationship only with leptin (t = 2.923, P < .01), insulin (t = 3.489, P < .001), and fasting blood glucose (t = 2.092, P < .05), and a negative independent relationship with HDL-cholesterol (t = -2.634, P < .05). In conclusion, the strong relationship between PAI-1 antigen and leptin irrespective of other variables known to influence these factors seems to indicate that leptin per se may potentially increase PAI-1 plasma concentrations in obese subjects.     

Relationship between plasma leptin levels and the tumor necrosis factor-alpha system in obese subjects.

OBJECTIVE: To evaluate the relationship between plasma leptin and the tumor necrosis factor-alpha (TNFalpha), TNF receptor p60 (TNF-R1) and TNF receptor p80 (TNF-R2) concentrations in obese subjects. DESIGN: Case-control study. SETTING: Outpatient's Service for Prevention and Treatment of Obesity at the University Hospital. MEASUREMENTS: Body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fasting plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance (HOMA IR), plasma leptin, TNFalpha, TNF-R1 and TNF-R2 concentrations were evaluated in obese subjects (n = 42) and in age- and gender-matched, lean healthy controls (n = 16). RESULTS: In obese subjects, fasting plasma glucose and insulin, HOMA IR, plasma leptin, TNFalpha, TNF-R1 and TNF-R2 concentrations were significantly higher than in controls. Furthermore, females showed higher leptin, TNF-R1 and TNF-R2 plasma concentrations compared to males, in both control and obese subjects. In control subjects, plasma leptin concentrations showed a direct correlation with BMI (r=0.74, P<0.001), hip circumference (r=0.94, P<0.001), TNF-R1 (r=0.79, P<0.001) and TNF-R2 (r=0.64, P<0.01), and a negative correlation with WHR (r=-0.58, P<0.05). In obese subjects, we found a direct correlation between plasma leptin concentrations and BMI (r=0.67, P<0.001), hip circumference (r=0.66, P<0.001), fasting glucose (r=0.37, P<0.05), fasting insulin (r=0.31, P<0.05), HOMA IR (r=0.38, P<0.05), TNF-R1 (r=0.71, P<0.001) and TNR-R2 (r=0.66, P<0.001), while a negative correlation was found between circulating leptin and WHR (r=-0.44, P<0.01). In multivariate analysis, plasma leptin concentrations were significantly associated with BMI (P=0.015) and gender (P=0.047) in the control group, while in obese subjects, plasma leptin showed a significant association with BMI (P=0.019) and TNF-R1 (P=0.012). CONCLUSIONS: Our results are consistent with the hypothesis that the TNFalpha system could be involved in the regulation of plasma leptin concentrations in obese subjects.     

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.     

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.     

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.     

Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity.

Fat tissue is a significant source of endogenous tumor necrosis factor alpha (TNFalpha), the pluripotent cytokine that plays an important role as a mediator of the peripheral insulin resistance found in obesity. The majority of evidence for this role of TNFalpha is from studies in animal models of obesity. To explore further the role of TNFalpha in the pathogenesis of obesity-related insulin resistance in humans, we compared plasma levels of TNFalpha and the other main endocrine cytokine, interleukin-6 ([IL-6] both measured by enzyme-linked immunosorbent assay), in 26 obese women (body mass index [BMI] > 30 kg/m2) and 13 female controls (BMI < 26 kg/m2) without a history of recent or active infection. Glucose and insulin levels were measured at 0, 1, and 2 hours after a 75-g oral glucose load. There was no significant difference in plasma TNFalpha or IL-6 levels between obese and non-obese subjects overall (2.10 +/- 0.19 v 1.65 +/- 0.18 pg/mL and 2.06 +/- 0.29 v 1.50 +/- 0.17 pg/mL, respectively). However, TNFalpha levels were significantly elevated in obese subjects with a 2-hour glucose level more than 140 mg/dL (n = 8) compared with the other obese subjects (n = 18) and the non-obese controls (2.88 +/- 0.46 v 1.75 +/- 0.10 and 1.65 +/- 0.18 pg/mL, respectively, P < .01). Furthermore, the TNFalpha level correlated significantly with the waist to hip ratio ([WHR] r = .53, P < .01) and fasting and post-oral glucose tolerance test (OGTT) insulin levels (r = .47, P < .02), but not with the BMI, and was higher in obese women with a WHR more than 0.90 (n = 14) in comparison to those with a WHR less than 0.90 (n = 12, 2.47 +/- 0.29 v 1.66 +/- 0.18 pg/mL, respectively, P < .03). The corresponding plasma leptin level was significantly higher in obese women versus the control group (41.6 +/- 2.5 v22.3 +/- 2.9 ng/mL, P < .001) and was related to the BMI (r = .60, P < .01) but not to TNFalpha or the WHR. There were no significant differences in the corresponding IL-6 concentration between groups, and IL-6 did not correlate with TNFalpha, leptin, BMI, WHR, or insulin levels. In conclusion, circulating TNFalpha levels are higher in abdominal obesity compared with peripheral obesity, and may contribute to the insulin resistance that more commonly complicates the former pattern of fat distribution.     

肿瘤坏死因子α和瘦素在肥胖及胰岛素抵抗中的作用

目的探讨血清TNFα及瘦素在肥胖和胰岛素抵抗中的作用。方法2型糖尿病病人84例,健康对照84例,分别测定血清TNFα、瘦素、血脂、空腹及餐后血糖、血清免疫反应性胰岛素(IRI)水平。并准确测量血压、身高、体重、腰臀围比(WHR)。结果肥胖者的TNFα及瘦素显著高于体重正常者,女性的瘦素血清水平高于男性2倍以上。相关分析结果显示,TNFα与HOMA胰岛素抵抗指数(HOMAIR)、WHR、空腹IRI呈正相关(r值分别为0.43、0.53、0.59,P<0.01),与高密度脂蛋白胆固醇呈负相关(r=-0.35,P<0.01)。瘦素与HOMAIR、空腹IRI呈正相关(r=0.31、0.29,P<0.05),男性的瘦素与WHR显著相关。TNFα与瘦素之间存在显著的正相关(r=0.29,P<0.05)。多元逐步回归分析表明,HOMAIR与TNFα的相关性最强,瘦素次之。血清TNFα水平与空腹血糖呈正相关。结论肥胖者的血清TNFα及瘦素水平与胰岛素抵抗密切相关,高水平的TNFα可能直接作用于脂肪组织调节瘦素的释放,而TNFα和瘦素协同作用诱导胰岛素的分泌,从而导致胰岛素抵抗。     

The degree of hyperinsulinemia and impaired glucose tolerance predicts plasma leptin concentrations in women only: a new exploratory paradigm

Plasma leptin has been shown to correlate positively with many indices of obesity, as well as insulin resistance. For a given body weight, the levels are higher in women than in men, but the reasons for this difference are not clear. Insulin has been shown to stimulate leptin production by adipose tissue in vivo and in vitro. Previous studies have reported that leptin levels are similar in diabetic and nondiabetic individuals. However, these studies were not performed in newly diagnosed diabetics, and other variables (such as gender) could have confounded the results. Therefore, the goal of the present cross-sectional study is to examine the effect of metabolic variables (such as glucose and insulin) on plasma leptin concentrations in men and women separately. We measured leptin levels in 48 subjects (17 with newly diagnosed type 2 diabetes mellitus, 13 with impaired glucose tolerance [IGT], and 18 normal individuals). The 3 groups were well matched for gender, age, and body mass index (BMI). When adjusted for the BMI and gender, a statistically significant gender-related difference in mean plasma leptin was observed across the 3 glucose tolerance subgroups (P < .03 by analysis of covariance [ANCOVA]). More specifically, plasma leptin levels were, on average, 44% lower in women with diabetes or IGT versus normal women (P < .02). No such between-group difference was observed in the men. In univariate analysis in the same female subgroup, plasma leptin correlated positively with fasting insulin (rs = +.43, P < .06) and negatively with 2-hour post-75-g glucose load plasma glucose concentration (rs = -.54, P < .02). In a multiple regression model controlling for the BMI in the female subgroup, circulating insulin and glucose concentrations 2 hours after the 75-g glucose load were good predictors of fasting plasma leptin (r = +.38, P = .02 and r = -.70, P < .001, respectively). Leptin levels in women appear to be influenced independently and to an important degree by ambient plasma glucose and plasma insulin concentrations. These findings suggest that the synthesis of leptin by adipose tissue is more susceptible to in vivo regulation by insulin and glucose in women than in men. Plasma leptin concentrations were also lower in women with IGT or type 2 diabetes versus normal women, suggesting that fasting and/or postprandial hyperglycemia interferes with the stimulatory effect of plasma insulin on the synthesis of leptin by adipose tissue in women only.     

Relative hypoleptinaemia in women with mild gestational diabetes mellitus.

AIMS: There is increasing evidence suggesting that leptin plays a major role in the regulation of energy homeostasis, as well as in the neuroendocrine and reproductive systems. Leptin is synthesized in the human placenta. The aim of this study was to relate serum leptin levels during pregnancy to glucose tolerance, body mass index (BMI) and specific metabolic variables, such as specific insulin and proinsulin. METHODS: A 2-h 75 g oral glucose tolerance test was performed in 221 pregnant women at 22-29 weeks of gestation (median 25th week). Serum leptin was measured using a radioimmunoassay. In 49 women, sequential leptin measurements were performed (during pregnancy and post partum (median 5 months)). RESULTS: During pregnancy serum leptin was significantly related to body weight (r = 0.49), BMI (r = 0.51), fasting immunoreactive insulin (r = 0.46), specific insulin (r = 0.43) and proinsulin (r = 0.29) (all P-values <0.0001). In women with mild gestational diabetes (GDM, n = 55), leptin levels were lower compared to women with normal glucose tolerance (n = 166) after adjusting for BMI and fasting insulin (26.9 vs. 19.4 ng/ml, P = 0.0001). Leptin was significantly higher during pregnancy compared to post partum (mean +/- SE: 24.3+/-1.5 vs. 19.6+/-1.6 ng/ml, P = 0.0003), even after adjustment for changes in BMI and changes in fasting insulin (P = 0.013). CONCLUSIONS: Leptin levels are elevated in pregnancy. Women with mild GDM presented with relative hypoleptinaemia compared to women with normal glucose tolerance.     

Can changes in plasma insulin concentration explain the variability in leptin response to weight loss in obese women with normal glucose tolerance?

The aim of this study was to test the hypothesis that the fall in circulating insulin concentration associated with moderate weight loss determines the associated decrease in plasma leptin concentration. For this purpose, 12 healthy, nondiabetic, obese women were studied before and after an average weight loss of 9.5 kg (11.2% of initial body weight). Plasma leptin concentrations fell from a mean (+/-SE) value of 35 +/- 3 to 17 +/- 2 ng/mL (P < 0.001) in association with the loss of weight. However, there was no correlation between the decline in leptin concentration and the associated fall in weight, body mass index, fat mass, or percent body fat. Furthermore, no correlation was seen among changes in fasting plasma glucose or insulin concentrations, the 8-h integrated plasma glucose response to breakfast and lunch, or the estimate of insulin-mediated glucose disposal. The only measured variable that correlated with the fall in plasma leptin concentration (r = 0.78; P < 0.005) was the decline in the 8-h integrated plasma insulin response after weight loss (from 304 +/- 44 to 232 +/- 36 microU/8 h x mL; P < 0.001). Finally, multivariate regression analysis, using various estimates of degree of obesity, insulin resistance, integrated glucose response, and integrated insulin response as dependent variables, indicated that only the insulin response was independently related to the decrease in leptin concentration (P = 0.035). The fall in integrated insulin response accounted for 66% of the variance in leptin concentrations after weight loss, and this was true no matter what the estimate of change in degree of obesity. In addition to offering an explanation for the variance in postweight loss leptin concentrations, these data provide further evidence of the importance of ambient insulin concentrations in the regulation of plasma leptin concentrations.     

Intra-abdominal fat is associated with decreased insulin sensitivity in healthy young men

To distinguish the relative role of intra-abdominal and subcutaneous abdominal fat in metabolic aberrations in upper body fat localization, we measured the relationship between regional fat distribution and insulin sensitivity in nine young men (28.6 +/- 0.7 years; body mass index [BMI], 24.7 +/- 1.3 kg/m2). Regional fat distribution was measured by anthropometric measurement and computed tomography (CT). Insulin sensitivity was measured by euglycemic hyperinsulinemic glucose clamp. Insulin sensitivity, expressed as the ratio of rate of glucose utilization to the mean plasma insulin concentration during the second hour of glucose clamp (M/I) was negatively correlated with BMI (r = -.91, P less than .001), waist to hip girth ratio (WHR) (r = -.80, P less than .01), subcutaneous abdominal fat area (r = -.90, P less than .001), and intra-abdominal fat area (r = -.88, P less than .01). Stepwise forward regression analysis showed that in addition to BMI, intra-abdominal fat area was a significant correlate of decrease in insulin sensitivity. These findings suggest that intra-abdominal fat play an important role in decreasing insulin sensitivity, even in healthy young men.     

Obesity, independent of insulin resistance, is a major determinant of blood pressure in normoglycemic Hong Kong Chinese

Obesity and insulin resistance are considered important links underlying the development of hypertension. In Caucasians, there have been many reports of an association between insulin resistance and hypertension. However, this relationship is not consistently found in other ethnic groups. In this study, we examined the involvement of insulin resistance (assessed as fasting insulin-glucose product, FIGP) and general and central obesity as potential links in the development of hypertension in 413 normoglycemic Hong Kong Chinese (56.9% hypertensive) subjects. Anthropometric parameters (waist circumference [WC], waist-to-hip ratio [WHR], body mass index [BMI]), surrogate measures of insulin resistance (fasting plasma glucose, insulin, FIGP), fasting lipids and systolic (SBP) and diastolic (DBP) blood pressure were measured. Both male and female hypertensives were more obese and dyslipidemic, and the females had higher indices of insulin resistance than the normotensive subjects of the same gender. Before adjustment for age, gender, and adiposity, FIGP correlated with SBP in the total (r = .19, P = .009) and low BMI (r = .23, P < .05) and low WHR (r = .25, P < .01) groups. However, after adjustment, there was no significant relationship between FIGP and blood pressure. In contrast, BMI and WC were strongly associated with blood pressure (r > or = .41, P < .001 for both DBP and SBP in the total population), although in the group with general obesity, the strength of the relationship was weaker (r > or = .13). These relationships persisted after adjustment for age, gender, and FIGP. Obesity, therefore, appears to have a predominant role compared with insulin resistance in determining blood pressure in these normoglycemic Chinese.     

Plasma insulin, cholecystokinin, galanin, neuropeptide Y and leptin levels in obese women with and without type 2 diabetes mellitus

Obesity is an important factor predisposing to type 2 diabetes mellitus, especially for postmenopausal women. Experimental studies provided evidences that leptin, cholecystokinin (CCK), galanin (GAL), neuropeptide Y (NPY) and insulin are involved in feeding behaviour. The aim of the study was to evaluate their possible relationships in obese and diabetic women. Three groups of postmenopausal women (FSH > 30 mIU/ml) were evaluated: 8 diabetic (mean age 56.6 +/- 6.9 y, BMI 29.8 +/- 5.3 kg/m2), 10 obese non-diabetic (mean age 49.6 +/- 5.4 y, BMI 36.0 +/- 3.7 kg/m2) and 12 non-diabetic controls (mean age 52.7 +/- 3.5 y, BMI 27.3 1.9 kg/m2). For each patient BMI and WHR were measured and calculated. Blood samples were collected at 8:00 a.m. after an overnight fast. Plasma concentrations of FSH, leptin, CCK, GAL, NPY and insulin were determined using commercial RIA kits. Mean plasma NPY concentration was significantly higher in diabetic women than in controls (190.1 pg/ml +/- 85.4 vs 120.4 +/- 36.6). Compared to controls, mean plasma leptin level was significantly higher in obese non-diabetic women (32.9ng/ml +/- 9.2 vs 18.9 +/- 9.1). No significant differences were found between obese non-diabetic and diabetic women. In diabetic subjects positive correlations were found between: CCK and leptin (r= 0.8295; P= 0.011), CCK and insulin (r=0.7832; P=0.022), leptin and insulin (r=0.9302; P=0.001). In obese subjects a positive correlation between WHR and GAL (r= 0.6624; P= 0.037) and a negative between GAL and insulin (r= -0.6795; P= 0.031) were found. In controls positive correlations were found between WHR and CCK (r=0.6412; P=0.025), GAL and insulin (r=0.630; P=0.028) and negative between CCK and NPY (r = -0.6505; P= 0.022). Our results, ie higher mean plasma NPY levels in postmenopausal diabetic women and positive correlation of CCK with leptin and insulin, may suggest the role of these neuropeptides in metabolic disorders leading to type 2 diabetes mellitus.     

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.     

The insulin resistance syndrome and the binding capacity of cortisol binding globulin (CBG) in men and women

BACKGROUND: Both insulin resistance and cortisol binding globulin (CBG) capacity have been found to correlate with plasma free fatty acid (FFA) concentration. OBJECTIVE: To examine the changes in CBG binding with varying degrees of insulin resistance and plasma FFA levels. SUBJECTS AND METHODS: Anthropometric parameters, serum cortisol levels, plasma CBG, CBG binding and insulin sensitivity (using the frequently sampled intravenous glucose tolerance test with minimal model analysis) were measured in a group of 38 healthy subjects (19 men, mean age 36.2 +/- 1.9; body mass index (BMI) 28.8 +/- 1.2, range 22.2-35.7), and 19 women, age 34.9 +/- 1.4; BMI 28.1 +/- 0.8, range 19-37.9)]. RESULTS: Plasma CBG levels did not differ between men and women. In men, CBG binding was associated with several parameters of the insulin resistance syndrome, including area under the curve for glucose during an oral glucose tolerance test (MBG, r = 0.45, P = 0.04), fasting insulin (r = 0.66, P = 0. 002), plasma triglycerides (r = 0.75, P < 0.0001), VLDL-triglycerides (r = 0.59, P = 0.007), fasting FFA (r = 0.72, P = 0.002), uric acid (r = 0.57 (P = 0.01) and insulin sensitivity (SI, r = - 0.58, P = 0.008). Free cortisol (estimated as the ratio of cortisol to CBG) was not associated with waist-to-hip ratio (WHR) or parameters of insulin sensitivity. In contrast to men, CBG binding was not associated with MBG, fasting insulin, plasma triglycerides, VLDL-triglycerides, FFA, uric acid or SI (all P = NS) in women. Serum free cortisol, however, correlated positively with WHR (r = 0. 62, P = 0.02) and negatively with SI (r = - 0.68, P = 0.01) in obese women. A multiple linear regression to predict CBG binding was constructed, with plasma CBG concentration and insulin sensitivity as independent variables. In this model, only SI entered the equation at a statistically significant level (P = 0.0012) contributing to 52% of the variance in CBG binding in men. When plasma FFA levels were added to the model, both SI (P = 0.04) and FFA levels (P = 0.039) contributed to 66% of the variance of CBG binding in men. In women, both plasma CBG concentration (P = 0.0005) and insulin sensitivity (P = 0.047) entered the equation at a statistically significant level, contributing to 60% of the variance in CBG binding. When plasma FFA levels were added to the model, only plasma CBG concentration (P = 0.043) was found to significantly contribute to 38% of the variance in CBG binding. The latter finding suggests that FFA levels constituted a confounding variable in the association between SI and CBG binding in women. CONCLUSIONS: Both plasma free fatty acid and insulin sensitivity influence cortisol binding globulin binding capacity in men. Whether cortisol binding globulin binding is a factor implicated in the pathophysiology of insulin resistance or represents an adaptative tool in this situation awaits further studies.     

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.     

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.     

血清瘦素水平与胰岛素原、真胰岛素及胰岛素敏感性的关系

目的　研究中国人群空腹瘦素水平与真胰岛素 (TI)、胰岛素原 (PI)、PI/TI比值及胰岛素敏感性之间的关系。方法　 90 2例非糖尿病者均系 2 0 0 0年接受糖尿病流行病学调查者。测定空腹瘦素、TI和PI浓度以及空腹及餐后 2h血糖。瘦素、TI及PI检测采用本室建立的特异的酶联免疫分析法 (ELISA)。胰岛素敏感性以HOMA胰岛素抵抗指数 (HOMA IR)评价。结果　血清瘦素水平女性高于男性。相关分析显示血清瘦素水平与空腹TI、PI及HOMA IR显著正相关 (男性 792例 ,r分别为0 345、0 2 36和 0 364 ;女性 1 1 0例 ,r分别为 0 574、0 375和 0 576 ,P <0 0 0 1 ) ,但与空腹血糖仅在男性呈弱相关 (r=0 1 5 ,P =0 0 1 5) ,与空腹PI/TI比值不相关。在调整年龄、体重指数 (BMI)和腰臀围比(WHR)后 ,尽管相关性减弱 ,瘦素水平仍然与TI、PI以及HOMA IR显著相关。结论　本组的血清瘦素浓度与TI、PI以及胰岛素抵抗显著正相关 ,且在一定程度上独立于肥胖和脂肪分布。瘦素水平高或瘦素抵抗的个体可能存在高胰岛素血症和胰岛素抵抗 ,提示其瘦素 胰岛素轴的调节异常。本研究未发现瘦素水平与空腹PI/TI比值的相关 ,提示瘦素可能与这一反映胰岛 β细胞的功能异常的标志无关。本研究揭示的高瘦素 高胰岛素血症或胰岛素抵抗之间的     

Elevated serum RBP4 is associated with insulin resistance in women with polycystic ovary syndrome

Retinol binding protein 4 (RBP4) is a novel adipocyte-secreted protein that contributes to systemic insulin resistance. Experiments in mice suggest that elevated RBP4 causes insulin resistance. In the present study, we determined serum RBP4 concentration and evaluated its association with insulin resistance in women with polycystic ovarian syndrome (PCOS); 39 PCOS women and 45 healthy control subjects were enrolled in this study. Serum RBP4, fasting plasma glucose (FPG) and fasting serum insulin (FINS) were measured in all subjects. Furthermore, oral glucose tolerance test (OGTT), Botnia clamp (an intravenous glucose tolerance test followed by an euglycemic hyperinsulinemic clamp), and measurements of sex hormones were performed in 13 control subjects and all the PCOS women. The levels of serum RBP4 were elevated in PCOS women compared with the control (11.69 +/- 6.72 versus 7.75 +/- 5.96 microg/mL, p = 0.006). RBP4 levels were positively correlated with WHR (r = 0.216, p = 0.048), and intravenous glucose tolerance test beta cell index (IVGTT-beta index) which reflected beta cell function (r = 0.309, p = 0.028), but were inversely correlated with M value during Botnia clamp, which represented insulin sensitivity (r = -0.362, p = 0.008). No correlation was found between RBP4 and age, BMI, blood pressure, FPG, FINS, 2-h postprandial glucose, 2-h postprandial insulin, free testosterone, total testosterone, follicle-stimulating hormone (FSH), or luteinizing hormone (LH). In a linear stepwise regression analysis with a model including age, BMI, WHR, free testosterone, IVGTT-beta index, and M value as independent variables, only M value showed significant correlation with serum RBP4 levels (r2 = 0.105, f = 6.640, p = 0.012). In conclusion, serum RBP4 levels are significantly increased in PCOS women and associated with insulin resistance, which indicates that RBP4 may be a contributing factor linking adipose tissue with insulin resistance in PCOS.