GH-binding protein in obese men with varying glucose tolerance: relationship to body fat distribution, insulin secretion and the GH-IGF-I axis

Bioelectrical impedance for measurement of total body fat and computed tomography for visceral and subcutaneous fat at umbilicus levels were performed in 34 obese and 10 lean men. Insulin secretion in response to an oral glucose tolerance test (OGTT) and a GH stimulation test by L-dopa, growth hormone-binding protein (GHBP) and IGF-I were measured. Obese subjects were divided into three groups according to the OGTT. The obese type II diabetes mellitus group had the highest GHBP levels and the most visceral fat. GHBP levels were most strongly correlated with the ratio of visceral fat area to body weight (VWR) above any other parameters (r = 0.725, P<0.001). The insulin and free fatty acid (FFA) areas under curves (AUC) during the OGTT, and the IGF-I level, were also positively correlated with GHBP levels (r = 0.474, P<0.005; r = 0.572, P<0.005; r = 0.453. P<0.005). GH-AUC to the L-dopa stimulation test was negatively correlated with GHBP levels (r = -0.432. P<0.005). Stepwise multiple linear regression analysis showed that VWR, FFA-AUC and insulin-AUC significantly contributed to the variability of GHBP (r2 = 0.58). In conclusion, we demonstrated that: (i) visceral fat amount mainly determined GHBP levels in obese men with varying glucose tolerance: (ii) hyperglycemia per se did not influence the GHBP level, whereas insulin and FFA could play a role in regulation of GHBP: and (iii) although GH was not the main regulator of GHBP, the unchanged IGF-I level despite GH hyposecretion suggests that increased GHBP levels reflect GH hypersensitivity in order to compensate for decreased GH secretion in obesity.     

Free fatty acids and insulin levels--relationship to leptin levels and body composition in various patient groups from South Africa.

OBJECTIVE: To investigate the relationship between leptin concentrations, various metabolic indices and body composition in six different groups. DESIGN AND MEASUREMENTS: Anthropometric measurements, fasting plasma glucose, serum insulin, C-peptide, FFA and leptin levels were performed. In the obese and diabetic subjects, body composition was analysed with bio-impedance equipment and as a 5 level CT scan. SUBJECTS: Five lipoatrophic diabetes mellitus (LDM) patients, five normal subjects (N), nine white and nine black obese women (WW, BW), and nine white and nine black diabetic women (DWW, DBW) were investigated after an overnight fast. RESULTS: In both ethnic groups there was a positive correlation between leptin and BMI (black group: r=0.8; P<0.0001, white group: r=0.7, P<0.002) and leptin and SC fat mass (black group: r=0.6; P<0.005, white group: r=0.6; P<0.004). CONCLUSIONS: Across the groups, there were positive linear correlations between leptin concentrations, BMI, SC fat mass and FFA levels. Leptin and FFA concentrations are higher and insulin levels lower in both groups of black women compared to the two groups of white women, despite a similar BMI and body fat mass. In the DBW the large increase in visceral fat mass may be indicative of a more complex relationship between compensatory insulin resistance, elevated FFA levels and leptin secretion.     

Evidence for insulin resistance in black women from South Africa

OBJECTIVE: The rate of glucose disposal was determined in 10 black and 10 white obese nondiabetic urban women from South Africa to assess insulin resistance. DESIGN AND METHODS: Euglycemic hyperinsulinemic clamp and body composition analysis. RESULTS: Age, body mass index (BMI), anthropometric measurements and body composition were similar in both groups of women. A five-level computed tomography (CT) scan showed a similar mean subcutaneous fat mass in both groups of women (black obese women 555 +/- 9.0 vs white obese women 532 +/- 6.0 cm2), but less visceral fat in black obese women (90 +/- 3.0 vs 121 +/- 3.1 cm2; P< 0.05). Black obese women had higher fasting free fatty acid (997 +/- 69 vs 678 +/- 93 micromol/l; P < 0.05) and lactate concentrations (1,462 +/- 94 vs 1,038 +/- 39 micromol/l; P < 0.05), but lower fasting insulin levels (87 +/- 12 vs 155 +/- 9 pmol/l; P < 0.001). Black obese women also had a more favorable HDL: total cholesterol ratio (30.5% vs 23.0%; P< 0.04). The mean glucose disposal rate (M) and disposal expressed as glucose sensitivity index (M/I) were reduced in the black obese women vs white obese women (M: 7.1 +/- 0.8 vs 13.7 +/- 1.0 mmol/kg min(-1) x 100; P< 0.01, and M/I: 0.12 +/- 0.01 vs 0.24 +/- 0.02 mmol/kg x min(-1)/pmol/1 x 1,000; P < 0.01). Only black obese women showed a significant decrease in C-peptide levels during the clamp (2.9 +/- 0.22 vs 1.2 +/- 0.12 nmol/l; P<0.001). During the euglycemic period, the black obese women had higher lactate levels at all time points, but only the white obese women had increased lactate levels (918 +/- 66 to 1,300 +/- 53 micromol/l; P< 0.05). CONCLUSION: Black obese women demonstrate a higher degree of insulin resistance, despite less visceral fat and a higher HDL: total-cholesterol ratio. In addition, endogenous beta-cell secretory function in black obese women appears to be more sensitive to the suppressive effect of exogenous insulin administration. The significant increase in lactate levels in white obese women confirms that they are more insulin sensitive.     

Associations between circulating free fatty acids, visceral adipose tissue accumulation, and insulin sensitivity in postmenopausal women

The aims of the study were to evaluate the contribution of visceral adipose tissue (AT) accumulation and insulin sensitivity to the determination of circulating free fatty acid (FFA) concentrations measured during a 2-hour euglycemic-hyperinsulinemic clamp and to verify whether elevated FFAs are associated with other components of the metabolic syndrome in postmenopausal women. This cross-sectional study included 115 postmenopausal women (46-68 years old). Visceral AT was estimated by computed tomography. Insulin sensitivity was assessed by a 2-hour euglycemic-hyperinsulinemic clamp. Free fatty acid concentration was measured in the fasting state and every 30 minutes during the clamp. Fasting plasma glucose and 2-hour plasma glucose were measured by an oral glucose tolerance test. Visceral AT was associated positively and insulin sensitivity negatively with FFA area under the curve (AUC) measured during the clamp. Women with high visceral AT accumulation and low insulin sensitivity had higher FFA AUC than women with high visceral AT accumulation and high insulin sensitivity or women with low visceral AT combined with either low or high insulin sensitivity. Free fatty acid AUC was positively associated with triglyceride (r = 0.25, P < .05), fasting plasma glucose (r = 0.26, P < .01), 2-hour plasma glucose (r = 0.27, P < .01), and diastolic blood pressure (r = 0.21, P < .05) independently of visceral AT and insulin sensitivity. In postmenopausal women, the presence of both high visceral AT and low insulin sensitivity is needed to observe an elevated FFA AUC. Moreover, FFA AUC is associated with some components of the metabolic syndrome, independently of visceral AT and insulin sensitivity.     

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.     

Visceral adipose tissue is an independent correlate of glucose disposal in older obese postmenopausal women

Older obese postmenopausal women have an increased risk for type 2 diabetes and cardiovascular disease. Increased abdominal obesity may contribute to these comorbidities. There is considerable controversy, however, regarding the effects of visceral adipose tissue as a singular predictor of insulin resistance compared to the other constituents of adiposity. To address this issue, we examined the independent association of regional adiposity and total fat mass with glucose disposal in obese older postmenopausal women. A secondary objective examined the association between glucose disposal with markers of skeletal muscle fat content (muscle attenuation) and physical activity levels. We studied 44 healthy obese postmenopausal women between 50 and 71 yr of age (mean +/- SD, 56.5 +/- 5.3 yr). The rate of glucose disposal was measured using the euglycemic/hyperinsulinemic clamp technique. Visceral and sc adipose tissue areas and midthigh muscle attenuation were measured from computed tomography. Fat mass and lean body mass were estimated from dual energy x-ray absorptiometry. Peak VO2 was measured from a treadmill test to volitional fatigue. Physical activity energy expenditure was measured from indirect calorimetry and doubly labeled water. Pearson correlations indicated that glucose disposal was inversely related to visceral adipose tissue area (r = -0.40; P < 0.01), but not to sc adipose tissue area (r = 0.17), total fat mass (r = 0.05), midthigh muscle attenuation (r = 0.01), peak VO2 (r = -0.22), or physical activity energy expenditure (r = -0.01). The significant association persisted after adjusting visceral adipose tissue for fat mass and abdominal sc adipose tissue levels (r = -0.45; P < 0.005; in both cases). Additional analyses matched two groups of women for fat mass, but with different visceral adipose tissue levels. Results showed that obese women with high visceral adipose tissue levels (283 +/- 59 vs. 137 +/- 24 cm2; P < 0.0001) had a lower glucose disposal per kg lean body mass compared to those with low visceral adipose tissue levels (0.44 +/- 0.14 vs. 0.66 +/- 0.28 mmol/kg x min; P < 0.05). Visceral adipose tissue is an important and independent predictor of glucose disposal, whereas markers of skeletal muscle fat content or physical activity exhibit little association in obese postmenopausal women.     

Early events involved in the development of insulin resistance in Zucker fatty rat

AIM: To clarify the mechanism by which insulin resistance develops in obesity, Zucker fatty rats (ZFR) and lean litter mates (ZLR) were temporally subjected to oral glucose tolerance tests (OGTT) at 6 and 15 weeks of age. METHOD: As candidates for causative factors of insulin resistance, plasma leptin, free fatty acids (FFA) and tumor necrosis factor (TNF)-alpha levels were evaluated. RESULTS: There was no difference in the body weight between the two groups at 6 weeks of age, but ZFR were significantly heavier than ZLR at 15 weeks of age. At 6 weeks of age, blood glucose levels and area under the curve of glucose (AUCg) during OGTT were not significantly different between the two groups, while plasma insulin levels and area under the curve of insulin (AUCi) in the ZFR group were significantly higher than those in the ZLR group. At 15 weeks of age, the blood glucose levels and AUCg as well as plasma insulin levels and AUCi in the ZFR group during OGTT were significantly higher than those in the ZLR group. The ratio of fasting insulin to glucose in the ZFR group was significantly higher than that in the ZLR group at 6 and 15 weeks of age. Peripheral and portal plasma leptin and FFA levels were significantly higher in ZFR than ZLR both at 6 weeks and 15 weeks of age. Meanwhile, at 6 weeks, plasma TNF-alpha levels and expression of TNF-alpha protein in subcutaneous and visceral fat tissues were similar in both groups; however at 15 weeks, these were significantly higher in the ZFR group than the ZLR group. CONCLUSION: These results suggest that FFA rather than TNF-alpha may play an important role in early events involved in the development of insulin resistance and TNF-alpha accelerates insulin resistance together with FFA in the later stage.     

Metabolic and endocrine consequences of acute suppression of FFAs by acipimox in polycystic ovary syndrome.

To evaluate the effects of acute lowering of FFAs on glucose-induced insulin secretion and GH response to GHRH in polycystic ovary syndrome (PCOS), 27 PCOS subjects (11 lean and 16 obese) and 17 body mass index-matched controls (8 lean and 9 obese) were investigated. Patients underwent an oral glucose tolerance test and a GHRH test before and after administration of the antilipolytic drug acipimox (250 mg orally 3 h and 1 h before the starting of the tests). Blood samples were collected for 2 h after GHRH bolus and for 4 h after the oral glucose tolerance test. Serum concentrations of GH, insulin, glucose, and c-peptide were assayed in each sample, and the results were expressed as area under the curve (AUC). No significant differences were found as to glucose, insulin, and c-peptide AUC before and after acute FFA plasma reduction in any of the investigated groups. Basally, lower GH-AUC was found in lean PCOS compared with body mass index-matched controls and in obese vs. lean controls; no significant differences were found as to the same variable between the two obese groups. The acipimox induced FFA suppression elicited in the four groups a sustained increase in the GH response to its trophic hormone; indeed, the GH-AUC nearly doubled with respect to basal evaluation in all the studied groups. However, the antilipolytic drug was not able to abolish the differences found between lean groups in basal conditions. In conclusion, the presented data confirm that FFAs have a main role in regulating GH secretion at the pituitary level; however, it does not seem that they could explain the GH as well as insulin dysfunction of PCOS.     

The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin-dependent diabetes mellitus

To investigate the mechanisms of insulin resistance in obesity and noninsulin-dependent diabetes mellitus (NIDDM), we examined oxidative and nonoxidative pathways of free fatty acid (FFA) and glucose metabolism in 14 lean and 17 obese (with normal oral glucose tolerance) nondiabetic subjects and in 8 lean and 8 obese subjects with NIDDM. FFA and glucose metabolism were measured using the sequential insulin clamp technique in combination with indirect calorimetry and infusion of [3-3H]glucose and [1-14C]palmitate. Obesity was characterized by enlarged fat mass, which correlated positively with the plasma FFA concentration (r = 0.62; P less than 0.01). FFA metabolism was less sensitive to insulin in obese than in lean nondiabetic subjects, but this defect could be overcome by increasing the plasma insulin concentration. NIDDM patients showed normal sensitivity to the inhibitory action of insulin on FFA metabolism; however, maximal suppression by insulin was impaired. The combination of obesity and NIDDM was associated with a further enhancement of reesterification of FFA than observed in either condition alone. In both obesity and NIDDM, the dose-response curve for suppression of hepatic glucose production by insulin was impaired. While obesity was primarily characterized by reduced sensitivity to the stimulatory action of insulin on oxidative and nonoxidative pathways of glucose metabolism, resistance to the effect of insulin on glucose metabolism in NIDDM was characterized by a reduced maximal response. The combination of obesity and NIDDM further impaired the sensitivity of liver glucose output and glucose oxidation to insulin. The hypothesis is advanced that in uncomplicated obesity, increased availability and oxidation of FFA leads, by the FFA/glucose cycle, to the impairment in glucose utilization. In NIDDM, on the other hand, the defect in glucose utilization is primary, and the enhanced rate of FFA oxidation may represent a compensatory phenomenon.     

Hyperglycemia alters tumor necrosis factor-alpha release from mononuclear cells in women with polycystic ovary syndrome

CONTEXT: Women with polycystic ovary syndrome (PCOS) are often insulin resistant and have chronic low-level inflammation. OBJECTIVE: The purpose of this study was to determine the effects of hyperglycemia on lipopolysaccharide (LPS)-stimulated TNFalpha release from mononuclear cells (MNC) in PCOS. DESIGN: The study was designed as a prospective controlled study. SETTING: The study was carried out at an academic medical center. PATIENTS: Sixteen reproductive age women with PCOS (eight lean, eight obese) and 14 age-matched controls (eight lean, six obese) participated in the study. MAIN OUTCOME MEASURES: Insulin sensitivity (IS) was derived from a 2-h 75-g oral glucose tolerance test (IS(OGTT)). Percentage of truncal fat was determined by dual-energy absorptiometry. TNFalpha release was measured from MNC cultured in the presence of LPS from blood samples drawn fasting and 2 h after glucose ingestion. RESULTS: IS(OGTT) was lower in women with PCOS compared with controls (3.9 +/- 0.4 vs. 6.3 +/- 1.0; P < 0.03) and was negatively correlated with percentage of truncal fat (r = 0.56; P < 0.002). Truncal fat was greater in lean women with PCOS compared with lean controls (29.8 +/- 2.6 vs. 23.8 +/- 2.5%; P < 0.04). The TNFalpha response was different between obese and lean controls (-96.9 +/- 21.2 vs. 24.4 +/- 21.6 pg/ml; P < 0.03) and obese and lean women with PCOS (-94.1 +/- 34.5 vs. 30.4 +/- 17.6 pg/ml; P < 0.002). Fasting plasma C-reactive protein was elevated (P < 0.003) in obese PCOS and obese controls compared with lean controls. CONCLUSION: An increase in abdominal adiposity and increased TNFalpha release from MNC after hyperglycemia may contribute to insulin resistance in lean PCOS patients. In contrast, obese PCOS patients have more profound chronic inflammation, and thus may have LPS tolerance that protects them from relatively mild excursions in blood glucose.     

Cortisol levels during an oral glucose tolerance test in lean and obese women

Because of the similarities between Cushing's syndrome and insulin resistance syndrome,cortisol metabolism in obesity has been investigated in numerous studies. Our study investigates serum glucose, insulin, and cortisol response to oral glucose stimulation in a group of obese and lean normotensive, normolipidemic, and glucose-tolerant premenopausal women. Twenty-one obese [body mass index (BMI) 37Z +/- 6.3 kg/m2) and 14 lean (BMI: 21.5 +/- 1.0 kg/m2) age-matched healthy premenopausal women were included in the study. Serum glucose, insulin, and cortisol levels were measured at 30-minute intervals during 120 minutes of oral glucose tolerance testing (OGTT). Mean serum glucose and insulin levels were significantly higher in the obese group compared with lean subjects, and cortisol levels were similar during OGTT. There was not a significant difference for cortisol area under the curve (AUC) during OGTT between the two groups. No correlation between cortisol AUC, insulin AUC, and glucose AUC was noted for both groups. During OGTT, a decrease in cortisol levels was observed in both groups. The decrement occurred at 30 minutes of the OGTT in the obese group and at 60 minutes of the OGTT in the lean group. At 90 and 120 minutes of the OGTT, serum cortisol levels were similar to basal levels in both the obese group and the lean group. Previous studies reported altered hypotalamic-pituitary-adrenal axis activity, altered levels of urinary cortisol excretion, and increased metabolic clearance of cortisol in obesity. In our study in obese women, the only detected difference from lean subjects was a quicker suppression and recovery in serum cortisol levels after glucose administration.     

Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects

BACKGROUND AND AIMS: Abdominal fat accumulation (visceral/hepatic) has been associated with hepatic insulin resistance (IR) in obesity and type 2 diabetes (T2DM). We examined the relationship between visceral/hepatic fat accumulation and hepatic IR/accelerated gluconeogenesis (GNG). METHODS: In 14 normal glucose tolerant (NGT) (body mass index [BMI] = 25 +/- 1 kg/m(2)) and 43 T2DM (24 nonobese, BMI = 26 +/- 1; 19 obese, BMI = 32 +/- 1 kg/m(2)) subjects, we measured endogenous (hepatic) glucose production (3-(3)H-glucose) and GNG ((2)H(2)O) in the basal state and during 240 pmol/m(2)/min euglycemic-hyperinsulinemic clamp, and liver (LF) subcutaneous (SAT)/visceral (VAT) fat content by magnetic resonance spectroscopy/magnetic resonance imaging. RESULTS: LF was increased in lean T2DM compared with lean NGT (18% +/- 3% vs 9% +/- 2%, P < .03), but was similar in lean T2DM and obese T2DM (18% +/- 3% vs 22% +/- 3%; P = NS). Both VAT and SAT increased progressively from lean NGT to lean T2DM to obese T2DM. T2DM had increased basal endogenous glucose production (EGP) (NGT, 15.1 +/- 0.5; lean T2DM, 16.3 +/- 0.4; obese T2DM, 17.2 +/- 0.6 micromol/min/kg(ffm); P = .02) and basal GNG flux (NGT, 8.6 +/- 0.4; lean T2DM, 9.6 +/- 0.4; obese T2DM, 11.1 +/- 0.6 micromol/min/kg(ffm); P = .02). Basal hepatic IR index (EGP x fasting plasma insulin) was increased in T2DM (NGT, 816 +/- 54; lean T2DM, 1252 +/- 164; obese T2DM, 1810 +/- 210; P = .007). In T2DM, after accounting for age, sex, and BMI, both LF and VAT, but not SAT, were correlated significantly (P < .05) with basal hepatic IR and residual EGP during insulin clamp. Basal percentage of GNG and GNG flux were correlated positively with VAT (P < .05), but not with LF. LF, but not VAT, was correlated with fasting insulin, insulin-stimulated glucose disposal, and impaired FFA suppression by insulin (all P < .05). CONCLUSIONS: Abdominal adiposity significantly affects both lipid (FFA) and glucose metabolism. Excess VAT primarily increases GNG flux. Both VAT and LF are associated with hepatic IR.     

Metabolic factors in the insulin resistance in human obesity

Insulin resistance is frequently observed in obese subjects. The present work was initiated to study its relationship with the increased lipid metabolism generally observed in obesity. A first group of five obese subjects (146 +/- 10% of their ideal body weight [IBW] with normal glucose tolerance was submitted to a 75-g oral glucose tolerance test (OGTT) as a control and during an intralipid infusion (20% fat emulsion, 1 mL/min, started 90 minutes prior to the glucose load). Lipid and glucose oxidation were measured by continuous indirect calorimetry. The significant rise over control conditions in both plasma FFA and lipid oxidation rate during the lipid infusion was accompanied by a marked decrease in glucose tolerance (two hours venous plasma glucose: 151 +/- 12 during intralipid infusion v 110 +/- 3 mg/dL, P less than .01) together with a rise of the plasma insulin curve. Glucose oxidation was significantly decreased. A second group of five obese subjects (146 +/- 7% of their IBW) with impaired glucose tolerance was submitted to a similar OGTT, as a control, and during an infusion of beta-pyridyl-carbinol, a nicotinic acid derivative, to lower FFA. Both plasma FFA and lipid oxidation rates were decreased already prior to the OGTT. The previously impaired glucose tolerance was normalized (two hours venous plasma glucose: 129 +/- 13 during the beta-pyridyl-carbinol infusion v 172 +/- 7 mg/dL, P less than .01), and the insulin curve lowered. Glucose oxidation was increased during the early phase of the OGTT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Decrease in visceral fat following diet-induced weight loss in upper body compared to lower body obese premenopausal women

BACKGROUND: Obesity is associated with numerous metabolic disturbances, such as insulin resistance, diabetes mellitus type 2, dyslipidemia, and hypertension. An excess of fat within the abdomen, so-called visceral adiposity, confers a greater and independent health risk of metabolic and cardiovascular complications than does adipose tissue accumulation elsewhere. The present study aimed to investigate a possible differential effect of diet-induced weight loss in visceral fat mass and metabolic parameters in obese individuals with the upper body (UBO) and lower body (LBO) obese phenotype. METHODS: The obese subjects were prescribed a liquid, very-low calorie diet to reduce 50% of their overweight (15% body weight loss). Specific body fat measurements (MRI, BIA), anthropometrics, and fasting metabolic parameters were obtained in control subjects and two groups of obese subjects (UBO and LBO) before and after weight loss. RESULTS: Weight loss was accompanied by significant decreases in total, subcutaneous, and visceral fat in both UBO and LBO women. The largest reduction in visceral fat mass was found in the UBO women (absolute decrease 223+/-32 cm(2) vs 122+/-91 cm(2) in LBO women; P=0.01), while the amount of visceral fat was reduced to normal levels in LBO women (155+/-25 cm(2) after weight loss vs 143+/-17 cm(2) in controls; P=NS). Furthermore, weight loss significantly lowered fasting glucose, total cholesterol, and LDL cholesterol concentrations in UBO women. CONCLUSION: The obese phenotype is preserved after body weight loss. UBO women have to lose a larger amount of overweight in order to bring the amount of fat in the visceral depot down to normal levels and to obtain normalization of their cardiovascular risk profile.     

Dynamics of Nampt/visfatin and high molecular weight adiponectin in response to oral glucose load in obese and lean women

Background High molecular weight adiponectin (HMWA) is the active circulating form of adiponectin. Nampt/visfatin is the enzyme secreted from adipocytes in an active form and is one of the putative regulators of insulin secretion. Objective To investigate the dynamics of total adiponectin (TA), HMWA and Nampt/visfatin in obese and lean women during oral glucose tolerance test (OGTT). Methods We studied normal glucose‐tolerant (NGT), age‐matched, 30 obese and 30 lean women. All subjects underwent a standard 75 g, 2‐h OGTT, and area under the curve (AUC) during OGTT for glucose, insulin, Nampt/visfatin, TA and HMWA was calculated. Body fat mass was assessed by bioimpedance analysis. Results Obese women had significantly higher basal and AUC values for insulin and Nampt/visfatin, whereas basal and AUC‐HMWA were significantly lower in this group. Alternatively, obese and lean groups had similar basal and AUC values for glucose and TA. Basal insulin levels were negatively correlated with HMWA levels, but not with basal Nampt/visfatin. AUC‐insulin was correlated positively with AUC‐visfatin, and negatively with AUC‐HMWA. Total and truncal body fat mass showed positive correlation with basal and AUC‐visfatin, and negative correlation with basal and AUC‐HMWA. Conclusion In the NGT state, obese women have higher Nampt/visfatin and lower HMWA levels, both basally and in response to oral glucose challenge. The dynamics of Nampt/visfatin and HMWA during OGTT appear to be linked with insulin and adiposity. Counter‐regulatory adaptations in HMWA and Nampt/visfatin might have an impact on suggested adipoinsular axis, contributing to maintenance of normal glucose tolerance.     

Human resistin gene polymorphism is associated with visceral obesity and fasting and oral glucose stimulated C-peptide in the Québec Family Study

Obesity and insulin resistance are common features of Type 2 Diabetes. A new protein called resistin has been shown to be secreted by adipocytes in mice and to influence insulin sensitivity. The goal of the present study was to investigate the associations between one polymorphism (g-420C>G) of the human resistin gene and phenotypes related to adiposity and glucose metabolism. We genotyped 725 (including 42 diabetics) adult subjects participating in the Quebec Family Study (QFS) by a minisequencing method. Forty-two were diabetic subjects. Phenotypes measured were: body mass index (BMI) and waist circumference (WC), % body fat (PFAT) and fat mass (FM) assessed by under water weighing, abdominal total, subcutaneous and visceral fat assessed by computed tomography and fasting plasma glucose, insulin and C-peptide and their responses to an oral glucose tolerance test (OGTT). Comparisons between genotypes were performed in non-diabetic men (no.=280) and women (no.=403) separately by analyses of covariance (ANCOVA). Among men, g-420 G homozygotes had less visceral fat (p < 0.05), lower levels of acute insulin responses to an OGTT and lower levels of C-peptide in a fasting state and in responses to an OGTT than carriers of the C allele (p < 0.01). These associations were independent of age and adiposity but were not observed in women. These results suggest that in men, the human resistin gene is associated with reduced amount of visceral obesity and lower insulin secretory responses to a glucose load.     

不同糖耐量者血清游离脂肪酸与胰岛素抵抗的关系

以口服糖耐量试验(OGTT)确定受试者为正常人,糖耐量低减(IGT)和2型糖尿病,并测定空腹和OGTT 2h的游离脂肪酸(FFA)、血糖和胰岛素浓度,计算胰岛素敏感指数(IAI)。2型糖尿病和IGT患者的空腹和OGTT 2 h FFA、血糖和胰岛素浓度均明显高于正常组(均P<0.05),IAI均明显低于正常对照组(均P<0.01)。空腹及OGTT 2 h FFA与IAI之间呈显著负相关(分别为r=-0.38,P<0.01和r=-0.32,P<0.05),体重指数与IAI呈显著负相关(r=-0.39,P<0.05)。上述结果提示脂毒性在2型糖尿病的发病机制中有重要作用。     

What are the physical characteristics associated with a normal metabolic profile despite a high level of obesity in postmenopausal women?

Although obesity is often associated with insulin resistance and a cluster of metabolic disturbances, the existence of a subgroup of healthy but obese individuals has been postulated. It is unclear why some obese individuals fail to show traditional risk factors associated with the insulin resistance syndrome despite having a very high accumulation of body fat. To address this issue, we identified and studied a subgroup of metabolically normal but obese (MNO) postmenopausal women to gain insight into potential physiological factors that may protect them against the development of obesity-related comorbidities. We carefully examined the metabolic characteristics of 43 obese, sedentary postmenopausal women (mean +/- SD, 58.0 +/- 6.0 yr). Subjects were classified as MNO or as metabolically abnormal obese (MAO) based on an accepted cut-point for insulin sensitivity (measured by the hyperinsulinemic/euglycemic clamp technique). Thereafter, we determined 1) body composition (fat mass and lean body mass), 2) body fat distribution (abdominal visceral and sc adipose tissue areas, midthigh sc adipose tissue and muscle attenuation), 3) plasma lipid-lipoprotein levels, 4) plasma glucose and insulin concentrations, 5) resting blood pressure, 6) peak oxygen consumption, 7) physical activity energy expenditure, and 8) age-related onset of obesity with a questionnaire as potential modulators of differences in the risk profile. We identified 17 MNO subjects who displayed high insulin sensitivity (11.2 +/- 2.6 mg/min.kg lean body mass) and 26 MAO subjects with lower insulin sensitivity (5.7 +/- 1.1 mg/min.kg lean body mass). Despite comparable total body fatness between groups (45.2 +/- 5.3% vs. 44.8 +/- 6.6%; P: = NS), MNO individuals had 49% less visceral adipose tissue than MAO subjects (141 +/- 53 vs. 211 +/- 85 cm(2); P: < 0.01). No difference was noted between groups for abdominal sc adipose tissue (453 +/- 126 vs. 442 +/- 144 cm(2); P: = NS), total fat mass (38.1 +/- 10.6 vs. 40.0 +/- 11.8 kg), muscle attenuation (42.2 +/- 2.6 vs. 43.6 +/- 4.8 Houndsfield units), and physical activity energy expenditure (1060 +/- 323 vs. 1045 +/- 331 Cal/day). MNO subjects had lower fasting plasma glucose and insulin concentrations and lower insulin levels during the oral glucose tolerance test (P: values ranging between 0.01-0.001). No difference was observed between groups for 2-h glucose levels and glucose area during the oral glucose tolerance test. MNO subjects showed lower plasma triglycerides and higher high density lipoprotein cholesterol concentrations than MAO individuals (P: < 0.01 in both cases). Results from the questionnaire indicated that 48% of the MNO women presented an early onset of obesity (<20 yr old) compared with 29% of the MAO subjects (P: = 0.09). Stepwise regression analysis showed that visceral adipose tissue and the age-related onset of obesity explained 22% and 13%, respectively, of the variance observed in insulin sensitivity (total r(2) = 0.35; P: < 0.05 in both cases). Our results support the existence of a subgroup of obese but metabolically normal postmenopausal women who display high levels of insulin sensitivity despite having a high accumulation of body fat. This metabolically normal profile is associated with a lower accumulation of visceral adipose tissue and an earlier age-related onset of obesity.     

Relation of C-reactive protein to body fat distribution and features of the metabolic syndrome in Europeans and South Asians

OBJECTIVE: To investigate the association between circulating C-reactive protein (CRP) concentrations and indices of body fat distribution and the insulin resistance syndrome in South Asians and Europeans. DESIGN:: Cross-sectional study. SUBJECTS: A total of 113 healthy South Asian and European men and women in West London (age 40-55 y, body mass index (BMI) 17-34 kg/m(2)). MEASUREMENTS: Fatness and fat distribution parameters (by anthropometry, dual-energy X-ray absorptiometry and abdominal CT scan); oral glucose tolerance test with insulin response; modified fat tolerance test; and CRP concentration by sensitive ELISA. RESULTS: Median CRP level in South Asian women was nearly double that in European women (1.35 vs 0.70 mg/1, P=0.05). Measures of obesity and CRP concentration were significantly associated in both ethnic groups. The correlation to CRP was especially strong among South Asians (P<0.01) for measures of central obesity (waist girth and visceral fat area), whereas BMI and percentage fat were more significantly associated with CRP in Europeans (P<0.05). In South Asians the associations of CRP with visceral fat area and waist girth persisted after adjustment for either BMI or percent fat (all, P<0.05). In age-, sex- and smoking-adjusted regression analyses CRP concentrations were significantly associated with fasting and 2 h insulin and lipid levels in both ethnic groups (P<0.05). When further statistical adjustment was made for visceral fat area these associations were abolished (P>0.15). CONCLUSION: We suggest that adiposity and in particular visceral adipose tissue is a key promoter of low-grade chronic inflammation. This observation may in part account for the association of CRP with markers of the metabolic syndrome. Future studies should confirm whether CRP concentrations are elevated in South Asians and whether losing weight by exercise or diet, or reduction in visceral fat mass, is associated with reduction in plasma CRP concentrations.     

Diet-induced thermogenesis and substrate oxidation are not different between lean and obese women after two different isocaloric meals, one rich in protein and one rich in fat

Reduction in diet-induced thermogenesis (DIT) may promote weight gain and maintenance. Data on differences in DIT and macronutrient oxidation between lean and obese subjects are conflicting. In this study, we sought for differences in DIT and macronutrient oxidation between lean and obese women after consumption of 2 different isocaloric meals, one rich in protein and one rich in fat. Fifteen lean and 15 obese women were studied on 2 occasions, 1 week apart. In one visit, they consumed a protein-rich meal; in the other visit, a fat-rich meal. The 2 meals were isocaloric ( approximately 2026 kJ each), of equal volume, and given in random order. Resting energy expenditure and macronutrient oxidation rates were measured and calculated in the fasting state and every 1 hour for 3 hours after meal consumption. Diet-induced thermogenesis was not significantly different between lean and obese subjects after consumption of either the protein-rich (P = .59) or the fat-rich meal (P = .68). Diet-induced thermogenesis was significantly higher (by almost 3-fold) after consumption of the protein-rich meal in comparison with the fat-rich meal in both study groups. In addition, no significant differences in macronutrient oxidation rates were found between lean and obese women after the test meals. The results indicate that DIT is higher after protein intake than after fat intake in both lean and obese participants; however, DIT and macronutrient oxidation rate are not different between lean and obese subjects after consumption of either a protein-rich or a fat-rich meal. Over the long term, a low DIT after regular or frequent fat intake may contribute to the development and maintenance of obesity.