Lactate and glycerol release from subcutaneous adipose tissue in black and white lean men.

To measure interstitial glycerol and lactate production from the sc adipose tissue of two regions in nine black and nine white lean men, sc microdialysis was performed in combination with adipose tissue blood flow rates measured with 133Xe clearance. In the postabsorptive state, the plasma glucose and insulin levels of the black men and white men were similar. The black men had higher plasma free fatty acids (825+/-97 vs. 439+/-58 micromol/L; P < 0.005), glycerol (99.5+/-5.1 vs. 54.1+/-3.3 micromol/L; P < 0.0001), and lactate (1056+/-95 vs. 729+/-45 micromol/L; P < 0.01). Interstitial glycerol concentrations in the black and white men were 227 vs. 163 micromol/L (P < 0.01) and 230 vs. 162 micromol/L (P < 0.05) in the abdominal and femoral regions. The adipose tissue blood flow rate was higher in the black men in the abdominal (7.9+/-0.9 vs. 3.1+/-0.5 mL/100 g x min; P < 0.01) and femoral area (5.2+/-0.6 vs. 2.8+/-0.3; P < 0.01). Interstitial lactate concentrations in black and white men were 1976 vs. 1364 micromol/L (P < 0.004) and 1953 vs. 1321 micromol/L (P < 0.004) in the abdominal and femoral regions, respectively. Glycerol release was higher in black men vs. white men for abdominal (0.21+/-0.02 vs. 0.14+/-0.02 micromol/100 g x min; P < 0.02) and femoral (0.22+/-0.02 vs. 0.15+/-0.01; P < 0.05) areas. Postprandially, black men had higher plasma glucose levels [1 h, 9.6+/-0.4 vs. 8.2+/-0.5 mmol/L (P < 0.05); 2 h, 8.9+/-0.4 vs. 7.2+/-0.4 mmol/L (P < 0.01)], but lower plasma insulin levels [1 h, 173+/-13 vs. 264+/-48 pmol/L (P < 0.05); 2 h, 136+/-20 vs. 209+/-34 pmol/L (P < 0.05)]. Plasma free fatty acid, lactate, and glycerol levels remained higher in the black men. After 1 h, lactate release was higher in the black men vs. that in the white men for abdominal (20.5+/-1.6 vs. 14.7+/-2.5 micromol/100 g x min;P < 0.05) and femoral (15.6+/-1.1 vs. 12.1+/-1.8; P < 0.03) areas. We conclude that the black men, who are relatively insulinopenic postprandially, have a brisker lipolysis and also release more lactate from sc fat tissue than white men. These differences in adipose tissue metabolism may be related to differences in the lipid profiles and glucose metabolism previously documented in these ethnic groups.     

Lactate and glycerol release from adipose tissue in lean, obese, and diabetic women from South Africa.

Abnormalities observed in intermediary metabolism may be related to the pathogenesis of obesity-related diseases such as type 2 diabetes. Glycerol and lactate production was estimated in the sc adipose tissue of two anatomical regions of 10 lean (LW), 10 obese (OW), and 10 matched diabetic (DW) black urban women. This was done with the sc microdialysis technique and combined with adipose tissue blood flow (ATBF) rates calculated from (133)Xe clearance. Biochemical measurements were made in the postabsorptive and postprandial state. Bioimpedance and computed tomography scans were used to define body composition. DW present with more visceral fat (DW, 138 +/- 5.0; OW, 66.6 +/- 5.0 cm; P < 0.01). This was associated with elevated free testosterone levels (DW, 1.21 +/- 0.1; OW, 0.75 +/- 0.1 nmol/L; P < 0.05). The fasting FFA, glycerol, and lactate levels increased across the three groups (LW < OW < DW). During the oral glucose tolerance test, glucose levels were elevated in DW, with higher insulin levels [0 h: DW, 207 +/- 8.6; OW, 100 +/- 7.2 pmol/L (P < 0.01); 1 h: DW, 410 +/- 15.2; OW, 320 +/- 10.9 pmol/L (P < 0.05)], but with a flat Cpeptide response (1 h: DW, 932 +/- 40; OW, 1764 +/- 40 pmol/L; P < 0.05). Plasma lactate levels increased significantly in LW and OW at 1 h (P < 0.001), but remained lower in LW vs. OW for all time points. ATBF was highest in LW [abdominal, 0 h: DW, 4.5 +/- 0.2; OW, 1.7 mL/100 g.min (P < 0.01); femoral, 0 h: DW, 3.4 +/- 0.2; OW, 1.8 +/- 0.3 mL/100 g.min (P < 0.01)]. ATBF did not increase in DW during the oral glucose tolerance test. Glycerol release (GR) was used to assess the lipolytic rate and was highest in LW in the abdominal area [0 h: LW, 1.7 +/- 0.2; OW, 1.1 +/- 0.2 micromol/kg.min (P < 0.05); DW, 0.78 +/- 0.05 micromol/kg.min (P < 0.05 vs. OW)]. By contrast, GR was higher in the femoral area of OW (0 h: OW, 1.6 +/- 0.2; LW, 1.15 +/- 0.1 micromol/kg.min; P < 0.05). Regional differences were observed for GR in both OW and DW (femoral > abdominal). Lactate release (LR) was low in DW [abdominal, 0 h: DW, 3.5 +/- 0.4; OW, 7.8 +/- 1.0 micromol/kg.min (P < 0.001); femoral, 0 h: DW, 3.1 +/- 0.3; OW, 9.0 +/- 0.9 micromol/kg.min (P < 0.001)]. LR was appropriately low for body fat mass in LW, with a brisk increase between 0 and 1.5 h. A negative correlation exists between GR (abdominal area) and insulin levels in the postabsorptive state (P < 0.0001). In conclusion, 1) the fasting lipolytic rate is associated with insulin levels; 2) OW and DW have more adipose tissue insulin resistance than LW; 3) OW and DW have a brisker lipolysis in the femoral area; and 4) in DW, higher visceral mass is associated with elevated free testosterone and FFA concentrations. Obesity in the black population is therefore characterized by a marked degree of adipose tissue lipolysis. This degree of resistance together with increasing body fat mass may predispose the obese women to developing type 2 diabetes. Once this disease is established, the onset of adipose tissue vascular insulin resistance will sustain ongoing insulin resistance, even in the presence of relative insulinopenia.     

Differences in basal and poststimulation glucose homeostasis in nondiabetic first degree relatives of black and white patients with type 2 diabetes mellitus.

Black Americans (blacks) have a higher prevalence and earlier onset of type 2 diabetes than white Americans (whites). To examine metabolic differences in both races, we measured the basal glucose turnover rates (D-]3-3H]glucose technique) and plasma glucose, insulin, and C-peptide levels before and after an oral glucose load in 24 glucose-tolerant black and 14 white female relatives of patients with type 2 diabetes. Eight black and 8 white female subjects with no family history of diabetes served as controls. Mean fasting and postglucose plasma glucose levels were not significantly different between the black and white relatives and the control subgroups. Mean fasting plasma insulin and C-peptide levels were slightly greater but not significantly different between the relatives. After oral glucose ingestion, mean incremental integrated plasma insulin areas were significantly (P less than 0.02) greater in the black than the white relatives (70 +/- 14 vs. 29 +/- 6 nM.min). In addition, incremental integrated C-peptide areas were greater in the black than the white relatives (303 +/- 55 vs. 115 +/- 33; P less than 0.005). Similarly, we found significantly greater integrated incremental insulin (61 +/- 11 vs. 22 +/- 3 nM.min; P less than 0.02) and C-peptide (248 +/- 58 vs. 47 +/- 16; P less than 0.005) areas in the black than the white controls, respectively. The estimated basal and postglucose hepatic insulin extraction values, expressed as molar ratios of C-peptide and insulin, were not significantly different between the relatives. While basal hepatic insulin extraction was significantly (P less than 0.05) lower in the black controls, the postprandial insulin clearance was not different between the black and white controls. Mean basal hepatic glucose production was greater (P less than 0.02) in the black than the white relatives (2.49 +/- 0.13 vs. 2.02 +/- 0.12 mg/kg.min). Similarly, the black controls had greater hepatic glucose production than the white controls (2.36 +/- 0.15 vs. 1.81 +/- 0.08 mg/kg.min; P less than 0.001). We conclude that basal and poststimulation glucose homeostatic regulation appear to be different in black and white females, regardless of family history of type 2 diabetes.     

Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes

Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 +/- 1.2 vs 11.4 +/- 1.2 mmol/l, P less than 0.01) without enhancing mean day-time plasma insulin (43 +/- 4 vs 50 +/- 7 mU/l, NS) or C-peptide levels (1.26 +/- 0.12 vs 1.38 +/- 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 +/- 0.16 vs 1.44 +/- 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 +/- 0.11 vs 1.38 +/- 0.11 mmol/l, P less than 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 +/- 38 vs 313 +/- 33 mg.m-2.min-1, P less than 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 +/- 5.8 vs 50.6 +/- 2.8 ml.m-2.min-1, P less than 0.05), whereas basal hepatic glucose production was unchanged (81 +/- 6 vs 77 +/- 4 mg.m-2.min-1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Association of obesity and distribution of obesity with glucose tolerance and cardiovascular risk factors in the elderly.

The association of obesity and fat distribution with glucose tolerance and cardiovascular risk factor levels were investigated in a population-based study in East Finland including 396 non-diabetic men and 673 women aged from 65 to 74 years. Obese men and women (BMI greater than 27 kg/m2) had higher levels (P less than 0.001) of fasting and 2 h plasma glucose and insulin as well as total triglycerides and diastolic blood pressure, and lower levels of HDL cholesterol than normal weight men and women. Central fat distribution (the highest vs. the lowest tertile of waist-hip ratio) was associated independently of obesity with high fasting glucose (5.7 vs. 5.5 mmol/l in non-obese subjects, 5.9 vs. 5.7 mmol/l in obese subjects, P less than 0.05) and insulin levels (13.7 vs. 10.6 mU/l in non-obese subjects, 18.4 vs. 15.6 mU/l in obese subjects, P less than 0.01) and with adverse changes (P less than 0.05) in lipid and lipoprotein levels (triglycerides: 1.59 vs. 1.41 mmol/l in non-obese subjects, 1.92 vs. 1.69 mmol/l in obese subjects; HDL cholesterol: 1.33 vs. 1.43 mmol/l in non-obese subjects, 1.20 vs. 1.32 mmol/l in obese subjects). There were no marked differences in metabolic aberrations related to obesity between men and women. However, the association between waist-hip ratio and risk factors was non-linear in men whereas it was linear in women. In conclusion, obesity per se rather than its distribution was a more significant determinant of glucose and insulin as well as total triglyceride and HDL cholesterol levels in elderly subjects.     

Insulin action and fibrinolysis influenced by vitamin E in obese Type 2 diabetes mellitus.

Increased oxidative stress, hypofibrinolysis and insulin resistance are present in obese Type 2 diabetic patients. It is supposed that treatment with antioxidant alpha-tocopherol (vitamin E) could not only decrease free radical production, but also ameliorate insulin action. We evaluated the effect of 3 months administration of vitamin E (600 mg daily) on insulin action examined by hyperinsulinemic clamp in 11 obese Type 2 diabetic patients. Oxidative stress and fibrinolysis were also determined. The administration of vitamin E caused a decrease of glucose disposal rate (26.6 +/- 9.5 vs 21.3 +/- 7.5 micromol/kg/min, P < 0.02) and of metabolic clearance rate of glucose (3.7 +/- 1.6 vs 2.9 +/- 0.8 ml/kg/min. P < 0.02). A decrease of insulin receptor number was observed on erythrocytes after vitamin E (284 +/- 84 vs 171 +/- 59 pmol/l, P < 0.01). Significantly higher plasma malondialdehyde (MDA) concentration documented an increased oxidative stress in diabetic patients as compared with healthy persons (3.13 +/- 0.68 vs 1.89 +/- 0.18 micromol/l, P<0.001). An inverse relationship was found between MDA concentration and insulin sensitivity expressed by glucose disposal rate (r = -0.73). Vitamin E further worsened the hypofibrinolysis documented by a decrease of tissue plasminogen activator (P < 0.01) without changes in its inhibitor PAI-1. In conclusion. our results demonstrate that higher doses of vitamin E may further deteriorate insulin action and fibrinolysis in obese Type 2 diabetic patients.     

Lack of insulin inhibition on insulin secretion in non-diabetic morbidly obese patients.

OBJECTIVE: Insulin inhibition of insulin secretion has been described in normal lean subjects. In this study, we examined whether this phenomenon also occurs in the morbidly obese who often have severe peripheral insulin resistance. SUBJECTS: Twelve obese patients, normotolerant to glucose (8 F/4 M, body mass index (BMI)=54.8+/-2.5 kg/m(2), 39 y) and 16 lean control subjects (10 F/6 M, BMI=22.0+/-0.5 kg/m(2), 31 y). DESIGN AND MEASUREMENTS: An experimental study using various parameters, including an euglycemic hyperinsulinemic clamp (280 pmol/min/m(2) of body surface), an oral glucose tolerance test (OGTT), electrical bioimpedance and indirect calorimetry. RESULTS: The obese subjects were insulin resistant (M=19.8+/-1.6 vs 48.7+/-2.6 micromol/min kg FFM, P<0.0001) and hyperinsulinemic in the fasted state and after glucose ingestion. Fasting plasma C-peptide levels (obese 1425+/-131 pmol/l vs lean 550+/-63 pmol/l; P<0.0001) decreased less during the clamp in the obese groups (-16.9+/-6.9% vs -43.0+/-5.6% relative to fasting values; P=0.007). In the lean group, the C-peptide decrease during the clamp (percentage variation) was related to insulin sensitivity, M/FFM (r=0.56, P=0.03), even after adjustment for the clamp glucose variation. CONCLUSION: We conclude that, in lean subjects, insulin inhibits its own secretion, and this may be related to insulin sensibility. This response is blunted in morbidly obese patients and may have a role in the pathogenesis of fasting hyperinsulinemia in these patients.     

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.     

Altered tumor necrosis factor alpha release from mononuclear cells of obese reproductive-age women during hyperglycemia

The aim of the study was to determine whether lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) release from mononuclear cells (MNCs) is altered in obese reproductive-age women in response to hyperglycemia. Six obese and 8 age-matched normal-weight women (18-40 years) underwent a 2-hour 75-g oral glucose tolerance test. Tumor necrosis factor alpha release was measured from MNCs cultured in the presence of LPS after isolation from blood samples drawn fasting and 2 hours after glucose ingestion. Insulin resistance was derived by homeostasis model assessment of insulin resistance. Total body fat (%) and truncal fat (%) were determined by dual-energy absorptiometry. Obese women had a higher (P < .03) body mass index (34.1 +/- 1.1 vs 21.9 +/- 0.8 kg/m2), percentage of total body fat (42.4% +/- 1.3% vs 28.7% +/- 1.8%), and percentage of truncal fat (42.1% +/- 1.2% vs 24.7% +/- 2.2%). Homeostasis model assessment of insulin resistance was greater in the obese group (58.0 +/- 10.6 vs 27.8 +/- 4.3, P < .02). Fasting plasma C-reactive protein (7787 +/- 884 vs 236 +/- 79 ng/mL, P < .0001) and TNF-alpha (2.37 +/- 0.09 vs 0.54 +/- 0.04 pg/mL, P < .05) were both elevated in obese women. Hyperglycemia resulted in a suppression of LPS-stimulated TNF-alpha release from MNCs of normal-weight subjects (154 +/- 21 vs 57 +/- 28 pg/mL, P < .003), but no change in obese women (148 +/- 36 vs 173 +/- 49 pg/mL). The TNF-alpha response was different between groups (-97 +/- 21 vs +24 +/- 22 pg/mL, P < .003). There was also a positive association between the incremental change in MNC-derived TNF-alpha and percentage of truncal fat (r = 0.75, P < .002). In conclusion, these data suggest that there is an absence of the "normal" suppression of TNF-alpha in MNCs after hyperglycemia in obese women, and this response may contribute to impaired glucose disposal and insulin resistance.     

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.     

Gln27Glu polymorphism in the beta2 adrenergic receptor gene and lipid metabolism during exercise in obese women

BACKGROUND: The Glu27Glu genotype in the beta-2-adrenergic receptor (ADRB2) is associated with fat mass, body mass index and obesity in females. In our population, we previously found an association of higher body mass index (BMI) among women who reported more physical activity and carried the Glu27 allele as compared to non carriers with the same level of activity. OBJECTIVE: To examine the lipid metabolism differences, both at rest and during submaximal exercise in ADRB2 Glu27Glu vs Gln27Gln obese women. SUBJECTS: Eight obese women with the Glu27Glu genotype (age, 43+/-5 y; body mass index (BMI), 31.7+/-0.9 kg/m(2); percentage fat mass, 42.0+/-1.3; WHR, 0.83+/-0.02; and VO(2max), 21.6+/-0.9 ml/kg/min) were compared with seven obese women with the Gln27Gln genotype (age, 43+/-5 y; BMI, 33.9+/-1.3 kg/m(2); percentage fat mass, 41.6+/-1.2; WHR, 0.83+/-0.02; and VO(2max), 20.6+/-0.8 ml/kg/min). MEASUREMENTS: The ADRB2 polymorphism was identified by PCR-RFLP. Respiratory quotient was determined by indirect calorimetry at baseline, during 1 h of walking on a treadmill and 1 h after the exercise. Plasma triglycerides, glycerol, FFA, hydroxybutyrate, glucose and lactate were assayed by spectrophotometric methods. Insulin, leptin and progesterone were measured by radioimmunoassay. Adrenaline and noradrenaline were quantified by high performance liquid chromatography. RESULTS: The ADRB2 Glu27Glu subjects had lower plasma glycerol (P=0.047) and lower hydroxybutyrate (P=0.001) throughout the study than the Gln27Gln group. Plasma triglycerides (P=0.001), lactate (P<0.05) and serum insulin (P<0.05) remained higher in the Glu27Glu group vs the Gln27Gln group. The respiratory quotient (RQ) was higher in the Glu27Glu obese women along the study (P=0.046), and fat oxidation was significantly lower in this group during the recovery (P=0.048). The other variables did not differ statistically between groups. CONCLUSION: These data suggest that both lipolysis and fat oxidation promoted by an acute submaximal exercise intervention could be blunted in the polymorphic ADRB2 Glu27Glu group of our female obese population.     

Weight-related differences in glucose metabolism and free fatty acid production in two South African population groups

OBJECTIVE: The effects of free fatty acids (FFA), leptin, tumour necrosis factor (TNF) alpha and body fat distribution on in vivo oxidation of a glucose load were studied in two South African ethnic groups. DESIGN AND MEASUREMENTS: Anthropometric and various metabolic indices were measured at fasting and during a 7 h oral glucose tolerance test (OGTT). Body composition was measured using bioelectrical impedance analysis and subcutaneous and visceral fat mass was assessed using a five- and two-level CT-scan respectively. Glucose oxidation was evaluated by measuring the ratio of (13)CO(2) to (12)CO(2) in breath following ingestion of 1-(13)C-labelled glucose. SUBJECTS: Ten lean black women (LBW), ten obese black women (OBW), nine lean white women (LWW) and nine obese white women (OWW) were investigated after an overnight fast. RESULTS: Visceral fat levels were significantly higher (P<0.01) in obese white than black women, despite similar body mass indexes (BMIs). There were no ethnic differences in glucose oxidation however; in the lean subjects of both ethnic groups the area under the curve (AUC) was higher than in obese subjects (P<0.05 for both) and was found to correlate negatively with weight (r=-0.69, P<0.01) after correcting for age. Basal TNF alpha concentrations were similar in all groups. Percentage suppression of FFAs at 30 min of the OGTT was 24+/-12% in OWW and -38+/-23% (P<0.05) in OBW, ie the 30 min FFA level was higher than the fasting level in the latter group. AUC for FFAs during the late postprandial period (120--420 min) was significantly higher in OWW than OBW (P<0.01) and LWW (P<0.01) and correlated positively with visceral fat mass independent of age (r=0.78, P<0.05) in the OWW only. Leptin levels were higher (P<0.01) both at fasting and during the course of the OGTT in obese women from both ethnic groups compared to the lean women. CONCLUSIONS: Glucose oxidation is reduced in obese subjects of both ethnic groups; inter- and intra-ethnic differences were observed in visceral fat mass and FFA production and it is possible that such differences may play a role in the differing prevalences of obesity-related disorders that have been reported in these two populations.     

Reduced antioxidant status in obese children with multimetabolic syndrome

BACKGROUND: In our previous study, the negative correlation found between plasma insulin levels and plasma alpha-tocopherol concentrations suggested that decreased antioxidant vitamin levels and reduced antioxidant capacity might be a characteristic feature of obese children with multimetabolic syndrome (MMS). OBJECTIVE: To investigate lipid-soluble antioxidant vitamin levels and total antioxidant status (TAS) in obese children with and without MMS and in controls. SUBJECTS: In total, 16 control children (age: 16.2+/-1.1 y, BMI: 20.7+/-1.9 kg/m(2), body fat (BF): 25.6+/-5.7%; mean+/-s.d.), 15 obese children (age: 13.4+/-2.1 y, BMI: 34.2+/-3.1 kg/m(2), BF: 36.9+/-5.8%,) and 17 obese children without MMS (age: 14.4+/-2.3 y, BMI: 30.4+/-6.2 kg/m(2), BF: 36.3+/-5.8%) were included in the study. METHODS: Body composition was determined by anthropometric methods. Vitamin analysis was carried out by high-performance liquid chromatography and TAS of the plasma was measured with commercially available kits. Plasma glucose, lipids and insulin were measured by standard laboratory methods. RESULTS: Plasma alpha-tocopherol and beta-carotene levels corrected for plasma lipids (cholesterol + triglyceride) were significantly (P<0.05) lower in obese children with MMS (2.4 (3.1) micromol/mmol and 12.3 (24.0) pmol/mmol, respectively, median (range from the first to the third quartile)), than in the obese without MMS (3.7 (0.9) micromol/mmol and 48.2 (27.7) pmol/mmol) and in the control group (3.8 (0.7) micromol/mmol and 86.6 (44.5) pmol/mmol). Plasma TAS values of the MMS group (1.2 (0.4) mmol/l) were also significantly (P<0.05) reduced as compared to obese children without MMS (1.62 (0.14) mmol/l) and to controls (1.58 (0.21) mmol/l). CONCLUSION: Obese children with MMS are prone to oxidative stress. Further investigations are necessary to determine if these children may benefit from vitamin E and beta-carotene supplementation.     

Increased gluconeogenesis in hepatocytes from GTG-obese mice is insensitive to inhibition by insulin.

The effect of a supraphysiological concentration of insulin on gluconeogenesis from L-[U14C] lactate was studied in hepatocytes isolated from control mice and mice made obese by a single injection of gold-thioglucose (GTG). At the time of experimentation (10-12 weeks post GTG injection) the obese mice weighted significantly more than controls (41.7 +/- 0.5 vs. 29.6 +/- 0.8 g respectively; P < 0.001), and exhibited fasting hyperinsulinaemia (35.9 +/- 4.6 vs. 21.3 +/- 4.2 microU/ml; P < 0.05) and hyperglycaemia (16.4 +/- 1.2 vs. 9.2 +/- 1.1 mmol/l; P < 0.001). The amount of lactate converted to glucose by hepatocytes isolated from GTG-obese mice was significantly greater than from lean controls (322 +/- 44 vs. 209 +/- 20 nmol/30 min/10(6) cells; P < 0.05). The addition of 10(-6)M insulin to the incubations significantly reduced lactate conversion to glucose by hepatocytes isolated from control mice (209 +/- 20 vs. 123 +/- 22 nmol/30 min/10(6) cells; P < 0.02), but there was no effect of insulin on glucose production from lactate by hepatocytes isolated from GTG-obese mice (322 +/- 44 vs. 294 +/- 47 nmol/30 min/10(6) cells). Glycogen production and triacylglycerol glycerol production from L-[U14C] lactate were also significantly increased in hepatocytes from GTG-obese mice compared with controls. There was no effect of 10(-6)M insulin on glycogen or triacylglycerol glycerol production from lactate by hepatocytes from GTG-obese mice but the addition of 10(-6)M insulin to the incubations of control hepatocytes significantly reduced the amount of lactate converted to glycogen and triacylglycerol glycerol.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of race and body habitus on bone mineral density of the radius, hip, and spine in premenopausal women

The incidence of osteoporosis and fractures of the hip are diminished in blacks and in obese subjects. To determine whether bone mass is increased in them, bone mineral density (BMD) of the lumbar spine, trochanter, and femoral neck was measured by dual photon absorptiometry in 89 nonobese white and 51 nonobese black women, all of whom were within 30% of their ideal body weight and between the ages of 20 and 50 yr, and in 21 obese white women and 21 obese black women, all of whom weighed 30% on more than their ideal body weight and were in the same age range. The BMD of the mid radius was also measured by single photon absorptiometry. The mean BMD of the mid radius was higher in black than in white nonobese women [0.73 +/- 0.01 (+/- SE) vs. 0.70 +/- 0.01 g/cm2; P less than 0.01] and was not altered by obesity in either group. The mean BMD was higher in the black than in the white nonobese women at the lumbar spine (1.23 +/- 0.02 vs. 1.16 +/- 0.01 g/cm2; P less than 0.01), trochanter (0.78 +/- 0.02 vs. 0.72 +/- 0.01 g/cm2; P less than 0.01) and femoral neck (0.96 +/- 0.02 vs 0.90 +/- 0.02 g/cm2; P less than 0.02). The mean body weight was higher in the obese than in the nonobese white women (92 +/- 2 vs. 61 +/- 1 kg; P less than 0.001) and black women (94 +/- 3 vs. 63 +/- 1 kg; P less than 0.001). The mean BMD was higher in the obese than in the nonobese white women at the lumbar spine (1.24 +/- 0.03 g/cm2; P less than 0.05), trochanter (0.89 +/- 0.04; P less than 0.001), and femoral neck (0.99 +/- 0.03; P less than 0.01) and was higher in the obese than in the nonobese black women at the lumbar spine (1.33 +/- 0.03 g/cm2; P less tham 0.01), trochanter (0.88 +/- 0.04 g/cm2; P less than 0.05), and femoral neck (1.04 +/- 0.03 g/cm2; P less than 0.05). Multivariate regression analysis revealed positive correlations between body weight and BMD at each of the 3 weight-bearing sites, but not at the mid radius, in both the black women and white women.(ABSTRACT TRUNCATED AT 400 WORDS)     

Adipose tissue, hepatic, and skeletal muscle insulin sensitivity in extremely obese subjects with acanthosis nigricans

We evaluated insulin action in skeletal muscle (glucose disposal), liver (glucose production), and adipose tissue (lipolysis) in 5 extremely obese women with acanthosis nigricans (AN), who had normal oral glucose tolerance, and 5 healthy lean subjects, by using a 5-stage pancreatic clamp and stable isotopically labeled tracer infusion. Basal plasma insulin concentration was much greater in obese subjects with AN than lean subjects (54.8 +/- 4.5 vs 8.0 +/- 1.3 microU/mL, P < .001), but basal glucose and free fatty acid concentrations were similar in both groups. During stage 1 of the clamp, glucose rate of appearance (R(a)) (2.6 +/- 0.3 vs 3.7 +/- 0.3 micromol x kg FFM(-1) x min(-1), P = .02) and palmitate R(a) (2.4 +/- 0.6 vs 7.0 +/- 1.5 micromol x kg FFM(-1) x min(-1), P < .05) were greater in obese subjects with AN than lean subjects despite slightly greater plasma insulin concentration in subjects with AN (3.0 +/- 0.7 vs 1.1 +/- 0.4 microU/mL, P < .05). The area under the curve for palmitate R(a) (1867 +/- 501 vs 663 +/- 75 micromol x kg FFM(-1) x 600 min(-1), P = .03) and glucose R(a) (1920 +/- 374 vs 1032 +/- 88 micromol x kg FFM(-1) x 600 min(-1), P = .02) during the entire clamp procedure was greater in subjects with AN than lean subjects. During intermediate insulin conditions (plasma insulin, approximately 35 microU/mL), palmitate R(a) was 5-fold greater in subjects with AN than in lean subjects (2.6 +/- 1.1 vs 0.5 +/- 0.2 micromol x kg FFM(-1) x min(-1), P = .05). Maximal glucose disposal was markedly lower in obese subjects with AN than in lean subjects (13.0 +/- 0.8 vs 23.4 +/- 1.8 mg x kg FFM(-1) x min(-1), P = .01) despite greater peak plasma insulin concentration (1842 +/- 254 vs 598 +/- 38 microU/mL, P < .05). These data demonstrate obese young adults with AN have marked insulin resistance in multiple tissues. However, marked insulin hypersecretion can compensate for impaired insulin action, resulting in normal glucose and fatty acid metabolism during basal conditions.     

Differential effect of weight loss on insulin resistance in surgically treated obese patients

PURPOSE: To compare the effects of equivalent weight loss induced by two bariatric surgical techniques on insulin action in severely obese patients. METHODS: Eighteen nondiabetic patients with severe obesity (mean [+/- SD] body mass index: 53.5 +/- 9.0 kg/m(2)) and 20 sex- and age-matched lean subjects (body mass index: 23.8 +/- 3.0 kg/m(2)) underwent metabolic studies, including measurement of insulin sensitivity by the insulin clamp technique. Patients then underwent either vertical banded gastroplasty with Roux-en-Y gastric bypass, or biliopancreatic diversion, and were restudied at 5 to 6 months and again at 16 to 24 months postsurgery. RESULTS: At baseline, patients were hyperinsulinemic (194 +/- 47 pmol/L vs. 55 +/- 25 pmol/L, P < 0.0001), hypertriglyceridemic (1.56 +/- 0.30 mmol/L vs. 0.78 +/- 0.32 mmol/L, P < 0.0001), and profoundly insulin resistant (insulin-mediated glucose disposal: 20.8 +/- 4.4 micromol/min/kg fat-free mass vs. 52.0 +/- 10.1 micromol/min/kg, P < 0.0001) as compared with controls. Weight loss by the two procedures was equivalent in both amount (averaging -53 kg) and time course. In the gastric bypass group, insulin sensitivity improved (23.8 +/- 6.0 micromol/min/kg at 5 months and 33.7 +/- 11.3 micromol/min/kg at 16 months, P < 0.01 vs. baseline and controls). In contrast, in the biliopancreatic diversion group, insulin sensitivity was normalized already at 6 months (52.5 +/- 12.4 micromol/min/kg, P = 0.72 vs. controls) and increased further at 24 months (68.7 +/- 9.5 micromol/min/kg, P < 0.01 vs. controls) despite a persistent obese phenotype (body mass index: 33.2 +/- 8.0 kg/m(2)). CONCLUSION: In surgically treated obese patients, insulin sensitivity improves in proportion to weight loss with use of predominantly restrictive procedures (gastric bypass), but is reversed completely by predominantly malabsorptive approaches (biliopancreatic diversion) long before normalization of body weight. Selective nutrient absorption and gut hormones may interact with one another in the genesis of the metabolic abnormalities of obesity.     

Effect of glycemic index on whole-body substrate oxidation in obese women

BACKGROUND: Glycemic index is hypothesized to determine fuel partitioning through serum plasma insulin modifications induced by dietary carbohydrates, thereby modulating fat accretion or oxidation. OBJECTIVE: To assess the glycemic effects on postprandial fuel oxidation and blood response. DESIGN: In all, 12 obese women were fed on a randomized crossover design with two test meals (breakfast+lunch). High- or low-glycemic meals were provided on separate days. Energy intake on high-glycemic meal was 7758+/-148 kJ and for low-glycemic meal was 7806+/-179 kJ. Carbohydrates supplied were 273+/-5 and 275+/-6 g, respectively. Macronutrient distribution was 55% carbohydrates, 30% fat and 15% protein. Fuel oxidation was measured continuously in a respiratory chamber for 10 h. Serum glucose, free fatty acids (FFA), insulin and glucagon samples were taken for 5 h after breakfast. RESULTS: Glucose AUC changed significantly in response to different glycemic breakfast. Low- vs high-glycemic breakfast was 211+/-84 and 379+/-164 mmol/l (P<0.05). Similarly, insulin changed from 94+/-37 and 170+/-87 nmol/l (P<0.05), respectively. The rate of increment for serum glucose and insulin reached by the high- vs low-glycemic meal was 1.8 times more with the high-glycemic breakfast. Serum FFA were similarly suppressed by both meal types by 3 h after meal intake, but then raised significantly more with the low-glycemic meal by the fourth and fifth hour (P<0.05). Plasma glucagon did not show a significant variation with glycemic index. Carbohydrate and fat oxidation was not modified by glycemic meal characteristics, being virtually the same for low- vs high-glycemic comparisons in the 5 h following breakfast and lunch (P=NS). CONCLUSION: This study demonstrates that dietary glycemic characteristics were unable to modify fuel partitioning in sedentary obese women.     

Plasma asymmetric dimethylarginine concentrations are elevated in obese insulin-resistant women and fall with weight loss

CONTEXT: Plasma asymmetric dimethylarginine (ADMA) concentrations are higher in apparently healthy, insulin-resistant (IR) individuals and decrease in response to thiazolidenedione treatment. OBJECTIVE: The objective of the study was to determine whether ADMA concentrations would also fall when insulin sensitivity is enhanced with weight loss in obese individuals. DESIGN/SETTING/PATIENTS/INTERVENTION: Twenty obese women classified as IR or insulin sensitive (IS) on the basis of their steady-state plasma glucose (SSPG) concentration during the insulin suppression test underwent 12 wk of dietary weight loss. OUTCOME MEASURES: Plasma glucose, insulin, and ADMA were measured at baseline and after weight loss; change in insulin resistance was quantified by repeating the SSPG after the dietary intervention. RESULTS: Although weight loss was similar in the two groups, significant improvements in SSPG, glucose, and insulin concentrations were confined to the IR group. Baseline plasma ADMA concentrations (mean +/- sd) were higher in IR subjects (1.69 +/- 0.44 vs. 1.18 +/- 0.45 micromol/liter, P = 0.02) and decreased to 1.20 +/- 0.22 micromol/liter (P < 0.001) with weight loss. In contrast, ADMA levels did not change with a similar extent of weight loss in the IS group. CONCLUSION: Plasma ADMA levels are higher in obese, IR women than in equally obese, IS women and decrease in response to weight loss when associated with enhancement of insulin sensitivity.     

Racial disparities in metabolism, central obesity, and sex hormone-binding globulin in postmenopausal women

Increased total and intraabdominal fat (IAF) obesity as well as other metabolic conditions associated with the insulin resistance syndrome (IRS) are related to low levels of sex hormone-binding globulin (SHBG) in young and older Caucasian (CAU) and young African-American (AA) women. We examined whether postmenopausal AA women, a population with a high incidence of obesity and IRS despite low IAF, would have higher levels of circulating SHBG compared with CAU women, and whether there would be negative relationships between indexes of obesity and risk factors associated with IRS and SHBG levels. We measured body composition, SHBG, free testosterone, leptin, glucose tolerance, insulin, and lipoprotein lipids in 55 CAU (mean +/- SD, 59 +/- 7 yr) and 35 AA (57 +/- 6 yr) sedentary women of comparable obesity (48% body fat, by dual energy x-ray absorptiometry). Compared with CAU women, AA women had larger waist (101 vs. 96 cm), larger fat mass (44.9 +/- 8.8 vs. 39.9 +/- 8.1 kg), larger sc fat area (552 +/- 109 vs. 452 +/- 109 cm(2)), and lower IAF/SC ratio (0.28 +/- 0.12 vs. 0.38 +/- 0.15; P < 0.01), but similar waist to hip ratio (0.83). Both groups had similar SHBG (117 vs. 124 nmol/L) and free testosterone (3.7 vs. 3.4 pmol/L) levels, but AA women had a 35% higher leptin, 34% higher fasting insulin, and 39% greater insulin response to a glucose load (P < 0.05) compared with CAU women. In CAU, but not AA, women SHBG correlated negatively with body mass index (r = -0.28; P < 0.05), waist (r = -0.36; P = 0.01), IAF (r = -0.34; P = 0.01), and insulin response to oral glucose (r = -0.37; P < 0.05) and positively with high density lipoprotein cholesterol (r = 0.30; P = 0.03). The relationship between insulin area and SHBG in CAU women disappeared after adjusting for IAF, whereas the relationship between high density lipoprotein cholesterol and SHBG persisted after adjusting for IAF, but not for fat mass. Leptin was positively related to fat mass (P < 0.05) in both groups, but it was related to insulin only in the Caucasian women (P< 0.01). There was a racial difference in the slopes (P< 0.05) of the relationships of leptin to fat mass (P < 0.05). Racial differences in leptin disappeared after adjustment for fasting insulin. These results suggest that the metabolic relationships between total and regional obesity, glucose, and lipid metabolism with SHBG in CAU women are different from those in postmenopausal obese AA women.