Fuel metabolism in adult individuals with a wide range of body mass index: effect of a family history of type 2 diabetes.

OBJECTIVE: To evaluate whether a family history of Type 2 diabetes mellitus (T2DM) is associated with changes of fuel metabolism in normal glucose tolerant men and women with a wide range of BMI. DESIGN: Cross-sectional study of resting energy expenditure (REE) and substrate oxidation in adult individuals. SUBJECTS: Ninety-seven normal weight, overweight, and obese men and women, aged 18-45 years: 44 (38 pre-menopausal women and 6 men) with a first-degree family history of T2DM (FH+) and 53 (45 pre-menopausal women and 8 men) with no family history of T2DM (FH-). MEASUREMENTS: REE, fat-free mass (FFM)-adjusted REE (REE/Kg FFM), respiratory quotient (RQ), substrate oxidation (carbohydrates, lipids, and proteins), energy intake, anthropometric parameters, body composition (evaluated by BIA), blood pressure, insulin sensitivity (as calculated by Homeostatic Model Assessment) and metabolic variables (fasting levels of insulin, glucose, and lipids). RESULTS: REE, REE/Kg FFM, and lipid oxidation were lower, whereas carbohydrate oxidation and RQ were higher in FH+ than in FH- individuals. CONCLUSIONS: This study suggests that a family history of T2DM decreases REE, REE/Kg FFM and lipid oxidation, thus possibly contributing to the development of obesity and to the adverse metabolic profile of subjects with a genetic background for T2DM.

C-reactive protein is independently associated with total body fat, central fat, and insulin resistance in adult women.

OBJECTIVE: To investigate whether C-reactive protein (CRP) concentrations are influenced by body composition, insulin resistance, and body fat distribution in healthy women. DESIGN: Cross-sectional study of CRP plasma levels in adult women. SUBJECTS: A total of 201 apparently healthy normal weight, overweight, and obese women, aged 18-60 y. MEASUREMENTS: CRP plasma levels, several fatness and body fat distribution parameters (by bioimpedance analysis and anthropometry), and insulin resistance (HOMA(IR)), as calculated by homeostatic model assessment. RESULTS: CRP was positively correlated with age, body mass index (BMI), waist, fasting glucose and insulin, HOMA(IR), fat-free mass (FFM) and fat mass (FM). After multivariate analyses, age, HOMA(IR), waist and FM maintained their independent association with CRP. CONCLUSION: Our study has shown an independent relationship of central fat accumulation and insulin resistance with CRP plasma levels, thus suggesting that mild, chronic inflammation may be a further component of the metabolic syndrome and a mediator of the atherogenic profile of this syndrome.

Plasma leptin is independently associated with the intima-media thickness of the common carotid artery.

OBJECTIVE: To investigate whether intima-media thickness (IMT) of the common carotid artery (CCA), an early marker of asymptomatic atherosclerosis, is significantly and independently associated with plasma concentrations of leptin, an adipose tissue hormone that has recently been proposed as a cardiovascular risk factor in obese patients. DESIGN: Cross-sectional sample of normal-weight and obese men and women. SUBJECTS: One-hundred and twenty healthy subjects (52 men and 68 women), aged 18-45 y and with a wide range of BMI, were recruited for the study. MEASUREMENTS: Fasting plasma leptin concentrations and the IMT of the CCA were measured in all subjects. Leptin concentrations were measured by radioimmunoassay and the IMT of the CCA was quantified by high resolution B-mode ultrasound imaging. Central fat (measured by waist circumference), smoking habits, blood pressure, insulin sensitivity (measured by the insulin tolerance test), and fasting plasma glucose, insulin and lipid pattern (cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol) were also measured. RESULTS: IMT of the CCA was positively correlated with log leptin concentrations (P<0.005 in men and P<0.001 in women), body mass index (P<0.001 in men and women), waist circumference (P<0.001 in men and women), age (P<0.001 in men and P<0.05 in women), and negatively associated with insulin sensitivity in both sexes (P<0.05). IMT was also directly correlated with cholesterol (P<0.05), LDL-cholesterol (P<0.01) and systolic blood pressure in men (P<0.05), and with diastolic blood pressure levels in women (P<0.05). When a multiple linear regression model was used without body mass index (BMI), the correlation between leptin and IMT was maintained in both men (P<0.01) and women (P<0.005), independent of age, insulin sensitivity, smoking habits, systolic blood pressure, fasting glucose, triglycerides, cholesterol, LDL-cholesterol and HDL-cholesterol. By contrast, BMI-adjusted leptin concentrations were not significantly associated with IMT (Pc (partial correlation): 0.41 in men and 0.15 in women). Moreover, when BMI was entered into a multiple linear regression model without leptin, the correlation between BMI and IMT was maintained in both men (P<0.005) and women (P<0.01), independent of the same parameters. CONCLUSION: Plasma leptin concentrations are independently associated with the IMT of the CCA, suggesting that the increase of adipose tissue mass (or leptin per se) may have an unfavourable influence on the development of atherosclerosis. However, the association between IMT and leptin seems to be dependent and/or confounded by the relationship between IMT and obesity.

Sleep-related breathing disorders, loud snoring and excessive daytime sleepiness in obese subjects.

OBJECTIVE: To investigate the prevalence of sleep breathing disorders, loud snoring and excessive daytime sleepiness in a group of obese subjects, and to identify the predictors of obstructive sleep apnea (OSA) severity in these patients. SUBJECTS: A total of 161 consecutive obese patients (body mass index (BMI)> or =30.0 kg/m(2)), ranging between 30.0 and 67.3, represented by 57 men and 104 women, aged 16-75 y. Forty (15 men and 25 women) age-matched (20-70 y) nonobese (BMI<27 kg/m(2)) volunteers were also recruited for the study. MEASUREMENTS: Respiratory function parameters, nocturnal sleep quality (evaluated by a specific questionnaire), nocturnal hypoventilation and OSA (evaluated by night polysomnography) were examined in all subjects. Anthropometric parameters (neck circumference, waist circumference, waist-to-hip ratio) were also investigated. RESULTS: Eighty-three obese patients (51.5% of the obese group) had a respiratory disturbance index (RDI)> or =10, corresponding to a moderate or severe sleep apnea. In particular, 24.8% (40/161), ie a quarter of all obese patients, were affected by severe OSA and this alteration was present in 42.1% of obese men (24/57) and in 15.4% (16/104) of obese women. When a stepwise multiple regression analysis was performed, neck circumference in men and BMI in women were shown to be the strongest predictors of sleep apnea. Twenty-nine percent of all obese subjects (40.3% of men and 23.1% of women) showed nocturnal hypoventilation; however, it was present as a unique breathing alteration in only 5% of the obese population. The percentage of patients having excessive daytime sleepiness was significantly higher than in nonobese subjects, even when only nonapneic obese patients were considered (P<0.001). CONCLUSION: This study shows that OSA is present in more than 50% of a population of obese patients with a mean BMI higher than 40.0, this percentage being much higher than that commonly reported in previous studies, particularly in women. Neck circumference in men and BMI in women seem to be the strongest predictors of the severity of OSA in obese patients. Nocturnal hypoventilation seems to be present in more than 29% of a severe obese population. Moreover, this study indicates that morbid obesity can be associated with excessive daytime sleepiness even in the absence of sleep apnea.

Urinary albumin excretion is independently associated with C-reactive protein levels in overweight and obese nondiabetic premenopausal women.

OBJECTIVES: C-reactive protein (CRP) and microalbuminuria are nowadays considered markers of chronic inflammation of the arterial wall and of endothelial dysfunction, respectively. An increase of CRP levels and of urinary albumin excretion (UAE) rate have both been reported to be independently associated with a higher risk of cardiovascular morbidity and mortality in the general population. The aim of the present study was to evaluate the possible correlation between UAE and CRP concentrations in overweight and obese premenopausal women. DESIGN AND SETTING: A cross-sectional study in a primary care setting. SUBJECTS, MAIN OUTCOME MEASURES: CRP levels and UAE rate were measured in 103 overweight and obese premenopausal women, aged 18-45 years. Other measurements included: central fat accumulation, as evaluated by waist circumference, insulin resistance, as calculated by homeostatic model assessment (HOMAIR); fat-free mass (FFM), as measured by bioimpedance analysis; blood pressure; and fasting plasma levels of glucose, insulin, and lipids. RESULTS: Urinary albumin excretion was positively correlated with body mass index (BMI) (P < 0.01), waist circumference (P < 0.001), diastolic blood pressure (P < 0.01), triglycerides (P < 0.01), HOMAIR (P < 0.05), and CRP levels (P < 0.05); and negatively associated with HDL cholesterol (P < 0.001). After multivariate analysis, diastolic blood pressure, HDL cholesterol, and CRP levels maintained their significant correlation with UAE. CONCLUSION: Our study shows a strong relationship between UAE and CRP concentrations, irrespective of age and other anthropometric and metabolic variables. On this basis, it can be argued that inflammation of the arterial wall, as indicated by higher CRP plasma levels, and endothelial dysfunction, as shown by higher UAE rate, might represent simultaneous phenomena in the development of atherosclerosis in overweight and obese premenopausal women.

Homocysteine plasma levels are independently associated with insulin resistance in normal weight, overweight and obese pre-menopausal women.

OBJECTIVES: The aim of the present study was to examine the relationship of homocysteine (Hcy) plasma levels to insulin resistance (IR). DESIGN: A cross-sectional study in a primary care setting. SUBJECTS AND METHODS: Fasting Hcy levels were measured in the plasma of 44 pre-menopausal women [17 normal weight (body mass index BMI 20.0-24.9 kg/m2), 7 overweight (BMI 25.0-29.9 kg/m2), 20 obese (BMI> or =30.0 kg/m2)], aged 18-45 yr. Other measurements included: central fat accumulation, as evaluated by waist circumference; IR, as calculated by homeostatic model assessment (HOMAIR); systolic and diastolic blood pressure; and fasting concentrations of glucose, insulin and lipids (total cholesterol, HDL-cholesterol, triglycerides). RESULTS: Hcy was positively correlated with insulin concentrations (p<0.01), HOMAIR (p<0.01), and systolic and diastolic blood pressure (p<0.01 and p<0.05, respectively). After multivariate analysis, only HOMAIR maintained an independent association with Hcy (p<0.05), irrespective of age and other anthropometric and biochemical variables. Lastly, we observed a gradual increase in Hcy plasma levels across the age- and BMI-matched quartiles in which the whole population was divided according to HOMAIR levels (F: 2.73, p<0.05 for linear trend). CONCLUSIONS: Our study shows that Hcy plasma levels are independently associated with IR in apparently healthy normal weight, overweight and obese pre-menopausal women, thus suggesting a possible role of IR and/or hyperinsulinaemia in increasing Hcy plasma levels. Since Hcy is a well-known cardiovascular risk factor, higher Hcy plasma levels may well be a further mechanism explaining the higher risk of coronary heart disease in patients affected by IR.

Lower insulin sensitivity as an independent risk factor for carotid wall thickening in normotensive, non-diabetic, non-smoking normal weight and obese premenopausal women.

OBJECTIVE: Increased thickness of the intima-media complex of the common carotid artery (IMT-CCA) is an early marker of atherosclerosis. The aim of the present study was to investigate the relationship between insulin resistance and IMT-CCA in premenopausal women. SUBJECTS: 86 young women, aged 18-31 y, were recruited for the study: 28 were normal weight (BMI<25 kg/m2), 23 were overweight (BMI 25-30 kg/m2) and 35 were obese (BMI>30 kg/m2). MEASUREMENTS: The IMT-CCA was measured by high resolution 'B-mode' ultrasonography; insulin sensitivity was determined by insulin tolerance test (ITT) and quantitated by calculation of KITT. Fasting plasma glucose and lipids (triglycerides, total and HDL-cholesterol) were also measured by enzymatic methods. Central fat accumulation was evaluated by measuring waist circumference (WC). RESULTS: IMT-CCA showed an inverse association with KITT (P<0.05). When the IMT-CCA was considered as the dependent variable in a forward stepwise multiple regression analysis, it maintained an independent association with KITT (P<0.05), after adjusting data for age, BMI, WC, mean blood pressure levels and plasma glucose and lipids. CONCLUSION: These results suggest that IMT-CCA is significantly associated with insulin resistance, independent of other well-known CVD risk factors. Since the IMT-CCA is an earlier asymptomatic sign of atherosclerosis, this study indicates that insulin resistance per se may accelerate atherogenesis.

Prevalence and mechanisms of diurnal hypercapnia in a sample of morbidly obese subjects with obstructive sleep apnoea.

It is well known that obstructive sleep apnoea is especially frequent in the morbidly obese. In these subjects diurnal chronic hypercapnia, whose mechanism is still debated, may be present. Our study was performed to evaluate the prevalence and the mechanism of diurnal hypercapnia in the morbidly obese affected by obstructive sleep apnoea. From a population referred to our centre because of suspicion of sleep related breathing disorders, we selected 285 subjects without cardiopulmonary, neuromuscular or endocrinological diseases: 89 (36 M and 53 F, aged 46+/-13 years) had body mass index (BMI) > or = 40 kg m(-2) (MO group: morbidly obese subjects) and 196 (99 M and 97 F, aged 48+/-16 years) had BMI <40 kg m(-2) (NMO group: non-morbidly obese subjects). Then the MO group was divided into three subgroups: normocapnic subjects without obstructive sleep apnoea, normocapnic subjects with obstructive sleep apnoea, hypercapnic subjects with obstructive sleep apnoea; while we found no hypercapnic subject without obstructive sleep apnoea. All subjects underwent anthropometric evaluations and bioelectrical impedance analyses, respiratory function tests and arterial blood gas analysis, a modified version of the Sleep and Healthy questionnaire and a full night polysomnography. Our results showed that hypercapnia (PaCO2 > or = 45 mm Hg) associated with obstructive sleep apnoea [respiratory disturbance index (RDI) > or = 10 h(-1)] was found in 27% of the morbidly obese subjects, but only in 11% of the nonmorbidly obese ones (P<0.01). The comparison among the three subgroups, in which we divided the morbidly obese subjects, shows that those with hypercapnia and obstructive sleep apnoea had significantly more important ventilatory restrictive defects [forced vital capacity (FVC)% of pred 73.27+/-14 81 vs. 82.37+/-16.93 vs. 87.25+/-18.14 respectively; total lung capacity (TLC)% of pred 63.83+/-16.35 vs. 79.11+/-14.15 vs. 87.01+/-10.5], a significantly higher respiratory disturbance index (RDI 46.34+/-26.90 vs. 31.79+/-22.47 vs. 4.98+/-3.29) a longer total sleep time with oxyhaemoglobin saturation<90% [total sleeptime (TST)SaO2<90% 63.40+/-33.86 vs. 25.95+/-29.34 vs. 8.22+/-22.12] and a lower rapid eye movement (REM) stage (9.5+/-1.2 vs. 14.0+/-0.9 vs. 17.05+/-1.2) than normocapnic subjects with obstructive sleep apnoea or subjects without obstructive sleep apnoea. The best model to predict PaCO2 resulted from a combination of TSTSaO2<90% (r2 = 0.22, P<0.001), forced expiratory volume in 1 sec (FEV1)% of pred (r2 = 0.09, P<0.01), FVC % of pred (r2 = 0.075, P<0.01). In conclusion our study suggests that diurnal hypercapnia is frequently associated with obstructive sleep apnoea in the morbidly obese without chronic obstructive pulmonary disorder (COPD) and that ventilatory restriction and sleep related respiratory disturbances correlate to diurnal hypercapnia.

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

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

Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men.

The purpose of this study was to examine the relationships between androgenic status and plasma levels of both prothrombotic and antithrombotic factors in men, irrespective of obesity, body fat distribution, and metabolic parameters. Sixty-four apparently healthy men, 40 with a body mass index (BMI) greater than 25 kg/m2 (overweight and obese [OO]) and 24 non-obese controls with a BMI less than 25, were selected and evaluated for (1) plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) antigen, PAI-1 activity, fibrinogen, von Willebrand factor (vWF) antigen, vWF activity, and factor VII (FVII) as the prothrombotic factors; (2) plasma levels of tissue plasminogen activator (TPA) antigen, protein C, and antithrombin III as the antithrombotic factors; (3) fasting plasma concentrations of insulin and glucose and the lipid pattern (triglycerides [TG] and total and high-density lipoprotein [HDL] cholesterol) as the metabolic parameters; and (4) free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) serum levels as the parameters of androgenicity. Body fat distribution was evaluated by the waist to hip ratio (WHR). In OO and non-obese subjects taken together, plasma levels of PAI-1 antigen, fibrinogen, and FVII were inversely associated with FT (r = .255, P < .05, r = -3.14, P < .05, and r = -.278, P < .05, respectively), and the negative relationships of both fibrinogen and FVII with FT were maintained after stepwise multiple regression analysis. Plasma concentrations of PAI-1 antigen and PAI-1 activity were also negatively correlated with SHBG (r = -.315, P < .05 and r = -.362, P < .01, respectively), and these associations held irrespective of the other parameters investigated. None of the antithrombotic and fibrinolytic factors were independently related to serum androgen levels. Subjects with a BMI higher than 25 kg/m2 had higher plasma concentrations of PAI-1 antigen, PAI-1 activity, and fibrinogen as compared with non-obese controls (P < .001, P < .001, and P < .01, respectively). In addition, in OO and control subjects as a whole, multiple stepwise regression analysis showed that the associations of BMI with PAI-1 activity, fibrinogen, vWF antigen, and vWF activity were independent of any other metabolic and hormonal parameters. Plasma concentrations of PAI-1 antigen, PAI-1 activity, and fibrinogen were also directly correlated with WHR in all subjects taken together, irrespective of the other parameters investigated. Evaluation of antithrombotic factors showed that OO subjects had higher TPA plasma concentrations than non-obese controls (P < .001), whereas protein C and antithrombin III did not differ in the two groups. TPA was also directly correlated with BMI (r = .415, P < .001) and WHR (r = .393, P < .001) in all subjects. The results of this study indicate that (1) men with lower FT serum levels have higher fibrinogen and FVII plasma concentrations, and those with lower SHBG serum levels also have higher levels of PAI-1 antigen and activity; (2) irrespective of other factors, obesity per se may account for higher concentrations of PAI-1, fibrinogen, and vWF; (3) plasma levels of PAI-1 (antigen and activity) and fibrinogen correlate independently with WHR; and (4) among the investigated antithrombotic factors (TPA antigen, protein C, antithrombin III), only TPA antigen plasma concentrations are higher in men with abdominal obesity. Thus, because of the increase in several prothrombotic factors, men with central obesity, particularly those with lower androgenicity, seem to be at greater risk for coronary heart disease (CHD). Apparently, this risk is not counteracted by a parallel increase in plasma concentrations of antithrombotic factors.

Increase in both pro-thrombotic and anti-thrombotic factors in obese premenopausal women: relationship with body fat distribution.

OBJECTIVES: To examine the relationship of obesity, body fat distribution, and fasting plasma insulin concentrations with the plasma levels of both pro-thrombotic and anti-thrombotic factors in premenopausal women. SUBJECTS: 32 obese women with BMI > 28 and 33 age-matched non-obese = women with BMI < 25. MEASUREMENTS: (i) plasma concentrations of plasminogen activator inhibitor-1 antigen (PAI-1 Ag), plasminogen activator inhibitor-1 activity (PAI-1 activity), fibrinogen, von Willebrand factor antigen (vWF Ag), von Willebrand factor activity (vWF activity), and factor VII activity as pro-thrombotic factors; (ii) plasma concentrations of tissue plasminogen activator antigen (t-PA Ag), protein C, and antithrombin III as anti-thrombotic factors; (iii) fasting plasma insulin and glucose concentrations, and the lipid pattern (triglycerides, total and HDL-cholesterol) as metabolic parameters. The body fat distribution was evaluated by measuring the waist circumference and the waist-to-hip ratio (WHR). RESULTS: Obese subjects had higher plasma concentrations of all pro-thrombotic factors as compared to non-obese controls (PAI-1 Ag, P < 0.001; PAI-1 activity, P < 0.05; fibrinogen, P < 0.001; vWF Ag, P < 0.001; vWF activity, P < 0.05; factor VII, P < 0.05). The plasma concentrations of PAI-1 Ag and vWF Ag were directly correlated with the waist circumference independently of other metabolic and non-metabolic variables (P < 0.05). Obese women were also characterized by higher plasma concentrations of anti-thrombotic factors such as t-PA Ag and protein C as compared to non-obese controls (P < 0.001 and P < 0.001, respectively), although these factors were not independently correlated with the waist circumference or the WHR. CONCLUSION: Plasma concentrations of the pro-thrombotic factors are increased in obese women as compared to non-obese controls, and plasma levels of PAI-1 Ag and vWF Ag correlate with central fat accumulation specifically. Plasma concentrations of anti-thrombotic factors (namely protein C and t-PA Ag) are also raised in obese women, but they are not correlated with parameters of body fat distribution. The increase in protein C levels may represent a protective response partly counteracting the increase in pro-thrombotic factors in these individuals.