Efficacy and safety of denosumab vs. bisphosphonates in postmenopausal women previously treated with oral bisphosphonates.

Transitioning postmenopausal women with osteoporosis from a bisphosphonate to denosumab appears to be safe and more effective at improving BMD than continuing treatment with a bisphosphonate. INTRODUCTION: We conducted a patient-level pooled analysis of four studies to estimate the efficacy and safety of transitioning to denosumab vs. continuing bisphosphonate treatment in postmenopausal women who previously received oral bisphosphonates. METHODS: Patients received 60 mg denosumab once every 6 months or a bisphosphonate (oral alendronate, risedronate, ibandronate, or intravenous zoledronic acid). Endpoints were change from baseline in lumbar spine, total hip, femoral neck, and 1/3 radius BMD at month 12, change from baseline in serum CTX-1 and P1NP, and incidence of adverse events. RESULTS: A total of 2850 randomized patients (1424 bisphosphonate:1426 denosumab) were included in the analysis. Percentage change in BMD was significantly greater (p < 0.001) for denosumab vs. bisphosphonate at each skeletal site; differences in BMD changes ranged from 0.6 to 2.0%. Percentage decrease in serum CTX-1 and P1NP was significantly greater (p < 0.0001) for denosumab vs. bisphosphonate at months 1, 6, and 12; in the denosumab group only, percentage change in serum CTX-1 at month 1 was significantly correlated with percentage change in lumbar spine and total hip BMD at month 12. The incidences of adverse events were similar between treatment groups. Three patients (one bisphosphonate and two denosumab) had atypical femoral fractures, all from the denosumab vs. zoledronic acid study. CONCLUSION: Postmenopausal women can safely transition from a bisphosphonate to denosumab, which is more effective at improving BMD than continuing with a bisphosphonate. CLINICAL TRIALS REGISTRATION: NCT00377819, NCT00919711, NCT00936897, NCT01732770.

Denosumab or Zoledronic Acid in Postmenopausal Women With Osteoporosis Previously Treated With Oral Bisphosphonates.

CONTEXT: Denosumab and zoledronic acid (ZOL) are parenteral treatments for patients with osteoporosis. OBJECTIVE: The objective of the study was to compare the effect of transitioning from oral bisphosphonates to denosumab or ZOL on bone mineral density (BMD) and bone turnover. DESIGN AND SETTING: This was an international, multicenter, randomized, double-blind trial. PARTICIPANTS: A total of 643 postmenopausal women with osteoporosis previously treated with oral bisphosphonates participated in the study. INTERVENTIONS: Subjects were randomized 1:1 to sc denosumab 60 mg every 6 months plus iv placebo once or ZOL 5 mg iv once plus sc placebo every 6 months for 12 months. MAIN OUTCOME MEASURES: Changes in BMD and bone turnover markers were measured. RESULTS: BMD change from baseline at month 12 was significantly greater with denosumab compared with ZOL at the lumbar spine (primary end point; 3.2% vs 1.1%; P < .0001), total hip (1.9% vs 0.6%; P < .0001), femoral neck (1.2% vs -0.1%; P < .0001), and one-third radius (0.6% vs 0.0%; P < .05). The median decrease from baseline was greater with denosumab than ZOL for serum C-telopeptide of type 1 collagen at all time points after day 10 and for serum procollagen type 1 N-terminal propeptide at month 1 and at all time points after month 3 (all P < .05). Median percentage changes from baseline in serum intact PTH were significantly greater at months 3 and 9 with denosumab compared with ZOL (all P < .05). Adverse events were similar between groups. Three events consistent with the definition of atypical femoral fracture were observed (two denosumab and one ZOL). CONCLUSIONS: In postmenopausal women with osteoporosis previously treated with oral bisphosphonates, denosumab was associated with greater BMD increases at all measured skeletal sites and greater inhibition of bone remodeling compared with ZOL.

sP-selectin plasma levels in obesity: association with insulin resistance and related metabolic and prothrombotic factors.

BACKGROUND AND AIM: Soluble P-selectin (sP-sel) represents a marker of platelet activation. This study was addressed to investigate the associations of sP-sel plasma levels with anthropometric parameters, insulin resistance, and related metabolic and prothrombotic factors. METHODS AND RESULTS: 50 non-diabetic women, 17 with normal weight and 33 overweight and obese, aged 18-55 years, were examined. Measurements included body mass index (BMI), central fat accumulation (evaluated by waist circumference), systolic and diastolic blood pressure levels, fasting plasma concentrations of sP-sel, glucose, lipids (triglycerides, total cholesterol and HDL-cholesterol), insulin, and prothrombotic factors (plasminogen activator inhibitor-1, von Willebrand factor, fibrinogen), and insulin resistance (estimated by the homeostasis model assessment: HOMA(IR)). Overweight and obese women had higher fasting plasma sP-sel concentrations compared to normal-weight controls (P<0.05). sP-sel concentrations were positively correlated with BMI, HOMA(IR), systolic and diastolic blood pressure, fasting insulin, triglyceride and PAI-1 plasma levels (P<0.05 for all the correlations). When a multiple regression analysis was performed, with P-sel as dependent variable and all the other parameters as independent variables, P-sel did not maintain a significant relationship with any of these variables. CONCLUSIONS: s-P-selectin plasma concentrations are higher in overweight and obese insulin resistant subjects, thus possibly contributing to the cardiovascular risk of these patients. However, body fatness and insulin resistance are not independent determinants of fasting plasma sP-sel concentrations.

Haptoglobin serum levels are independently associated with insulinemia in overweight and obese women.

BACKGROUND: Obesity is associated with a chronic low-grade inflammatory condition. Haptoglobin is a glycoprotein involved in the acute-phase response to inflammation, and it is increased in obese subjects. The possibility that hyperinsulinemia and/or insulin resistance may directly increase haptoglobin levels has never been tested. The aim of this study was to investigate the associations of haptoglobin serum levels with anthropometric parameters, insulin levels, insulin resistance and related metabolic variables in overweight and obese women. PATIENTS AND METHODS: This is a cross-sectional study of 194 non-diabetic overweight and obese subjects, aged 18-68 yr. Measurements included body mass index (BMI), central fat accumulation [evaluated by waist circumference (WC)], systolic and diastolic blood pressure, and fasting concentrations of haptoglobin, insulin, glucose, lipids (triglycerides, total cholesterol, and HDL-cholesterol), and insulin resistance as estimated by the homeostasis model assessment (HOMAIR). RESULTS: Haptoglobin serum levels showed a positive association with BMI (p<0.001), WC (p<0.001), HOMAIR (p<0.001), and fasting insulin (p<0.001), triglyceride (p<0.001) and glucose (p<0.05) blood levels. However, only insulin maintained a significant independent association with haptoglobin (p<0.001) when a multiple regression analysis was performed and age, BMI (or WC), blood pressure levels, HOMAIR, and fasting insulin, glucose, and lipid blood concentrations were entered as independent variables. CONCLUSIONS: Higher haptoglobin serum levels seem to be a strong marker of hyperinsulinemia, independently of BMI, body fat distribution, insulin resistance and related parameters.

WNT10B mutations in human obesity.

AIMS/HYPOTHESIS: Recent studies suggest that wingless-type MMTV integration site family, member 10B (WNT10B) may play a role in the negative regulation of adipocyte differentiation in vitro and in vivo. In order to determine whether mutations in WNT10B contribute to human obesity, we screened two independent populations of obese subjects for mutations in this gene. SUBJECTS AND METHODS: We studied 96 subjects with severe obesity of early onset (less than 10 years of age) from the UK Genetics of Obesity Study and 115 obese Italian subjects of European origin. RESULTS: One proband with early-onset obesity was found to be heterozygous for a C256Y mutation, which abrogated the ability of WNT10B to activate canonical WNT signalling and block adipogenesis and was not found in 600 control alleles. All relatives of the proband who carried this allele were either overweight or obese. Three other rare missense variants were found in obese probands, but these did not clearly cosegregate with obesity in family studies and one (P301S), which was found in three unrelated subjects with early-onset obesity, had normal functional properties. CONCLUSIONS/INTERPRETATION: These mutations represent the first naturally occurring missense variants of WNT10B. While the pedigree analysis in the case of C256Y WNT10B does not provide definitive proof of a causal link of this variant with obesity, the finding of a non-functioning WNT10B allele in a human family affected by obesity should encourage further study of this gene in other obese populations.

High prevalence of previously unknown subclinical hypothyroidism in obese patients referred to a sleep clinic for sleep disordered breathing.

BACKGROUND AND AIM: To evaluate the prevalence of previously unknown hypothyroidism in adult male and female patients with a wide range of body mass index (BMI) values, referred to a Sleep Clinic because of sleep disordered breathing (SDB). METHODS AND RESULTS: Serum concentrations of thyroid stimulating hormone (TSH) and free thyroxin (fT4), as well as forced vital capacity (FVC), PaO2, PaCO2, the Epworth sleepiness scale (ESS), respiratory disturbance index (RDI), loud snoring, and the percentage of total sleep time (TST) with <90% oxyhemoglobin saturation (TST(saO2<90%)) were measured in 78 overweight and obese adult subjects with no previous diagnosis of hypothyroidism (age: 18-72 years). The prevalence of previously undiagnosed subclinical hypothyroidism in the population as a whole was 11.5%. BMI, TSH and ESS were significantly higher in the hypothyroid than the euthyroid subjects, but there was no significant between-group difference in RDI, TST(saO2<90%) or the other investigated variables, including the prevalence of obstructive sleep apnea (OSA). Among the hypothyroid individuals, BMI, neck circumference, ESS, RDI and TST(Sao2<90%) were significantly higher in those with than in those without OSA. Furthermore, there was a clear trend towards a lower FVC% and higher snoring score in the OSA patients. CONCLUSIONS: Our results demonstrate a higher prevalence of hypothyroidism than that commonly reported in overweight and obese individuals referred to a Sleep Clinic for polysomnography because of SDB, thus suggesting that thyroid function should be evaluated in all obese patients suffering from SDB despite economic concerns.

Diurnal PaCO2 tension in obese women: relationship with sleep disordered breathing.

OBJECTIVE: Several obese subjects show a wide array of respiratory disturbances during sleep due to an increased upper-airway resistance. The aim of the present study was to evaluate diurnal PaCO(2) tension in nonsmoking obese women and the possible relationship of this parameter with the presence of sleep disordered breathing (SDB). DESIGN: Cross-sectional study of PaCO(2) tension in obese women. PATIENTS AND METHODS: A total of 91 nonsmoking obese women (BMI > or =30 kg/m(2), aged 42.8+/-15.7 y) were recruited and evaluated for general and anthropometric parameters, respiratory function, sleep-related symptoms, and sleep disorders of breathing. RESULTS: A total of 10 subjects (10.9%) had diurnal hypercapnia (PaCO(2)> or =43 mmHg). Age, BMI, neck circumference, apnoea/hypopnoea index, and nocturnal desaturation (expressed as TST(SaO(2<90%)); TST(SaO(2<90%))=percentage of total sleep time with oxyhaemoglobin saturation <90%) were significantly higher in obese patients with diurnal hypercapnia, compared to normocapnic women. Moreover, hypercapnic patients had reduced forced expiratory volume in 1 s compared to normocapnic individuals. By using multiple regression analysis, the best fitting model (r=0.62, P<0.001) for predicting diurnal PaCO(2) tension in the study population showed that 24.23% of the variance may be explained by TST(SaO(2<90%)), according to the equation: PaCO(2)=0.09 age+0.07 TST(SaO(2<90%))+33.00. CONCLUSIONS: This study suggests that severity of SDB is the most important factor in determining diurnal PaCO(2) tension in apparently healthy nonsmoking obese women.

Gender, age and menopause effects on the prevalence and the characteristics of obstructive sleep apnea in obesity.

BACKGROUND: In the 1970s and 80s it was believed that obstructive sleep apnea (OSA) was primarily a disease of men. The present study was addressed to evaluate the effect of gender and menopause on the prevalence and the characteristics of OSA and on anthropometric, clinical, respiratory and polysomnographic data in a population of obese individuals. PATIENTS AND METHODS: A total of 230 obese subjects (BMI >/= 30 kg m-2), 148 women and 82 men, aged 16-75 years, were recruited and evaluated for general and anthropometric parameters, respiratory function, sleep-related symptoms and sleep disorders of breathing. RESULTS: Respiratory disturbance index (RDI) and the prevalence of OSA were lower in women than in men (P < 0.001 and P < 0.001, respectively). Among subjects < 55 years, neck circumference, percentage of predicted normal neck circumference (PPNC), waist-to-hip ratio (WHR), PaCO2, RDI and the prevalence of OSA were lower in female subjects (P = 0.05, P < 0.05, P < 0.001, P < 0.01 and P < 0.01, respectively). BMI, neck circumference, PPNC, WHR, RDI and the prevalence of OSA were higher in postmenopausal compared with premenopausal women (P < 0.01, P < 0.01, P < 0.01, P < 0.01 and P < 0.01, respectively). CONCLUSIONS: Our study demonstrates that (i) the male dominance regarding the prevalence and the severity of OSA disappears in men older than 55 years, and (ii) menopause seems to play a pivotal role in modulating both the presence and the degree of sleep disorder.

Effect of shift work on body mass index: results of a study performed in 319 glucose-tolerant men working in a Southern Italian industry.

OBJECTIVE: To examine the influence of shift work on metabolic and cardiovascular risk factors in subjects working in an industry sited in Apulia, Southern Italy. DESIGN: Cross-sectional study of metabolic effects of shift work in glucose tolerant workers in a chemical industry in southern Italy. SUBJECTS: The subjects included 319 glucose tolerant male individuals, aged 35-60 y. MEASUREMENTS: Anthropometric parameters (body mass index (BMI) and waist-to-hip ratio (WHR)), fasting concentrations of glucose, insulin, and lipids (total cholesterol, HDL-cholesterol, triglycerides), the sum of glucose levels during 75 g-oral glucose tolerance test (Sigma-OGTT), and systolic and diastolic blood pressure (SBP and DBP, respectively). RESULTS: The prevalence of obesity was higher among shift workers compared to day workers, whereas body fat distribution was not different between the two groups. Shift workers had higher BMI than day workers, and shift working was associated with BMI, independently of age and work duration. Shift workers had significantly higher SBP levels, which were independently influenced by BMI, but not by shift work, thus suggesting that the difference in SBP may well be mediated by the increased body fatness. CONCLUSION: In workers of an industry sited in Southern Italy, shift work may be directly responsible for increased body fatness and is indirectly associated with higher blood pressure levels and some features of metabolic syndrome.

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.

Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men.

OBJECTIVE: To evaluate the relation between free testosterone (FT) levels and the intima-media thickness of the common carotid artery (IMT-CCA) in overweight and obese glucose-tolerant (NGT) young adult men. DESIGN: Cross-sectional study of FT and IMT-CCA in obese men. SUBJECTS: A total of 127 overweight and obese NGT male individuals, aged 18-45 y. MEASUREMENTS: FT plasma levels; IMT-CCA, as measured by high-resolution B-mode ultrasound imaging; central fat accumulation, as evaluated by waist circumference; body composition, as measured by bioimpedance analysis; insulin resistance, as calculated by homeostatic model assessment (HOMA(IR)); systolic and diastolic blood pressure; and fasting concentrations of glucose, insulin, and lipids. RESULTS: IMT-CCA was positively correlated with age, body mass index (BMI), fat mass (FM), waist circumference, and fasting glucose concentrations, and inversely associated with FT levels. After multivariate analysis, IMT-CCA maintained an independent association with BMI, FM, and FT levels. This study indicates that IMT-CCA is negatively associated with FT levels, independent of age, total body fat, central fat accumulation, and fasting glucose concentrations in overweight and obese NGT patients. CONCLUSION: Hypotestosteronemia may accelerate the development of atherosclerosis and increase the risk for CHD in obese men.

Low sleep quality and daytime sleepiness in obese patients without obstructive sleep apnoea syndrome.

OBJECTIVES: To evaluate sleep quality, sleep-related symptoms, and degree of excessive daytime sleepiness (EDS) in severe obesity, independently of obstructive sleep apnoea syndrome (OSAS). DESIGN: A cross-sectional study. SETTING: Primary-care setting. SUBJECTS, MAIN OUTCOME MEASURES: Anthropometric parameters, respiratory function data and sleep related symptoms were evaluated in 78 severely obese patients (aged 16-75 years) without OSAS and in 40 healthy sex- and age-matched normal weight subjects, who underwent a full-night polysomnography. RESULTS: Obese patients and control subjects had similar sleep latency and rapid eye movement (REM) latency, but they showed lower percentage of REM (P < 0.01) and sleep efficiency (P < 0.05) than controls. All sleep-related symptoms (observed or reported apnoea, awakenings, choking and unrefreshing sleep) were significantly more frequent in obese patients than in control subjects. Loud snoring was present in 46.7% of the obese patients and in 8.1% of the control individuals (P < 0.01). Excess daytime sleepiness was reported by 34.7% of the obese patients and by 2.7% of the normal weight subjects (P < 0.01). The Epworth Sleepiness Scale (ESS) was higher in the obese group than in the control group (P < 0.01), whereas arousals were not different between the two groups. CONCLUSIONS: This study clearly shows that severe obesity, even in the absence of OSAS, is associated with sleep-related disorders and EDS. All these alterations may be partly responsible for a lower quality of life, a higher prevalence of medical complications, an increased risk of occupational injury, and both social and family problems characterizing obese patients, independently of the presence of OSAS.

A family history of Type 2 diabetes is associated with increased plasma levels of C-reactive protein in non-smoking healthy adult women.

AIMS: The aim of our study was to test whether a family history of Type 2 diabetes (FH) in women is associated with plasma C-reactive protein (CRP). METHODS: CRP plasma levels were measured in 162 women, aged 18-60 years; 95 had a positive family history of Type 2 diabetes in a parent or grandparent (FH+), and 67 gave no family history of this disease (FH-). Other measurements included: central fat accumulation, as evaluated by waist circumference; insulin resistance, as calculated by homeostatic model assessment (HOMAIR); systolic and diastolic blood pressure; and fasting concentrations of glucose, insulin, and lipids. RESULTS: CRP plasma levels were significantly higher in FH+ than in FH- subjects. Moreover, CRP was independently associated with age, body mass index, waist circumference, HOMAIR, and FH. CONCLUSIONS: Our study, performed in a selected population of women free from well-known risk factors for atherothrombosis, demonstrates that subjects with a family history of Type 2 diabetes have higher CRP plasma levels than age- and BMI-matched controls with no family history. Our results show that a family history of Type 2 diabetes is an independent contributor of CRP concentrations, in addition to age, total fatness, central fat accumulation, and insulin resistance.

Coagulation and fibrinolysis abnormalities in obesity.

Abnormalities in coagulation and haemostasis represent a well-known link between obesity and thrombosis (both arterial and venous). Several studies have shown that obese patients have higher plasma concentrations of all pro-thrombotic factors (fibrinogen, vonWillebrand factor (vWF), and factor VII), as compared to non-obese controls, with a positive association with central fat. Similarly, plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be higher in obese patients as compared to non-obese controls and to be directly correlated with visceral fat. Furthermore, obesity is characterized by higher plasma concentrations of anti-thrombotic factors, such as tissue-type plasminogen activator (t-PA) and protein C, as compared to non-obese controls, the increase in these factors being likely to represent a protective response partly counteracting the increase in pro-thrombotic factors. The issue of whether adipose tissue contributes directly to plasma PAI-1, its products stimulating other cells to produce PAI-1, or whether it primarily contributes indirectly has not yet been resolved. It has been proposed that the secretion of interleukin-6 (IL-6) by adipose tissue, combined with the actions of adipose tissue-expressed TNF-alpha in obesity, could underlie the association of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease. The role of leptin in impairing haemostasis and promoting thrombosis has been recently reported. Finally, some hormonal abnormalities (androgen, F, catecholamines) associated with the accumulation of body fat may contribute to the impairment of coagulative pathway in obesity. As to intervention strategies, dietary (i.e., low-fat high-fiber diet) and lifestyle (i.e., physical activity) measures have been demonstrated to be effective in improving the obesity-associated pro-thrombotic risk profile.

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.

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.