Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome

OBJECTIVE: The polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance predisposing to diabetes mellitus type 2 and atherosclerosis. Adiponectin is a recently discovered adipocytokine with insulin-sensitizing and putative antiatherosclerotic properties. The aim of the study was to elucidate determinants of circulating adiponectin levels and to investigate the potential role of adiponectin in insulin resistance in PCOS women. PATIENTS AND MEASUREMENTS: Plasma adiponectin and parameters of obesity, insulin resistance and hyperandrogenism were measured In 62 women with PCOS and in 35 healthy female controls. RESULTS: Both in PCOS and controls, adiponectin levels were lower in overweight or obese women than in normal-weight women, without any difference between PCOS and controls after adjustment for body mass index (BMI). In PCOS and in controls there was a significant correlation of adiponectin with BMI (r = -0.516, P < 0.001), fasting insulin (r = -0.404, P < 0.001), homeostasis model sensitivity (HOMA %S) (r = -0.424, P < 0.001) and testosterone (r = -0.279, P < 0.01), but no correlation with androstenedione (r = -0.112, P = 0.325), 17-OH-progesterone (r =-0.031, P = 0.784) or the LH/FSH ratio (r =-0.033, P = 0.753). Multiple linear regression analysis revealed that BMI and HOMA %S but not testosterone were independently associated with adiponectin plasma levels, explaining 16% (BMI) and 13% (HOMA %S) of the variability of adiponectin, respectively. In PCOS patients insulin sensitivity, as indicated by continuous infusion of glucose with model assessment (CIGMA %S) was significantly correlated with adiponectin (r = 0.55; P < 0.001), BMI (r =-0.575; P < 0.001), waist-to-hip ratio (WHR) (r =-0.48; P = 0.001), body fat mass assessed by dual-energy X-ray-absorptiometry (DEXA) [Dexa-fat (total) (r = -0.61; P < 0.001) and Dexa-fat (trunk) (r = -0.59; P < 0.001)] and with testosterone (r = -0.42; P = 0.001). Multiple linear regression analysis demonstrated that markers of obesity such as BMI, total or truncal fat mass, age and adiponectin were independently associated with CIGMA %S, and that circulating adiponectin accounted for about 18% of the degree of insulin resistance in PCOS. By contrast, testosterone was not a significant factor, suggesting that PCOS per se did not affect insulin sensitivity independent from obesity, age and adiponectin. Metformin treatment for 6 months in insulin-resistant PCOS women (n = 9) had no effect on plasma adiponectin (P = 0.59) despite significant loss of weight and fat mass and improvement in hyperandrogenaemia. CONCLUSIONS: PCOS per se is not associated with decreased levels of plasma adiponectin. However, circulating adiponectin is independently associated with the degree of insulin resistance in PCOS women and may contribute to the development and/or maintenance of insulin resistance independent from adiposity.     

Adipose tissue oxygenation is associated with insulin sensitivity independently of adiposity in obese men and women

Adipose tissue (AT) dysfunction contributes to the pathophysiology of insulin resistance and type 2 diabetes. Previous studies have shown that altered AT oxygenation affects adipocyte functionality, but it remains to be elucidated whether altered AT oxygenation is more strongly related to obesity or insulin sensitivity. In the present study, we tested the hypothesis that AT oxygenation is associated with insulin sensitivity rather than adiposity in humans. Thirty‐five lean and obese individuals (21 men and 14 women, aged 40‐65 years) with either normal or impaired glucose metabolism participated in a cross‐sectional single‐centre study. We measured abdominal subcutaneous AT oxygenation, body composition and insulin sensitivity. AT oxygenation was higher in obese insulin resistant as compared to obese insulin sensitive (IS) individuals with similar age, body mass index and body fat percentage, both in men and women. No significant differences in AT oxygenation were found between obese IS and lean IS men. Moreover, AT oxygenation was positively associated with insulin resistance (r = 0.465; P = .005), even after adjustment for age, sex and body fat percentage (standardized β = 0.479; P = .005). In conclusion, abdominal subcutaneous AT oxygenation is associated with insulin sensitivity both in men and women, independently of adiposity. AT oxygenation may therefore be a promising target to improve insulin sensitivity.     

Fitness and abdominal obesity are independently associated with cardiovascular risk

Objectives. To examine the relationship between cardiovascular fitness (VO₂max) and abdominal obesity (waist circumference) and individual cardiovascular disease (CVD) risk factors, as well as a clustered risk factor profile, and to study the impact of gender, age and smoking on these relationships. Design. Cross‐sectional. Setting. Astrand Laboratory of Work Physiology, Swedish School of Sport and Health Sciences, Stockholm, Sweden. Subjects. Men (n = 781) and women (n = 890) from two random population‐based samples of Swedish women and men aged 20 to 65 years. Main outcomes. Odds ratios. Results. Each unit of higher fitness was associated with a decrease in all individual risk factors ranging from 2% to 4% independent of waist circumference, each unit of higher waist circumference was associated with an increased risk ranging from 2% to 5% independent of fitness. For clustering of three or more of the risk factors, each unit of fitness was associated with a 5% decrease in risk and each unit of waist circumference with a 5% increase in risk. The clustered risk was higher in unfit participants who were older or smoked daily, regardless of waist circumference. Obese participants were at higher risk if they were men or older, regardless of fitness level. However, neither a higher fitness level nor lean status reduced the risk associated with smoking. Conclusions. Higher fitness and lower waist circumference are each independently associated to a similar extent with a lower CVD risk. Simultaneous evaluation of both fitness and abdominal obesity status in clinical practice is important.     

Sleep-related disturbances and physical inactivity are independently associated with obesity in adults

OBJECTIVE: To study relationships between obesity, physical inactivity and sleep-related disturbances (obstructive sleep apnea (OSA), sleep duration, sleep disturbances concomitant with daytime tiredness) in adults (> or =30 years). DESIGN: Cross-sectional study with a random population sample. PARTICIPANTS: A total of 3377 men (mean age 52.3, s.d. 14.8, years) and 4264 women (56.4, s.d. 17.2, years). MAIN OUTCOME MEASURES: Dependent variables, measured: Waist circumference (WC) and body mass index (BMI). Independent variables, from a detailed interview/questionnaire: probable OSA, other sleep-related disturbances, sleep duration, type and frequency of leisure physical activity. Age, mental health, smoking and education were included in analyses as potential confounders. RESULTS: In men, OSA and physical inactivity increased likelihood for abdominal obesity (WC > or =102 cm). Physical inactivity also increased, but long (> or =9 h/day) sleep decreased likelihood for abdominal overweight (WC: 94-101 cm) in men. In women, abdominal obesity (WC > or =88 cm) was associated positively with OSA, moderate sleep-related disturbances, and physical inactivity. Education modulated the influence of age on abdominal obesity in both genders. Using BMI as the dependent variable did not change the general information obtained by the model. In addition, abdominal obesity was found to be an independent risk factor also in multivariable models predicting categories of a combined sleep duration and sleep disturbances. CONCLUSIONS: Sleep duration and sleep-related disturbances are associated with obesity, even after controlling for OSA and physical inactivity. The results support the hypothesis of vicious circle between sleep and obesity.     

Effects of a long-term treatment with raloxifene on insulin sensitivity in postmenopausal women

Aims/hypothesis Our aim was to investigate the effect of long-term administration of raloxifene, a selective estrogen receptor modulator, on insulin sensitivity, glucose tolerance and plasma lipid concentrations in a group of postmenopausal women.Methods A total of 24 women with postmenopausal osteoporosis were consecutively enrolled and randomly assigned to take raloxifene, 60 mg/day for 12 months or placebo. At baseline and after 6 and 12 months, in each subject insulin sensitivity (M-index) was assessed by means of an euglycaemic hyperinsulinaemic clamp. Plasma concentrations of total cholesterol, triglycerides and HDL-cholesterol were also measured and glucose tolerance was evaluated.Results In the raloxifene-treated group, the M index decreased after 6 and 12 months with respect to the placebo group (–21%, p=0.042 and –23%, p=0.018, respectively). Neither fasting plasma glucose nor glucose tolerance changed in the raloxifene-treated group, compared to the placebo group. Low density lipoprotein cholesterol concentrations decreased at 12 months (–13%, p=0.047).Conclusion/interpretation A long-term treatment with raloxifene in osteoporotic, otherwise healthy post-menopausal women can reduce insulin sensitivity without affecting glucose tolerance.     

Raloxifene does not modify insulin sensitivity and glucose metabolism in postmenopausal women

Insulin sensitivity (Si), glucose tolerance, and lipid metabolism were investigated in osteopenic postmenopausal women before and after 6 months of treatment with raloxifene (60 mg/d) or placebo. In a group of women (n = 34), glucose metabolism was evaluated by means of an oral glucose tolerance test (75 g). In another group of women (n = 24), Si and peripheral glucose utilization not dependent on insulin were evaluated by means of a frequently sampled iv glucose tolerance test associated with the minimal model method. No metabolic modification was observed in women receiving placebo. Raloxifene did not significantly modify high density lipoprotein-cholesterol and triglycerides, whereas it significantly decreased low density lipoprotein (LDL) cholesterol (4.84 +/- 0.34 mmol/liter vs. 3.83 +/- 0.49 mmol/liter; P = 0.014) and LDL/high density lipoprotein cholesterol ratio (3.21 +/- 0.31 mmol/liter vs. 2.46 +/- 0.44 mmol/liter; P = 0.012). Fasting levels and responses to the oral glucose tolerance test of glucose, insulin, C-peptide, and C-peptide/insulin were not modified by raloxifene. Similarly, raloxifene did not modify Si (4.22 +/- 4.1 vs. 5.13 +/- 1.75), or insulin (0.025 +/- 0.003 vs. 0.019 +/- 0.002). The present data show that in osteopenic postmenopausal women raloxifene reduces LDL levels but does not modify insulin sensitivity and glucose metabolism.     

Effect of oral phytoestrogen on androgenicity and insulin sensitivity in postmenopausal women

Aim: The aim of this study was to determine and compare the effect of treatment with transdermal oestrogen and phytoestrogen on insulin sensitivity and sex hormone-binding globulin (SHBG) levels in healthy postmenopausal women. Methods: Forty-three healthy postmenopausal women aged 68 ± 7 (mean ± SD) years who were not receiving hormonal replacement therapy completed a 3 month randomized drug therapy study. The participants were randomized to one of four groups: 0.05 mg or 0.1 mg transdermal oestrogen/day, or 40 or 80 mg oral phytoestrogen (Promensil)/day insulin sensitivity was indirectly measured using the quantitative insulin sensitivity check index (QUICKI). SHBG, total testosterone, oestradiol, and fasting glucose and insulin levels for calculation of insulin sensitivity were obtained at baseline and at monthly intervals during the 3 months of therapy. Results: In healthy nondiabetic postmenopausal women, the rate of change in QUICKI was significantly different between the red clover based phytoestrogen and transdermal oestrogen groups, so that after three months of therapy, QUICKI with red clover based phytoestrogen therapy was lower than that in the transdermal oestrogen group, p = 0.01. Red clover based phytoestrogen therapy was not associated with any changes in SHBG levels whereas transdermal estrogen therapy significantly increased SHBG levels, p = 0.05. Conclusions: In contrast to transdermal oestrogen therapy, oral phytoestrogen therapy does not decrease androgenicity and is associated with a decrease in insulin sensitivity. These effects are similar to those of raloxifene and consistent with phytoestrogen's selective oestrogen receptor modulator properties.     

Differential effects of raloxifene and estrogen on insulin sensitivity in postmenopausal women

OBJECTIVES: To test the hypothesis that both raloxifene and estrogen would improve insulin sensitivity in postmenopausal women and that the magnitude of the effect would be similar for both drugs. DESIGN: Placebo-controlled, double-blind, randomized study. SETTING: The General Clinical Research Center of the University of Michigan Medical Center, a university hospital. PARTICIPANTS: Forty-four healthy postmenopausal women 73 +/- 7 years old (mean age +/- standard deviation) who were not receiving hormone replacement therapy. INTERVENTION: Eight weeks of drug therapy with randomization to raloxifene (n = 16), estrogen (n = 14), or placebo (n = 14). MEASUREMENTS: These subjects underwent a frequently sampled intravenous glucose tolerance test to determine insulin sensitivity (SI) and total and regional (central) body composition measurements by dual-energy x-ray absorptiometry at baseline and after 8 weeks of drug therapy. RESULTS: There were no statistically significant differences in age, body mass index, total or central fat mass, or SI between the three groups at baseline. The major outcome variable was SI. After 8 weeks of drug therapy, there was no significant change in SI in the placebo group or in the estrogen group and a significant decrease in SI in the raloxifene group, P =.003. CONCLUSION: In contrast to estrogen's ability to maintain insulin sensitivity, raloxifene decreases insulin sensitivity in healthy nondiabetic postmenopausal women. The clinical significance of this effect of raloxifene to impair insulin sensitivity in postmenopausal women warrants further evaluation in future studies.     

Association of acylated and nonacylated ghrelin with insulin sensitivity in overweight and obese postmenopausal women

OBJECTIVE: Ghrelin [acylated (AG) and nonacylated (NAG)] has been shown to play a pivotal role in the regulation of food intake and insulin sensitivity. It is presently unclear whether variation in insulin sensitivity is related to AG and NAG levels in obese individuals. To address this issue, we determined whether insulin-sensitive overweight or obese (ISO) and insulin-resistant overweight or obese (IRO) individuals display different total ghrelin (TotG), AG, and NAG profiles during a euglycemic/hyperinsulinemic clamp (EHC). DESIGN: Eighty-nine nondiabetic overweight and obese postmenopausal women underwent EHC to evaluate insulin sensitivity. Body composition and blood lipid profiles were assessed. Subjects within the highest tertile of insulin sensitivity were described as ISO (n = 31), whereas those within the lowest tertile of insulin sensitivity were considered as IRO (n = 29). Plasma TotG, AG, and NAG profiles were assessed by RIA at 0, 60, 160, 170, and 180 min during the EHC. RESULTS: TotG and NAG levels were significantly decreased for ISO and IRO individuals during the EHC, whereas only ISO subjects displayed a significant reduction of AG concentrations (P < 0.05). AG area under the curve value and the ratio of AG/NAG (fasting and area under the curve) were significantly decreased in ISO individuals. Furthermore, maximal reduction of TotG and AG concentrations was greater in ISO compared with IRO individuals (P < 0.05). Insulin sensitivity was significantly correlated with maximal reduction of TotG (r = 0.36; P < 0.01) and AG (r = 0.36; P < 0.05) concentrations. CONCLUSION: The dysregulation of ghrelin secretion profiles during EHC is associated with insulin resistance. AG may contribute to the variation of insulin sensitivity in overweight or obese postmenopausal women.     

Vitamin D receptor gene polymorphisms are associated with the risk of fractures in postmenopausal women, independently of bone mineral density

CONTEXT: Osteoporosis is a systemic disease with a strong genetic component. Vitamin D receptor (VDR) gene polymorphisms explain only a small part of the genetic influence on the level of bone mineral density (BMD), whereas their effect on fracture remains uncertain. OBJECTIVE: The objective of this study was to investigate the relationships between VDR genotypes and fracture risk. DESIGN: A prospective population-based cohort was studied. SUBJECTS: A total of 589 postmenopausal women (mean age, 62 yr) were followed prospectively during a median (interquartile) of 11 (1.1) yr. MAIN OUTCOME MEASURE: The study measured incidents of vertebral and nonvertebral fractures. RESULTS: VDR allele B was significantly and dose dependently overrepresented in women who fractured, including 34 and 86 women with first incident vertebral and nonvertebral fragility fractures, respectively. This corresponded to an odds ratio of 1.5 (95% confidence interval, 0.95-2.40) for heterozygous carriers (bB, n = 286) and 2.10 (95% confidence interval, 1.16-3.79) for homozygous carriers (BB, n = 90) of the B allele, compared with women with the bb genotype (n = 213). VDR genotype groups did not differ for demographics, physical activity, grip strength, personal and maternal history of fracture, and calcium intake. The association was independent of BMD of the spine, hip, and radius, and of the BMD loss at the radius. The relationship between VDR polymorphisms and fracture risk was not altered after adjustment for baseline circulating levels of bone turnover markers, estradiol, dehydroepiandrosterone sulfate, SHBG, IGF-I, intact PTH, and 25 hydroxyvitamin D. CONCLUSION: VDR genotypes are associated with the risk of fracture in postmenopausal women independently of BMD, rate of postmenopausal forearm BMD loss, bone turnover, and endogenous hormones. The mechanisms by which VDR genotypes influence bone strength remain to be determined.     

FABP2 genotype is associated with insulin sensitivity in older women

This study determined whether sequence variations in genes related to glucose and insulin metabolism are associated with insulin sensitivity in postmenopausal women after accounting for habitual physical activity levels, body composition, and hormone-replacement therapy (HRT). Eighteen sedentary, 19 physically active, and 23 athletic postmenopausal white women underwent a frequently sampled intravenous glucose tolerance test to determine insulin sensitivity (S(I)) and dual-energy x-ray absorptiometry to determine body composition. After accounting for the effects of body composition, habitual physical activity levels, and HRT status, S(I) was 26% lower in subjects with the Thr54 fatty acid-binding protein 2 (FABP2) allele compared with Ala54 homozygotes (4.3 +/- 0.5 v 5.8 +/- 0.6 microU x 10(-4)/min/mL; P <.05). Angiotensin-converting enzyme genotype was not significantly associated with S(I). There were no significant associations between Gln27Glu beta(2)-adrenergic receptor or Pro12Ala peroxisome proliferator-activated receptor gamma variants and glucose or insulin kinetic parameters. It was concluded that FABP2 genotype influences insulin sensitivity independent of body composition, habitual physical activity levels, and HRT status in postmenopausal white women.     

Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome.

Insulin resistance (IR) and central obesity are common features of the polycystic ovary syndrome (PCOS). Vitamin D is thought to play a role in the pathogenesis of type 2 diabetes by affecting insulin metabolism. The aim of our study was to investigate the effect of 25-hydroxyvitamin D (25-OH-VD) on metabolic parameters and IR in PCOS. In 120 untreated PCOS patients (median age 28 years) levels of 25-OH-VD (radioimmunoassay method provided by DiaSorin), calcium and anorganic phosphate were measured. In addition, endocrine and metabolic variables were evaluated and a glucose tolerance test was performed to assess indices of IR. In the entire PCOS cohort, 25-OH-VD concentrations were negatively correlated with body mass index (r=-0.2765), body fat (r=-0.2490), HOMA-IR (r=-0.1947), hyperinsulinemia (r=-0.1892) and leptin levels (r=-0.2834), and positively correlated with HDL cholesterol (r=0.2630) (all p<0.05). Subgroup analysis of lean, overweight and obese women revealed significant higher 25-OH-VD levels in lean women. Differences remained significant when women were divided according to their 25-OH-VD levels. Women with hypovitaminosis D (<9 ng/ml) had higher mean BMI, indices of IR and leptin levels compared to women with normal serum levels (all p<0.05). Analysis of vitamin D and biochemical endocrine PCOS features revealed a significant correlation only between 25-OH-VD and sex hormone-binding globulin as well as the free androgen index. In conclusion, in PCOS women, low 25-OH-VD levels are associated with obesity and insulin resistance but not with PCOS per se.     

Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women

BACKGROUND: Leptin is a crucial mediator of satiety signals and energy balance, and its circulating levels are increased in obesity. It has recently been shown that plasma leptin levels in humans correlate with circulating insulin and to insulin secretion. This indicates that leptin may be an important link in metabolic consequences of the insulin resistance syndrome. Whether this includes abnormalities in fibrinolysis has not been studied. METHODS AND RESULTS: Healthy subjects (n = 165; 85 men and 80 women) from the Northern Sweden MONICA population were investigated. Anthropometric measurements, oral glucose tolerance tests and sampling for plasma leptin, lipids, fibrinogen and fibrinolytic variables were made. Leptin levels were 342% higher in women than in men and were in both sexes strongly correlated to body mass index (BMI). After adjustments for age and BMI, leptin levels correlated significantly to pre/post glucoseload insulin levels in both sexes. After further adjustment for baseline insulin levels, leptin levels were in males significantly associated with increased waist circumference (P<0.001), low HDL cholesterol (P<0.05), low tPA activity (P<0.01) and high PAI-1 activity (P<0.001). In postmenopausal females, a significant association between leptin and low tPA activity/high PAI-1 activity was seen after adjustment for age and BMI (P<0.05). Conclusions. Circulating levels of leptin are associated with components of the insulin resistance syndrome, including defective fibrinolysis, in men and postmenopausal women. This suggests that leptin may be involved in the mediation of consequences of insulin resistance.     

Insulin sensitivity is associated with thigh adipose tissue distribution in healthy postmenopausal women

ObjectiveEvidence suggests intermuscular adipose tissue (IMAT) may be linked to insulin resistance, whereas thigh subcutaneous adipose tissue (SAT) may be related favorably with indices of metabolic health. However, whether adipose tissue depots of the thigh are differentially related to insulin sensitivity independent of total adiposity and other adipose tissue depots has not been determined. The objective of this study was to identify independent associations of the subcompartments of adipose tissue of the thigh with insulin sensitivity among 97 healthy early postmenopausal women.Materials and MethodsComputed tomography (CT) scans of the mid-thigh were used to assess Thigh-SAT, Thigh perimuscular adipose tissue (PMAT), and Thigh-IMAT. CT scans at the L4-L5 intervertebral space were used to assess intra-abdominal adipose tissue (IAAT) and Abdominal-SAT. Total body fat was measured by dual-energy X-ray absorptiometry (DXA). The insulin sensitivity index (S_I) was assessed by using a frequently sampled intravenous glucose tolerance test with minimal model analysis.ResultsResults indicated S_I was positively associated with Thigh-SAT independent of total fat mass and other adipose tissue compartments. Among all women combined, S_I was inversely associated with Thigh-IMAT independent of total fat mass. However, the relationship between S_I and Thigh-IMAT was independent of IAAT only among women with high levels of Thigh-IMAT and IAAT.ConclusionsThis is the first study to demonstrate independent, opposing relationships of Thigh-SAT and Thigh-IMAT with insulin sensitivity in healthy postmenopausal women. Further research is needed to determine if these associations are causal in nature.     

Fasting insulin levels independently associated with coronary heart disease in non-diabetic Turkish men and women

BACKGROUND: Levels of plasma insulin have been recognized as a weak risk indicator for coronary or cardiovascular risk in the general population with ethnic background and gender modifying this relationship. We assessed whether insulin concentrations are associated with or would serve as a marker of prevalent coronary heart disease risk in a cross-sectional study of a population having low cholesterol levels (just under 5 mmol/l) but higher prevalence of components of the metabolic syndrome. METHODS: In 688 participants of the Turkish Adult Risk Factor Survey in 2001, plasma insulin values as well as other risk variables were evaluated, and coronary heart disease was diagnosed based on clinical findings and Minnesota coding of resting electrocardiograms. Nearly equal numbers of men and women (>30 years of age) constituted the population sample from the two largest regions of Turkey. Concentrations of insulin were determined by the chemiluminescent immunometric method. RESULTS: Geometric mean value was 50 pmol/l (interquartile range 37-68 pmol/l), without revealing a significant difference in genders. Fasting insulin was correlated in both genders with many variables, notably those involving central obesity, triglycerides, blood pressure, physical inactivity and, inversely, with high-density lipoprotein (HDL)-cholesterol. In a regression model, waist circumference and body mass index were strongly associated with log insulin, after controlling for age and presence of coronary heart disease. The age- and obesity-adjusted odds ratio for coronary heart disease in the highest as opposed to the lowest quartile was 2-fold in both genders (P<0.05). Even after adjustment for dyslipidemia, blood pressure, glucose intolerance, physical activity and smoking status, an over 2-fold increased coronary heart disease risk still persisted with regard to hyperinsulinemia (>or=10 mU/l, 69.5 pmol/l). When C-reactive protein which was correlated with fasting insulin only in women, was added to the model, the impact of hyperinsulinemia on coronary heart disease risk remained unchanged. CONCLUSION: Hyperinsulinemia (i) may provide information on the coronary heart disease likelihood over and above that provided by the other risk factors, including HDL-cholesterol, and (ii) may contribute, within the frame of insulin resistance, to the coronary heart disease risk independently of the classical risk factors.