Circulating concentration of adiponectin and its expression in subcutaneous adipose tissue in patients with highly active antiretroviral therapy-associated lipodystrophy

Highly active antiretroviral therapy (HAART) has dramatically reduced HIV-related mortality, but is associated with severe metabolic adverse events, such as lipodystrophy and insulin resistance, the mechanisms of which are unknown. Adiponectin is a adipocytokine that is decreased in insulin resistant conditions. In mice, adiponectin decreases liver and muscle fat content and enhances insulin sensitivity. We determined serum adiponenctin and adiponectin mRNA concentrations in subcutaneous adipose tissue in HIV-positive HAART-treated patients with (HAART+LD+, n = 30) and without lipodystrophy (HAART+LD-, n = 13). The HAART+ LD+ group had significantly less subcutaneous and more intra-abdominal fat than the HAART+LD- group. Liver fat content (spectroscopy), serum insulin, C-peptide and triglyceride concentrations were significantly higher, and HDL cholesterol concentration lower in the HAART+LD+ than the HAART+LD- group. Serum adiponectin (3.4 +/- 0.4 vs 8.5 +/- 1.0 micro g/mL, p < 0.001) and adiponectin mRNA concentration in subcutaneous adipose tissue (7 +/- 1 x 10(-4) vs 24 +/- 6 x 10(-4), p < 0.001) were significantly lower in the HAART+LD+ than the HAART+LD- group. Both serum adiponectin and mRNA concentrations correlated closely with features of insulin resistance, including liver fat content. These data suggest that the decreased production of adiponectin in lipoatrophic adipose tissue may contribute to hepatic insulin resistance in these patients.     

Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices

HIV-related lipodystrophy is characterized by adipose redistribution, dyslipidemia, and insulin resistance. Adiponectin is an adipose-derived peptide thought to act as a systemic regulator of glucose and lipid metabolism. We investigated adiponectin concentrations in 10 HIV-infected patients during acute HIV infection (viral load, 2.0 x 10(6) +/- 1.0 x 10(6) copies/ml) and then 6-8 months later, as well as cross-sectionally in 41 HIV-infected patients (21 with evidence of fat redistribution and 20 without evidence of fat redistribution) in comparison with 20 age- and body mass index-matched healthy control subjects. Circulating adiponectin concentrations did not change with treatment of acute HIV infection (5.8 +/- 0.4 vs. 5.9 +/- 0.7 micro g/ml, P = 0.96) but were reduced in patients with chronic HIV infection and fat redistribution (7.8 +/- 0.9 micro g/ml), compared with age- and body mass index-matched HIV-infected patients without fat redistribution (12.7 +/- 1.7 micro g/ml) and healthy control subjects (11.9 +/- 1.7 micro g/ml, P < 0.05 vs. HIV-infected patients without fat redistribution and vs. control subjects). Adiponectin concentrations correlated with body composition [correlation coefficient (r) = -0.47, P = 0.002 vs. trunk fat:total fat; r = 0.51, P < 0.001 vs. extremity fat:total fat], insulin response to glucose challenge (r = -0.36, P = 0.03), triglyceride (r = -0.39, P = 0.01), and high-density lipoprotein (r = 0.37, P = 0.02) among the HIV-infected patients. Adiponectin remained a significant correlate of insulin response to GTT, controlling for medication use and body composition changes in HIV-infected patients. These data suggest a strong relationship between adiponectin and body composition in HIV-infected patients. Changes in adiponectin may contribute to the metabolic dysregulation in this group of patients.     

Relationship of regional adiposity to insulin resistance and serum triglyceride levels in nonobese Japanese type 2 diabetic patients

The aim of this study was to investigate the relationships between insulin resistance and regional abdominal fat area, body mass index (BMI), and serum lipid profile in nonobese Japanese type 2 diabetic patients. A total of 63 nonobese Japanese type 2 diabetic patients aged 45 to 83 years were examined. The duration of diabetes was 8.4 +/- 0.8 years. BMI, glycosylated hemoglobin (HbA(1c)) levels, and fasting concentrations of plasma glucose, serum lipids (total cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides), and serum insulin were measured. The low-density lipoprotein (LDL) cholesterol level was calculated using the Friedewald formula (LDL cholesterol = total cholesterol - HDL cholesterol - 1/5 triglycerides). Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). Computed tomography (CT) was used to measure cross-sectional abdominal subcutaneous and visceral fat areas in all the patients. Adipose tissue areas were determined at the umbilical level. Subcutaneous and visceral abdominal fat areas were 136.5 +/- 6.0 and 86.0 +/- 4.1 cm(2), respectively. Univariate regression analysis showed that insulin resistance was positively correlated with subcutaneous (r =.544, P <.001) and visceral (r =.408, P =.001) fat areas, BMI (r =.324, P =.009), HbA(1c) (r =.254, P =.001), serum triglycerides (r =.419, P <.001), and serum LDL cholesterol (r =.290, P =.019) levels and was negatively correlated with serum HDL cholesterol level (r =.254, P =.041). Multiple regression analyses showed that insulin resistance was independently predicted by the areas of subcutaneous (F = 6.76, P <.001) and visceral (F = 4.61, P <.001) abdominal fat and serum triglycerides (F = 8.88, P <.001) level, which explained 36.9% of the variability of insulin resistance. Moreover, the present study demonstrated that whereas BMI was positively correlated with visceral (r =.510, P <.001) and subcutaneous (r =.553, P <.001) fat areas, serum triglyceride level was positively associated with visceral (r =.302, P =.015), but not with subcutaneous (r =.222, P =.074) fat area. From these results, it can be suggested that (1) both subcutaneous and visceral abdominal fat areas are independently associated with insulin resistance and (2) visceral fat area, but not the subcutaneous one, is associated with serum triglyceride levels in our nonobese Japanese type 2 diabetic patients.     

Circulating resistin levels are not associated with fat redistribution, insulin resistance, or metabolic profile in patients with the highly active antiretroviral therapy-induced metabolic syndrome

CONTEXT: The mechanisms underlying the development of the highly active antiretroviral therapy (HAART)-induced metabolic syndrome remain to be fully elucidated. OBJECTIVE: The objective of this study was to investigate whether the adipocyte-secreted hormone, resistin, is associated with anthropometric and metabolic abnormalities of the HAART-induced metabolic syndrome. DESIGN, SETTING, AND PATIENTS: We conducted a cross-sectional study of 227 HIV-positive patients (37 women and 190 men) recruited from the infectious diseases clinics. On the basis of history, physical examination, dual-energy x-ray absorptiometry, and single-slice computed tomography, patients were classified into four groups: non-fat redistribution (n = 85), fat accumulation (n = 42), fat wasting (n = 35), and mixed fat redistribution (n = 56). MAIN OUTCOME MEASURES: The main outcome measures were serum resistin levels and anthropometric and metabolic variables. RESULTS: Mean serum resistin levels were not significantly different among subjects with fat accumulation, fat wasting, or mixed fat redistribution or between these groups and the non-fat redistribution group. We found a weak, but significant, positive correlation between resistin and percent total body fat (r = 0.20; P < 0.01), total extremity fat (r = 0.18; P < 0.01), and abdominal sc fat (r = 0.19; P < 0.01), but not abdominal visceral fat (r = -0.10; P = 0.16) or waist to hip ratio (r = -0.05; P = 0.43). When adjustments were made for gender (women, 3.92 +/- 2.71 ng/ml; men, 2.96 +/- 2.61 ng/ml; P = 0.05), correlations between resistin and the above parameters were no longer significant. Importantly, resistin levels were not correlated with fasting glucose, insulin, homeostasis model assessment of insulin resistance index, triglycerides, or cholesterol levels in the whole group. CONCLUSIONS: Resistin is related to gender, but is unlikely to play a major role in the insulin resistance and metabolic abnormalities of the HAART-induced metabolic syndrome.     

Obstructive sleep apnoea syndrome, plasma adiponectin levels, and insulin resistance

OBJECTIVE: To investigate whether sleep-disordered breathing and/or plasma adiponectin levels are associated with insulin resistance independent of obesity or fat distribution in obstructive sleep apnoea syndrome (OSAS). DESIGN: Cross-sectional clinical study. PATIENTS: Two-hundred and thirteen Japanese patients with OSAS aged 27-80 years were divided into three groups: 30 with mild OSAS [apnoea-hypopnoea index (AHI) = 10.3 +/- 0.9 episodes/h, minimum oxygen saturation (min SpO2) = 87.3 +/- 0.9%], 98 with moderate OSAS (AHI = 28.9 +/- 0.6 episodes/h, min SpO2 = 82.1 +/- 0.7%), and 85 with severe OSAS (AHI = 68.1 +/- 2.8 episodes/h, min SpO2 = 72.3 +/- 1.6%). Twenty-one patients undergoing diabetic treatments (two mild, nine moderate and 10 severe) were excluded from the assessment of insulin resistance and plasma adiponectin measurements. MEASUREMENTS: Fat distribution [evaluated according to visceral (V) and subcutaneous (S) fat areas using computed tomography scanning at the umbilical level], blood pressure, metabolic parameters and hormones including insulin and adiponectin were measured. After full polysomnography, venous blood was collected between 0600 and 0700 h. RESULTS: Severe OSAS patients were more hypertensive than mild and moderate OSAS. Fasting plasma glucose (FPG) and fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR) levels were all higher in severe OSAS than mild and moderate OSAS patients. HOMA-IR was correlated not only with obesity [body mass index (BMI), V and S areas] but also with apnoea (AHI, min SpO2 and desaturation time). Additionally, HOMA-IR was correlated positively with haemoglobin (Hb)A1c, systolic (SBP) and diastolic blood pressure (DBP), triglycerides and free fatty acids (FFA), and negatively with high density lipoprotein (HDL)-cholesterol, suggesting that insulin resistance is a key component of the metabolic syndrome in OSAS. Plasma adiponectin levels were not different between mild, moderate and severe OSAS groups. Plasma adiponectin levels were correlated with HOMA-IR and V area, but not AHI or min SpO2. Stepwise multiple regression analysis, however, revealed that BMI, AHI and plasma adiponectin were independently associated with HOMA-IR. CONCLUSION: Sleep-disordered breathing was associated with insulin resistance independent of obesity. Although plasma adiponectin was also an independent determinant of HOMA-IR in OSAS patients, plasma adiponectin was more closely related to obesity than to sleep apnoea. Although treatment of sleep-disordered breathing with nasal continuous positive airway pressure reportedly improves insulin sensitivity, our findings suggest that treatment of obesity is also essential in ameliorating insulin resistance at least through increased plasma adiponectin levels in OSAS.     

Serum adiponectin and leptin levels in patients with lipodystrophies

Lipodystrophies are characterized by selective but variable loss of body fat and metabolic complications of insulin resistance. We hypothesized that reduced synthesis and secretion of adipocyte-specific proteins may be related to the metabolic complications of lipodystrophy. Therefore, we compared fasting serum concentrations of adiponectin and leptin, in 18 patients with congenital generalized lipodystrophy (CGL), 11 with acquired generalized lipodystrophy (AGL), 46 with familial partial lipodystrophy-Dunnigan variety (FPLD) and 18 with acquired partial lipodystrophy (APL) and studied their relationship to metabolic parameters. Patients with CGL and AGL had markedly reduced serum adiponectin levels compared to those with FPLD and APL (median [range]: 1.5 [0.4-7.5], 3.2 [0.6-7.7], 6.9 [1.9-23.2] and 7.9 [3.1-13.3] microg/mL, respectively, p < 0.0001); the same trend was noted for serum leptin levels (0.63 [0.05-3.7], 2.18 [0.05-11.30], 2.86 [0.23-9.00] and 6.24 [1.21-10.4] ng/mL, respectively, p < 0.0001). Serum adiponectin levels correlated negatively with fasting serum triglycerides (r = -0.6, p < 0.001) and insulin levels (r = -0.5, p < 0.0001) and positively with serum high-density lipoprotein cholesterol levels (r = 0.5, p < 0.001). Serum adiponectin levels were lower in patients with diabetes compared to non-diabetic subjects (3.0 vs. 7.1 microg/mL, p < 0.001). Our results indicate that serum adiponectin and leptin levels are extremely low in patients with generalized lipodystrophies and may be related to severe insulin resistance and its metabolic complications in lipodystrophies.     

Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy

OBJECTIVES: Adipocytokines, secreted by adipose tissue, may regulate fat metabolism, lipid and glucose homeostasis and insulin sensitivity. We analysed the relations between circulating concentrations of adiponectin, leptin, interleukin-6, tumor necrosis factor alpha and its soluble receptors sTNFR1 and R2, lipodystrophic phenotypes and metabolic alterations in patients under highly active antiretroviral therapy (HAART). METHODS: We studied 131 consecutive HIV-infected males under protease inhibitor (PI)-based HAART, with body mass index < 27 kg/m2 and C-reactive protein (CRP) < 10 mg/l. Patients were classified in four groups according to clinical examination: no lipodystrophy (NL), lipohypertrophy (LH), lipoatrophy (LA) and mixed lipodystrophy (ML). In addition to adipocytokines, we measured plasma fasting levels of triglycerides, cholesterol, cardiovascular risk markers (high-sensitivity CRP and apolipoproteins B/A1 ratio), fasted and 2 h post-glucose loading glycemia and insulinemia and calculated the quantitative insulin sensitivity check index. RESULTS: The patients were HIV-infected and PI-treated for a mean of 8.2 and 1.6 years respectively; 74% presented lipodystrophy, 38% altered glucose tolerance and 42% hypertriglyceridemia. Insulin sensitivity correlated positively with adiponectin and negatively with leptin and interleukin-6. Adiponectin, but not leptin, negatively correlated with all metabolic parameters. Insulin resistance, metabolic defects and cardiovascular risk markers were strongly negatively correlated with the adiponectin/leptin ratio (A/L), and positively with sTNFR1. LA patients had a longer duration of infection but ML patients presented the most severe metabolic alterations, insulin resistance and A/L decrease. CONCLUSIONS: These results suggest that adiponectin and the TNFalpha system are related to lipodystrophy, insulin resistance and metabolic alterations in patients under PI-based HAART. A/L and sTNFR1 could predict insulin sensitivity and potential cardiovascular risk in these patients.     

Lipodystrophy, insulin resistance, and adiponectin concentration in HIV-infected children and adolescents

Alterations of fat distribution and insulin resistance are associated with increased risk of metabolic derangements and cardiovascular disease. HIV-infected adult patients on antiretroviral treatment often show lipodystrophy, insulin resistance and hypoadiponectinemia, but data in children are controversial. We investigated serum adiponectin concentration in a cohort of HIV-infected youths, and we assessed the relationships with lipodystrophy and insulin resistance. We studied 36 HIV-infected patients (aged 5.0 - 19.4 years), and 171 healthy subjects (aged 4.9 - 17.9 years) for adiponectin measurements. All patients underwent body composition assessment by dual-energy x-ray absorptiometry, and an oral glucose tolerance test to determine the fasting insulin concentration, the insulin area under the curve (AUC), and the HOMA index. Adiponectin serum concentration was measured by an immunoenzymatic assay. Sixteen patients had central fat accumulation, 6 had peripheral lipoatrophy, 5 had a mixed phenotype, and the remaining 9 were non-lipodystrophic. Fasting insulin, insulin AUC, and HOMA index were significantly higher in patients with central fat adiposity and mixed phenotype than in the other two groups. The patients of the former two groups had adiponectin concentration much lower than healthy controls, and patients with peripheral lipoatrophy or normal phenotype had normal concentration. Low adiponectin concentration is associated to central fat and mixed lipohypertrophy, and to signs of insulin resistance in HIV-infected youths. Strict monitoring of metabolic and cardiovascular evolution should be performed in these patients.     

Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance

CONTEXT: Adipose tissue-derived adipokines may contribute to insulin resistance. OBJECTIVE: We tested the hypothesis that adipokines are associated with insulin resistance in a community-based cohort and that associations are maintained in people with and without the metabolic syndrome (high vs. low risk of diabetes). DESIGN, SETTING, AND PARTICIPANTS: We studied a cross-sectional sample of 2356 individuals attending the seventh examination (1998-2001) of the Framingham Offspring Study. We measured levels of glucose, insulin, adiponectin, resistin, and TNFalpha in fasting blood samples and defined metabolic syndrome by updated National Cholesterol Education Program criteria. We used ANOVA to test associations of adipokines with insulin resistance and multivariable logistic regression models to assess joint associations of adipokines and metabolic syndrome with insulin resistance. MAIN OUTCOME MEASURE: Homeostasis model (HOMA-IR), with insulin resistance defined by HOMA-IR greater than the 75th percentile, was measured. RESULTS: Age- and sex-adjusted HOMA-IR levels were inversely related to adiponectin (r = -0.40, P < 0.0001) and positively related to resistin (r = 0.13, P < 0.0001) and TNFalpha (r = 0.12, P < 0.0001). The prevalence of insulin resistance increased with decreasing tertiles of adiponectin (from 10.9% in the third to 42.5% in the first tertile; P < 0.0001) and increasing tertiles of resistin (from 19.3 to 30.9%; P < 0.0001) and TNFalpha (from 18.8 to 32.0%; P < 0.0001). Results were similar after adjustment for body mass index. These associations were present in individuals with or without the metabolic syndrome. In multivariable regression models, metabolic syndrome and adipokines individually and jointly were significantly associated with insulin resistance. CONCLUSION: Adverse levels of adipokines are associated with insulin resistance in individuals at low or high diabetes risk.     

Relationship between plasma adiponectin levels and the metabolic syndrome among Korean people

We investigated the relationship between plasma adiponectin levels and the parameters of the metabolic syndrome among Koreans. In 67 male and 115 female subjects, aged from 30 to 70 years, plasma adiponectin levels were positively correlated with HDL-cholesterol levels (r = 0.295, P<0.001), but negatively correlated with waist circumference (r = -0.140, P = 0.020), triglycerides (r = -0.174, P = 0.021), fasting plasma glucose (r = -0.159, P = 0.036), fasting plasma insulin (r = -0.172, P = 0.023) and HOMA-IR (r = -0.182, P<0.001), after adjustment for age, sex, and BMI. Stepwise multiple regression analyses revealed that HDL-cholesterol, sex, and HOMA-IR were the independent associated factors for plasma adiponectin levels. Multiple logistic analyses demonstrated that HOMA-IR, BMI, and age were the predominant independent factors associated with the metabolic syndrome, while plasma adiponectin levels exhibited a protective effect against the presence of the metabolic syndrome according to both NCEP ATP III criteria and IDF definition. Hypoadiponectinemia is associated with the phenotype of the metabolic syndrome as well as components of the metabolic syndrome.     

Interleukin 6, adiponectin, leptin, and insulin resistance in nonobese Japanese type 2 diabetic patients

The aim of the present study was to investigate the relationships between interleukin 6 (IL-6) and insulin resistance, serum leptin, serum adiponectin, or serum lipids including triglycerides in 98 nonobese Japanese type 2 diabetic patients. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). Serum IL-6 concentration was negatively correlated to high-density lipoprotein cholesterol (r = -0.295, P = .004), but was not associated with HOMA-IR (r = 0.016, P = .871), body mass index (BMI) (r = 0.090, P = .375), systolic (r = 0.169, P = .116) and diastolic (r = -0.061, P = .570) blood pressures, leptin (r = 0.062, P = .544), and adiponectin (r = -0.020, P = .841) in these patients. In contrast, serum leptin level was positively correlated to HOMA-IR (r = 0.291, P = .004), BMI (r = 0.338, P < .001), and systolic blood pressure (r = 0.241, P = .025). Serum adiponectin level was negatively correlated to HOMA-IR (r = -0.288, P = .005), BMI (r = -0.308, P = .002), diastolic blood pressure (r = -0.269, P = .012), and triglycerides (r = -0.338, P < .001), and positively correlated to high-density lipoprotein cholesterol (r = 0.300, P = .003) in our patients. From these results, it can be suggested that fasting serum IL-6 is not a major factor responsible for the evolution of insulin resistance in nonobese Japanese type 2 diabetic patients.     

Adiponectin and its correlates of cardiovascular risk in young adults: the Bogalusa Heart Study

Adiponectin, a novel adipocytokine produced exclusively in the adipose tissue, plays a major role in the development of metabolic syndrome, type 2 diabetes mellitus, and related cardiovascular (CV) diseases. However, information is scant regarding the association of adiponectin with measures of CV risk in young adults. This aspect was examined in a biracial (black-white) community-based sample of 1153 individuals (mean age, 36.2 years; 70% white, 43% male) who participated in the Bogalusa Heart Study. Adiponectin levels showed race (white > black, P < .0001) and sex (female > male, P < .0001) differences, and correlated significantly in a beneficial manner to measures of obesity (body mass index, waist circumference, and abdominal height), mean arterial blood pressure, lipoprotein variables (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), measures of glucose homeostasis (insulin, glucose, homeostasis model assessment of insulin resistance [HOMA-IR]), and uric acid, after adjusting for age, race, sex, and cigarette smoking. In multivariate analysis that used either body mass index or abdominal height as a measure of general and visceral adiposity in 2 separate models, HOMA-IR was the major contributor explaining 18.4% and 18.1% of the variance, respectively. There was a significant interaction between abdominal height and HOMA-IR on adiponectin level in that the inverse association between adiponectin and insulin resistance was pronounced at higher level of visceral adiposity. Furthermore, adiponectin levels decreased with increasing number of metabolic syndrome risk factors defined by the National Cholesterol Education Program Adult Treatment Panel III (P for trend <.0001). Moreover, adiponectin levels were low among those with positive parental histories of coronary heart disease (P = .03), hypertension (P = .04), and type 2 diabetes mellitus (P = .01), considered as surrogate measures of risk. These findings, by showing an inverse association of adiponectin with insulin resistance, visceral adiposity, and related metabolic syndrome, and also with positive parental histories of coronary heart disease, hypertension, and type 2 diabetes mellitus, underscore the value of adiponectin in CV and type 2 diabetes mellitus risk assessments in young adults.     

Increased abdominal visceral fat is associated with reduced bone density in HIV-infected men with lipodystrophy

OBJECTIVE: To examine the relationship between bone density and changes in regional and whole body composition in HIV-infected men with and without lipodystrophy. DESIGN: Cross-sectional, observational study of HIV-infected men with and without lipodystrophy and matched HIV-negative controls. SETTING: Tertiary care academic medical institution. PATIENTS: A total of 59 men, belonging to three different groups: HIV-positive men with lipodystrophy (n = 21), HIV-positive men without lipodystrophy (n = 20), and age-matched and body mass index-matched HIV-negative controls (n = 18). METHODS: Bone density, markers of bone turnover and indices of calcium metabolism were measured in all subjects. Quantitative computed tomography was used both to determine volumetric bone density of the spine and to quantify abdominal visceral fat. Dual energy X-ray absorptiometry was used to determine whole body composition and bone density. Statistical comparisons were performed according to lipodystrophy categorization and protease inhibitor exposure. RESULTS: Men with HIV-associated lipodystrophy had reduced lumbar spine bone density compared with both HIV-infected non-lipodystrophic men [mean +/- SD, 132 +/- 29 versus 154 +/- 30 mg/cm(3); P = 0.02] and HIV-negative controls [mean +/- SD 132 +/- 29 versus 148 +/- 18) mg/cm(3); P = 0.04]. Lumbar spine bone density was reduced significantly in HIV lipodystrophy patients independently of protease inhibitor use. In an analysis among all HIV-infected subjects, increased visceral abdominal fat area was associated with decreased lumbar spine bone density (r, -0.47; P = 0.002). The association between visceral fat and bone density remained significant (P = 0.007) after controlling for age, body mass index, lowest body weight, protease inhibitor use, and extremity fat in a multivariate regression model. Markers of bone turnover were not related to bone density or lipodystrophy status. CONCLUSIONS: Lumbar spine bone density is reduced in association with increased visceral fat in HIV-infected men with lipodystrophy. Further studies are needed to determine the mechanisms of osteopenia in HIV lipodystrophy and whether increased marrow fat occurs in such patients and affects bone density.     

Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy

OBJECTIVE: To determine liver fat content in patients with highly active antiretroviral therapy (HAART)-associated lipodystrophy. BACKGROUND: Lipodystrophy in several animal models is associated with fat accumulation in insulin-sensitive tissues, such as the liver. This causes hyperinsulinaemia, dyslipidaemia and other features of insulin resistance. DESIGN: A cross-sectional study. SUBJECTS AND METHODS: Three age- and weight-matched groups were compared: 25 HIV-positive men with HAART-associated lipodystrophy (HAART+LD+), nine HIV-positive men receiving HAART, but without lipodystrophy (HAART+LD-), and 35 HIV-negative healthy men (HIV-). Liver fat content was measured using proton spectroscopy. Intra-abdominal and subcutaneous fat were determined using magnetic resonance imaging. RESULTS: Liver fat content was significantly higher in the HAART+LD+ (8 +/- 10%) than the HIV- (5 +/- 7%; P < 0.05) or the HAART+LD- (3 +/- 5%; P < 0.01) group. Liver fat content correlated with serum fasting insulin in the HAART+LD+ (r = 0.47; P < 0.05) and HIV- groups (r = 0.65; < 0.001), but not with the amount of intra-abdominal fat. Within the HAART+LD+ group, serum insulin did not correlate with the amount of intra-abdominal fat. The HAART+LD+ group had a lower serum leptin concentration when compared to the two other groups. Features of insulin resistance, including hepatic fat accumulation, were not found in HAART+LD-group. CONCLUSIONS: The severity of the insulin resistance syndrome in patients with HAART-associated lipodystrophy is related to the extent of fat accumulation in the liver rather than in the intra-abdominal region. Fat accumulation in the liver may therefore play a causative role in the development of insulin resistance in these patients.     

Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy.

We evaluated metabolic and clinical features of 71 HIV-infected patients with lipodystrophy by comparing them with 213 healthy control subjects, matched for age and body mass index, from the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were compared separately with 90 matched control subjects from the Framingham Offspring Study. Fasting glucose, insulin, and lipid levels; glucose and insulin response to standard oral glucose challenge; and anthropometric measurements were determined. HIV-infected patients with lipodystrophy demonstrated significantly increased waist-to-hip ratios, fasting insulin levels, and diastolic blood pressure compared with controls. Patients with lipodystrophy were more likely to have impaired glucose tolerance, diabetes, hypertriglyceridemia, and reduced levels of high-density lipoprotein (HDL) cholesterol than were controls. With the exception of HDL cholesterol level, these risk factors for cardiovascular disease (CVD) were markedly attenuated in patients without lipodystrophy and were not significantly different in comparison with controls. These data demonstrate a metabolic syndrome characterized by profound insulin resistance and hyperlipidemia. CVD risk factors are markedly elevated in HIV-infected patients with fat redistribution.     

Circulating adiponectin levels, body composition and obesity-related variables in Prader-Willi syndrome: comparison with obese subjects

BACKGROUND: People with obesity and/or the metabolic syndrome have an increased risk for developing diabetes and cardiovascular disease and may have low adiponectin levels. The obesity associated with Prader-Willi syndrome (PWS) would be expected to have similar complications. However, it was recently reported that, despite their adiposity, people with PWS have reduced visceral fat and are less likely to develop diabetes mellitus or the metabolic syndrome compared with people with simple obesity. OBJECTIVE: To determine if plasma adiponectin levels and other variables relevant to diabetes and cardiovascular risk are different in a cohort of PWS subjects with known genetic subtypes compared with age-, sex- and weight-matched control subjects. RESULTS: Fasting plasma glucose, C-peptide, triglycerides, leptin and cholesterol levels were similar in PWS and obese subjects. Our 20 PWS subjects (mean age = 27.7 years) had higher percent body fat (54.1 vs 48.5%) determined by DEXA measurements and lower percent lean mass (45.9 vs 51.5%) compared with 14 obese controls (mean age = 26.9 year). Plasma adiponectin levels were significantly higher in PWS (15.5 +/- 8.2 microg/ml) than in obese controls (7.5 +/- 2.7 microg/ml). A significant positive correlation was found with insulin sensitivity in PWS subjects (r = 0.75, P = 0.0003) but not in obese controls (r = 0.36, P = 0.20). DISCUSSION: Our study confirmed an earlier observation of higher adiponectin levels in PWS subjects and less insulin resistance proportionate to their obesity status than found in subjects with simple obesity. Furthermore, no differences were seen in PWS subjects with the chromosome 15 deletion or maternal disomy 15. The reported excessive visceral adiposity in subjects with simple obesity compared with PWS may be associated with decreased production and lower circulating levels of adiponectin.     

Serum lipids,glucose homeostasis and abdominal adipose tissue distribution in protease inhibitor-treated and naive HIV-infected children

OBJECTIVE: To determine the extent and degree of abnormalities of serum lipids, glucose homeostasis and abdominal adipose tissue distribution in protease inhibitor (PI)-treated and PI-naive HIV-infected children. DESIGN: A cross-sectional study involving HIV-infected children, 3-18 years of age, in a paediatric tertiary care centre. MAIN OUTCOME MEASURES: Total, HDL and LDL-cholesterol, triglycerides, glucose, insulin, proinsulin and C-peptide were determined in the fasting state. Insulin resistance was assessed using the homeostatic model assessment-insulin resistance (HOMA-IR). Abdominal adipose tissue distribution was determined by single-slice computed tomography at the umbilical level. RESULTS: Thirty PI-treated and 20 PI-naive children were evaluated (76% prepubertal). PI-treated children had significantly higher total cholesterol (P = 0.0021), LDL-cholesterol (P = 0.019) and triglycerides (P = 0.0018). Serum glucose, insulin, proinsulin and C-peptide, the insulin : glucose ratio, HOMA-IR and abdominal adipose tissue distribution were similar in the two groups. Clinical and immunological HIV categories, viral load, CD4 cell count and stavudine therapy were not significantly associated with serum lipids, insulin resistance or abdominal adipose tissue distribution. The predictor variable most strongly associated with fasting serum insulin and HOMA-IR was the Tanner stage. Age was the most significant predictor variable of the visceral : subcutaneous adipose tissue ratio. CONCLUSION: In this cohort of predominantly prepubertal HIV-infected children, PI therapy was associated with an atherogenic dyslipidemia but not with insulin resistance or abnormal abdominal adipose tissue distribution. The results suggest that children, particularly prepubertal children, are less susceptible than adults to PI-induced changes in glucose homeostasis and abdominal adipose tissue distribution.     

Sex-specific determinants of serum adiponectin in older adults: the role of endogenous sex hormones

OBJECTIVE: To assess the sex-specific association of adiponectin with multiple factors thought to influence its levels, with a special emphasis on endogenous sex hormones. DESIGN AND METHODS: A cross-sectional study of determinants of serum adiponectin in 873 men and 673 postmenopausal women, ages 50-92. Factors evaluated include age, body size, fat distribution, lifestyle (exercise, smoking, alcohol intake), insulin resistance, renal function and endogenous sex hormone levels (total and bioavailable testosterone and estradiol). RESULTS: Median serum adiponectin was 50% higher in women than men (P<0.001). In unadjusted analyses, adiponectin was positively related to age, alcohol intake, high-density lipoprotein (HDL) and testosterone, and negatively related to waist girth, body mass index, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), triglycerides and bioavailable estradiol in both sexes (all P<0.01). Adiponectin was positively related to blood urea nitrogen, a measure of renal function, in men only (P<0.001). Sex-specific multivariate linear regressions adjusting for HDL and triglycerides showed that only age, HOMA-IR and sex hormones independently predicted circulating adiponectin for both men and women. Higher levels of endogenous testosterone and lower bioavailable estradiol concentrations each predicted higher adiponectin; this was true for both sexes, and was not explained by differences in age, adiposity, alcohol intake, insulin resistance or lipoprotein levels. CONCLUSIONS: The association of adiponectin with the factors studied here is strikingly similar for men and women. Sex differences in circulating adiponectin levels in older adults cannot be explained by sex hormone regulation.