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Aims/hypothesis: Ceramides are sphingolipids that contribute to insulin resistance in preclinical studies. We hypothesised that plasma ceramides would be associated with body fat distribution, insulin resistance and incident type 2 diabetes in a multi-ethnic cohort., Methods: A total of 1557 participants in the Dallas Heart Study without type 2 diabetes underwent measurements of metabolic biomarkers, fat depots by MRI and plasma ceramides by liquid chromatography-mass spectrometry. Diabetes outcomes were assessed after 7 years. Associations of body fat and insulin resistance with ceramides at baseline and of ceramides with incident diabetes outcomes were analysed., Results: The cohort had a mean age of 43 years, with 58% women, 45% black participants and a mean BMI of 28 kg/m 2 . Total cholesterol levels were associated with all ceramides, but higher triacylglycerols and lower HDL-cholesterol and adiponectin were associated only with saturated fatty acid chain ceramides (p < 0.0003). After adjusting for clinical characteristics and total body fat, visceral adipose tissue was positively associated with saturated fatty acid ceramides (per SD, β = 0.16 to 0.18) and inversely associated with polyunsaturated fatty acid ceramides (β = -0.14 to -0.16, p < 0.001 for all). Lower-body subcutaneous fat showed an opposite pattern to that for visceral fat. HOMA-IR was positively associated with saturated (β = 0.08 to 0.09, p < 0.001) and inversely with polyunsaturated ceramides (β = -0.06 to -0.07, p < 0.05). Ceramides were not associated with incident type 2 diabetes after adjustment for clinical factors., Conclusions/interpretation: Plasma ceramides demonstrate a biologically complex relationship with metabolic and imaging indicators of dysfunctional adiposity. The role of ceramides in a shared pathway of metabolic dysfunction linking visceral adiposity and insulin resistance requires further investigation.

Context: The risk of type 2 diabetes mellitus is heterogeneous among obese individuals. Factors that discriminate prediabetes or diabetes risk within this population have not been well characterized. A dysfunctional adiposity phenotype, characterized by excess visceral fat and insulin resistance, may contribute to diabetes development in those with obesity., Objective: To investigate associations between adiposity phenotypes and risk for incident prediabetes and diabetes in a multiethnic, population-based cohort of obese adults., Design, Setting, and Participants: Among 732 obese participants (body mass index ≥30) aged 30 to 65 years without diabetes or cardiovascular disease enrolled between 2000 and 2002 in the Dallas Heart Study, we measured body composition by dual energy x-ray absorptiometry and magnetic resonance imaging (MRI); circulating adipokines and biomarkers of insulin resistance, dyslipidemia, and inflammation; and subclinical atherosclerosis and cardiac structure and function by computed tomography and MRI., Main Outcome Measures: Incidence of diabetes through a median 7.0 years (interquartile range, 6.6-7.6) of follow-up. In a subgroup of 512 participants with normal fasting glucose values at baseline, incidence of the composite of prediabetes or diabetes was determined., Results: Of the 732 participants (mean age, 43 years; 65% women; 71% nonwhite), 84 (11.5%) developed diabetes. In multivariable analysis, higher baseline visceral fat mass (odds ratio [OR] per 1 SD [1.4 kg], 2.4; 95% CI, 1.6-3.7), fructosamine level (OR per 1 SD [1.1 μmol/L], 2.0; 95% CI, 1.4-2.7), fasting glucose level (OR per 1 SD [1.1 μmol/L], 1.9; 95% CI, 1.4-2.6), family history of diabetes (OR, 2.3; 95% CI, 1.3-4.3), systolic blood pressure (OR per 10 mm Hg, 1.3; 95% CI, 1.1-1.5), and weight gain over follow-up (OR per 1 kg, 1.06; 95% CI, 1.02-1.10) were independently associated with diabetes, with no associations observed for body mass index, total body fat, or abdominal subcutaneous fat. Among the 512 participants with normal baseline glucose values, the composite outcome of prediabetes or diabetes occurred in 39.1% and was independently associated with baseline measurements of visceral fat mass; levels of fasting glucose, insulin, and fructosamine; older age; nonwhite race; family history of diabetes; and weight gain over follow-up (P < .05 for each) but not with measurements of general adiposity., Conclusion: Excess visceral fat and insulin resistance, but not general adiposity, were independently associated with incident prediabetes and type 2 diabetes mellitus in obese adults.

Background: Following our previous reports of an increased prevalence of insulin resistance and adiposity among acute lymphoblastic leukemia (ALL) survivors, particularly women treated with cranial radiotherapy (CRT), we aimed to (1) assess the relationships between adipokines (leptin and adiponectin), CRT, and measures of body fatness and (2) determine correlates of insulin resistance, by gender., Methods: We conducted cross-sectional evaluation of 116 ALL survivors (median age: 23.0 years; range: 18-37; average time from treatment: 17.5 years), including fasting laboratory testing (adiponectin, leptin, insulin, and glucose), anthropometric measurements (weight, height, and waist circumference), DXA (total body fat and truncal-to-lower-body-fat ratio), and abdominal CT (visceral fat). We estimated insulin resistance using the homeostasis model for assessment of insulin resistance (HOMA-IR). Analytic approaches included regression models and Wilcoxon rank sum testing., Results: Mean leptin per kilogram fat mass was higher for females (0.7 ng/ml/kg) than males (0.4 ng/ml/kg, P < 0.01), and among subjects who had received CRT compared to those who had not received CRT (females CRT =0.9 ng/ml/kg, no CRT = 0.7 ng/ml/kg; P = 0.1; males CRT = 0.5 ng/ml/kg, no CRT = 0.3 ng/ml/kg; P < 0.01). Elevated HOMA-IR was nearly uniformly present, even among subjects with BMI < 25 kg/m(2), and was associated with higher leptin:adiponectin ratio (LA ratio; P < 0.01)., Conclusions: Among survivors of childhood leukemia, higher leptin levels were associated with measures of body fat and insulin resistance. Anthropomorphic and metabolic changes many years after ALL treatment remain a major health problem facing survivors and may be related to central leptin resistance., (Copyright © 2011 Wiley Periodicals, Inc.)

Unlabelled: Nonalcoholic fatty liver disease is a burgeoning problem. We have previously shown that Hispanics were at greater risk for nonalcoholic fatty liver disease than were African-Americans despite a similar prevalence of risk factors between these groups. We have performed the largest, population-based study to date (n = 2170) utilizing proton magnetic resonance (MR) spectroscopy, dual-energy x-ray absorptiometry, and multislice abdominal MR imaging to determine the contribution of body fat distribution to the differing prevalence of hepatic steatosis in the three major U.S. ethnic groups (African-American, Hispanic, Caucasian). Despite controlling for age and total adiposity, African-Americans had less intraperitoneal (IP) fat and more lower extremity fat than their Hispanic and Caucasian counterparts. The differences in hepatic triglyceride content (HTGC) between these groups remained after controlling for total, abdominal subcutaneous, and lower extremity adiposity; however, controlling for IP fat nearly abolished the differences in HTGC, indicating a close association between IP and liver fat regardless of ethnicity. Despite the lower levels of IP and liver fat in African-Americans, their prevalence of insulin resistance was similar to Hispanics, who had the highest levels of IP and liver fat. Furthermore, insulin levels and homeostasis model assessment values were highest and serum triglyceride levels were lowest among African-Americans after controlling for IP fat., Conclusion: IP fat is linked to HTGC, irrespective of ethnicity. The differing prevalence of hepatic steatosis between these groups was associated with similar differences in visceral adiposity. The metabolic response to obesity and insulin resistance differs in African-Americans when compared to either Hispanics or Caucasians: African-Americans appear to be more resistant to both the accretion of triglyceride in the abdominal visceral compartment (adipose tissue and liver) and hypertriglyceridemia associated with insulin resistance.

Abstract Lipoprotein lipase (LPL), the enzyme responsible for hydrolyzing triglyceride (TG) in plasma lipoproteins, is a key regulator of plasma TG levels. In Caucasians, postheparin-LPL (PH-LPL) activity is impaired in the presence of insulin resistance and leads to elevated TG levels. However, African Americans are often both insulin-resistant and normotriglyceridemic. But in African Americans, the effect of insulin resistance on PH-LPL activity has not been studied. In African Americans, if insulin resistance is not associated with a decrease in PH-LPL activity, this could account for the simultaneous presence of insulin resistance and normotriglyceridemia. Therefore, our goal was to determine in African Americans the relationship between insulin resistance and PH-LPL activity. In a cross-sectional study of 107 nondiabetic African Americans (57 men and 50 women; age mean +/- SD, 35 +/- 8 years, range 22-50 years; body mass index 31.6 +/- 7.9 kg/m 2 , range 18.5-54.7 kg/m 2 ), fasting TG levels and PH-LPL activity were determined. Visceral adipose tissue was measured by abdominal computed tomographic scan. Insulin resistance was determined by the insulin sensitivity index ( S I ). Subjects were divided into tertiles by S I . The range of S I in each tertile was 12.75 to 3.99, 3.87 to 2.20, 2.06 to 0.17 mU . L -1 . min -1 . Insulin resistance was defined as being in the third tertile. TG levels in the men and women were 82.2 +/- 35.5 versus 56.4 +/- 30.1 mg/dL, P < .001. There were no sex difference in PH-LPL activity (8.9 +/- 2.5 vs 9.6 +/- 3.2 mmol/h per liter, P = .30) or S I (3.65 +/- 2.59 vs 3.23 +/- 1.89 L . mU -1 . min -1 , P = .49). Although 47% of the subjects were obese, only 4% of subjects had hypertriglyceridemia (TG > or =150 mg/dL). By 2 separate analyses, PH-LPL was a major determinant of TG levels. First, there was a significant inverse correlation between PH-LPL activity and TG levels (men: r = -0.46, P < .001; women: r = -0.28, P = .046). Second, in the multiple regression analysis with TG as the dependent variable and PH-LPL, age, sex, S I , and visceral adipose tissue as independent variables, adjusted R 2 was 54% and the effect of PH-LPL on TG levels was highly significant( P < .001). However, insulin resistance did not appear to influence PH-LPL activity. This is demonstrated in 3 ways: first, PH-LPL activity was not different in the S I tertiles (9.10 +/- 2.75, 9.52 +/- 2.91, 9.13 +/- 2.89 mmol/h per liter, P = .78); the correlation between PH-LPL and S I was not significant (men: r = 0.09, P = .51; women: r = -0.03, P = .78), and a multiple regression with PH-LPL as the dependent variable and age, S I , body mass index, and sex as independent variables, adjusted R 2 was <2% and the contribution of S I was not significant ( P = .53). Hence, in African Americans, increased PH-LPL activity is associated with a decrease in TG levels. The lack of an effect of insulin resistance on PH-LPL could allow LPL to clear TG even in the presence of insulin resistance and explain the coexistence of insulin resistance and normotriglyceridemia in African Americans.

Periwal V, Chow CC, Bergman RN, Ricks M, Vega GL, Sumner AE. Evaluation of quantitative models of the effect of insulin on lipolysis and glucose disposal. Am J Physiol Regul Integr Comp Physiol 295: R1089-R1096, 2008. First published August 6, 2008; doi:l0.1152/ajpregu.90426.2008.-The effects of insulin on the suppression of lipolysis are neither fully understood nor quantified. We examined a variety of mathematical models analogous to the minimal model of glucose disposal (MMG) to quantify the combined influence of insulin on lipolysis and glucose disposal during an insulin-modified frequently sampled intravenous glucose tolerance test. The tested models, which include two previously published ones, consisted of separate compartments for plasma free fatty acids (FFA), glucose, and insulin. They differed in the number of compartments and in the action of insulin to suppress lipolysis that decreased the plasma FFA level. In one category of models, a single insulin compartment acted on both glucose and FFA simultaneously. In a second category, there were two insulin compartments, each acting on FFA and glucose independently. For each of these two categories, we tested 11 variations of how insulin suppressed lipolysis. We also tested a model with an additional glucose compartment that acted on FFA. These 23 models were fit to the plasma FFA and glucose concentrations of 102 subjects individually. Using Bayesian model comparison methods, we selected the model that best balanced fit and minimized model complexity. In the best model, insulin suppressed lipolysis via a Hill function through a remote compartment that acted on both glucose and FFA simultaneously, and glucose dynamics obeyed the classic MMG. [ABSTRACT FROM AUTHOR]

African Americans often have normal high-density lipoprotein cholesterol (HDL-C) and low triglyceride levels despite insulin resistance and obesity. The higher than expected HDL-C levels are usually attributed to low levels of hepatic triglyceride lipase activity (HTGL). Factors that regulate HTGL in African Americans are not well delineated. In the current study, HTGL levels were examined in relation to body fat (body mass index (BMI) and waist circumference (WC)), insulin resistance indices (fasting plasma insulin and HOMA index) and adiponectin. Sixty-three African Americans (33 Men, 30 Women, median age 31 y, range 20-50 y, median BMI 28.6 kg/m², range 19.7-54.7 kg/m²) had anthropometry and measurement of post-heparin lipase activities (HTGL), plasma HDL-C, triglycerides and plasma adiponectin. HTGL correlated strongly with HDL-C (r =-0.52, P<0.0001) and adiponectin (r = -0.49, P<0.001). HTGL increased with BMI and WC (r =0.297, P=-0.018 and r =0.301, P=0.016, resp). Adiponectin correlated strongly with HDL-C (r =0.50, P<0.0001) and triglycerides (r = -0.493, P<0.001). Four multiple regression models predicted HTGL variability (P<0.001) in the study group: Model 1 with an adjusted R²=0.242 and a linear combination of adiponectin, BMI, and HOMA (log[sub e]); Model 2 (R²=0.229) with adiponectin + BMI + HOMA (log[sub e] + triglycerides (log[sub e]; Model 3 (R²=0.241) with adiponectin + age + BMI and Model 4 (R² =0.215) adiponectin + age + BMI + HOMA (logo + triglycerides (log[sub e]). It is apparent that about 23% of HTGL variability among African Americans can be explained by adiponectin levels in combination with markers of obesity and insulin resistance. In each model, the beta-coefficient for adiponectin with HTGL is in the range of 0.44 to 0.47 (P <0.002) rendering this parameter a major factor in HTGL variability. The data suggests that adiponectin is a strong determinant of HTGL levels and plasma triglyceride levels in African Americans. [ABSTRACT FROM AUTHOR]

Objectives: The goal of this study was to investigate the association between natriuretic peptides and body fat distribution in a multiethnic cohort. Background: Natriuretic peptides stimulate lipolysis, reduce weight gain, and promote adipocyte browning in animal models, but data are lacking in humans. Methods: A total of 2,619 participants without heart failure in the Dallas Heart Study underwent measurements of 1) B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP); and 2) body fat distribution by dual energy x-ray absorptiometry and magnetic resonance imaging. Cross-sectional associations of natriuretic peptides with adiposity phenotypes were examined after adjustment for age, sex, race, comorbidities, and body mass index. Results: Median BNP and NT-proBNP levels in the study cohort (mean age 44 years; 56% women, 48% African Americans, 32% obese) were 3.0 and 28.1 pg/ml, respectively. Natriuretic peptide levels above the median were associated with a more favorable body fat profile and less insulin resistance, including lower visceral fat, liver fat, and homeostasis model assessment of insulin resistance index, and increased lower body fat and higher adiponectin (p < 0.05 for each). In multivariable analyses, NT-proBNP remained inversely associated with visceral fat (beta coefficient = −0.08; p < 0.0001) and liver fat (beta coefficient = −0.14; p < 0.0001) and positively associated with lower body fat (beta coefficient = 0.07; p < 0.0001) independent of age, sex, race, and obesity status; findings were similar with BNP. Adjustment for body composition, homeostasis model assessment of insulin resistance index, circulating androgens, and adipocytokines did not attenuate the associations. Conclusions: Higher natriuretic peptide levels were independently associated with a favorable adiposity profile, characterized by decreased visceral and liver fat and increased lower body fat, suggesting a link between the heart and adipose tissue distribution mediated through natriuretic peptides. [Copyright &y& Elsevier]