Quantitation of Human Whole-Body Synthesis-Secretion Rates of Docosahexaenoic Acid and Eicosapentaenoate Acid from Circulating Unesterified α-Linolenic Acid at Steady State.

The rate at which dietary α-linolenic acid (ALA) is desaturated and elongated to its longer-chain n-3 polyunsaturated fatty acid (PUFA) in humans is not agreed upon. In this study, we applied a methodology developed using rodents to investigate the whole-body, presumably hepatic, synthesis-secretion rates of esterified n-3 PUFA from circulating unesterified ALA in 2 healthy overweight women after 10 weeks of low-linoleate diet exposure. During continuous iv infusion of d5-ALA, 17 arterial blood samples were collected from each subject at -10, 0, 10, 20, 40, 60, 80, 100, 120, 150, 180, and 210 min, and at 4, 5, 6, 7, and 8 h after beginning infusion. Plasma esterified d5-n-3 PUFA concentrations were plotted against the infusion time and fit to a sigmoidal curve using nonlinear regression. These curves were used to estimate kinetic parameters using a kinetic analysis developed using rodents. Calculated synthesis-secretion rates of esterified eicosapentaenoate, n-3 docosapentaenoate, docosahexaenoic acid, tetracosapentaenate, and tetracosahexaenoate from circulating unesterified ALA were 2.1 and 2.7; 1.7 and 5.3; 0.47 and 0.27; 0.30 and 0.30; and 0.32 and 0.27 mg/day for subjects S01 and S02, respectively. This study provides new estimates of whole-body synthesis-secretion rates of esterified longer-chain n-3 PUFA from circulating unesterified ALA in human subjects. This method now can be extended to study factors that regulate human whole-body PUFA synthesis-secretion in health and disease.

Calorie for Calorie, Dietary Fat Restriction Results in More Body Fat Loss than Carbohydrate Restriction in People with Obesity.

Dietary carbohydrate restriction has been purported to cause endocrine adaptations that promote body fat loss more than dietary fat restriction. We selectively restricted dietary carbohydrate versus fat for 6 days following a 5-day baseline diet in 19 adults with obesity confined to a metabolic ward where they exercised daily. Subjects received both isocaloric diets in random order during each of two inpatient stays. Body fat loss was calculated as the difference between daily fat intake and net fat oxidation measured while residing in a metabolic chamber. Whereas carbohydrate restriction led to sustained increases in fat oxidation and loss of 53 ± 6 g/day of body fat, fat oxidation was unchanged by fat restriction, leading to 89 ± 6 g/day of fat loss, and was significantly greater than carbohydrate restriction (p = 0.002). Mathematical model simulations agreed with these data, but predicted that the body acts to minimize body fat differences with prolonged isocaloric diets varying in carbohydrate and fat.

Weight Loss Programs May Have Beneficial or Adverse Effects on Fat Mass and Insulin Sensitivity in Overweight and Obese Black Women.

OBJECTIVE: Weight loss interventions have produced little change in insulin sensitivity in black women, but mean data may obscure metabolic benefit to some and adverse effects for others. Accordingly, we analyzed insulin sensitivity relative to fat mass change following a weight loss program. DESIGN AND METHODS: Fifty-four black women (BMI range 25.9 to 54.7 kg/m2) completed the 6-month program that included nutrition information and worksite exercise facilities. Fat mass was measured by dual-energy X-ray absorptiometry, and insulin sensitivity index (SI) was calculated from an insulin-modified intravenous glucose tolerance test using the minimal model. RESULTS: Baseline SI (range 0.74 to 7.58 l/mU-1•min-1) was inversely associated with fat mass (r = -0.516, p < 0.001), independent of age. On average, subjects lost fat mass (baseline 40.8 ± 12.4 to 39.4 ± 12.6 kg [mean ± SD], P < 0.01), but 17 women (32 %) actually gained fat mass. SI for the group was unchanged (baseline 3.3 ± 1.7 to 3.2 ± 1.6, P = 0.67). However, the tertile with greatest fat mass loss (-3.6 kg, range -10.7 to -1.7 kg) improved insulin sensitivity (SI +0.3 ± 1.2), whereas the tertile with net fat mass gain (+0.9 kg, range -0.1 to +3.8 kg) had reduced insulin sensitivity (SI -0.7 ± 1.3) from baseline values (P < 0.05 by ANOVA). CONCLUSIONS: Black women in a weight loss program who lose fat mass may have improved insulin sensitivity, but fat mass gain with diminished sensitivity is common. Additional support for participants who fail to achieve fat mass loss early in an intervention may be required for success.

Free fatty acid flux in African-American and Caucasian adults--effect of sex and race.

OBJECTIVE: Obesity, insulin resistance, and diabetes disproportionately affect African-American (AA) women. Abnormal adipose tissue free fatty acid (FFA) release is associated with these conditions. Resting energy expenditure (REE) and sex predict FFA release in Caucasians, but whether this is true in AA is unknown. The sex-specific relationships between FFA release, REE, and race was compared. DESIGN AND METHODS: 100 adults (47% AA, 50% male, age 32 ± 8 years [mean ± SD]) from three different centers underwent duplicate measures of FFA release ([U-13C] palmitate) and REE (indirect calorimetry). Body composition was determined by DXA and abdominal imaging. RESULTS: AA participants had lower REE, but similar FFA concentrations and flux compared with Caucasian participants. The significant predictors of palmitate release were REE, sex, and race. REE and FFA flux were correlated in both sexes and both races. In a multiple linear regression analysis with palmitate flux as the dependent variable and REE, sex, race, total fat mass, fat-free mass, and insulin as independent variables, REE was the only independent predictor of FFA release in men. Both REE and race predicted palmitate flux in women. CONCLUSIONS: FFA flux is related to REE, but the relationship differs in AA and Caucasian women.

Fatty acid and very low density lipoprotein metabolism in obese African American and Caucasian women with type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is associated with increased plasma triglyceride (TG) concentrations, but African Americans (AA) have lower plasma TG than Caucasians (CC). We evaluated the hypothesis that obese AA women have lower plasma TG than obese CC women do because of differences in lipid kinetics. Eleven AA and 11 CC obese women with T2DM, matched on body mass index (BMI) (AA = 37 ± 1, CC = 37 ± 1 kg/m(2)), age, duration of diabetes, percentage body fat, and insulin sensitivity (S(I), determined by an intravenous glucose tolerance test), were studied. Plasma TG concentration (AA = 1.14 ± 0.11, CC = 1.88 ± 0.18 mmol/l), FFA rate of appearance (R(a)) into plasma (AA = 419 ± 27, CC = 503 ± 31 µmol·min(-1)), and total VLDL-TG secretion rate (AA = 18 ± 2, CC = 29 ± 4 µmol·min(-1)) were lower in AA than CC women (all P < 0.05). In contrast, plasma total apolipoprotein (apo)B-100 concentration (AA = 1,542 ± 179, CC = 1,620 ± 118 nmol/l) and VLDL-apoB-100 secretion rate (AA = 1.3 ± 0.1, CC = 1.3 ± 0.1 nmol·min(-1)) were similar in both groups, so the molar ratio of VLDL-TG secretion rate to VLDL-apoB-100 secretion rate was lower in AA women than in CC women. VLDL-TG concentration was lower in AA women due to lower total VLDL-TG secretion rate. However, the VLDL-apoB-100 secretion rate was the same in both groups, demonstrating that AA women secrete smaller VLDL particles containing less TG than do CC women.

Bayesian functional integral method for inferring continuous data from discrete measurements.

Inference of the insulin secretion rate (ISR) from C-peptide measurements as a quantification of pancreatic ß-cell function is clinically important in diseases related to reduced insulin sensitivity and insulin action. ISR derived from C-peptide concentration is an example of nonparametric Bayesian model selection where a proposed ISR time-course is considered to be a "model". An inferred value of inaccessible continuous variables from discrete observable data is often problematic in biology and medicine, because it is a priori unclear how robust the inference is to the deletion of data points, and a closely related question, how much smoothness or continuity the data actually support. Predictions weighted by the posterior distribution can be cast as functional integrals as used in statistical field theory. Functional integrals are generally difficult to evaluate, especially for nonanalytic constraints such as positivity of the estimated parameters. We propose a computationally tractable method that uses the exact solution of an associated likelihood function as a prior probability distribution for a Markov-chain Monte Carlo evaluation of the posterior for the full model. As a concrete application of our method, we calculate the ISR from actual clinical C-peptide measurements in human subjects with varying degrees of insulin sensitivity. Our method demonstrates the feasibility of functional integral Bayesian model selection as a practical method for such data-driven inference, allowing the data to determine the smoothing timescale and the width of the prior probability distribution on the space of models. In particular, our model comparison method determines the discrete time-step for interpolation of the unobservable continuous variable that is supported by the data. Attempts to go to finer discrete time-steps lead to less likely models.

Relationship between treatment preference and weight loss in the context of a randomized controlled trial.

Randomized controlled trials (RCTs) are considered the gold standard used to assess the efficacy of treatment. While a well implemented RCT can produce an unbiased estimate of the relative difference between treatment groups, the generalizability of these findings may be limited. Specific threats to the external validity include treatment preference. The purposes of this study were to: (i) assess whether receiving one's treatment preference was associated with weight loss and retention and (ii) whether receiving one's treatment preference modified the relationship between the treatments and weight loss. Treatment preference was assessed in 250 subjects prior to but independent of randomization into either low-carbohydrate or low-fat diets. Treatment preference was a predictor of weight loss (P = 0.002) but not retention (P = 0.90). Participants who received their preference lost less weight (-7.7 kg, 95% confidence interval (CI): -9.3 to -6.1) than participants who did not receive their preference (-9.7 kg, 95% CI: -11.4 to -8.1) and participants who did not report a strong preference at baseline (-11.2 kg, 95% CI: -12.6 to -9.7) (P = 0.04 and P = 0.0004, respectively). Treatment preference did not modify the effect of the treatment on weight loss. Contrary to conceptual predictions, this study failed to identify an interaction between treatment preference and weight loss in the setting of a randomized trial. Until treatment preference effects are definitively ruled out in this domain, future studies might consider stratifying their randomization procedure by treatment preference rather than excluding participants with strong treatment preferences.

Metabolic syndrome does not detect metabolic risk in African men living in the U.S.

OBJECTIVE: Metabolic risk and metabolic syndrome (MetSyn) prevalence were compared in Africans who immigrated to the U.S. and African Americans. If MetSyn were an effective predictor of cardiometabolic risk, then the group with a worse metabolic risk profile would have a higher rate of MetSyn. RESEARCH DESIGN AND METHODS: Cross-sectional analyses were performed on 95 men (39 Africans, 56 African Americans, age 38 ± 6 years [mean ± SD]). Glucose tolerance was determined by oral glucose tolerance test, visceral adipose tissue (VAT) was determined by computerized tomography, and MetSyn was determined by the presence of three of five factors: central obesity, hypertriglyceridemia, low levels of HDL cholesterol, hypertension, and fasting hyperglycemia. RESULTS: MetSyn prevalence was similar in Africans and African Americans (10 vs. 13%, P = 0.74), but hypertension, glycemia (fasting and 2-h glucose), and VAT were higher in Africans. CONCLUSIONS: African immigrants have a worse metabolic profile than African Americans but a similar prevalence of MetSyn. Therefore, MetSyn may underpredict metabolic risk in Africans.

Higher acute insulin response to glucose may determine greater free fatty acid clearance in African-American women.

CONTEXT: Obesity and diabetes are more common in African-Americans than whites. Because free fatty acids (FFA) participate in the development of these conditions, studying race differences in the regulation of FFA and glucose by insulin is essential. OBJECTIVE: The objective of the study was to determine whether race differences exist in glucose and FFA response to insulin. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at a clinical research center. PARTICIPANTS: Thirty-four premenopausal women (17 African-Americans, 17 whites) matched for age [36 ± 10 yr (mean ± sd)] and body mass index (30.0 ± 6.7 kg/m²). INTERVENTIONS: Insulin-modified frequently sampled iv glucose tolerance tests were performed with data analyzed by separate minimal models for glucose and FFA. MAIN OUTCOME MEASURES: Glucose measures were insulin sensitivity index (S(I)) and acute insulin response to glucose (AIRg). FFA measures were FFA clearance rate (c(f)). RESULTS: Body mass index was similar but fat mass was higher in African-Americans than whites (P < 0.01). Compared with whites, African-Americans had lower S(I) (3.71 ± 1.55 vs. 5.23 ± 2.74 [×10⁻4 min⁻¹/(microunits per milliliter)] (P = 0.05) and higher AIRg (642 ± 379 vs. 263 ± 206 mU/liter⁻¹ · min, P < 0.01). Adjusting for fat mass, African-Americans had higher FFA clearance, c(f) (0.13 ± 0.06 vs. 0.08 ± 0.05 min⁻¹, P < 0.01). After adjusting for AIRg, the race difference in c(f) was no longer present (P = 0.51). For all women, the relationship between c(f) and AIRg was significant (r = 0.64, P < 0.01), but the relationship between c(f) and S(I) was not (r = -0.07, P = 0.71). The same pattern persisted when the two groups were studied separately. CONCLUSION: African-American women were more insulin resistant than white women, yet they had greater FFA clearance. Acutely higher insulin concentrations in African-American women accounted for higher FFA clearance.

Change in food cravings, food preferences, and appetite during a low-carbohydrate and low-fat diet.

The study objective was to evaluate the effect of prescribing a low-carbohydrate diet (LCD) and a low-fat diet (LFD) on food cravings, food preferences, and appetite. Obese adults were randomly assigned to a LCD (n = 134) or a LFD (n = 136) for 2 years. Cravings for specific types of foods (sweets, high-fats, fast-food fats, and carbohydrates/starches); preferences for high-sugar, high-carbohydrate, and low-carbohydrate/high-protein foods; and appetite were measured during the trial and evaluated during this secondary analysis of trial data. Differences between the LCD and LFD on change in outcome variables were examined with mixed linear models. Compared to the LFD, the LCD had significantly larger decreases in cravings for carbohydrates/starches and preferences for high-carbohydrate and high-sugar foods. The LCD group reported being less bothered by hunger compared to the LFD group. Compared to the LCD group, the LFD group had significantly larger decreases in cravings for high-fat foods and preference for low-carbohydrate/high-protein foods. Men had larger decreases in appetite ratings compared to women. Prescription of diets that promoted restriction of specific types of foods resulted in decreased cravings and preferences for the foods that were targeted for restriction. The results also indicate that the LCD group was less bothered by hunger compared to the LFD group and that men had larger reductions in appetite compared to women.

The triglyceride/high-density lipoprotein cholesterol ratio fails to predict insulin resistance in African-American women: an analysis of Jackson Heart Study.

BACKGROUND: Compared to whites, insulin-resistant African Americans have worse outcomes. Screening programs that could identify insulin resistance early enough for intervention to affect outcome often rely on triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels. Racial differences in TG and HDL-C may compromise the efficacy of these programs in African Americans. A recommendation currently exists to use the TG/HDL-C ratio ≥2.0 to predict insulin resistance in African Americans. The validity of this recommendation needs examination. Therefore, our aim was to determine the ability of TG/HDL-C ratio to predict insulin resistance in African Americans. METHODS: In 1,903 African Americans [895 men, 1,008 women, age 55 ± 12 years, mean ± standard deviation (SD), range 35-80 years, body mass index (BMI) 31.0 ± 6.4 kg/m(2), range 18.5-55 kg/m(2)] participating in the Jackson Heart Study, a population-based study of African Americans, Jackson, Mississippi tricounty region, insulin resistance was defined by the upper quartile (≥4.43) of homeostasis model assessment of insulin resistance (HOMA-IR). An area under the receiver operating characteristic curve (AUC-ROC) of >0.70 was required for prediction of insulin resistance by TG/HDL-C. The optimal test cutoff was determined by the Youden index. RESULTS: HOMA-IR was similar in men and women (3.40 ± 2.03 vs. 3.80 ± 2.46, P = 0.60). Women had lower TG (94 ± 49 vs. 109 ± 65 mg/dL P < 0.001) and TG/HDL-C (1.9 ± 1.4 vs. 2.7 ± 2.1, P < 0.001). For men, AUC-ROC for prediction of insulin resistance by TG/HDL-C was: 0.77 ± 0.01, mean ± standard error (SE), with an optimal cutoff of ≥2.5. For women, the AUC-ROC was 0.66 ± 0.01, rendering an optimal cutoff indefinable. When women were divided in two groups according to age, 35-50 years and 51-80 years, the results did not change. CONCLUSIONS: In African-American men, the recommended TG/HDL-C threshold of 2.0 should be adjusted upward to 2.5. In African-American women, TG/HDL-C cannot identify insulin resistance. The Jackson Heart Study can help determine the efficacy of screening programs in African-Americans.

Effect of moderate diet-induced weight loss and weight regain on cardiovascular structure and function.

OBJECTIVES: The objective of this prospective, single-site, 2-year dietary intervention study was to evaluate the effects of moderate weight reduction and subsequent partial weight regain on cardiovascular structure and function. BACKGROUND: Obesity is associated with adverse cardiac and vascular structural and functional alterations. METHODS: Sixty obese subjects (age 46 + or - 10 years, body mass index 37 + or - 3 kg/m(2)) were evaluated during their participation in a weight loss study. Cardiac and vascular ultrasound studies were performed at baseline and at 3, 6, 12, and 24 months after start of intervention. RESULTS: Forty-seven subjects (78%) completed the entire 2-year follow-up. Average weight loss was 7.3 + or - 4.0%, 9.2 + or - 5.6%, 7.8 + or - 6.6%, and 3.8 + or - 7.9% at 3, 6, 12, and 24 months, respectively. Age- and sex-adjusted mixed linear models revealed that the follow-up time was significantly associated with decreases in weight (p < 0.0001), left ventricular (LV) mass (p = 0.001), and carotid intima-media thickness (p < 0.0001); there was also significant improvement in LV diastolic (p < or = 0.0001) and systolic (p = 0.001) function. Partial weight regain diminished the maximal observed beneficial effects of weight loss, however cardiovascular parameters measured at 2 years still showed a net benefit compared with baseline. CONCLUSIONS: Diet-induced moderate weight loss in obese subjects is associated with beneficial changes in cardiovascular structure and function. Subsequent weight regain is associated with partial loss of these beneficial effects. (The Safety and Effectiveness of Low and High Carbohydrate Diets; NCT00079547).

Effect of lifestyle intervention on metabolic coronary heart disease risk factors in obese older adults.

BACKGROUND: Coronary heart disease (CHD) risk factors increase with age and body mass index (BMI; in kg/m2). However, whether lifestyle intervention ameliorates metabolic CHD risk factors in obese older adults is unknown. OBJECTIVE: The objective was to determine whether lifestyle intervention improves metabolic CHD risk factors in obese older adults. DESIGN: A 6-mo outpatient randomized controlled trial was conducted in obese (BMI >or= 30) older (>or=65 y) adults randomly assigned to diet and exercise therapy (treatment group; n = 17) or no therapy (control group; n = 10). The main outcomes were CHD risk factors. RESULTS: Body weight decreased by 8.4% (8.2 kg) in the treatment group; weight did not change significantly (0.7 kg) in the control group (P < 0.001 between groups). Changes between the control and treatment groups, respectively, in waist circumference (1 and -10 cm), plasma glucose (4 and -4 mg/dL), serum triacylglycerols (0 and -45 mg/dL), and systolic (-2 and -10 mm Hg) and diastolic (0 and -8 mm Hg) blood pressure were different (P < 0.05 for all). The number of subjects with the metabolic syndrome decreased by 59% in the treatment group but did not change significantly in the control group (P < 0.05). Serum free fatty acids increased by 10 micromol/L in the control group and decreased by 99 micromol/L in the treatment group (P < 0.05). Changes between the control and treatment groups, respectively, in C-reactive protein (0.8 and -2.5 mg/L) and interleukin 6 (1.6 and -2.4 pg/mL) were different (P < 0.05 for both). CONCLUSIONS: Lifestyle intervention decreases multiple metabolic CHD risk factors simultaneously in obese older adults.

An evaluation of the atkins' diet.

Low-carbohydrate (LC) weight-reducing diets are popular choices for self-dieters. Eighteen adults (BMI >/= 25 kg/m(2)) were enrolled in this short-term longitudinal study to evaluate dietary intake and weight on their "usual" diets and LC diet. Subjects were instructed to follow the first two phases of the diet described in Dr. Atkins' New Diet Revolution (2 weeks each). Total daily intake of calories and nutrients were calculated from 3-day food diaries. Body weight was measured at the end of each 2-week diet session. All enrolled subjects completed the study (age = 39.8 +/- 8.1 years, BMI = 36.6 +/- 6.6 kg/m(2)). Mean caloric intakes were 1400 +/- 472 kcal/day (Induction diet) and 1558 +/- 490 kcal/day (Ongoing Weight Loss diet) both p