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1.  Genetic Determinant for Amino Acid Metabolites and Changes in Body Weight and Insulin Resistance in Response to Weight-loss Diets: the POUNDS LOST Trial 
Circulation  2013;127(12):10.1161/CIRCULATIONAHA.112.000586.
Circulating branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) were recently related to insulin resistance and diabetes in prospective cohorts. We tested the effects of a genetic determinant of BCAA/AAA ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial.
Methods and Results
We genotyped BCAA/AAA ratio associated variant rs1440581 near PPM1K gene in 734 overweight or obese adults who were randomly assigned to one of four diets varying in macronutrient content. At 6 months, we observed that dietary fat significantly modified genetic effects on changes in weight, fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR), after adjustment for confounders (all P for interaction ≤ 0.006). Further adjustment for weight change did not appreciably change the interactions for fasting insulin and HOMA-IR. In the high-fat diet group, the C allele was related to less weight loss and smaller decreases in serum insulin and HOMA-IR (all P ≤ 0.02 in an additive pattern); while an opposite genotype effect on changes in insulin and HOMA-IR was observed in low-fat diet group (P = 0.02 and 0.04, respectively). At 2 years, the gene–diet interactions remained significant for weight loss (P = 0.008); but became null for changes in serum insulin and HOMA-IR due to weight regain.
Individuals carrying C allele of BCAA/AAA ratio associated variant rs1440581 may benefit less in weight loss and improvement of insulin sensitivity than those without this allele when undertake an energy restricted high-fat diet.
PMCID: PMC3860590  PMID: 23446828
Branched-chain amino acids; gene-diet interaction; insulin resistance; weight loss
2.  The Relationship of Waist Circumference and BMI to Visceral, Subcutaneous, and Total Body Fat: Sex and Race Differences 
Obesity (Silver Spring, Md.)  2010;19(2):402-408.
The purpose of this study was to examine sex and race differences in the relationship between anthropometric measurements and adiposity in white and African-American (AA) adults. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured with computed tomography (CT). Fat mass (FM) was measured with dual-energy-X-ray absorptiometry (DXA). Correlation coefficients were used to assess the relationship of waist circumference (WC) and BMI to VAT, SAT, and FM within sex-by-race groups. General linear models were used to compare relationships between WC or BMI, and adiposity across sex and race, within age groups (18–39 and 40–64 years). The sample included 1,667 adults (men: 489 white; 120 AA; women: 666 white, 392 AA). WC and BMI correlations were highest for FM and SAT compared to VAT. Women had higher FM levels than men regardless of WC, but the sex difference in FM was attenuated in younger AA adults with a high BMI. For a given level of WC or BMI, women had higher levels of SAT than men; however, significant interactions indicated that the relationship was not consistent across all levels of BMI and WC. Sex and race differences in VAT varied significantly with WC and BMI. In general, white adults had higher levels of VAT than AA adults at higher levels of BMI and WC. Sex differences, and in some instances race differences, in the relationships between anthropometry and fat-specific depots demonstrate that these characteristics need to be considered when predicting adiposity from WC or BMI.
PMCID: PMC3960785  PMID: 20948514
3.  Consistency of fat mass–fat-free mass relationship across ethnicity and sex groups 
The British journal of nutrition  2010;105(8):1272-1276.
The model developed by Forbes (1987) of how body fat mass (FM) and fat-free mass (FFM) change during periods of weight loss or gain (Δ body weight (BW)) assumed that they change in relationship to a constant C = 10·4, where ΔFFM/ΔBW = 10·4/(10·4 + FM). Forbes derived C based on aggregated, cross-sectional data from a small sample of women. The objective of the present study was to reanalyse the relationship described by Forbes and to explore whether this relationship is consistent across ethnicity and sex groups using cross-sectional data from a large sample of white and African-American men and women. Baseline data from white and African-American men and women aged 18–60 years, who participated in a clinical study at the Pennington Biomedical Research Center since 2001 and who underwent dual-energy X-ray absorptiometry scans, were available for analysis. To overcome differences in BMI distributions among the ethnicity-by-sex groups, a stratified random sample of participants was selected within each group such that numbers in each BMI category (<25, 25–29·9, 30–34·9, 35–39·9, 40+ kg/m2) were proportional to those within the group with the smallest sample size, yielding a sample of 1953 individuals. Linear regression models assessed the FM–FFM relationship across the four ethnicity-by-sex groups. The FM–FFM relationship varied little by ethnicity (P=0·57) or by sex (P=0·26). The constant describing the FM–FFM relationship was estimated to be 9·7 (95 % CI 9·0, 10·3). In conclusion, results from our large, biethnic sample of men and women found a FM–FFM relationship very close to that originally described by Forbes, absent of significant variability by ethnicity or sex.
PMCID: PMC3960800  PMID: 21156087
Body composition; Obesity; Weight loss
4.  Energy and Fructose From Beverages Sweetened With Sugar or High-Fructose Corn Syrup Pose a Health Risk for Some People12 
Advances in Nutrition  2013;4(2):220-225.
Sugar intake in the United States has increased by >40 fold since the American Revolution. The health concerns that have been raised about the amounts of sugar that are in the current diet, primarily as beverages, are the subject of this review. Just less than 50% of the added sugars (sugar and high-fructose corn syrup) are found in soft drinks and fruit drinks. The intake of soft drinks has increased 5-fold between 1950 and 2000. Most meta-analyses have shown that the risk of obesity, diabetes, cardiovascular disease, and metabolic syndrome are related to consumption of beverages sweetened with sugar or high-fructose corn syrup. Calorically sweetened beverage intake has also been related to the risk of nonalcoholic fatty liver disease, and, in men, gout. Calorically sweetened beverages contribute to obesity through their caloric load, and the intake of beverages does not produce a corresponding reduction in the intake of other food, suggesting that beverage calories are “add-on” calories. The increase in plasma triglyceride concentrations by sugar-sweetened beverages can be attributed to fructose rather than glucose in sugar. Several randomized trials of sugar-containing soft drinks versus low-calorie or calorie-free beverages show that either sugar, 50% of which is fructose, or fructose alone increases triglycerides, body weight, visceral adipose tissue, muscle fat, and liver fat. Fructose is metabolized primarily in the liver. When it is taken up by the liver, ATP decreases rapidly as the phosphate is transferred to fructose in a form that makes it easy to convert to lipid precursors. Fructose intake enhances lipogenesis and the production of uric acid. By worsening blood lipids, contributing to obesity, diabetes, fatty liver, and gout, fructose in the amounts currently consumed is hazardous to the health of some people.
PMCID: PMC3649102  PMID: 23493538
5.  Ethnic-Specific BMI and Waist Circumference Thresholds 
Obesity (Silver Spring, Md.)  2011;19(6):1272-1278.
BMI and waist circumference (WC) are used to identify individuals with elevated obesity-related health risks. The current thresholds were derived largely in populations of European origin. This study determined optimal BMI and WC thresholds for the identification of cardiometabolic risk among white and African-American (AA) adults. The sample included 2,096 white women, 1,789 AA women, 1,948 white men, and 643 AA men aged 18–64 years. Elevated cardiometabolic risk was defined as ≥2 risk factors (blood pressure ≥130/85 mm Hg; glucose ≥100 mg/dl; triglycerides ≥150 mg/dl; high-density lipoprotein-cholesterol <40 mg/dl (men) or <50 mg/dl (women)). Receiver Operating Characteristic (ROC) curves were used to identify optimal BMI and WC thresholds in each sex-by-ethnicity group. The optimal BMI thresholds were 30 kg/m2 in white women, 32.9 kg/m2 in AA women, 29.1 kg/m2 white men, and 30.4 kg/ m2 in AA men, whereas optimal WC thresholds were 91.9 cm in white women, 96.8 cm in AA women, 99.4 in white men, and 99.1 cm in AA men. The sensitivities at the optimal thresholds ranged from 63.5 to 68.5% for BMI and 68.4 to 71.0% for WC and the specificities ranged from 64.2 to 68.8% for BMI and from 68.5 to 71.0% for WC, respectively. In general, the optimal BMI and WC thresholds approximated currently used thresholds in men and in white women. There are no apparent ethnic differences in men; however, in AA women the optimal BMI and WC values are ~3 kg/m2 and 5 cm higher than in white women.
PMCID: PMC3933952  PMID: 21212770
6.  Depression as a Predictor of Weight Regain Among Successful Weight Losers in the Diabetes Prevention Program 
Diabetes Care  2013;36(2):216-221.
To determine whether depression symptoms or antidepressant medication use predicts weight regain in overweight individuals with impaired glucose tolerance (IGT) who are successful with initial weight loss.
A total of 1,442 participants who successfully lost at least 3% of their baseline body weight after 12 months of participation in the randomized controlled Diabetes Prevention Program (DPP) continued in their assigned treatment group (metformin, intensive lifestyle, or placebo) and were followed into the Diabetes Prevention Program Outcome Study (DPPOS). Weight regain was defined as a return to baseline DPP body weight. Participant weight and antidepressant medication use were assessed every 6 months. Depression symptoms (Beck Depression Inventory [BDI] score ≥11) were assessed every 12 months.
Only 2.7% of the overall cohort had moderate to severe depression symptoms at baseline; most of the participants with BDI score ≥11 had only mild symptoms during the period of observation. In unadjusted analyses, both depression symptoms (hazard ratio 1.31 [95% CI 1.03–1.67], P = 0.03) and antidepressant medication use at either the previous visit (1.72 [1.37–2.15], P < 0.0001) or cumulatively as percent of visits (1.005 [1.002–1.008], P = 0.0003) were predictors of subsequent weight regain. After adjustment for multiple covariates, antidepressant use remained a significant predictor of weight regain (P < 0.0001 for the previous study visit; P = 0.0005 for the cumulative measure), while depression symptoms did not.
In individuals with IGT who do not have severe depression and who initially lose weight, antidepressant use may increase the risk of weight regain.
PMCID: PMC3554307  PMID: 23002085
7.  Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors 
To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes.
Methods and Results
CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
PMCID: PMC3908828  PMID: 23175674
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone
9.  Zonisamide for Weight Reduction in Obese Adults A 1-Year Randomized Controlled Trial 
Archives of internal medicine  2012;172(20):1557-1564.
Obese individuals who have failed to achieve adequate weight loss with lifestyle changes have limited non-surgical therapeutic options. We evaluated the efficacy and tolerability of zonisamide, an antiepileptic drug, for enhancing weight loss in obese patients receiving diet and lifestyle guidance.
This was a 1-year randomized, double-blind, placebo-controlled trial conducted between January 2006 and September 2011 at Duke University Medical Center. Patients were 225 obese (mean [SD] body mass index 37.6 [4.9]) women (134 [59.6%]) and men (91 [40.4%]) without diabetes. Interventions were daily dosing with placebo (n=74), zonisamide 200 mg (n=76), orzonisamide 400 mg (n=75), in addition to diet and lifestyle counseling by a dietitian for 1 year. Primary outcome was change in body weight at 1-year.
Of the 225 randomized patients, 218 (97%) provided 1-year follow-up assessments. Change(least-squares mean) in body weight was -4.0 kg (−3.7%; 95% CI, −5.8 kg to −2.3 kg) for placebo, −4.4 kg (−3.9%; −6.1 to −2.6, P=.79vs placebo) for zonisamide 200 mg, and −7.3 kg (−6.8%; −9.0 to −5.6, P=.009vs placebo) for zonisamide 400 mg. In the categorical analysis,23 (31%) on placebo, 26 (34%; P=.71) on zonisamide 200 mg, and 41 (55%; P=.007) onzonisamide 400 mg achieved ≥5% weight loss; for ≥10% weight loss, the corresponding numbers were 6 (8%), 17 (22%; P=.022), and 24 (32%; P=.001). Gastrointestinal, nervous system and psychiatric adverse events occurred at a higher incidence with zonisamide than with placebo.
Zonisamide 400 mg/d moderately enhanced weight loss achieved with diet and lifestyle counseling, but had a high incidence of adverse events.
PMCID: PMC3753218  PMID: 23147455
randomized controlled trial; obesity; weight loss; antiobesity drugs; weight loss drugs; zonisamide; antiepileptic drugs
10.  Anthropometric Markers of Obesity and Mortality in White and African American Adults: The Pennington Center Longitudinal Study 
Obesity (Silver Spring, Md.)  2013;21(5):1070-1075.
The purpose of this study was to determine the association between anthropometric measures of obesity and all-cause mortality in white and African American men and women. The sample included 14,343 adults 18 to 89 years of age. Height, weight, and waist and hip circumferences were measured, and the BMI (kg/m2), body adiposity index (BAI = ([hip circumference in centimeters]/[height in meters])1.5–18), waist-to-height ratio (WHtR) and waist-to-hip ratio (WHR) were computed. Vital status of the participants was determined from linkage with the National Death Index through 2009. Cox regression was used to assess the association between anthropometry and all1cause mortality, adjusting for age, sex, year of baseline examination, study code, smoking status, alcohol consumption and physical activity. Hazard ratios (HR) are expressed per standard deviation of each variable. A total of 438 deaths occurred during 120,637 person-years of follow-up. All anthropometric markers demonstrated significant associations with all-cause mortality in white subjects. In multivariable-adjusted models, BMI (HR 1.34; 95% CI: 1.19 - 1.50), waist circumference (1.41; 1.25 - 1.60), BAI (1.34; 1.17 - 1.53), WHtR (1.46; 1.28 - 1.65) and WHR (1.40; 1.23 - 1.61) all demonstrated significant relationships with mortality in white participants, but not in African Americans. In categorical analyses, there was a significant association between BMI status and mortality in whites but not African Americans. However, the risk associated with elevated waist circumference was almost identical in whites (1.49; 1.15 – 1.94) and African Americans (1.60; 1.06 – 2.40). In summary, this study has demonstrated race differences in the association between anthropometry and all-cause mortality.
PMCID: PMC3695407  PMID: 23784912
11.  Patterns of Weight Change Associated with Long-Term Weight Change and Cardiovascular Disease Risk Factors in the Look AHEAD Study 
Obesity (Silver Spring, Md.)  2012;20(10):2048-2056.
This paper provides an assessment of the associations that weight loss patterns during the first year of an intensive lifestyle intervention have with four year maintenance and health outcomes. Two components described patterns of weight change during the first year of intervention: one reflected the typical pattern of weight loss over the 12 months, but distinguished those who lost larger amounts across the monthly intervals from those who lost less. The second component reflected the weight change trajectory, and distinguished a pattern of initial weight loss followed by regain versus a more sustained pattern of weight loss 2,438 individuals aged 45–76 years with type 2 diabetes mellitus, who enrolled in the weight loss intervention of a randomized clinical trial, were assigned scores according to how their weight losses reflected these patterns. Relationships these scores had with weight losses and health outcomes (glycosolated hemoglobin – HbA1c; systolic blood pressure, HDL-cholesterol, and triglycerides) over four years were described. Both individuals who had larger month-to-month weight losses in year 1 and whose weight loss was more sustained during the first year had better maintenance of weight loss over four years, independent of characteristics traditionally linked to weight loss success (p<0.001). While relationships with year 4 weight loss were stronger, the pattern of larger monthly weight loss during year 1 was also independently predictive of year 4 levels of HbA1c, HDL-cholesterol, and systolic blood pressure.
PMCID: PMC3632374  PMID: 22327053
weight loss; type 2 diabetes mellitus; principal components analysis
12.  Effect of Dietary Composition of Weight Loss Diets on High Sensitivity C-Reactive Protein: The Randomized POUNDS LOST Trial 
Obesity (Silver Spring, Md.)  2013;21(4):681-689.
Overweight and obesity are associated with increased high sensitivity C-reactive protein (hsCRP) levels. The purpose of this study was to determine if weight loss diets differing in fat, protein, or carbohydrate composition differentially reduce hsCRP. POUNDS (Preventing Overweight Using Novel Dietary Strategies) LOST was a two-year trial of overweight and obese adults randomly allocated to one of four weight loss diets with targeted percentages of energy derived from fat, protein, and carbohydrates (20,15,65%;20,25,55%;40,15,45%;40,25,35%, respectively). hsCRP was measured at baseline, 6, and 24 months among 710 participants, and adiposity as measured by dual X-ray absorptiometry (N=340) or abdominal computed tomography (N=126) was correlated with hsCRP change. At 6 months, hsCRP was reduced in all trial participants by −24.7% (IQR +7%,−50%), weight by −6.7% (IQR −3%,−11%), and waist circumference by −6.0% (IQR −3%,−10%) (all P<.002), with no significant differences according to dietary composition. The percent change in hsCRP at 6 and 24 months correlated modestly with change in weight, waist circumference, fasting insulin, fasting glucose, HOMA, and most lipid levels. Reductions in hsCRP persisted despite an approximate 50% regain of weight by 24 months. The percent change in hsCRP at 24 months significantly correlated with changes in total body fat (r=0.42), total abdominal adiposity (r=0.52), subcutaneous abdominal adiposity (r=0.52), visceral adiposity (r=0.47), and hepatic tissue density (r=−0.34) (all P<0.0006). In conclusion, weight loss decreased hsCRP by similar magnitude, irrespective of dietary composition. Clinicians concerned about inflammation and cardiovascular risk should recommend weight loss diets most likely to succeed for their patients.
PMCID: PMC3671388  PMID: 23712970
13.  Effect of Dietary Protein Content on Weight Gain, Energy Expenditure, and Body Composition During Overeating 
The role of diet composition in response to overeating and energy dissipation in humans is unclear.
To evaluate the effects of overconsumption of low, normal, and high protein diets on weight gain, energy expenditure, and body composition.
Design, Setting, and Participants
A single-blind, randomized controlled trial of 25 US healthy, weight-stable male and female volunteers, aged 18 to 35 years with a body mass index between 19 and 30. The first participant was admitted to the inpatient metabolic unit in June 2005 and the last in October 2007.
After consuming a weight-stabilizing diet for 13 to 25 days, participants were randomized to diets containing 5% of energy from protein (low protein), 15% (normal protein), or 25% (high protein), which they were overfed during the last 8 weeks of their 10- to 12-week stay in the inpatient metabolic unit. Compared with energy intake during the weight stabilization period, the protein diets provided approximately 40% more energy intake, which corresponds to 954 kcal/d (95% CI, 884–1022 kcal/d).
Main Outcome Measures
Body composition was measured by dual-energy x-ray absorptiometry biweekly, resting energy expenditure was measured weekly by ventilated hood, and total energy expenditure by doubly labeled water prior to the overeating and weight stabilization periods and at weeks 7 to 8.
Overeating produced significantly less weight gain in the low protein diet group (3.16 kg; 95% CI, 1.88–4.44 kg) compared with the normal protein diet group (6.05 kg; 95% CI, 4.84–7.26 kg) or the high protein diet group (6.51 kg; 95% CI, 5.23–7.79 kg) (P=.002). Body fat increased similarly in all 3 protein diet groups and represented 50% to more than 90% of the excess stored calories. Resting energy expenditure, total energy expenditure, and body protein did not increase during overfeeding with the low protein diet. In contrast, resting energy expenditure (normal protein diet: 160 kcal/d [95% CI, 102–218 kcal/d]; high protein diet: 227 kcal/d [95% CI, 165–289 kcal/d]) and body protein (lean body mass) (normal protein diet: 2.87 kg [95% CI, 2.11–3.62 kg]; high protein diet: 3.18 kg [95% CI, 2.37–3.98 kg]) increased significantly with the normal and high protein diets.
Among persons living in a controlled setting, calories alone account for the increase in fat; protein affected energy expenditure and storage of lean body mass, but not body fat storage.
PMCID: PMC3777747  PMID: 22215165
14.  Effect of diet composition and weight loss on resting energy expenditure in the POUNDS LOST study 
Obesity (Silver Spring, Md.)  2012;20(12):2384-2389.
Weight loss reduces energy expenditure, but it is unclear whether dietary macronutrient composition affects this reduction. We hypothesized that energy expenditure might be modulated by macronutrient composition of the diet. The POUNDS LOST study, a prospective, randomized controlled trial in 811 overweight/obese people who were randomized in a 2×2 design to diets containing 20en% or 40en% fat and 15en% or 25en% (diets with 65%, 55%, 45% and 35% carbohydrate) provided the data to test this hypothesis. Resting energy expenditure (REE) was measured at baseline, 6 and 24 months using a ventilated hood. REE declined at 6 months by 99.5±8.0 kcal/d in men and 55.2±10.6 kcal/d in women during the first 6 months. This decline was related to the weight loss, and there was no difference between the diets. REE had returned to baseline by 24 months, but body weight was still 60% below baseline. Measured REE at 6 months was significantly lower than the predicted (−18.2±6.7 kcal/d) and was the result of significant reductions from baseline in the low fat diets (65% or 55% carbohydrate), but not in the high fat diet groups. By 24 months the difference had reversed with measured REE being slightly but significantly higher than predicted (21.8±10.1 kcal/d). In conclusion, we found that REE fell significantly after weight loss but was not related to diet composition. Adaptive thermogenesis was evident at 6 months, but not at 24 months.
PMCID: PMC3760199  PMID: 22627912
15.  Use of a Computerized Tracking System to Monitor and Provide Feedback on Dietary Goals for Calorie-Restricted Diets: The POUNDS LOST Study 
The use of self-monitoring as a tool to facilitate behavioral modification is common in many lifestyle-based weight loss interventions. Electronic tracking programs, including computer-based systems and smart phone applications, have been developed to allow individuals to self-monitor their behavior digitally. These programs offer an advantage over traditional self-report modalities in that they can provide users with direct feedback about dietary and/or physical activity adherence levels and thereby assist them in real-time decision making. This article describes the use of an Internet-based computerized tracking system (CTS) that was developed specifically for the POUNDS LOST study, a 2-year randomized controlled trial designed to test the efficacy of four macronutrient diets for weight and fat reduction in healthy, overweight men and women (body mass index range = 25.0–39.9 kg/m2). The CTS served many functions in this study, including data collection, dietary and exercise assessment and feedback, messaging system, and report generation. Across all groups, participants with high usage of the CTS during the initial 8 weeks lost greater amounts of weight than participants with low usage (8.7% versus 5.5% of initial body weight, respectively; p < .001) at week 32. Rates of CTS utilization were highest during the first year of this 2-year intervention, and utilization of the CTS declined steadily over time. The unique features of the CTS combined with technological developments, such as smart phone applications, offer significant potential to improve the user’s self-monitoring experience and adherence to health promotion programs designed specifically for individuals with obesity and type 2 diabetes.
PMCID: PMC3570857  PMID: 23063049
computerized tracking system; self-monitoring; smart phones; weight loss
16.  Effect of One Year of an Intentional Weight Loss Intervention on Bone Mineral Density in Type 2 Diabetes: Results from the Look AHEAD Randomized Trial 
Intentional weight loss is an important component of treatment for overweight patients with type 2 diabetes, but the effects on bone density are not known. We used data from the Look AHEAD trial to determine the impact of an intensive lifestyle weight loss intervention (ILI) compared to diabetes support and education (DSE) on changes in bone mineral density (BMD) over 12 months. Overweight and obese adults with type 2 diabetes were randomly assigned to ILI or DSE. In a sub-study of BMD conducted at 5 of 16 clinical centers, hip, spine and whole body dual x-ray absorptiometry scans were obtained at baseline and one year later on 642 of 739 ILI and 632 of 740 DSE participants. At baseline, mean age was 58.4 years, and average body mass index was 35.2 kg/m2. Total hip BMD T-score was <−2.5 in 1% and <−1.0 in 8%. At one year, weight loss was greater in ILI than DSE (−8.6% versus −0.7%), and glycemic control and fitness were also improved. Bone loss over one year was greater in ILI at the total hip (−1.4% versus −0.4%; p<0.001) and femoral neck (−1.5% versus −0.8%; p=0.009), but change in BMD for the lumbar spine and whole body did not differ between groups. In ILI, bone loss at the total hip was independently associated with weight loss in men and women and with poorer glycemic control in men, but was not associated with changes in fitness. One year of an intensive lifestyle intervention in adults with type 2 diabetes, resulting in weight loss, was associated with a modest increase in hip bone loss despite improved fitness and glycemic control.
PMCID: PMC3410035  PMID: 22354851
bone mineral density; weight loss; type 2 diabetes; obesity; glycemic control; physical fitness
17.  Parental Longevity and Diabetes Risk in the Diabetes Prevention Program 
Longevity clusters in families, and parental longevity may be associated with lower risk of chronic diseases in their children. It is unknown if diabetes risk is associated with parental longevity.
We evaluated participants in the Diabetes Prevention Program with a parental history questionnaire at study entry. We classified them into five groups: premature death (parental death at age < 50 years), parental longevity (living to at least 80 years), and three intermediate groups (alive by age 49 but dying at age 50–59, 60–69, or 70–79). Those with alive parents and younger than 80 years were excluded. We analyzed separately effects of paternal (n = 2,165) and maternal (n = 1,739) longevity on diabetes incidence and risk after an average follow-up of 3.2 years.
At baseline, more diabetes risk factors (parental history of diabetes, coronary heart disease, higher body mass index, homeostasis model assessment for insulin resistance, and corrected insulin response) were found in participants whose parents died prematurely. Diabetes incidence was 9.5 cases/100 person-years in the 229 whose fathers died prematurely. In the 618 with paternal longevity, the rate was 6.6 cases/100 person-years (hazard ratio [95% confidence interval] = 0.68 [0.49–0.94]). The rates were 10.7 cases/100 person-years (n = 156) and 7.3 cases/100 person-years (n = 699, hazard ratio = 0.67 [95% confidence interval 0.47–0.95]) for those with maternal premature death or longevity, respectively. Associations with demographic and diabetes risk factors had minimal influence on the reduced risk found in those with paternal (adjusted hazard ratio = 0.78, 95% confidence interval 0.52–1.16) and maternal (adjusted hazard ratio = 0.64, 95% confidence interval 0.41–1.01) longevity.
Parental longevity is associated with lower diabetes incidence in adults at high risk of type 2 diabetes.
PMCID: PMC3193521  PMID: 21852284
Parental longevity; Diabetes risk; Diabetes Prevention Program
18.  Obesity resistant S5B rats showed greater cocaine conditioned place preference than the obesity prone OM rats 
Physiology & behavior  2010;101(5):713-718.
Dopamine (DA) and the DA D2 receptor (D2R) are involved in the rewarding and the conditioned responses to food and drug rewards. Osborne-Mendel (OM) rats are genetically prone and S5B/P rats are genetically resistant to obesity when fed a high-fat diet. We hypothesized that the differential sensitivity of these two rat strains to natural rewards may also be reflected in sensitivity to drugs of abuse. Therefore, we tested whether OM and S5B/P rats showed a differential preference to cocaine using conditioned place preference (CPP). To also evaluate whether there is specific involvement of the D2R in this differential conditioning sensitivity, we then tested whether the D2R agonist bromocriptine (BC) would differentially affect the effects of cocaine in the two strains.
OM and S5B/P rats were conditioned with cocaine (5 or 10mg/kg) in one chamber and saline in another for 8 days. Rats were then tested for cocaine preference. The effects of BC (0.5, 1, 5, 10, 20mg/kg) on cocaine preference were then assessed in subsequent test sessions.
OM rats did not show a significant preference for the cocaine-paired chamber on test day. Only the S5B/P rats showed cocaine CPP. Later treatment with only the highest dose of BC resulted in reduced cocaine CPP in S5B/P rats when treated with 5mg/kg cocaine and in OM rats treated with 10mg/kg cocaine.
Our results indicated obesity-resistant S5B rats showed greater cocaine CPP than the obesity-prone OM rats. These findings do not support a theory of common vulnerability for reinforcer preferences (food and cocaine). However, they show that BC reduced cocaine conditioning effects supporting at least a partial regulatory role of D2R in conditioned responses to drugs.
PMCID: PMC3477469  PMID: 20801137
addiction; psychostimulant; bromocriptine; conditioned place preference
19.  Lifestyle Change and Mobility in Obese Adults with Type 2 Diabetes 
The New England Journal of Medicine  2012;366(13):1209-1217.
Adults with type 2 diabetes mellitus often have limitations in mobility that increase with age. An intensive lifestyle intervention that produces weight loss and improves fitness could slow the loss of mobility in such patients.
We randomly assigned 5145 overweight or obese adults between the ages of 45 and 74 years with type 2 diabetes to either an intensive lifestyle intervention or a diabetes support-and-education program; 5016 participants contributed data. We used hidden Markov models to characterize disability states and mixed-effects ordinal logistic regression to estimate the probability of functional decline. The primary outcome was self-reported limitation in mobility, with annual assessments for 4 years.
At year 4, among 2514 adults in the lifestyle-intervention group, 517 (20.6%) had severe disability and 969 (38.5%) had good mobility; the numbers among 2502 participants in the support group were 656 (26.2%) and 798 (31.9%), respectively. The lifestyle-intervention group had a relative reduction of 48% in the risk of loss of mobility, as compared with the support group (odds ratio, 0.52; 95% confidence interval, 0.44 to 0.63; P<0.001). Both weight loss and improved fitness (as assessed on treadmill testing) were significant mediators of this effect (P<0.001 for both variables). Adverse events that were related to the lifestyle intervention included a slightly higher frequency of musculoskeletal symptoms at year 1.
Weight loss and improved fitness slowed the decline in mobility in overweight adults with type 2 diabetes. (Funded by the Department of Health and Human Services and others; number, NCT00017953.)
PMCID: PMC3339039  PMID: 22455415
20.  Effect of Diet Composition on Energy Expenditure during Weight Loss: The POUNDS LOST Study 
Weight loss reduces energy expenditure, but the contribution of different macronutrients to this change is unclear.
We tested the hypothesis that macronutrient composition of the diet might affect the partitioning of energy expenditure during weight loss.
A sub-study of 99 participants from the POUNDS LOST trial had total energy expenditure (TEE) measured by doubly labeled water and resting energy expenditure (REE) measured by indirect calorimetry at baseline and repeated at 6 months in 89 participants. Participants were randomly assigned to one of 4 diets with either 15% or 25% protein and 20% or 40% fat.
TEE and REE were positively correlated with each other and with fat free mass and body fat, at baseline and 6 months. The average weight loss of 8.1±0.65 kg (LSmean±SE) reduced TEE by 120±56 kcal/d and REE by 136±18 kcal/d. A greater weight loss at 6 months was associated with a greater decrease in TEE and REE. Participants eating the high fat diet lost significantly more fat free mass (1.52±0.55 kg) than the low fat diet group (p<0.05). Participants eating the low fat diet had significantly higher measures of physical activity than the high fat group.
A greater weight loss was associated with a larger decrease in both TEE and REE. The low fat diet was associated with significant changes in fat free body mass and energy expenditure from physical activity compared to the high fat diet.
PMCID: PMC3289771  PMID: 21946707
21.  Insulin receptor substrate 1 (IRS1) gene variation modifies insulin resistance response to weight-loss diets in a two-year randomized trial 
Circulation  2011;124(5):563-571.
Common genetic variants in the IRS1 gene have been recently associated with insulin resistance and hyperinsulinemia. We examined whether the best-associated variant modifies the long-term changes in insulin resistance and body weight in response to weight-loss diets in the Pounds Lost Trial.
Methods and Results
We genotyped IRS1 rs2943641 in 738 overweight adults (61% were women) who were randomly assigned to one of four diets varying in macronutrient contents for 2 years. We assessed the progress in fasting insulin, insulin resistance (HOMA-IR) and weight loss by genotypes. At 6 months, participants with the risk-conferring CC genotype had greater decreases in insulin (P=0.009), HOMA-IR (P=0.015) and weight loss (P=0.058) than those without this genotype in the highest carbohydrate diet group, while an opposite genotype effect on changes in insulin and HOMA-IR (P≤0.05) was observed in participants assigned to the lowest carbohydrate diet group. No significant differences were observed across genotypes in other 2 diet groups. The tests for genotype by intervention interactions were all significant (P<0.05). At 2 years, the genotype effect on changes in insulin and HOMA-IR remained significant in the highest carbohydrate diet group (P<0.05). The highest carbohydrate diet led to a greater improvement of insulin and HOMA-IR (P for genotype-time interaction≤0.009) in participants with the CC genotype than those without this genotype across 2-year intervention.
Individuals with the IRS1 rs2943641 CC genotype might obtain more benefits in weight loss and improvement of insulin resistance than those without this genotype by choosing a high-carbohydrate and low-fat diet.
PMCID: PMC3171189  PMID: 21747052
diet; genetic variation; insulin; gene-diet interaction; weight-loss trial
22.  Trunk Versus Extremity Adiposity and Cardiometabolic Risk Factors in White and African American Adults 
Diabetes Care  2011;34(6):1415-1418.
To determine contributions of trunk and extremity adiposity to cardiometabolic risk factors (blood pressure, fasting blood glucose, HDL cholesterol, and triglycerides) among white and African American adults.
The sample consisted of 1,129 white women, 779 African American women, 1,012 white men, and 300 African American men.
Higher trunk adiposity was significantly associated with an increased risk of having two or more cardiometabolic risk factors among African American and white men and women. After adjustment for trunk and arm adiposity, higher leg adiposity was significantly associated with a decreased risk of having two or more cardiometabolic risk factors among white men and women and African American women.
In contrast with adverse risk with high trunk adiposity, high leg adiposity is associated with a decreased risk of having two or more cardiometabolic risk factors in both African American and white adults.
PMCID: PMC3114357  PMID: 21505210
23.  Bromocriptine Increased Operant Responding for High Fat Food but Decreased Chow Intake in Both Obesity-Prone and Resistant Rats 
Behavioural brain research  2010;217(1):165-170.
Dopamine (DA) and DA D2 receptors (D2R) have been implicated in obesity and are thought to be involved in the rewarding properties of food. Osborne Mendel (OM) rats are susceptible to diet induced obesity (DIO) while S5B/P (S5B) rats are resistant when given a high-fat diet. Here we hypothesized that the two strains would differ in high-fat food self-administration (FSA) and that the D2R agonist bromocriptine (BC) would differently affect their behavior. Ad-libitum fed OM and S5B/P rats were tested in a FSA operant chamber and were trained to lever press for high-fat food pellets under a fixed-ratio (FR1) and a progressive ratio (PR) schedule. After sixteen days of PR sessions, rats were treated with three different doses of BC (1, 10 and 20 mg/kg). No significant differences were found between the two strains in the number of active lever presses. BC treatment (10mg/kg and 20mg/kg) increased the number of active lever presses (10mg/kg having the strongest effect) whereas it decreased rat chow intake in the home cage with equivalent effects in both strains. These effects were not observed on the day of BC administration but on the day following its administration. Our results suggest that these two strains have similar motivation for procuring high fat food using this paradigm. BC increased operant responding for high-fat pellets but decreased chow intake in both strains, suggesting that D2R stimulation may have enhanced the motivational drive to procure the fatty food while correspondingly decreasing the intake of regular food. These findings suggest that susceptibility to dietary obesity (prior to the onset of obesity) may not affect operant motivation for a palatable high fat food and that differential susceptibility to obesity may be related to differential sensitivity to D2R stimulation.
PMCID: PMC3018148  PMID: 21034777
hyperphagia; addiction; Dopamine; D2; Diet
24.  Sugar-Sweetened Beverages and Risk of Metabolic Syndrome and Type 2 Diabetes 
Diabetes Care  2010;33(11):2477-2483.
Consumption of sugar-sweetened beverages (SSBs), which include soft drinks, fruit drinks, iced tea, and energy and vitamin water drinks has risen across the globe. Regular consumption of SSBs has been associated with weight gain and risk of overweight and obesity, but the role of SSBs in the development of related chronic metabolic diseases, such as metabolic syndrome and type 2 diabetes, has not been quantitatively reviewed.
We searched the MEDLINE database up to May 2010 for prospective cohort studies of SSB intake and risk of metabolic syndrome and type 2 diabetes. We identified 11 studies (three for metabolic syndrome and eight for type 2 diabetes) for inclusion in a random-effects meta-analysis comparing SSB intake in the highest to lowest quantiles in relation to risk of metabolic syndrome and type 2 diabetes.
Based on data from these studies, including 310,819 participants and 15,043 cases of type 2 diabetes, individuals in the highest quantile of SSB intake (most often 1–2 servings/day) had a 26% greater risk of developing type 2 diabetes than those in the lowest quantile (none or <1 serving/month) (relative risk [RR] 1.26 [95% CI 1.12–1.41]). Among studies evaluating metabolic syndrome, including 19,431 participants and 5,803 cases, the pooled RR was 1.20 [1.02–1.42].
In addition to weight gain, higher consumption of SSBs is associated with development of metabolic syndrome and type 2 diabetes. These data provide empirical evidence that intake of SSBs should be limited to reduce obesity-related risk of chronic metabolic diseases.
PMCID: PMC2963518  PMID: 20693348
25.  Adherence is a multi-dimensional construct in the POUNDS LOST trial 
Journal of behavioral medicine  2009;33(1):35-46.
Research on the conceptualization of adherence to treatment has not addressed a key question: Is adherence best defined as being a uni-dimensional or multi-dimensional behavioral construct? The primary aim of this study was to test which of these conceptual models best described adherence to a weight management program. This ancillary study was conducted as a part of the POUNDS LOST trial that tested the efficacy of four dietary macro-nutrient compositions for promoting weight loss. A sample of 811 overweight/obese adults was recruited across two clinical sites, and each participant was randomly assigned to one of four macronutrient prescriptions: (1) Low fat (20% of energy), average protein (15% of energy); (2) High fat (40%), average protein (15%); (3) Low fat (20%), high protein (25%); (4) High fat (40%), high protein (25%). Throughout the first 6 months of the study, a computer tracking system collected data on eight indicators of adherence. Computer tracking data from the initial 6 months of the intervention were analyzed using exploratory and confirmatory analyses. Two factors (accounting for 66% of the variance) were identified and confirmed: (1) behavioral adherence and (2) dietary adherence. Behavioral adherence did not differ across the four interventions, but prescription of a high fat diet (vs. a low fat diet) was found to be associated with higher levels of dietary adherence. The findings of this study indicated that adherence to a weight management program was best conceptualized as being multi-dimensional, with two dimensions: behavioral and dietary adherence.
PMCID: PMC3153914  PMID: 19856202
Adherence; Overweight; Obesity; Randomized controlled trial; Lifestyle behavior modification

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