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1.  Overfeeding of Polyunsaturated Versus Saturated Fatty Acids Reduces Ectopic Fat 
Diabetes  2014;63(7):2222-2224.
PMCID: PMC4392897  PMID: 24962923
2.  Baseline Adiponectin Levels Do Not Influence the Response to Pioglitazone in ACT NOW 
Diabetes Care  2014;37(6):1706-1711.
Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status.
A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years.
Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group.
Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin.
PMCID: PMC4179517  PMID: 24705615
3.  Effect of a Long-Term Behavioral Weight Loss Intervention on Nephropathy in Overweight or Obese Adults with Type 2 Diabetes: the Look AHEAD Randomized Clinical Trial 
Long-term effects of behavioral weight loss interventions on diabetes complications are unknown. We assessed whether an intensive lifestyle intervention (ILI) affects the development of nephropathy in Look AHEAD, a multicenter randomized clinical trial in type 2 diabetes.
5145 overweight or obese persons aged 45–76 years with type 2 diabetes were randomized to ILI designed to achieve and maintain weight loss through reduced caloric consumption and increased physical activity or to a diabetes support and education (DSE) group. Randomization to ILI or DSE, in a 1:1 ratio, was implemented in a central web-based data management system, stratified by clinical center, and blocked with random block sizes. Outcomes assessors and laboratory staff were masked to treatment. The interventions ended early because of lack of effect on the primary outcome of cardiovascular disease events. Albuminuria and estimated glomerular filtration rate were prespecified “other” outcomes and were assessed from baseline through 9.6 years (median) of follow-up until the interventions ended. They were combined post-hoc to define the main outcome for this report: very-high-risk chronic kidney disease (CKD) based on the 2013 Kidney Disease Improving Global Outcomes classification. Data were analyzed by intention to treat. The trial is registered as NCT00017953.
The incidence rate of very-high-risk CKD was 31% lower in ILI than DSE with hazard rates of 0.90 cases/100 person-years in DSE and 0.63 in ILI (difference=0.27 cases/100 person-years, hazard ratio and 95% confidence interval: HR=0.69, 0.55 to 0.87). This effect was partly attributable to reductions in weight, HbA1c, and blood pressure.
Weight loss should be considered as an adjunct to medical therapies to prevent or delay progression of CKD in overweight or obese persons with type 2 diabetes.
Primary Funding
National Institute of Diabetes and Digestive and Kidney Diseases.
PMCID: PMC4443484  PMID: 25127483
4.  Effect of a 3-day high-fat feeding period on carbohydrate balance and ad-libitum energy intake in humans 
A reduction in glycogen after the switch to an isoenergetic high-fat diet might promote a compensatory increase in food intake in order to reestablish carbohydrate balance. We assessed the effect of an isoenergetic switch from a 49%-carbohydrate to 50%-fat diet on nutrient balance and ad-libitum food intake. We hypothesized that carbohydrate balance would be inversely related to ad-libitum energy intake.
In 47 males and 11 females (22.6 ± 0.4 y; 26.1 ± 0.5 kg/m2), fuel balance was measured in a respiration chamber over 4 days. During the first day, an isoenergetic, high-carbohydrate diet was provided followed by a 3-day isoenergetic, high-fat diet. At the end of this period and after 16 hours of fasting, three options of foods (cookies, fruit salad and turkey sandwich) were offered ad-libitum for 4 hours. The relationships between post-chamber ad-libitum intake and macronutrient oxidation and balance measured day-to-day and over the 4-day respiration chamber stay were studied.
After switching to a high-fat diet, 24-h respiratory quotient decreased from 0.87 ± 0.02 to 0.83 ± 0.02 (p<0.0001) resulting in a 4-d cumulative carbohydrate, fat and protein balances of −183 ± 368, 342 ± 480 and 65 ± 267 kcal, respectively. Cumulative energy balance (224 ± 362 kcal/4 d) did not influence ad-libitum energy intake. However, we detected that 4-d carbohydrate balance was a positive and independent predictor of post-chamber ad-libitum energy intake (R2=0.10; p=0.01), whereas no significant influence of fat and protein balances was found.
In response to an isoenergetic change from a high-carbohydrate to high-fat diet, higher carbohydrate balance related to increased energy intake.
PMCID: PMC4381993  PMID: 20195283
food intake; satiety; appetite; carbohydrate oxidation; fat balance
5.  Olfactory bulbectomy impairs the feeding response to 2-deoxy-D-glucose in rats 
Brain research  2010;1367:207-212.
An early study reported that, unlike sham-operated rats, rats made anosmic by olfactory bulbectomy (OBX) failed to compensate for the dilution of their diet with nonnutritive bulk by increasing their food intake. In the present study, the effects of a glucoprivic challenge, intraperitoneal-administered 350 mg/kg 2-deoxy-D-glucose (2-DG), on food intake were measured in OBX and sham-operated female rats. Sham-operated rats significantly increased their food intake, but in two separate experiments OBX rats displayed no increase in food intake during the first 2 h following administration. Blood glucose levels were nearly identical in both groups. Body weights and daily food intakes of OBX rats did not differ from the sham-operated controls throughout the studies. Bulbectomized rats also displayed a normal drinking response after an intraperitoneal injection of 1 M hypertonic saline. Hypothalamic nuclei and the neural pathways mediating taste have been implicated in the feeding response to 2-DG. The present results suggest that olfactory input and olfactory neural pathways also mediate, at least in part, the feeding response to a glucoprivic challenge induced by intraperitoneal injection of 2-DG.
PMCID: PMC4239690  PMID: 20969838
Olfactory bulbs; Glucoprivic challenges; Anosmia; Food intake; Water intake
6.  Prediction of Diabetes Based on Baseline Metabolic Characteristics in Individuals at High Risk 
Diabetes Care  2013;36(11):3607-3612.
Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance.
We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years.
In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, ∆G0–120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln ∆I0–120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [∆I0–120/∆G0–120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [∆I0–120/∆G0–120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes.
In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).
PMCID: PMC3816921  PMID: 24062330
7.  Prevention of Diabetes With Pioglitazone in ACT NOW 
Diabetes  2013;62(11):3920-3926.
We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0–120/ΔG0–120, ΔIS rate [ISR]0–120/ΔG0–120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15–0.49]; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54–0.80]), IS (OR 0.61 [95% CI 0.50–0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19–0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.
PMCID: PMC3806596  PMID: 23863810
8.  IRS1 Genotype Modulates Metabolic Syndrome Reversion in Response to 2-Year Weight-Loss Diet Intervention 
Diabetes Care  2013;36(11):3442-3447.
Genetic variants near IRS1 are associated with features of the metabolic syndrome (MetS). We examined whether genetic variants near IRS1 might modulate the effects of diets varying in fat content on the MetS status in a 2-year weight-loss trial.
Two variants near IRS1, rs1522813 and rs2943641, were genotyped in 738 overweight/obese adults (age 60 ± 9 years; BMI 32.7 ± 3.9 kg/m2) randomly assigned to one of four weight-loss diets (a deficit of 750 kcal/day of caloric intake from baseline) varying in macronutrient contents for 2 years. We compared MetS status of high-fat (40% of caloric intake; n = 370) and low-fat (20% caloric intake; n = 368) diet groups differentiated by genotypes (rs1522813 A-allele carriers and noncarriers and rs2943641T-allele carriers and noncarriers).
Among rs1522813 A-allele carriers, the reversion rates of the MetS were higher in the high-fat diet group than those in the low-fat diet group over the 2-year intervention (P = 0.002), while no significant difference between diet groups was observed among noncarriers (P = 0.27). The genetic modulation on dietary effect was independent of weight changes. The odds ratio (OR) for the 2-year reversion of the MetS was 2.88 (95% CI 1.25–6.67) comparing the high-fat and low-fat diets among rs1522813 A-allele carriers, while the corresponding OR was 0.83 (0.36–1.92) in noncarriers. The variant rs2943641 was not observed to modulate dietary effects on the MetS status.
Our data suggest that high-fat weight-loss diets might be more effective in the management of the MetS compared with low-fat diets among individuals with the A-allele of the rs1522813 variant near IRS1.
PMCID: PMC3816909  PMID: 24009303
9.  High Fat Diet Differentially Regulates the Expression of Olfactory Receptors in the Duodenum of Obesity-Prone and Obesity-Resistant Rats 
The gastrointestinal tract is important in the regulation of food intake, nutrient sensing and nutrient absorption. Obesity-prone Osborne-Mendel (OM) rats are less sensitive to the satiating effects of a duodenal infusion of fatty acids than obesity-resistant S5B/Pl (S5B) rats, suggesting that the gastrointestinal tract differentially senses the presence of fat in these two strains. A microarray analysis was conducted to identify genes that were differentially expressed in the duodenal enterocytes of OM and S5B rats.
The present experiment evaluated the expression of olfactory receptors in the duodenal enterocytes of OM and S5B rats. It was hypothesized that olfactory receptors present in the duodenum of OM and S5B rats would be differentially regulated by the intake of a high fat diet.
The mRNA levels of four olfactory receptors (Olr1744, Olr50, Olr124, Olr1507) were assessed from the duodenal enterocytes of OM and S5B rats consuming a high fat diet for 14 days.
The duodenal mRNA levels of Olr1744, Olr124 and Olr1507 were significantly elevated in OM rats fed the high fat diet, but not S5B rats. No differences in the expression of Olr50 receptor mRNA were detected.
These data suggest that several olfactory receptors present in the duodenum are selectively regulated by high fat diet intake in obesity-prone OM rats. Therefore, these receptors may play a role in the sensing and regulation of dietary fat, and may be important for the individual susceptibility to obesity in these two strains.
PMCID: PMC4201503  PMID: 23053893
Obesity-prone; Obesity-resistant; Olfactory receptors; Duodenum; High fat diet
10.  CD36 mRNA in the Gastrointestinal Tract Is Differentially Regulated by Dietary Fat Intake in Obesity-Prone and Obesity-Resistant Rats 
Digestive diseases and sciences  2012;58(2):363-370.
The gastrointestinal tract (GI) is important for detection and transport of consumed nutrients and has been implicated in susceptibility to diet-induced obesity in various rat strains.
The current studies investigated the regulation of CD36, a receptor which facilitates uptake of long-chain fatty acids, in the GI tract of obesity-prone Osborne–Mendel and obesity-resistant S5B rats fed a high-fat diet.
Osborne–Mendel and S5B rats consumed a high-fat diet (HFD, 55 % kcal from fat) or a low-fat diet (10 % kcal from fat) for either 3 or 14 days. CD36 messenger RNA (mRNA) levels were measured from circumvallate papillae of the tongue and from duodenal enterocytes.
In Osborne–Mendel rats, consumption of HFD for 3 and 14 days led to an increase in CD36 mRNA on circumvallate papillae and in duodenal enterocytes. CD36 mRNA levels were positively correlated with body weight gain and kilocalories consumed at 3 days. In S5B rats, consumption of HFD for 3 days did not alter CD36 mRNA levels on circumvallate papillae or in the duodenum. Duodenal CD36 levels were elevated in S5B rats following 14 days of HFD consumption. CD36 mRNA levels in the duodenum were positively correlated with body weight gain and kilocalories consumed at 14 days.
These data support the differential sensing of nutrients by two regions of the GI tract of obesity-prone and obesity-resistant rats consuming HFD and suggest a role for CD36 in the strain-specific susceptibility to obesity.
PMCID: PMC4201504  PMID: 22915197
Obesity-prone; Obesity-resistant; CD36; Taste bud; Duodenum; High-fat diet
11.  Diet Type and Changes in Food Cravings following Weight Loss: Findings from the POUNDS LOST Trial 
Eating and weight disorders : EWD  2012;17(2):e101-e108.
Few well-controlled trials have evaluated the effects that macronutrient composition has on changes in food cravings during weight loss treatment. The present study, which was part of the POUNDS LOST trial, investigated whether the fat and protein content of four different diets affected changes in specific food cravings in overweight and obese adults. A sample of 811 adults were 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) Moderate fat (40%), average protein (15%); (3) Low fat (20%), high protein (25%); (4) Moderate fat (40%), high protein (25%). With few exceptions, the type of diet that participants were assigned did not differentially affect changes in specific food cravings. Participants assigned to the high fat diets, however, had reduced cravings for carbohydrates at Month12 (p< .05) and fruits and vegetables at Month 24. Also, participants assigned to high protein diets had increased cravings for sweets at Month 6 (p< .05). Participants in all four dietary conditions reported significant reductions in food cravings for specific types of foods (i.e., high fat foods, fast food fats, sweets, and carbohydrates/starches; all ps< .05). Cravings for fruits and vegetables, however, were increased at Month 24 (p< .05). Calorically restricted diets (regardless of their macronutrient composition) yielded significant reductions in cravings for fats, sweets, and starches whereas cravings for fruits and vegetables were increased.
PMCID: PMC4189179  PMID: 23010779
Macronutrient composition; Caloric restriction; Food type; Fat; Carbohydrate; Protein
12.  Hyperphagia: Current Concepts and Future Directions Proceedings of the 2nd International Conference on Hyperphagia 
Obesity (Silver Spring, Md.)  2014;22(0 1):S1-S17.
Hyperphagia is a central feature of inherited disorders (e.g., Prader–Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms and treatments. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present as are a lack of mechanistic of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments.
Design and Methods
International conference with 28 experts, including scientists and caregivers, providing presentations, panel discussions, and debates.
The reviewed collective research and clinical experience provides a critical body of new and novel information on hyperphagia at levels ranging from molecular to population. Gaps in understanding and tools needed for additional research were identified.
This report documents the full scope of important topics reviewed at a comprehensive international meeting devoted to the topic of hyperphagia and identifies key areas for future funding and research.
PMCID: PMC4159941  PMID: 24574081
13.  FGF21 is an endocrine signal of protein restriction 
The Journal of Clinical Investigation  2014;124(9):3913-3922.
Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the liver, and both baseline and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.
PMCID: PMC4153701  PMID: 25133427
14.  Intensive Weight Loss Intervention in Individuals Ages 65 Years or Older: Results from the Look AHEAD Type 2 Diabetes Trial 
To compare the relative effects of four years of intensive lifestyle intervention on weight, fitness, and cardiovascular disease risk factors among older versus younger individuals
A randomized controlled clinical trial
16 US clinical sites
Individuals with type 2 diabetes: 1,053 aged 65–76 years and 4,092 aged 45–64 years
An intensive behavioral intervention designed to promote and maintain weight loss through caloric restriction and increased physical activity compared to a condition of diabetes support and education.
Standardized assessments of weight, fitness (based on graded exercise testing), and cardiovascular disease risk factors
Across four years, older individuals had greater intervention-related mean weight losses than younger participants, 6.2% versus 5.1% (interaction p=0.006) and comparable relative mean increases in fitness, 0.56 versus 0.53 metabolic equivalents (interaction p=0.72). These benefits were seen consistently across subgroups of older adults formed by many demographic and health factors. Among a panel of age-related health conditions, only self-reported worsening vision was associated with poorer intervention-related weight loss in older individuals. The intensive lifestyle intervention produced mean increases in high density lipoprotein cholesterol (2.03 mg/dl; p<0.001) and decreases in glycated hemoglobin (0.21%; p<0.001) and waist girth (3.52 cc; p<0.001) across 4 years that were at least as large in older compared to younger individuals.
Intensive lifestyle intervention targeting weight loss and increased physical activity is effective in overweight and obese older individuals to produce sustained weight loss and improvements in fitness and cardiovascular risk factors.
PMCID: PMC4123658  PMID: 23668423
Behavioral intervention; Weight loss; Physical activity; Type 2 diabetes mellitus; Cardiovascular disease risk factors
15.  Short-term overeating results in incomplete energy intake compensation regardless of energy density or macronutrient composition 
Obesity (Silver Spring, Md.)  2013;22(1):119-130.
To evaluate the effects of overeating (140% of energy requirements) a high-fat low-energy density diet (HF/LED, 1.05kcal/g), high-fat high-energy density diet (HF/HED, 1.60kcal/g), and high-carbohydrate (HC) LED (1.05kcal/g) for 2-days on subsequent 4-day energy intake (EI), activity levels, appetite, and mood.
Design and Methods
Using a randomized cross-over design, energy expenditure and EI were standardized during overeating.
In 20 adults with a mean±SD BMI of 30.7±4.6kg/m2, EI was not suppressed until the second day after overeating and accounted for ~30% of the excess EI. Reductions in EI did not differ among the 3 diets or across days. Overeating had no effect on subsequent energy expenditure but steps/day decreased after the HC/LED and HF/HED. Sleep time was increased after the HF/HED compared to both LEDs. After overeating a HF/HED vs. HF/LED, carbohydrate cravings, hunger, prospective food consumption, and sadness increased and satisfaction, relaxation, and tranquility decreased.
Diet type, time, or their interaction had no impact on compensation over 4 days. No adaptive thermogenesis was observed. The HF/HED vs. HF/LED had detrimental effects on food cravings, appetite, and mood. These results suggest short-term overeating is associated with incomplete compensation.
PMCID: PMC3873377  PMID: 23913807
hyperphagia; appetite; spontaneous physical activity; energy expenditure; hunger; sleep
16.  Adipose tissue expression of adipose (WDTC1) gene is associated with lower fat mass and enhanced insulin sensitivity in humans 
Obesity (Silver Spring, Md.)  2013;21(11):2244-2248.
The overexpression of the adipose gene (adp/WDTC1) in mice inhibits lipid accumulation and improves the metabolic profile.
We evaluated subcutaneous fat adp expression in humans and its relation to metabolic parameters.
Design, Setting and Methods
Abdominal subcutaneous fat adp expression, insulin sensitivity (clamp) and respiratory quotient (RQ; indirect calorimetry) were assessed in: 36 obese and 56 BMI-, race- and sex-matched type 2 diabetic volunteers (Look AHEAD Adipose Ancillary Study); 37 non-diabetic Pima Indians including obese (n=18) and non-obese (n=19) subjects and; 62 non-obese non-diabetic subjects at the Pennington Center in the ADAPT study.
In the Look AHEAD Study, adp expression normalized for cyclophilin B was higher in males vs. females (1.27±0.06 vs. 1.11±0.04; p<0.01) but not after controlling for body fat. Adp expression was not influenced by the presence of diabetes but was related to body fat (r=−0.23; p=0.03), insulin sensitivity (r=0.23; p=0.03) and fasting/insulin-stimulated RQ (r=0.31 & 0.33; p<0.01). In Pima Indians, adp expression was also higher in males vs. females (1.00±0.05 vs. 0.77±0.05; p=0.02) and higher in non-obese vs. obese (1.02±0.05 vs. 0.80±0.06; p=0.03). In the ADAPT study, there was no difference in adp expression between males and females.
Consistent with animal studies, our results suggest that, high adp expression in human adipose tissue is associated with lower adiposity and enhanced glucose utilization.
PMCID: PMC3695019  PMID: 23512946
obesity; insulin sensitivity; body fat
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
25.  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

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