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Adaptive thermogenesis during prolonged energy deficit refers to the greater than expected reduction in energy expenditure (EE) independent of concomitant loss of metabolically active body mass. As inter-individual variability in the magnitude of adaptive thermogenesis may influence the extent of energy deficit thereby predicting the amount of weight reduction, we investigated whether early adaptive thermogenesis is a determinant of weight loss after 6 weeks of daily 50% caloric restriction in an inpatient setting. The current study reports the results of an exploratory, secondary analysis in overweight but otherwise healthy subjects (n = 11, 7 men, 35 ± 9y, BMI = 40 ± 7 kg/m2, body fat = 63.3 ± 5.3%). Body composition and 24-h EE (24hEE) measurement in a whole-room indirect calorimeter were used to calculate the magnitude of adaptive thermogenesis while on caloric restriction after 1, 3 and 6 weeks. Energy deficit during caloric restriction was quantified via food, stool, and urine bomb calorimetry. Fasting hormonal concentrations (FT4, FT3, FGF21, leptin) were obtained at baseline and at weeks 3 and 6 during caloric restriction. The magnitude of adaptive thermogenesis in 24hEE after 1 week of caloric restriction was −178 ± 137 kcal/day (mean ± SD), was overall stable during and following caloric restriction, and demonstrated remarkable intra-individual consistency. A relatively greater decrease in 24hEE of 100 kcal/d after 1 week of caloric restriction was associated on average with reduced energy deficit by 8195 kcal over 6 weeks and predicted 2.0 kg less weight loss, of which 0.5 kg was fat mass, after 6 weeks. No correlations were found between hormonal concentrations and weight loss. The extent of weight loss is influenced by the magnitude of adaptive thermogenesis in the early stage of caloric restriction. Although these results need replication in larger study groups with adequate statistical power, targeting adaptive thermogenesis may help to optimize long-term interventions in obesity therapy. • Adaptive thermogenesis (AT) refers to metabolic slowing during caloric restriction. • AT can be detected as early as the first week of daily caloric restriction (CR). • AT is consistent during prolonged CR and affects daily energy balance during CR. • Early AT predicts subsequent weight loss and fat mass loss following 6-week of CR. [ABSTRACT FROM AUTHOR]

Aim: Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset. Materials and Methods: Baseline body composition, insulin sensitivity by hyperinsulinaemic‐euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min; M‐low and M‐high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow‐up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin‐to‐creatinine ratio ≥30 mg/g). Separate associations of M‐low, M‐high and AIR (per 1‐SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%). Results: Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M‐low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p =.03; M‐high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p =.02; mg/kg‐metabolic body size/min (log)]. In separate adjusted models, lower M‐low and M‐high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p =.004; HR 1.31, 95% CI 1.06, 1.63, p =.01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p =.3). Conclusions: Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe the individual and joint associations of baseline factors with glycemia, and also with differential effectiveness of medications added to metformin. RESEARCH DESIGN AND METHODS: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) participants (with type 2 diabetes diagnosed for <10 years, on metformin, and with HbA1c 6.8–8.5%; N = 5,047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide 1 agonist (liraglutide), or dipeptidyl peptidase 4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate and multivariate regression and classification and regression tree (CART) analyses were used to assess the association of baseline factors with the glycemic outcome at years 1 and 4. RESULTS: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, higher HbA1c, fasting glucose, and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and/or 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after multiple baseline factors were controlled for. CART analyses indicated that failure to maintain HbA1c <7% by year 4 was more likely for younger participants and those with baseline HbA1c ≥7.4%. CONCLUSIONS: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help in targeting patients for more aggressive management. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We examined longitudinal associations between emotional distress (specifically, depressive symptoms and diabetes distress) and medication adherence in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing four glucose-lowering medications added to metformin in adults with relatively recent-onset type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: The Emotional Distress Substudy assessed medication adherence, depressive symptoms, and diabetes distress in 1,739 GRADE participants via self-completed questionnaires administered biannually up to 3 years. We examined baseline depressive symptoms and diabetes distress as predictors of medication adherence over 36 months. Bidirectional visit-to-visit relationships were also examined. Treatment satisfaction, beliefs about medication, diabetes care self-efficacy, and perceived control over diabetes were evaluated as mediators of longitudinal associations. RESULTS: At baseline, mean ± SD age of participants (56% of whom were White, 17% Hispanic/Latino, 18% Black, and 66% male) was 58.0 ± 10.2 years, diabetes duration 4.2 ± 2.8 years, HbA1c 7.5% ± 0.5%, and medication adherence 89.9% ± 11.1%. Higher baseline depressive symptoms and diabetes distress were independently associated with lower adherence over 36 months (P < 0.001). Higher depressive symptoms and diabetes distress at one visit predicted lower adherence at the subsequent 6-month visit (P < 0.0001) but not vice versa. Treatment assignment did not moderate relationships. Patient-reported concerns about diabetes medications mediated the largest percentage (11.9%–15.5%) of the longitudinal link between emotional distress and adherence. CONCLUSIONS: Depressive symptoms and diabetes distress both predict lower adherence to glucose-lowering medications over time among adults with T2DM. Addressing emotional distress and concerns about anticipated negative effects of taking these treatments may be important to support diabetes treatment adherence. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare the effects of insulin sensitivity and β-cell function over time on HbA1c and durability of glycemic control in response to dual therapy. RESEARCH DESIGN AND METHODS: GRADE participants were randomized to glimepiride (n = 1,254), liraglutide (n = 1,262), or sitagliptin (n = 1,268) added to baseline metformin and followed for mean ± SD 5.0 ± 1.3 years, with HbA1c assessed quarterly and oral glucose tolerance tests at baseline, 1, 3, and 5 years. We related time-varying insulin sensitivity (HOMA 2 of insulin sensitivity [HOMA2-%S]) and early (0–30 min) and total (0–120 min) C-peptide (CP) responses to changes in HbA1c and glycemic failure (primary outcome HbA1c ≥7% [53 mmol/mol] and secondary outcome HbA1c >7.5% [58 mmol/mol]) and examined differential treatment responses. RESULTS: Higher HOMA2-%S was associated with greater initial HbA1c lowering (3 months) but not subsequent HbA1c rise. Greater CP responses were associated with a greater initial treatment response and slower subsequent HbA1c rise. Higher HOMA2-%S and CP responses were each associated with lower risk of primary and secondary outcomes. These associations differed by treatment. In the sitagliptin group, HOMA2-%S and CP responses had greater impact on initial HbA1c reduction (test of heterogeneity, P = 0.009 HOMA2-%S, P = 0.018 early CP, P = 0.001 total CP) and risk of primary outcome (P = 0.005 HOMA2-%S, P = 0.11 early CP, P = 0.025 total CP) but lesser impact on HbA1c rise (P = 0.175 HOMA2-%S, P = 0.006 early CP, P < 0.001 total CP) in comparisons with the glimepiride and liraglutide groups. There were no differential treatment effects on secondary outcome. CONCLUSIONS: Insulin sensitivity and β-cell function affected treatment outcomes irrespective of drug assignment, with greater impact in the sitagliptin group on initial (short-term) HbA1c response in comparison with the glimepiride and liraglutide groups. [ABSTRACT FROM AUTHOR]

Background: Plasma albumin is reduced during inflammation. Obesity, a strong risk factor for type 2 diabetes (T2D), is associated with adipose tissue inflammation. However, whether albumin is associated with adipose tissue inflammation and whether it predicts T2D are unclear. Methods: Adults (predominantly American Indian) from a longitudinal study were included. Macrophage content and gene expression related to recruitment/activation were measured from subcutaneous adipose tissue (n = 51). The relationship between plasma albumin and adiposity (dual-energy X-ray absorptiometry or hydrodensitometry), glucose (oral glucose tolerance test), insulin action (hyperinsulinemic-euglycemic clamp), and insulin secretion (intravenous glucose tolerance test) were evaluated (n = 422). Progression to T2D was evaluated by Cox regression (median follow-up 8.8 years; 102 progressors). Results: Albumin was associated with macrophage markers including C1QB (r = − 0.30, p = 0.04), CSF1R (r = − 0.30, p = 0.03), and CD11b (r = − 0.36, p = 0.01). Albumin was inversely associated with body fat percentage (r = − 0.14, p = 0.003), fasting plasma glucose (r = − 0.17, p = 0.0003), and 2 h plasma glucose (r = − 0.11, p = 0.03), and was reduced in impaired glucose regulation compared with normal glucose regulation (mean ± SD: 39.4 ± 3.6 g/l and 40.1 ± 3.9 g/l, respectively; p = 0.049). Albumin predicted T2D, even after adjustment for confounders (HR, 0.75; 95% CI 0.58–0.96; p = 0.02; per one SD difference in albumin). Conclusions: Reduced albumin is associated with an unfavorable metabolic profile, characterized by increased adipose tissue inflammation, adiposity, and glucose, and with an increased risk for T2D. [ABSTRACT FROM AUTHOR]

A higher 24-h respiratory quotient (24-h RQ) predicts weight gain. This observation was interpreted to indicate that subjects who rely less on fat oxidation as a substrate for energy production may have a greater tendency to gain weight, as they may be more prone to store excess energy as fat. A lower 24-h carbohydrate balance (24-h CHO-Bal) also predicts weight and fat gains. Whether these relationships are mediated by the effects of substrate oxidation and balance on food intake and/or energy storage is not known. This study tested the hypothesis that substrate oxidation and balance on a weight maintenance diet predict ad-libitum food intake during 3 subsequent days, as evaluated by a previously validated automated food selection system. After 3 d of energy balance, substrate oxidation and balance were measured for 24 h in a respiratory chamber in 112 non-diabetic subjects (83 Pima Indians, 29 whites; 67M, 45F, age 33 ± 8 y). Subjects then self-selected their food ad-libitum for the following 3 d. Ad-libitum food intake as a percent of weight maintenance energy needs (%WMEN) was positively associated with 24-h RQ (r=0.27, p=0.004, adjusted for race, sex, age, percent body fat, and 24-h energy balance) and with 24-h carbohydrate oxidation (24-h CHO-Ox) (r=0.40, p<0.0001, adjusted for race, sex, age, fat-free-mass (FFM), fat mass (FM), and 24-h energy balance), and negatively correlated with 24-h CHO-Bal (r=-0.34, P=0.0003), but not with 24-h fat oxidation (24-h FAT-Ox) or 24-h fat balance. In a multiple regression model adjusted for race, sex, age, FFM, FM, and 24-h energy balance (R²: 0.35, P<0.0001), 24-h CHO-Ox, but not 24-h FAT-Ox, was an independent determinant of %WMEN, explaining 15% of its variance. The weight change over the 3-d ad-libitum period (1 ± 1 kg) was associated with adjusted 24-h CHO-Ox and with 24-h CHO-Bal (r=0.23, p=0.01 and r=-0.20, p=0.03, respectively), but was no longer significant after adjustment for food intake. This study indicates that carbohydrate oxidation and balance predict subsequent ad-libitum food intake which can influence short-term weight changes, supporting the hypothesis that food intake is driven primarily to maintain carbohydrate balance. [ABSTRACT FROM AUTHOR]

Presents the study "Hematocrit and the Incidence of Type 2 Diabetes in the Pima Indians." Conditions associated with insulin resistance; Aim of the study; Results of the study.

Presents a letter to the editor about the clinical presentation of Chiari malformation type 1 associated with osteoporosis in patient.

Background Accurate prediction of 24-hour energy expenditure (24EE) relies on knowing body composition, in particular fat-free mass (FFM), the largest determinant of 24EE. FFM is closely correlated with hematologic volumes: blood volume (BV), red cell mass (RCM), and plasma volume (PV). However, it is unknown whether predicted hematologic volumes, based on easily collected variables, can improve 24EE prediction. Objective The aim was to develop and validate equations to predict 24EE based on predicted BV, RCM, and PV and to compare the accuracy and agreement with models developed from FFM and with the Mifflin-St Jeor equation, which is recommended for clinical use by the Academy of Nutrition and Dietetics. Design Participants had body composition measured by underwater weighing and 24EE by respiratory chamber. BV, RCM, and PV were calculated from five published equations. Participants/setting Native American and white men and women were studied (n=351). Participants were healthy adults aged 18 to 49 years from the Phoenix, AZ, metropolitan area. Main outcome measure Accuracy to within ±10% of measured 24EE and agreement by Bland-Altman analysis. Statistical analysis Regression models to predict 24EE from hematologic and body composition variables were developed in half the dataset and validated in the other half. Results Hematologic volumes were all strongly correlated with FFM in both men and women ( r ≥0.94). Whereas the accuracy of FFM alone was 69%, four hematologic volumes were individually more accurate (75% to 78%) in predicting 24EE. Equations based on hematologic volumes plus demographics had mean prediction errors comparable to those based on body composition plus demographics; although the Mifflin-St Jeor had modestly better mean prediction error, body composition, hematologic, and Mifflin-St Jeor models all had similar accuracy (approximately 80%). Conclusions Prediction equations based on hematologic volumes were developed, validated, and found to be comparable to Mifflin-St Jeor and body composition models in this population of healthy adults. [ABSTRACT FROM AUTHOR]

The size of subcutaneous (SAT) and visceral adipose tissue (VAT) in the abdomen is negatively associated with insulin action. Deep portion of SAT (below subcutaneous fascia) and intraperitoneal portion of VAT (within abdominal cavity) are thought to be the principal determinants of this relationship, which according to some studies, is further modified by sex and obesity status. We studied obese Pima Indian men (n= 37) and women (n= 22) with normal glucose tolerance (mean age 27 [SD 8] years, BMI 36 [5] kg.m[sup -2]) who had measurements of body composition by DEXA, abdominal adipose tissue distribution by magnetic resonance imaging and insulin-mediated glucose disposal rate (M) by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU.m[sup -2]min[sup -1]). Women had more body fat (BF) and more superficial SAT compared to men (both P< 0.0001). After adjustment for age and BF, the differences in superficial SAT were no longer significant, while men had more total (P= 0.001) and deep SAT (P< 0.0001), and more total (P= 0.002) and intraperitoneal VAT (P= 0.003) compared to women. After adjustment for age and sex, M was related to SAT (r= -0.26, P= 0.05), deep SAT (r= -0.27, P=- 0.00), VAT (r= -0.36, P=0.006) and intraperitoneal VAT (r= -0.43, P= 0.0007). In sex specific analysis, deep SAT (r= -0.38, P= 0.02) and intraperitoneal VAT (r= -0.45, P= 0.006) were significant determinants of M in men but not in women (P= 0.7 and P= 0.1 respectively). Superficial SAT was the only significant determinant of M in women (-0.55, P= 0.01). The latter association was confirmed in the general linear regression analysis as significant gender-to-superficial SAT interaction (P= 0.000). Our results showed a sex-specific association between fat distribution in abdomen and insulin action in obese Pima Indians. This indicates that different mechanisms may underlie the association between abdominal obesity and insulin resistance in men and women. [ABSTRACT FROM AUTHOR]

Adipose tissue macrophage content increases with adiposity, and precedes obesity-induced hyperinsulinemia in animal models of insulin resistance. We investigated whether macrophage content in subcutaneous adipose tissue was associated with adiposity and insulin action in non-diabetic humans. We studied 65 Pima Indians (mean age 31 years [SD 8], BMI 34 [7] kg.m[sup -2], 24 women) who were enrolled in an ongoing study of risk factors for diabetes. For each subject measurements of body composition by DEXA, insulin action (M), as assessed by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU.m[sup -2].min[sup -1]), and aspiration biopsy of subcutaneous abdominal adipose tissue were obtained. Macrophage content was estimated by the number of CD68-expressing cells as determined by immunohistochemistry (CD68[sup +], in 45 subjects) and from the expression levels of macrophage markers (Cd68, Csf1r, Cd11b) determined by quantitative reverse transcriptase-polymerase chain reaction. The fraction of CD68[sup +] cells was associated with body fat (r= 0.33, P= 0.02) as was expression of macrophage markers (Cd68: r= 0.33, P= 0.007; Csf1r: r= 0.55, P< 0.0001; Cd11b: r=0.44, P= 0.0003) and these associations persisted after adjustment for age and sex (CD68[sup +]: P= 0.04; Cd68: P=0.05; Csf1r and Cd11b: P= 0.0008 both). M was. associated with body fat (r= -0.34, P= 0.006), expression of Csf1r (r= -0.33, P= 0.007) and Cd11b (r= -0.26, P=-0.04), and weakly with Cd68 expression (r= -0.24, P=0.06). M was not associated with the fraction of CD68[sup +] cells (r= -0.12, P= 0.4). The associations of M with Csf1r and Cd11b expression were not significant after adjustment for body fat (P= 0.2 and P= 0.5 respectively). Macrophage content in subcutaneous abdominal adipose tissue is associated with adiposity in Pima Indians. Our data indicate that increased macrophage content in subcutaneous adipose tissue does not provide a mechanistic link between increasing adiposity and worsening of insulin action. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease is emerging as an important risk factor for cardiovascular disease (CVD). The underlying etiology may be related to changes in hemostatic and inflammatory markers that occur with worsening renal disease. We examined the association of inflammatory and hemostatic markers with microvascular complications in 104 young adult Pima Indians (69 women, mean age 32±4y) with early onset type 2 diabetes (T2DM) (age of onset < 30years) and in 59 individuals (29 women, 32±4) with normal glucose regulation (NGR, fasting plasma glucose < 110 mg/dl and 2 hour plasma glucose < 140 mg/dl). Each individual underwent a physical exam including direct fundoscopy with dilated pupils, measurement of urine for albumin and creatinine, fasting blood for serum creatinine, C-reactive protein, interleukin-6, fibrinogen, D-dimer, plasmin antiplasmin complex, and plasminogen activator inhibitor-1. Glomerular filtration rate (GFR) was estimated with the Modification of Diet in Renal Disease equation. Severity of retinopathy was classified in the worst eye by direct ophthalmoscopy as none, background or proliferative. Of the markers measured, only fibrinogen was correlated with GFR (r=-0.22, p< 0.05) and ACR (r=0.25, p< 0.01). After adjustment for age, gender, percentage Pima heritage, duration of T2DM, blood pressure and use of aspirin, antihypertensive and antihyperglycemic agents, GFR (ml/min/ 1.73m²) (β=-0.76, p< 0.03) and ACR (mg/g) (β=0.03, p< 0.001) remained significant determinants of fibrinogen concentration (mg/dl). Fibrinogen was also associated with increasing severity of retinopathy (p< 0.01 for whole study population, n=163 and p< 0.04 for T2DM only, n= 104) after adjustment for the same confounders and ACR or GFR. Increased plasma fibrinogen concentrations were associated with microvascular complications, in particular worsening nephropathy. As both renal disease and fibrinogen are risk factors for CVD, this finding could be an etiologic link. [ABSTRACT FROM AUTHOR]

Background Molecular stable isotope ratios are a novel type of dietary biomarker with high sensitivity and specificity for certain foods. Among these, fatty acid carbon isotope ratios (CIRs) have strong potential but have not been investigated as dietary biomarkers. Objectives We evaluated whether fatty acid CIRs and mass proportions were associated with meat, fish, and sugar-sweetened beverage (SSB) intake. Methods Thirty-two men [aged 46.2 ± 10.5 y; BMI (kg/m2): 27.2 ± 4.0] underwent a 12-wk inpatient dietary intervention at the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, Arizona. Men were randomly assigned to 1 of 8 dietary treatments varying the presence/absence of dietary meat, fish, and SSBs in all combinations. Fatty acid CIRs and mass proportions were measured in fasting blood samples and adipose tissue biopsies that were collected pre- and postintervention. Dietary effects were analyzed using multivariable regression and receiver operating characteristic AUCs were calculated using logistic regression. Results CIRs of the several abundant SFAs, MUFAs and arachidonic acid (20:4n-6) in plasma were strongly associated with meat, as were a subset of these fatty acids in RBCs. Effect sizes in plasma ranged from 1.01‰ to 1.93‰ and were similar but attenuated in RBCs. Mass proportions of those fatty acids were not associated with diet. CIRs of plasma dihomo-γ-linolenic acid (20:3n–6) and adipose palmitic acid (16:0) were weakly associated with SSBs. Mass proportions of plasma odd-chain fatty acids were associated with meat, and mass proportions of plasma EPA and DHA (20:5n–3 and 22:6n–3) were associated with fish. Conclusions CIRs of plasma and RBC fatty acids show promise as sensitive and specific measures of dietary meat. These provide different information from that provided by fatty acid mass proportions, and are informative where mass proportion is not. This trial is registered at www.clinicaltrials.gov as NCT01237093. [ABSTRACT FROM AUTHOR]

Background: The natural abundance nitrogen stable isotope ratio (NIR) of whole tissue correlates with animal protein intakes, including meat and fish. Amino acid (AA) NIRs (NIRAAs) are more variable than the whole-tissue NIRs and may thus better differentiate among foods.Objectives: We evaluated whether NIRAAs were associated with intakes of fish and meat and whether these dietary associations were larger than with whole-tissue NIRs.Methods: Men were recruited at the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, Arizona, and randomly assigned to one of eight 12-wk inpatient dietary interventions, which varied the presence/absence of fish, meat, and sugar-sweetened beverages (SSBs) in all possible combinations. Fasting blood was drawn pre- and postintervention and plasma and RBC NIRAAs (free and protein-bound) were measured as secondary outcomes in 32 participants. Multivariable regression was used to determine responses of postintervention NIRAAs to dietary variables, and logistic regression was used to calculate receiver operating characteristic AUCs.Results: Most plasma NIRAAs increased with fish and meat intakes, but to a greater extent with fish intake. The largest increase in response to fish intake was plasma NIRLeucine (β = 2.19, SE = 0.26). The NIRThreonine decreased with both fish and meat intakes. Fewer RBC NIRAAs increased with fish intake, and only RBC NIRProline increased with meat intake. No plasma or RBC NIRAA responded to SSB intake. We identified fish intake with a high degree of accuracy using plasma NIRLeucine (corrected AUC, cAUC = 0.96) and NIRGlutamic acid/glutamine (cAUC = 0.93), and meat intake to a lower degree using plasma NIRProline (cAUC = 0.80) and RBC NIRProline (cAUC = 0.85).Conclusions: Plasma and RBC NIRAAs were associated with fish and meat intakes but were not superior to whole-tissue stable isotope biomarkers in identifying these intakes in a US diet. This trial is registered at www.clinicaltrials.gov as NCT01237093. [ABSTRACT FROM AUTHOR]

Transcranial direct stimulation (tDCS) targeted to the dorsolateral prefrontal cortex (DLPFC) reduces food intake and hunger, but its effects on circulating factors are unclear. We assessed the effect of repeated administration of tDCS to the left DLPFC (L-DLPFC) on concentrations of pro/anti-inflammatory and appetitive hormone concentrations. Twenty-nine healthy adults with obesity (12 M; 42±11 y; BMI=39±8 kg/m2) received 3 consecutive inpatient sessions of either anodal or sham tDCS targeted to the L-DLPFC during a period of ad libitum food intake. Fasting plasma concentrations of IL-6, orexin, cortisol, TNF-α, IL-1β, ghrelin, PYY, and GLP-1 were measured before the initial and after the final tDCS sessions. IL-6 (β=-0.92 pg/ml p=0.03) decreased in the anodal group compared with sham, even after adjusting for kcal intake; there were no changes in other hormones. Mean kcal intake was associated with higher IL-1β and ghrelin concentrations after the ad libitum period (β=0.00018 pg/ml/kcal, p=0.03; β=0.00011 pg/ml/kcal, p=0.02; respectively), but not differ by intervention groups. IL-6 concentrations were reduced following anodal tDCS to the L-DLPFC independent of ad libitum intake. IL-6 concentrations reflect the inflammatory state of adiposity and may affect eating behavior and weight gain. These findings provide evidence of therapeutic benefit of tDCS. • Anodal tDCS to the L-DLPFC diminished IL-6, a chronic inflammatory marker in obesity. • Reduction of IL-6 following tDCS was independent of ad libitum food intake. • tDCS affects IL-6 levels by modulating brain and sympathetic nervous system activity. • Study pioneers tDCS as a potential obesity intervention by influencing cytokines. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes.Research Design and Methods: This was a prespecified analysis of 6,823 participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) taking metformin as the sole glucose-lowering drug who completed a 4- to 14-week (mean ± SD 7.9 ± 2.4) run-in in which metformin was adjusted to 2,000 mg/day or a maximally tolerated lower dose. Participants had type 2 diabetes for <10 years and an HbA1c ≥6.8% (51 mmol/mol) while taking ≥500 mg of metformin/day. Participants also received diet and exercise counseling. The primary outcome was the change in HbA1c during run-in.Results: Adjusted for duration of run-in, the mean ± SD change in HbA1c was -0.65 ± 0.02% (-7.1 ± 0.2 mmol/mol) when the dose was increased by ≥1,000 mg/day, -0.48 ± 0.02% (-5.2 ± 0.2 mmol/mol) when the dose was unchanged, and -0.23 ± 0.07% (-2.5 ± 0.8 mmol/mol) when the dose was decreased (n = 2,169, 3,548, and 192, respectively). Higher HbA1c at entry predicted greater reduction in HbA1c (P < 0.001) in univariate and multivariate analyses. Weight loss adjusted for duration of run-in averaged 0.91 ± 0.05 kg in participants who increased metformin by ≥1,000 mg/day (n = 1,894).Conclusions: Optimizing metformin to 2,000 mg/day or a maximally tolerated lower dose combined with emphasis on medication adherence and lifestyle can improve glycemia in type 2 diabetes and HbA1c values ≥6.8% (51 mmol/mol). These findings may help guide efforts to optimize metformin therapy among persons with type 2 diabetes and suboptimal glycemic control. [ABSTRACT FROM AUTHOR]

• The spendthrift phenotype is more prone to weight-loss and resistant to weight-gain. • Greater anhedonia traits were associated with the spendthrift metabolic phenotype. • Healthy participants with anhedonia may respond better to their homeostatic needs. • This association weakens when depressive symptoms increase. Obesity rates are increasing and affecting mental health. It is important to understand how behavioral traits such as anhedonia are associated with physiologic traits that may predict weight-change in clinical and non-clinical populations. We studied whether 24-hour energy expenditure (24hEE) changes with fasting and overfeeding are associated with anhedonia in a healthy cohort. We performed behavioral assessments (physical anhedonia scale (PAS) and inventory for depressive symptoms (IDS)) followed by measures of 24hEE and urinary catecholamines in a whole-room indirect calorimeter (respiratory chamber) during energy balance, and then randomly during fasting and 2 different overfeeding diets. Participants (n=98) were medically healthy, between 18 and 55 years of age, with normal glucose regulation and weight-stable 6 months before admission. Women were premenopausal and not pregnant. Higher PAS was significantly associated with lesser decrease in 24hEE with fasting and higher urinary catecholamine excretion rates – consistent with spendthrift metabolism. As IDS increased, the association between anhedonia and the change in 24hEE from energy balance to fasting decreased (B-values were lower for change in EE). Here, higher PAS scores may reflect the ability to respond with appropriate homeostatic reactions which balance energy needs. IDS scores blunting this response may explain how anhedonia and depression can lead to weight gain. [ABSTRACT FROM AUTHOR]

Physiological systems controlling water and energy ingestion are coordinated. Whether maladaptive eating behavior and appetite for water are linked is unknown. Thus, we sought to investigate the association between maladaptive eating and both thirst and water drinking behavior with two dehydrating conditions. Twenty-two lean men and 20 men with obesity (mean age 32.3 ± 8.4 years and 30.0 ± 11.1 years, respectively) completed the Three-Factor Eating Questionnaire (TFEQ) and Gormally Binge Eating Scale. On separate days, volunteers were dehydrated by a 2-h hypertonic saline infusion and a 24-h water deprivation, and thirst was measured on a 100-mm visual analogue scale (VAS) during each procedure. After each dehydrating condition, ad libitum water intake was measured. In the saline infusion, higher Disinhibition on the TFEQ was associated with thirst in the lean group (β = 4.2 mm VAS, p = 0.03) but not in the group with obesity (p = 0.51). In the water-deprivation condition, higher Disinhibition was also associated with thirst in the lean group (β = 5.6 mm VAS, p = 0.01) with the strength of relationship being 3.5-fold stronger than that observed in the group with obesity (β = 1.6 mm VAS, p = 0.0003). Hunger, Restraint, and binge-eating scores were not associated with thirst in either dehydrating condition (all p > 0.05). Maladaptive eating behaviors were not associated with ad libitum water intake (all p > 0.05). Disinhibition is associated with higher thirst perception in healthy weight individuals and may be attenuated in obesity. The characteristics of disinhibition which typically includes a heightened readiness to eat, may reflect a more general phenotype that also reflects a readiness to drink. [ABSTRACT FROM AUTHOR]

Background: Theory posits that macronutrient intake is regulated by protein consumption and adequate intake of protein results in consumption of less carbohydrates and fat. The current study investigates the effect of protein intake on calorie and macronutrient content using an ad libitum vending machine paradigm.Methods: Healthy volunteers (n = 287; 177 m; Age = 36 ± 11; BMI = 32 ± 8) were admitted to our clinical research unit. Macronutrient meal content (grams) and energy intake (Kcal) were quantified by specialized food processing software and collected on an hourly basis over a three-day period using a validated ad libitum vending machine paradigm. Body composition was assessed by DXA. Lagged multi-level models accounting for age, sex, race/ethnicity, fat and fat free mass indices were fitted to examine the impact of prior macronutrient content on subsequent meals.Results: Protein intake was associated with decreased energy intake (Kcal; B = -1.67 kcal, p = 0.0048), lower protein and carbohydrate intake (B = -0.08 g, p = 0.0006; B = -0.21 g, p = 0.0003, respectively) at subsequent meals. Daily Macronutrient intake and subsequent intake were positively associated.Conclusions: Dietary protein exhibits a negative regulatory effect on a short-term meal-to-meal rather than day-to-day basis. In the setting of readily available food, protein intake impacts energy intake only over very short time courses. [ABSTRACT FROM AUTHOR]

Abstract: The anorexigenic gastrointestinal hormone Peptide YY plays an important role in the communication between the gastrointestinal tract and the central nervous system. PYY has been shown to modulate brain activity in regions implicated in reward and food related behavior. Its effects on brain structure however, remain unknown. Voxel-based morphometry was used to investigate the relationship between fasting and postprandial plasma PYY concentrations and regional gray matter volume (GMV). For this analysis twenty adult, non diabetic Caucasians were included (18F/2M, age 31±9y, percentage of body fat [PFAT] 32±8%) who had volumetric brain magnetic resonance images and underwent H2 15O positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF), a marker of local neuronal activity, and measurements of plasma total PYY, prior to (fasting) and following a satiating liquid meal. Voxel-wise analysis revealed a regional positive association between postprandial PYY and gray matter volume bilaterally in the caudate nuclei. These associations remained significant (p<0.05) after small volume correction for multiple comparisons. Based on these findings we investigated whether postprandial PYY is associated with PET measured rCBF of the caudate nucleus. We found a significant negative association between average postprandial caudate rCBF and postprandial plasma PYY concentrations (r=−0.60, p<0.02, age, sex and PFAT adjusted). Average postprandial caudate rCBF was also negatively associated with rCBF in the right medial orbitofrontal cortex and the right hippocampal formation (p<0.05, corrected for multiple comparisons). Total PYY is positively associated with gray matter but negatively with postprandial activity in the caudate nuclei while caudate activity is negatively associated with rCBF in prefrontal and paralimbic regions implicated in reward behavior. Thus, PYY may act centrally to modulate eating behavior via striatal networks. [Copyright &y& Elsevier]

McCune-Albright syndrome (MAS) is defined by the triad of café-au-lait skin pigmentation, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies, such as precocious puberty, hyperthyroidism, GH excess, and Cushing's syndrome. This disorder is caused by sporadic, postzygotic activating mutations in the GNAS1 gene, which codes for the G(s)alpha protein in the cAMP signaling cascade. Nodular and diffuse goiters (with and without hyperthyroidism), as well as benign thyroid nodules, have been reported in association with MAS. Herein we report two cases of thyroid carcinoma in patients with MAS. The first is a case of papillary thyroid cancer detected incidentally during a hemithyroidectomy for hyperthyroidism in a 14-yr-old girl. The second is one of a 41-yr-old woman with long-standing MAS and an enlarging thyroid nodule, which was diagnosed as a clear cell thyroid carcinoma, a rare variant of thyroid cancer. Molecular analysis revealed that foci of malignancy and adjacent areas of hyperplasia and some areas of normal thyroid harbored activating mutations of Arg(201) in the GNAS1 gene. These findings suggest that the infrequent development of thyroid carcinoma in MAS patients involves additional mutational or epigenetic events.