Reduced plasma interleukin-6 concentration after transcranial direct current stimulation to the prefrontal cortex.

OBJECTIVES: 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. MATERIALS AND METHODS: 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-1ß, ghrelin, PYY, and GLP-1 were measured before the initial and after the final tDCS sessions. RESULTS: IL-6 (ß=-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-1ß and ghrelin concentrations after the ad libitum period (ß=0.00018 pg/ml/kcal, p=0.03; ß=0.00011 pg/ml/kcal, p=0.02; respectively), but not differ by intervention groups. CONCLUSIONS: 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.

Hepatic Insulin Resistance Increases Risk of Gallstone Disease in Indigenous Americans in the Southwestern United States.

OBJECTIVES: Animal models indicate that hepatic insulin resistance (IR) promotes cholesterol gallstone disease (GSD). We sought to determine whether hepatic and whole-body IR are associated with incident GSD. METHODS: At baseline, 450 Southwestern Indigenous American adults without GSD were included. Participants had a 2-step hyperinsulinemic-euglycemic clamp with glucose tracer at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min) for whole-body IR (M-low and M-high) and hepatic glucose production (HGP) before and during submaximal insulin infusion (HGP-basal and HGP-insulin). Incident GSD was identified during follow-up visits conducted at ∼2-year intervals. The associations of HGP (basal, insulin, and % suppression), M-low, and M-high with risk of GSD were assessed by Cox regression models adjusted for age, sex, body fat (%), glucose, and insulin. RESULTS: Sixty participants (13%) developed GSD (median follow-up: 11.6 years). Participants who developed GSD were of similar age and whole-body IR as those who did not (p's> 0.07), but were more likely to be female, have higher body fat, higher HGP-basal, and HGP-insulin, and lower % suppression of HGP (p's<0.02). In separate adjusted models, higher HGP-insulin and lower % suppression of HGP were associated with increased risk for GSD (hazard ratio [HR] per SD: HR 1.38, 95% CI 1.12, 1.69, p=0.002; HR 1.41 95% CI 1.16-1.72, p=0.0007). HGP-basal, M-low, and M-high were not associated with GSD in adjusted models (p's>0.22). CONCLUSIONS: Resistance to insulin suppression of HGP increases risk for GSD. Hepatic IR is a link between GSD and other conditions of the metabolic syndrome.

A mixed meal tolerance test predicts onset of type 2 diabetes in Southwestern Indigenous adults.

BACKGROUND/OBJECTIVE: To identify predictors of incident type 2 diabetes using a mixed meal tolerance test (MMTT). METHODS: Adult Indigenous Americans without diabetes (n = 501) from a longitudinal cohort underwent at baseline a 4-h MMTT, measures of body composition, an oral glucose tolerance test, an intravenous glucose tolerance test for acute insulin response (AIR), and a hyperinsulinemic-euglycemic clamp for insulin action (M). Plasma glucose responses from the MMTT were quantified by the total and incremental area under the curve (AUC/iAUC). RESULTS: At follow-up (median time 9.6 [inter-quartile range: 5.6-13.5] years), 169 participants were diagnosed with diabetes. Unadjusted Cox proportional hazards models, glucose AUC180-min (HR: 1.98, 95% CI: 1.67, 2.34, p < 0.0001), AUC240-min (HR: 1.93, 95% CI: 1.62, 2.31, p < 0.0001), and iAUC180-min (HR: 1.43, 95% CI: 1.20, 1.71, p < 0.0001) were associated with an increased risk of diabetes. After adjustment for covariates (age, sex, body fat percentage, M, AIR, Indigenous American heritage) in three subsequent models, AUC180-min (HR: 1.44, 95% CI: 1.10, 1.88, p = 0.007) and AUC240-min (HR: 1.41, 95% CI: 1.09, 1.84, p < 0.01) remained associated with increased risk of diabetes. CONCLUSIONS: Glucose responses to a mixed meal predicted the development of type 2 diabetes. This indicates that a mixed nutritional challenge provides important information on disease risk. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov identifier : NCT00340132, NCT00339482.

Acid accumulation is associated with metabolic alterations; higher energy, fat, and protein intake; and energy expenditure.

OBJECTIVE: The objective of this study was to study how acid accumulation (lower plasma bicarbonate and higher anion gap [AG] and corrected anion gap [CAG]) correlates with metabolic parameters, food intake, and 24-h energy expenditure (EE). METHODS: Acid accumulation was measured in 286 healthy adults with estimated glomerular filtration rate > 60 mL/min/1.73 m2. Measurements included body composition by dual-energy x-ray absorptiometry scan, ad libitum energy intake by a vending machine paradigm over 3 days, and 24-h EE in a whole-room indirect calorimeter. RESULTS: Lower bicarbonate, higher AG, and higher CAG were correlated with higher waist and thigh circumferences, body fat (percentage), fat mass, triglycerides, and lower high-density lipoprotein cholesterol. Acid accumulation markers were correlated with higher total energy (CAG partial r = 0.17; p = 0.02), fat (CAG partial r = 0.17; p = 0.02), protein intake (CAG partial r = 0.20; p = 0.006), and 24-h EE (CAG partial r = 0.24; p = 0.0007). A mediation analysis of CAG and total energy intake found that 24-h EE was a partial mediator (40%), but the association remained significant (ß = 0.15; p < 0.0001). CONCLUSIONS: In healthy individuals, acid accumulation was associated with an unfavorable metabolic phenotype; higher 24-h EE; and increased total energy, fat, and protein intake. Acid accumulation markers, as putative markers of higher dietary acid load (e.g., from protein), may affect energy balance physiology promoting weight gain.

Secular trends and determinants of ad libitum energy intake measured in a research setting from 1999-2020.

Introduction: Historically, secular and seasonal trend analyses have been examined using self-report measures of intake. Rarely are objective measures and known determinants of dietary intake used in these analyses. Our objective was to quantify the seasonal and secular differences in an objective ad libitum intake paradigm while considering the contribution of determinants, such as fat-free mass (FFM) index and spontaneous physical activity (SPA) limited to the restricted space of a whole-room calorimeter. Methods: For this study, recruitment of N = 292 healthy, diabetes free, adults occurred from 1999 to 2020. Assessment during their 10-day stay included body composition (by DXA), SPA (by an approximately 24-h stay in whole-room calorimetry), and ad libitum intake (by a vending machine for 3 days). This secondary analysis used general linear models (GLM) to investigate secular and seasonal differences while adjusting for sex, age, FFM index, FM (fat mass) index, SPA, and race/ethnicity. Results: FFM index and SPA were positively associated with all intake measures (p < 0.05). In all adjusted seasonal models, season did not affect intake. Adjusted secular trends models (kcals/year) demonstrated a decrease in total kcals (ß = -55), intake as percent weight maintaining energy needs (ß = -2), protein kcals (ß = -10), fat kcals (ß = -27), and carbohydrates kcals (ß = -22) (all p < 0.05). After further adjustment for SPA, significance remained in all intake measures (p < 0.05). Secular trends in body composition revealed no changes in weight, BMI, and percent body fat (all p > 0.20). Discussion: Our results indicate that over time, ad libitum intake decreased in this controlled research setting and remained significant even after accounting for positive determinants of intake. A significant ad libitum decrease, coupled with no change in body composition, may highlight a participant bias toward calorie restriction in a controlled setting over time and deserves further investigation.

An E115A Missense Variant in CERS2 Is Associated With Increased Sleeping Energy Expenditure and Hepatic Insulin Resistance in American Indians.

Genetic determinants of interindividual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-h EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp. Association analysis of 10,084 genetic variants within 28 genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in exon 4 of CERS2 that was associated with higher sleeping EE (116 kcal/day) and increased rates of endogenous glucose production during basal (5%) and insulin-stimulated (43%) conditions, both indicators of hepatic insulin resistance. The rs267738 variant did not affect ceramide synthesis in HepG2 cells but resulted in a 30% decrease in basal mitochondrial respiration. In conclusion, we provide evidence that the CERS2 rs267738 missense variant may influence hepatic glucose production and postabsorptive sleeping metabolic rate.

Impaired metabolic flexibility to fasting is associated with increased ad libitum energy intake in healthy adults.

OBJECTIVE: We investigated how changes in 24-h respiratory exchange ratio (RER) and substrate oxidation during fasting versus an energy balance condition influence subsequent ad libitum food intake. METHODS: Forty-four healthy, weight-stable volunteers (30 male and 14 female; mean [SD], age 39.3 [11.0] years; BMI 31.7 [8.3] kg/m2) underwent 24-h energy expenditure measurements in a respiratory chamber during energy balance (50% carbohydrate, 30% fat, and 20% protein) and 24-h fasting. Immediately after each chamber stay, participants were allowed 24-h ad libitum food intake from computerized vending machines. RESULTS: Twenty-four-hour RER decreased by 9.4% (95% CI: -10.4% to -8.5%; p < 0.0001) during fasting compared to energy balance, reflecting a decrease in carbohydrate oxidation (mean [SD], -2.6 [0.8] MJ/day; p < 0.0001) and an increase in lipid oxidation (2.3 [0.9] MJ/day; p < 0.0001). Changes in 24-h RER and carbohydrate oxidation in response to fasting were correlated with the subsequent energy intake such that smaller decreases in fasting 24-h RER and carbohydrate oxidation, but not lipid oxidation, were associated with greater energy intake after fasting (r = 0.31, p = 0.04; r = 0.40, p = 0.007; and r = -0.27, p = 0.07, respectively). CONCLUSIONS: Impaired metabolic flexibility to fasting, reflected by an inability to transition away from carbohydrate oxidation, is linked with increased energy intake.

An algorithm to simulate missing data for mixed meal tolerance test response curves.

BACKGROUND: Response curves formed by analyte concentrations measured at sampled time points after consuming a mixed meal are increasingly being used to characterize responses to differing diets. Unfortunately, owing to a variety of reasons, analyte concentrations for some of the time points may be missing. OBJECTIVES: This study aimed to develop an algorithm to estimate the missing values at sampled time points in the analyte response curve to a mixed meal tolerance test (MMTT). METHODS: We developed an algorithm to simulate the missing postprandial concentration values for an MMTT. The algorithm was developed to handle any number of missing values for 2 or less consecutive missing values. The algorithm was tested on MMTT response curve data for glucose and triglyceride measurements in data from 3 different studies with 2119 postprandial MMTT response curves. The algorithm was validated by removing concentration values that were not missing and replacing them with the algorithm simulated values. The AUC error between the actual curve and simulated curves were also calculated. A web-based application was developed to automatically simulate missing values for an uploaded MMTT data set. RESULTS: The algorithm was programmed in Python and the resulting web-based application and a video tutorial were provided. The validation indicated good agreement between actual and simulated values with error increasing for less frequently sampled time points. The study with the mean minimum error of glucose concentrations was 6.2 ± 2.1 mg/dL and study with the mean maximum error of glucose concentrations was 11.3 ± 4.7 mg/dL. Triglycerides had 16.1 ± 6.2 mg/dL mean error. The AUC error was small ranging between 0.01% and 0.28%. CONCLUSIONS: The presented algorithm reconstructs postprandial response curves with estimations of values that are missing.

Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.

The emerging field of precision nutrition is based on the notion that inter-individual responses across diets of different calorie-macronutrient content may contribute to inter-individual differences in metabolism, adiposity, and weight gain. Free-living diet studies have been traditionally challenged by difficulties in controlling adherence to prescribed calories and macronutrient content and rarely allow a period of metabolic stability prior to metabolic measures (to minimize influences of weight changes). In this context, key physiologic measures central to precision nutrition responses may be most precisely quantified via whole room indirect calorimetry over 24-h, in which precise control of activity and nutrition can be achieved. In addition, these studies represent unique "N of 1" human crossover metabolic-physiologic experiments during which specific molecular pathways central to nutrient metabolism may be discerned. Here, we quantified 263 circulating metabolites during a ≈40-day inpatient admission in which up to 94 participants underwent seven monitored 24-h nutritional interventions of differing macronutrient composition in a whole-room indirect calorimeter to capture precision metabolic responses. Broadly, we observed heterogenous responses in metabolites across dietary chambers, with the exception of carnitines which tracked with 24-h respiratory quotient. We identified excursions in shared metabolic species (e.g., carnitines, glycerophospholipids, amino acids) that mapped onto gold-standard calorimetric measures of substrate oxidation preference and lipid availability. These findings support a coordinated metabolic-physiologic response to nutrition, highlighting the relevance of these controlled settings to uncover biological pathways of energy utilization during precision nutrition studies.

Twenty-Four-Hour Urinary Sugars Biomarker in a Vending Machine Intake Paradigm in a Diverse Population.

Accurately measuring dietary sugars intake in large-scale epidemiological studies is necessary to understand dietary sugars' true impact on health. Researchers have developed a biomarker that can be used to assess total sugars intake. Our objective is to test this biomarker in diverse populations using an ad libitum intake protocol. Healthy adult participants (n = 63; 58% Indigenous Americans/Alaska Natives; 60% male; BMI (mean ± SD) = 30.6 ± 7.6 kg.m2) were admitted for a 10-day inpatient stay. On day 2, body composition was measured by DXA, and over the last 3 days, ad libitum dietary intake was measured using a validated vending machine paradigm. Over the same days, participants collected daily 24 h urine used to measure sucrose and fructose. The 24 h urinary sucrose and fructose biomarker (24hruSF) (mg/d) represents the sum of 24 h urinary sucrose and fructose excretion levels. The association between the 3-day mean total sugars intake and log 24uSF level was assessed using the Pearson correlation. A linear mixed model regressing log-biomarker on total sugars intake was used to investigate further the association between biomarker, diet, and other covariates. Mean (S.D.) total sugars intake for the group was 197.7 g/d (78.9). Log 24uSF biomarker was moderately correlated with total sugars intake (r = 0.33, p = 0.01). In stratified analyses, the correlation was strongest in females (r = 0.45, p = 0.028), the 18-30 age group (r = 0.44, p = 0.079), Indigenous Americans (r = 0.51, p = 0.0023), and the normal BMI category (r = 0.66, p = 0.027). The model adjusted for sex, age, body fat percent, and race/ethnicity demonstrated a statistically significant association between 24uSF and total sugars intake (ß = 0.0027, p < 0.0001) and explained 31% of 24uSF variance (marginal R2 = 0.31). Our results demonstrated a significant relationship between total sugars intake and the 24uSF biomarker in this diverse population. However, the results were not as strong as those of controlled feeding studies that investigated this biomarker.

Dietary Adherence Is Associated with Perceived Stress, Anhedonia, and Food Insecurity Independent of Adiposity.

We examined whether perceived stress, anhedonia, and food insecurity were associated with dietary adherence during a 6-week intervention. Sixty participants (23 m; 53 ± 14 y) completed psychosocial measures and were provided with full meals. Individuals with obesity were randomized to a weight-maintaining energy needs (WMENs) (n = 18; BMI 33 ± 4) or a 35% calorie-reduced diet (n = 19; BMI 38 ± 9); normal-weight individuals (n = 23; BMI 23 ± 2) were assigned to a WMENs diet. Adherence scores were determined via weekly assessments and daily ecological momentary assessments (EMAs) of real-time behavior in a natural environment. Perceived stress and anhedonia were associated with % body fat (all r-values > 0.25, all p-values < 0.05), but food insecurity and adherence were not. Higher perceived stress (r = -0.31, p = 0.02), anhedonia (r = -0.34, p = 0.01), and food insecurity (r = -0.27, p = 0.04) were associated with lower adherence scores, even after adjusting for age, sex, and % body fat. In all adjusted models, % body fat was not associated with adherence. Higher measures of stress, anhedonia, and food insecurity predicted lower adherence independently of body fat, indicating that psychosocial factors are important targets for successful adherence to dietary interventions, regardless of body size.

Insulin resistance before type 2 diabetes onset is associated with increased risk of albuminuria after diabetes onset: A prospective cohort study.

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.

Adipocyte size, adipose tissue calories, and circulating adipokines, before and after diet-induced weight loss in humans.

OBJECTIVE: Adipose tissue (AT) contains a bimodal population of large and small adipocytes. Changes in fat cell size (FCS) distribution and AT caloric density (kcal/g) with weight loss are unclear. We aimed to evaluate changes in FCS and AT calories in weight loss and determine associations with anthropometrics. MATERIALS AND METHODS: Healthy adults (6 men/4 women; age 33 ± 11 years; BMI 35 ± 6 kg/m2) underwent DXA and subcutaneous abdominal/thigh fat biopsies, before and after 6 weeks of caloric restriction. AT calories (bomb calorimetry) and hormones (adiponectin, leptin, FGF21) were measured. RESULTS: Abdominal large cell diameter (LCD; Δ = -13.2 µm, p = 0.01) and nadir (Δ = -7.3 µm, p = 0.03) decreased. In repeated measures correlations (rrm), abdominal and thigh LCD and nadir were associated with fat mass (FM) loss (rrm = 0.68; rrm = 0.63; rrm = 0.66; rrm = 0.62, p's < 0.05, respectively) and waist circumference decrease (rrm = 0.70; rrm = 0.60, p's ≤ 0.05). Small cell percentage did not change and was not associated with FM changes. Abdominal AT calories were unchanged with weight loss. Change in leptin was associated with change in abdominal LCD (rrm = 0.77, p = 0.01). CONCLUSIONS: Caloric restriction reduces adipocyte LCD and nadir. These changes are associated with FM loss. Larger fat cells should be considered as phenotypic targets for weight loss. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov identifier: NCT00687115, May 29, 2008.

Impact of Insulin Sensitivity and ß-Cell Function Over Time on Glycemic Outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE): Differential Treatment Effects of Dual Therapy.

OBJECTIVE: To compare the effects of insulin sensitivity and ß-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 ß-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.

Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial.

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.

Emotional Distress Predicts Reduced Type 2 Diabetes Treatment Adherence in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

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.

Investigation of seasonality of human spontaneous physical activity and energy expenditure in respiratory chamber in Phoenix, Arizona.

OBJECTIVE: The existence of seasonal changes in energy metabolism is uncertain. We investigated the relationship between the seasons and spontaneous physical activity (SPA), energy expenditure (EE), and other components measured in a respiratory chamber. METHODS: Between 1985-2005, 671 healthy adults (aged 28.8 ± 7.1 years; 403 men) in Phoenix, Arizona had a 24-hour stay in the respiratory chamber equipped with radar sensors; SPA (expressed as a percentage over the time interval), the energy cost of SPA, EE, and respiratory exchange ratio (RER) were measured. RESULTS: In models adjusted for known covariates, SPA (%) was lower during summer (7.2 ± 2.9, p = 0.0002), spring (7.5 ± 2.9, p = 0.025), and fall (7.6 ± 3, p = 0.038) compared to winter (8.3 ± 3.5, reference). Conversely, energy cost of SPA (kcal/h/%) was higher during summer (2.18 ± 0.83, p = 0.0008), spring (2.186 ± 0.83, p = 0.017), and fall (2.146 ± 0.75, p = 0.038) compared to winter (2.006 ± 0.76). Protein (292 ± 117 kcal/day, ß = -21.2, p = 0.08) oxidation rates was lower in the summer compared to winter. Carbohydrate and lipid oxidation rates (kcal/day) did not differ across seasons. RER and 24-h EE did not differ by season. CONCLUSION: SPA, representing fidgeting-like behavior in the chamber, demonstrated a winter peak and summer nadir in humans living in a desert climate. These findings indicate that the physiological propensity for movement may be affected by seasonal factors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00340132, NCT00342732.

New insights in the mechanisms of weight-loss maintenance: Summary from a Pennington symposium.

Obesity is a chronic disease that affects more than 650 million adults worldwide. Obesity not only is a significant health concern on its own, but predisposes to cardiometabolic comorbidities, including coronary heart disease, dyslipidemia, hypertension, type 2 diabetes, and some cancers. Lifestyle interventions effectively promote weight loss of 5% to 10%, and pharmacological and surgical interventions even more, with some novel approved drugs inducing up to an average of 25% weight loss. Yet, maintaining weight loss over the long-term remains extremely challenging, and subsequent weight gain is typical. The mechanisms underlying weight regain remain to be fully elucidated. The purpose of this Pennington Biomedical Scientific Symposium was to review and highlight the complex interplay between the physiological, behavioral, and environmental systems controlling energy intake and expenditure. Each of these contributions were further discussed in the context of weight-loss maintenance, and systems-level viewpoints were highlighted to interpret gaps in current approaches. The invited speakers built upon the science of obesity and weight loss to collectively propose future research directions that will aid in revealing the complicated mechanisms involved in the weight-reduced state.

Validation of Total Water Intake from the Automated Self-Administered 24-h Recall, 4-d Food Records, and a Food Frequency Questionnaire Using Doubly Labeled Water.

BACKGROUND: Although prior evidence indicates that water intake is important for health, the ability to accurately measure community-dwelling intake is limited. Only a few studies have evaluated self-reported water intake against an objective recovery biomarker. OBJECTIVES: The aim was to compare preformed water intakes (all sources including food) by multiple Automated Self-Administered 24-h recalls (ASA24s), food frequency questionnaires (FFQs), and 4-d food records (4DFRs) against a recovery biomarker, doubly labeled water (DLW), to assess measurement error. METHODS: Over 1 y, 1082 women and men (50%), aged 50 to 74 y, were asked to complete 6 ASA24s, 2 FFQs, 2 unweighted 4DFRs, and an administration of DLW (n = 686). Geometric means of water intake by self-report tools were compared with DLW. Attenuation factors and correlation coefficients between self-reported and the recovery biomarker (DLW) were estimated. RESULTS: Mean water intakes by DLW were 2777 mL/d (interquartile range, 2350 to 3331) in women and 3243 mL/d (interquartile range, 2720 to 3838) in men. Compared with DLW, water intake was underestimated by 18% to 31% on ASA24s and 43% to 44% on 4DFRs. Estimated geometric means from FFQs differed from DLW by -1% to +13%. For a single ASA24, FFQ, and 4DFR, attenuation factors were 0.28, 0.27, and 0.32 and correlation coefficients were 0.46, 0.48, and 0.49, respectively. Repeated use of 6 ASA24s, 2 FFQs, and 2 4DFRs improved attenuation factors to 0.43, 0.32, and 0.39 and correlation coefficients to 0.58, 0.53, and 0.54, respectively. CONCLUSIONS: FFQs may better estimate population means for usual water intake compared with ASA24 and 4DFR. Similar attenuation factors and correlation coefficients across all self-report tools indicate that researchers have 3 feasible options if the goal is understanding intake-disease relationships. The findings are useful for planning future nutrition studies that set policy priorities for populations and to understand the health impact of water. This trial was registered at clinicaltrials.gov as NCT03268577.