Coronary Artery Calcium and Cognitive Decline in the Diabetes Prevention Program Outcomes Study.

Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.

No sustained effects of an intervention to prevent excessive GWG on offspring fat and lean mass at 54 weeks: Yet a greater head circumference persists.

BACKGROUND: LIFT (Lifestyle Intervention for Two) trial found that intervening in women with overweight and obesity through promoting healthy diet and physical activity to control gestational weight gain (GWG) resulted in neonates with greater weight, lean mass and head circumference and similar fat mass at birth. Whether these neonate outcomes are sustained at 1-year was the focus of this investigation. METHODS: Measures included body composition by PEA POD air displacement plethysmography (ADP) and Echo Infant quantitative magnetic resonance (QMR) and head circumference at birth (n = 169), 14 (n = 136) and 54 weeks (n = 137). Differences in fat and lean mass between lifestyle intervention (LI) and Usual care (UC) groups were examined using ANCOVA adjusting for maternal age and BMI, GWG, offspring sex and age. RESULTS: Compared to UC, LI infants had similar weight (112 ± 131 g; P = .40), fat mass (14 ± 80 g; P = .86), lean mass (100 ± 63 g; P = .12) at 14 weeks and similar weight (168 ± 183 g; P = .36), fat mass (148 ± 124 g; P = .24), lean mass (117 ± 92 g; P = .21) at 54 weeks. Head circumference was greater in LI at 54 weeks (0.46 ± 2.1 cm P = .03). CONCLUSIONS: Greater lean mass observed at birth in LI offspring was not sustained at 14 and 54 weeks, whereas the greater head circumference in LI offspring persisted at 54 weeks.

Effects of Weight Loss on Obstructive Sleep Apnea Severity. Ten-Year Results of the Sleep AHEAD Study.

Rationale: Weight loss is recommended to treat obstructive sleep apnea (OSA).Objectives: To determine whether the initial benefit of intensive lifestyle intervention (ILI) for weight loss on OSA severity is maintained at 10 years.Methods: Ten-year follow-up polysomnograms of 134 of 264 adults in Sleep AHEAD (Action for Health in Diabetes) with overweight/obesity, type 2 diabetes mellitus, and OSA were randomized to ILI for weight loss or diabetes support and education (DSE).Measurements and Main Results: Change in apnea-hypopnea index (AHI) was measured. Mean ± SE weight losses of ILI participants of 10.7 ± 0.7, 7.4 ± 0.7, 5.1 ± 0.7, and 7.1 ± 0.8 kg at 1, 2, 4, and 10 years, respectively, were significantly greater than the 1-kg weight loss at 1, 2, and 4 years and 3.5 ± 0.8 kg weight loss at 10 years for the DSE group (P values ≤ 0.0001). AHI was lower with ILI than DSE by 9.7, 8.0, and 7.9 events/h at 1, 2, and 4 years, respectively (P values ≤ 0.0004), and 4.0 events/h at 10 years (P = 0.109). Change in AHI over time was related to amount of weight loss, baseline AHI, visit year (P values < 0.0001), and intervention independent of weight change (P = 0.01). OSA remission at 10 years was more common with ILI (34.4%) than DSE (22.2%).Conclusions: Participants with OSA and type 2 diabetes mellitus receiving ILI for weight loss had reduced OSA severity at 10 years. No difference in OSA severity was present between ILI and DSE groups at 10 years. Improvement in OSA severity over the 10-year period with ILI was related to change in body weight, baseline AHI, and intervention independent of weight change.

Long-term Change in Physiological Markers and Cognitive Performance in Type 2 Diabetes: The Look AHEAD Study.

CONTEXT: The effects of physiological improvements on cognitive function among persons with type 2 diabetes mellitus (T2DM) are not fully understood. OBJECTIVE: To determine whether improvements in physiological markers (body weight, blood sugar control, and physical activity) during intensive lifestyle intervention (ILI) are associated with enhancements in cognitive function in older adults with T2DM. DESIGN: Multisite randomized controlled trial. SETTING: Academic research centers. PATIENTS OR OTHER PARTICIPANTS: Participants were aged 45-76 years, with T2DM. INTERVENTION: The Action for Health in Diabetes (Look AHEAD) study, a randomized, controlled clinical trial of ILI. MAIN OUTCOME MEASURE: Two to 3 cognitive assessments were collected from 1089 participants, the first and last occurring a mean (standard deviation) of 8.6 (1.0) and 11.5 (0.7) years after enrollment. RESULTS: Greater improvement in blood sugar control was associated with better cognitive scores (fasting glucose and Rey Auditory Verbal Learning Test [AVLT]: P = 0.0148; fasting glucose and Digit Symbol Coding (DSC): P = 0.0360; HbA1C and DSC: P = 0.0477); but weight loss had mixed associations with cognitive scores (greater body mass index [BMI] reduction and worse AVLT overall: P = 0.0053; and greater BMI reduction and better DSC scores among those overweight but not obese at baseline: P = 0.010). Associations were strongest among those who were overweight (not obese) at baseline, and among those with a history of cardiovascular disease (CVD) at baseline. CONCLUSIONS: Improvements in glycemic control, but not necessarily weight status, during ILI may be associated with better subsequent cognitive performance. These associations may differ by adiposity and CVD history.

Reliability and responsiveness of virtual portion size creation tasks: Influences of context, foods, and a bariatric surgical procedure.

Food portion size influences energy intake and sustained high-energy intake often leads to obesity. Virtual portion creation tasks (VPCTs), in which a participant creates portions of food on a computer screen, predict intake in healthy individuals. The objective of this study was to determine whether portions created in VPCTs are stable over time (test-retest reliability) and responsive to factors known to influence food intake, such as eating contexts and food types, and to determine if virtual portions can predict weight loss. Patients with obesity scheduled for bariatric surgery (n = 29), and individuals with a normal BMI (18.5-24.9 kg/m2, controls, n = 29), were instructed to create virtual portions of eight snack foods, which varied in energy density (low and high) and taste (sweet and salty). Portions were created in response to the following eating situations, or "contexts": What they would a) eat to stay healthy (healthy), b) typically eat (typical), c) eat to feel comfortably satisfied (satisfied), d) consider the most that they could tolerate eating (maximum), and e) eat if nothing was limiting them (desired). Tasks were completed before, and 3 months after, surgery in patients, and at two visits, 3 months apart, in controls. Body weight (kg) was recorded at both visits. Virtual portions differed significantly across groups, visits, eating contexts, energy densities (low vs. high), and tastes (sweet vs. salty). Portions created by controls did not change over time, while portions created by patients decreased significantly after surgery, for all contexts except healthy. For patients, desired and healthy portions predicted 3-month weight loss. VPCTs are replicable, responsive to foods and eating contexts, and predict surgical weight loss. These tasks could be useful for individual assessment of expectations of amounts that are eaten in health and disease and for prediction of weight loss.

High-Resolution Three-Dimensional Photonic Scan-Derived Equations Improve Body Surface Area Prediction in Diverse Populations.

OBJECTIVE: Equations for predicting body surface area (BSA) produce flawed estimates, especially for individuals with obesity. This study aimed to compare BSA measured by a three-dimensional photonic scanner (3DPS) with BSA predicted by six commonly cited prediction equations and to develop new prediction equations if warranted. METHODS: The 3DPS was validated against manual measurements by breadth caliper for body thicknesses measured at three anatomical sites on a mannequin. BSA was derived from 3DPS whole-body scans of 67 males and 201 females, aged 18 to 83 years, with BMI between 17.8 and 77.8 kg/m2 and varied races/ethnicities. RESULTS: Width and depth measurements by 3DPS and caliper were within 1%, except for hip, with an error of 1.8%. BSA3DPS differed from BSA predicted by each equation (P < 0.05), except for males by DuBois and DuBois (P = 0.60), Tikuisis (P = 0.27), and Yu (P = 0.45) and for females by Tikuisis (P = 0.70). The combined and sex-specific equations obtained by regressing ln(BSA) on ln(weight in kilograms [W]) and ln(height in meters [H]) are as follows (R2 and SEE correspond to ln[BSA]): combined, BSA3DPS = 0.03216 × W0.4904 × H0.3769 , R2 = 0.982, SEE = 0.021; males, BSA3DPS = 0.01624 × W0.4725 × H0.5231 ; and females, BSA3DPS = 0.01522 × W0.4921 × H0.5231 , R2 = 0.986, SEE = 0.019. CONCLUSIONS: New height and weight BSA equations improve BSA estimation in individuals with BMI ≥ 40 and in African Americans, Hispanic Americans, and Asian Americans.

Increased Visceral Adipose Tissue Without Weight Retention at 59 Weeks Postpartum.

OBJECTIVE: This study aimed to determine whether controlling maternal gestational weight gain (GWG) influences adipose tissue distribution at 1 year postpartum. METHODS: Women with overweight or obesity (n = 210, BMI ≥ 25 or ≥ 30) were randomized to a lifestyle intervention (LI) designed to control GWG or to usual obstetrical care (UC). Measures included anthropometry, whole-body magnetic resonance imaging for visceral (VAT), intermuscular, and subcutaneous adipose tissue, and cardiometabolic risk factors in pregnancy (15 and 35 weeks) and after delivery (15 and 59 weeks). RESULTS: Baseline (15 weeks) characteristics were similar (mean [SD]: age, 33.8 [4.3] years; weight, 81.9 [13.7] kg; BMI, 30.4 [4.5]; gestational age at randomization, 14.9 [0.8] weeks). LI had less GWG (1.79 kg; P = 0.003) and subcutaneous adipose tissue gain at 35 weeks gestation (P < 0.01). UC postpartum weight (2.92 kg) was higher at 15 weeks but not different from baseline or LI at 59 weeks postpartum. Postpartum VAT increased from baseline in LI by 0.23 kg at 15 weeks and 0.55 kg at 59 weeks; in UC, it increased by 0.34 kg at 15 and 59 weeks. Intermuscular adipose tissue remained elevated in LI (0.22 kg) at 59 weeks. VAT was associated with several cardiometabolic risk factors at 59 weeks. CONCLUSIONS: Despite no weight retention at 59 weeks postpartum, women had increased VAT by ~30%. Postpartum modifiable behaviors are warranted to lower the risk of VAT retention.

Abnormal Exercise Test or CVD History on Weight Loss or Fitness: the Look AHEAD Trial.

PURPOSE: Obesity and type 2 diabetes are associated with an increased risk of cardiovascular disease (CVD) and the combination of weight loss and increased physical exercise are commonly recommended to reduce CVD. This study examined whether people with obesity and type 2 diabetes with an abnormal graded exercise tolerance test (GXT) or a history of CVD would have less success in achieving weight loss and improved fitness, compared to adults without these conditions. METHODS: The Look AHEAD Study examined whether an intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) reduced cardiovascular events in adults with overweight/obesity and type 2 diabetes. Participants underwent a baseline maximal GXT and provided medical history data. Weight loss and fitness change were examined in 5011 participants over four years in those with or without an abnormal baseline GXT and/or history of CVD. RESULTS: After four years, weight loss in both ILI and DSE were significantly greater in those without a prior history of CVD than in those with a CVD history (6.69% vs 5.98%, p=0.02, in ILI and 0.73 vs -.07% (weight gain), p=0.01, in DSE). Likewise, those without a prior history of CVD experienced greater improvements in fitness in both ILI and DSE relative to those with a history of CVD. Having an abnormal GXT at baseline did not affect weight loss or fitness. CONCLUSIONS: A history of CVD at baseline modestly lessened weight loss and fitness changes at 4 years, whereas having any abnormality on the baseline GXT did not affect these outcomes. Thus, weight loss and improved fitness are achievable in adults with a history of CVD or ECG abnormalities.

Reliability of the EchoMRI Infants System for Water and Fat Measurements in Newborns.

OBJECTIVE: The precision and accuracy of a quantitative magnetic resonance (EchoMRI Infants) system in newborns were determined. METHODS: Canola oil and drinking water phantoms (increments of 10 g to 1.9 kg) were scanned four times. Instrument reproducibility was assessed from three scans (within 10 minutes) in 42 healthy term newborns (12-70 hours post birth). Instrument precision was determined from the coefficient of variation (CV) of repeated scans for total water, lean mass, and fat measures for newborns and the mean difference between weight and measurement for phantoms. In newborns, the system accuracy for total body water (TBW) was tested against deuterium dilution (D2 O). RESULTS: In phantoms, the repeatability and accuracy of fat and water measurements increased as the weight of oil and water increased. TBW was overestimated in amounts >200 g. In newborns weighing 3.14 kg, fat, lean mass, and TBW were 0.52 kg (16.48%), 2.28 kg, and 2.40 kg, respectively. EchoMRI's reproducibility (CV) was 3.27%, 1.83%, and 1.34% for total body fat, lean mass, and TBW, respectively. EchoMRI-TBW values did not differ from D2 O; mean difference, -1.95 ± 6.76%, P = 0.387; mean bias (limits of agreement), 0.046 kg (-0.30 to 0.39 kg). CONCLUSIONS: The EchoMRI Infants system's precision and accuracy for total body fat and lean mass are better than established techniques and equivalent to D2 O for TBW in phantoms and newborns.

Central effects of insulin detemir on feeding, body weight, and metabolism in rats.

Insulin detemir (DET) is a basal insulin analog that, in contrast to other long-acting forms of insulin, has significant weight-gain-sparing effects in diabetic patients. We hypothesized that this effect of DET may be due to its enhanced catabolic action in the central nervous system. We investigated the long-term effects of single third ventricular (3V) microinjections of equimolar doses of DET and regular insulin in normal male rats on feeding, body weight, energy expenditure (EE), and respiratory quotient (RQ). Also, in acute testing, we assessed the ability of lower doses of DET to alter feeding, EE, and RQ when microinjected directly into the paraventricular nucleus (PVN). The anabolic peptide ghrelin served as a positive control in acute testing. 3V administration of both DET (0.5-2.0 mU) and regular insulin (2.0-8.0 mU) significantly reduced feeding and body weight over 48 and 120 h, respectively, with DET yielding greater inhibitory effects. DET also stimulated greater elevations of EE and reductions of RQ over 72 and 48 h postinjection, respectively. In acute (4 h) testing, microinjections of DET (0.5 mU) into the PVN reduced feeding, increased EE, and reduced RQ, while ghrelin (100 pmol) had the opposite effects. When administered sequentially into the PVN, DET (0.25 and 0.5 mU) reversed ghrelin-induced feeding, EE, and RQ effects. These data support the notion that the weight-sparing effect of DET is at least in part based on its central catabolic action and that enhanced EE and reduced RQ may participate in this effect.

Effects of a lifestyle intervention on REM sleep-related OSA severity in obese individuals with type 2 diabetes.

The aim of this study was to determine if an intensive lifestyle intervention (ILI) reduces the severity of obstructive sleep apnea (OSA) in rapid-eye movement (REM) sleep, and to determine if longitudinal changes in glycaemic control are related to changes in OSA severity during REM sleep over a 4-year follow-up. This was a randomized controlled trial including 264 overweight/obese adults with type 2 diabetes (T2D) and OSA. Participants were randomized to an ILI targeted to weight loss or a diabetes support and education (DSE) control group. Measures included anthropometry, apnea-hypopnea index (AHI) during REM sleep (REM-AHI) and non-REM sleep (NREM-AHI) and glycated haemoglobin (HbA1c) at baseline and year 1, year 2 and year 4 follow-ups. Mean baseline values of REM-AHI were significantly higher than NREM-AHI in both groups. Both REM-AHI and NREM-AHI were reduced significantly more in ILI versus DSE, but these differences were attenuated slightly after adjustment for weight changes. Repeated-measure mixed-model analyses including data to year 4 demonstrated that changes in HbA1c were related significantly to changes in weight, but not to changes in REM-AHI and NREM-AHI. Compared to control, the ILI reduced REM-AHI and NREM-AHI during the 4-year follow-up. Weight, as opposed to REM-AHI and NREM-AHI, was related to changes in HbA1c. The findings imply that weight loss from a lifestyle intervention is more important than reductions in AHI for improving glycaemic control in T2D patients with OSA.

Metformin, Lifestyle Intervention, and Cognition in the Diabetes Prevention Program Outcomes Study.

OBJECTIVE: We examined the association of the Diabetes Prevention Program (DPP) intervention arms (lifestyle intervention, metformin, and placebo) with cognition in the Diabetes Prevention Program Outcomes Study (DPPOS). We also examined metformin use, incident type 2 diabetes, and glycemia as exposures. RESEARCH DESIGN AND METHODS: The DPP lasted 2.8 years, followed by a 13-month bridge to DPPOS. Cognition was assessed in DPPOS years 8 and 10 (12 and 14 years after randomization) with the Spanish English Verbal Learning Test (SEVLT), letter fluency and animal fluency tests, Digit Symbol Substitution Test (DSST), and a composite cognitive score. RESULTS: A total of 2,280 participants (749 lifestyle, 776 metformin, and 755 placebo) aged 63.1 ± 10.7 years underwent cognitive assessments; 67.7% women, 54.6% non-Hispanic white, 20.7% non-Hispanic black, 14.6% Hispanic, 5.5% American Indian, and 4.6% Asian; 26.6% were homozygous or heterozygous for APOE-ε4. At the time of cognitive assessment, type 2 diabetes was higher in the placebo group (57.9%; P < 0.001) compared with lifestyle (47.0%) and metformin (50.4%). Metformin exposure was higher in the metformin group (8.72 years; P < 0.001) compared with placebo (1.43 years) and lifestyle (0.96 years). There were no differences in cognition across intervention arms. Type 2 diabetes was not related to cognition, but higher glycated hemoglobin at year 8 was related to worse cognition after confounder adjustment. Cumulative metformin exposure was not related to cognition. CONCLUSIONS: Exposure to intensive lifestyle intervention or metformin was not related to cognition among DPPOS participants. Higher glycemia was related to worse cognitive performance. Metformin seemed cognitively safe among DPPOS participants.

General and Abdominal Adiposity and Risk of Death in HBV Versus Non-HBV Carriers: A 10-Year Population-based Cohort Study.

Both obesity and hepatitis B virus (HBV) infection increase the risk of death. We investigate the association between general and central obesity and all-cause mortality among adult Taiwanese HBV versus non-HBV carriers.A total of 19,850 HBV carriers and non-hepatitis C virus (HCV) carriers, aged 20 years and older at enrollment in 1998 to 1999 in Taiwan, were matched to 79,400 non-HBV and non-HCV carriers (1:4). Cox proportional-hazards models were used to estimate the relative risks for all-cause mortality during a maximum follow-up period of 10 years. Four obesity-related anthropometric indices-body mass index (BMI), waist circumference, waist-to-hip ratio, and waist-to-height ratio-were the main variables of interest.During the follow-up period, 628 and 2366 participants died among HBV and non-HBV carriers, respectively. Both underweight and general obesity were associated with an increased risk of death. The highest risk of all-cause death in relation to BMI was found in the HBV carriers with underweight (BMI <18.5 kg/m2) and non-HBV carriers with obesity (BMI ≥30 kg/m2). The lowest risks of all-cause death in relation to abdominal adiposity were found at the third quartiles of waist circumference, waist-to-hip ratio, and waist-to-height ratio among HBV carriers, but in the second quartiles among non-HBV carriers. For those with pre-existing liver disease among HBV carriers, patients with underweight have higher risk of death than those with obesity.Hepatitis B virus carriers with underweight have higher risk of death than non-HBV carriers. HBV carriers with mild abdominal obesity have the lowest risk of death, but not in the non-HBV carriers.

A 6-month telephone-based weight loss intervention in overweight and obese subjects with idiopathic intracranial hypertension.

OBJECTIVES: The purpose of this paper is to measure the change in body weight after a 6-month telephone-based weight loss intervention in overweight and obese subjects with idiopathic intracranial hypertension (IIH) and mild visual loss randomized to receive either acetazolamide or placebo. METHODS: One hundred sixty-five subjects with IIH, aged 29.1 ± 7.5 (mean ± SD) and BMI 39.9 + 8.3 kg/m2, enrolled at 38 academic and private practice sites in North America, participated in this trial. This was a randomized, double-masked, placebo-controlled trial of acetazolamide in subjects with IIH and mild visual loss. All participants received a reduced-sodium, weight-reduction diet and a 6-month telephone-based weight loss intervention. Six-month changes from baseline in body weight, perimetric mean deviation as assessed by automated perimetry and quality of life using the National Eye Institute Visual Function Questionnaire 25 and the 36-item Short Form Health Survey were measured. RESULTS: Mean percent weight change at 6 months was -5.9% ± 6.7% of initial body weight overall, -3.5% ± 5.9% in the placebo group and -7.8% ± 6.8% in the acetazolamide group. Weight change was not associated with changes in either mean deviation or quality of life scores. CONCLUSION: Patients with IIH and mild visual loss assigned to either acetazolamide or placebo, all of whom received a 6-month telephone-based weight loss intervention, lost an average of 5.9% of initial body weight, consistent with NHLBI guidelines of 5% to 10% of body weight loss for clinically significant health benefit.

The Effect of Changes in Cardiorespiratory Fitness and Weight on Obstructive Sleep Apnea Severity in Overweight Adults with Type 2 Diabetes.

STUDY OBJECTIVES: To examine the effect of changes in cardiorespiratory fitness on obstructive sleep apnea (OSA) severity prior to and following adjustment for changes in weight over the course of a 4-y weight loss intervention. METHODS: As secondary analyses of a randomized controlled trial, 263 overweight/obese adults with type 2 diabetes and OSA participated in an intensive lifestyle intervention or education control condition. Measures of OSA severity, cardiorespiratory fitness, and body weight were obtained at baseline, year 1, and year 4. Change in the apnea-hypopnea index (AHI) served as the primary outcome. The percentage change in fitness (submaximal metabolic equivalents [METs]) and change in weight (kg) were the primary independent variables. Primary analyses collapsed intervention conditions with statistical adjustment for treatment group and baseline METs, weight, and AHI among other relevant covariates. RESULTS: At baseline, greater METs were associated with lower AHI (B [SE] = -1.48 [0.71], P = 0.038), but this relationship no longer existed (B [SE] = -0.24 [0.73], P = 0.75) after adjustment for weight (B [SE] = 0.31 [0.07], P < 0.0001). Fitness significantly increased at year 1 (+16.53 ± 28.71% relative to baseline), but returned to near-baseline levels by year 4 (+1.81 ± 24.48%). In mixed-model analyses of AHI change over time without consideration of weight change, increased fitness at year 1 (B [SE] = -0.15 [0.04], P < 0.0001), but not at year 4 (B [SE] = 0.04 [0.05], P = 0.48), was associated with AHI reduction. However, with weight change in the model, greater weight loss was associated with AHI reduction at years 1 and 4 (B [SE] = 0.81 [0.16] and 0.60 [0.16], both P < 0.0001), rendering the association between fitness and AHI change at year 1 nonsignificant (B [SE] = -0.04 [0.04], P = 0.31). CONCLUSIONS: Among overweight/obese adults with type 2 diabetes, fitness change did not influence OSA severity change when weight change was taken into account. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identification number NCT00194259.

Advances in the Science, Treatment, and Prevention of the Disease of Obesity: Reflections From a Diabetes Care Editors' Expert Forum.

As obesity rates increase, so too do the risks of type 2 diabetes, cardiovascular disease, and numerous other detrimental conditions. The prevalence of obesity in U.S. adults more than doubled between 1980 and 2010, from 15.0 to 36.1%. Although this trend may be leveling off, obesity and its individual, societal, and economic costs remain of grave concern. In June 2014, a Diabetes Care Editors' Expert Forum convened to review the state of obesity research and discuss the latest prevention initiatives and behavioral, medical, and surgical therapies. This article, an outgrowth of the forum, offers an expansive view of the obesity epidemic, beginning with a discussion of its root causes. Recent insights into the genetic and physiological factors that influence body weight are reviewed, as are the pathophysiology of obesity-related metabolic dysfunction and the concept of metabolically healthy obesity. The authors address the crucial question of how much weight loss is necessary to yield meaningful benefits. They describe the challenges of behavioral modification and predictors of its success. The effects of diabetes pharmacotherapies on body weight are reviewed, including potential weight-neutral combination therapies. The authors also summarize the evidence for safety and efficacy of pharmacotherapeutic and surgical obesity treatments. The article concludes with an impassioned call for researchers, clinicians, governmental agencies, health policymakers, and health-related industries to collectively embrace the urgent mandate to improve prevention and treatment and for society at large to acknowledge and manage obesity as a serious disease.

Improving Adiponectin Levels in Individuals With Diabetes and Obesity: Insights From Look AHEAD.

OBJECTIVE: This study investigated whether fitness changes resulting from lifestyle interventions for weight loss may independently contribute to the improvement of low adiponectin levels in obese individuals with diabetes. RESEARCH DESIGN AND METHODS: Look AHEAD (Action for Health in Diabetes) randomized overweight/obese individuals with type 2 diabetes to intensive lifestyle intervention (ILI) for weight loss or to diabetes support and education (DSE). Total and high-molecular weight adiponectin (adiponectins), weight, and cardiorespiratory fitness (submaximal exercise stress test) were measured in 1,397 participants at baseline and at 1 year, when ILI was most intense. Regression analyses examined the associations of 1-year weight and fitness changes with change in adiponectins. RESULTS: ILI resulted in greater improvements in weight, fitness, and adiponectins at 1 year compared with DSE (P < 0.0001). Weight loss and improved fitness were each associated with changes in adiponectins in men and women (P < 0.001 for all), after adjusting for baseline adiponectins, demographics, clinical variables, and treatment arm. Weight loss contributed an additional 4-5% to the variance of change in adiponectins than did increased fitness in men; in women, the contributions of improved fitness (1% greater) and of weight loss were similar. When weight and fitness changes were both accounted for, weight loss in men and increased fitness in women retained their strong associations (P < 0.0001) with adiponectin change. CONCLUSIONS: Improvements in fitness and weight with ILI were favorably but distinctly associated with changes in adiponectin levels in overweight/obese men and women with diabetes. Future studies need to investigate whether sex-specific biological determinants contribute to the observed associations.

A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes.

Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized trial comparing the cardiovascular benefits of ILI-induced weight loss and physical activity compared with diabetes support and education among overweight/obese individuals with Type 2 diabetes. In a subsample of Look AHEAD with adiponectin data and genetic consent (n=1,351), we evaluated the effects of 24 genetic variants, demonstrated by GWAS to be cross-sectionally associated with adiponectin, on adiponectin change 1-yr postintervention. We explored via mediational analyses whether any differential effects by treatment arm were occurring through weight loss and/or improved fitness. A variant, rs222857, in the CLDN7 locus, potentially associated with epithelial barrier integrity and tight junction physiology, and a putative cis expression quantitative trail locus for elongator acetyltransferase complex subunit 5 (ELP5), predicted adiponectin increases within ILI (log-adiponectin in overall sample per copy: ß±SE=0.05±0.02, P=0.008; in non-Hispanic whites: 0.06±0.02, P=0.009). The favorable effects of rs222857 (minor allele frequency 45.5%) appeared to be mediated by mechanisms associated with improved fitness, and not weight loss. This is the first study to identify a genetic variant that modifies adiponectin response to lifestyle intervention in overweight/obese diabetic individuals.

Changes in adipose tissue depots and metabolic markers following a 1-year diet and exercise intervention in overweight and obese patients with type 2 diabetes.

OBJECTIVE: We aim to characterize the effects on total body fat and distribution of a 1-year intensive lifestyle intervention (ILI) for weight loss in overweight and obese adults with type 2 diabetes and to examine whether changes in adipose tissue (AT) depots were associated with changes in metabolic biomarkers. RESEARCH DESIGN AND METHODS: Participants were 54 females and 38 males (age 57.8 ± 6.7 years [mean ± SD]; BMI 31.7 ± 3.5 kg/m(2)) enrolled in the Look AHEAD (Action for Health in Diabetes) trial randomized to ILI or diabetes support and education (DSE) from whom baseline and 1-year MRI measures of total AT (TAT) and regional (arm, trunk, leg) AT, including subcutaneous AT (SAT), visceral AT (VAT), and intermuscular AT (IMAT), were acquired. We tested whether mean changes in ILI and DSE were equal and, within groups, whether changes were different from zero. Regression models tested whether changes in AT compartments were associated with metabolic variable changes. RESULTS: Body weight changed -0.52 ± 3.62 kg (P = 0.31) in DSE and -7.24 ± 5.40 kg (P < 0.0001) in ILI. Mean ILI changes were different from DSE (P < 0.001 for TAT, SAT, and IMAT and P < 0.01 for VAT in females). Within ILI, SAT and VAT decreased in males and females (P < 0.0001), but IMAT was unchanged (0.00 ± 0.54 kg; P = 0.99). In DSE, SAT and VAT did not change, but IMAT increased by 0.46 ± 0.55 kg (P < 0.001). Controlling for weight loss, reduction of specific AT depots was associated with improvement in metabolic biomarkers. CONCLUSIONS: Weight loss of 7-10% from an ILI over 1 year reduced SAT and VAT and prevented an increase in IMAT. Reductions in AT depots were associated with improvements in biomarkers.