George A. Bray

Top metabolomic risk score quintile linked to ~280% higher incident type 2 diabetes risk in women.

Declines in plasma erythritol levels and improvements in insulin sensitivity and glucose metabolism: POUNDS lost trial

BrayMedical Sciences

Beyond Obesity

Impact of Parental or First-Degree Family History of Diabetes on Diabetes Incidence and Progression During Long-term Follow-up in the Diabetes Prevention Program Outcomes Study

Longitudinal Metabolic Trajectories in Diabetes Prevention Program Participants Reveal Subgroups With Varying Micro- and Macrovascular Complication Risks

KnowlerDiabetes Care

Analysis of Long-term Follow-up of a Randomized Clinical Trial With Departures From Assigned Treatments: Estimation of Metformin Effects on Diabetes and Its Complications in the Diabetes Prevention Program Outcomes Study

HermanDiabetes Care

Nonglycemic and Glycemic Risk Factors for Painful Neuropathic Symptoms and for Distal Symmetrical Polyneuropathy (DSPN) in the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study

OBJECTIVE: The clinical presentation, symptoms, and signs of neuropathy vary substantially. We determined whether painful neuropathic symptoms and distal symmetrical polyneuropathy (DSPN) were associated with different risk factors in a longitudinal study of Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS) participants. RESEARCH DESIGN AND METHODS: We assessed neuropathy in 1,779 DPP/DPPOS participants ∼21 years after DPP randomization. Symptoms were assessed using the Michigan Neuropathy Screening Instrument (MNSI) questionnaire and signs using pinprick, vibration, and monofilament testing. We defined four mutually exclusive neuropathy phenotypes: 1) no symptoms or signs of DSPN, 2) neuropathic pain without signs, 3) other neurologic symptoms without pain or signs, and 4) DSPN (MNSI questionnaire score ≥4 or any signs). We used multinomial logistic regression models to compare nonglycemic and glycemic risk factors among participants to better understand risk factors associated with painful neuropathic symptoms and DSPN. RESULTS: Among the participants, 501 (28%) had no symptoms or signs, 144 (8%) had painful neuropathic symptoms without signs, and 473 (27%) had DSPN. Compared with participants with neither symptoms nor signs, those with painful neuropathic symptoms were more likely to be women, to have greater weight, and lower estimated glomerular filtration rate. Painful symptoms were not associated with glycemia. In contrast, DSPN, when compared with painful symptoms, was associated with older age, White race, and glycemic exposure. CONCLUSIONS: In this cohort, risk factors for painful neuropathic symptoms and DSPN differed. Improved recognition of painful neuropathic symptoms and better consensus on diagnostic criteria may facilitate research into their causes, prevention, and treatment.

The Diabetes Prevention Program and Its Outcomes Study: NIDDK’s Journey Into the Prevention of Type 2 Diabetes and Its Public Health Impact

The current-day epidemic of type 2 diabetes, largely driven by increased adiposity and reduced physical activity in the setting of genetic susceptibility, is a major public health challenge. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) presciently proposed the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial, designed by investigators in conjunction with NIDDK staff and initiated in 1996. The primary goal of DPP was to determine whether an intensive lifestyle intervention (ILS) or metformin in comparison with placebo would reduce the development of diabetes in a high-risk population with prediabetes. After mean 2.8 years, ILS reduced diabetes risk by 58% and metformin by 31%, leading to study termination ahead of schedule due to demonstrated efficacy of both interventions. In 2002, an extension of the DPP study, the Diabetes Prevention Program Outcomes Study (DPPOS), was initiated for examination of the longer-term course and consequences of diabetes prevention. Over 21 years of median total follow-up, in comparison with the placebo group, cumulative diabetes incidence was reduced by 24% and 17% in the original ILS and metformin groups, respectively, with median increases in diabetes-free survival of 3.5 and 2.5 years/person. During long-term follow-up, there were no significant effects of the original DPP interventions on microvascular or cardiovascular outcomes. However, compared with prevalence of microvascular outcomes among participants who progressed to diabetes, prevalence among those who did not progress was significantly lower. Longer-term follow-up of the cohort continues with examination of relationships between diabetes and prediabetes and an expanded array of diabetes- and aging-related morbidities.

Baseline Body Fat Percentage Is Associated to Weight and Fat Mass Gain From High-Fat Overfeeding Over 8 Weeks

Context Epidemiological data suggest that participants with lower vs higher body mass index (BMI) resist exposure to the obesogenic environment. Objective To test this, we analyzed the relationship between overfeeding-induced weight and fat mass gains with baseline BMI and body fat percentage. Methods In this controlled intervention study, 34 men (age 26 ± 5 years; BMI 25.5 ± 2.4 kg/m2; body fat [by dual-energy x-ray absorptiometry] 19.3 ± 5.1%) consumed for 8 weeks 40% more energy than needed at weight maintenance. The energy costs of weight and fat mass gain were calculated as the 8-week excess energy consumed divided by weight or fat mass gain. Energy expenditure (baseline and after overfeeding) was determined using a metabolic chamber and doubly labeled water. Transcriptomic analysis was conducted from abdominal subcutaneous adipose tissue samples. Results Body weight increased 7.2 ± 2.1 kg and fat mass 4.0 ± 1.4 kg. There was no statistical association between baseline BMI and weight and fat mass gains. However, baseline body fat percentage was significantly associated with weight (r = 0.57) and fat mass (r = 0.59) gains. Body fat percentage was also statistically associated with energy cost of weight (r = −0.38) and fat mass (r = −0.40) gains. Metabolic adaptation in energy expenditure (adaptive thermogenesis) was unrelated to the energy cost of weight and fat mass gains. Transcriptomics analysis showed that high energy cost of weight gain was associated with upregulation of inflammation-related pathways. Conclusion Body fat percentage at baseline was inversely associated with overfeeding-induced weight and fat gain resistance. The underlying compensatory response appears unrelated to changes in energy expenditure.

BrayValue in Health

Cost-Utility Analysis of Antipsychotic Reduction and Discontinuation in Patients With Long-Term Schizophrenia and Psychosis in English Mental Health Trusts: The RADAR Study

OBJECTIVES: The current recommended treatment for patients with recurrent episodes of schizophrenia and related conditions is antipsychotic medication. However, many antipsychotic users remain functionally impaired and experience serious physical and mental side effects. This study aims to assess the cost-effectiveness of a gradual antipsychotic reduction and discontinuation strategy compared with maintenance treatment over 24 months from mental health services, health and social care, and societal perspectives. METHODS: Nineteen mental health trusts recruited patients to the Research into Antipsychotic Discontinuation and Reduction (RADAR) randomized controlled trial. Quality-adjusted life-years were calculated from patient-reported EQ-5D-5L, with years of full capability calculated from the patient-reported ICECAP-A. Mental health services use and medication was collected from medical records. Other resource use and productivity loss was collected using self-completed questionnaires. Costs were calculated from published sources. RESULTS: A total of 253 participants were randomized: 126 assigned to antipsychotic dose reduction and 127 to maintenance. There were no significant differences between arms in total costs for any perspectives. There were no significant difference in quality-adjusted life-years (-0.035; 95% CI: -0.123 to 0.052), whereas years of full capability were significantly lower in the reduction arm compared with the maintenance arm (baseline-adjusted difference: -0.103; 95% CI: -0.192 to -0.014). The reduction strategy was dominated by maintenance for all analyses and was not likely to be cost-effective. CONCLUSIONS: It is unlikely that gradual antipsychotic reduction and discontinuation strategy is cost-effective compared with maintenance over 2-years for patients with schizophrenia and other recurrent psychotic disorders who are on long-term antipsychotics.

BrayNutrients

Is There an Ideal Diet? Some Insights from the POUNDS Lost Study

Diets for weight loss have a long history but an ideal one has not yet been clearly identified. To compare low-fat and lower carbohydrate diets, we designed The Preventing Overweight by Novel Dietary Strategies (POUNDS) Lost study. This is a 2 × 2 factorial study with diets of 20% or 40% fat and 15% or 25% protein with a graded carbohydrate intake of 35, 45, 55 and 65%. Weight loss, overall, was modest at nearly 6% with all four diets, and no significant dietary difference. The variability in weight loss in each diet group was significant, ranging from greater than 20% to a small weight gain. Studies of genetic variations in relation to weight loss showed that the diet that was selected could significantly affect weight loss, emphasizing that there is no ideal diet and more than one diet can be used to treat obesity. Weight loss was also influenced by the level of baseline triiodothyronine or thyroxine, and baseline carbohydrate and insulin resistance. Achieving a stable Health Eating Food Diversity Index, eating more protein, eating more fiber, engaging in more physical activity, sleeping better and eating less ultra-processed foods were beneficial strategies for weight loss in this trial. Although there is no "ideal diet", both the DASH diet and the Mediterranean diet have clinical trials showing their significant benefit for cardiovascular risk factors. Finally, the lesson of the "Last Chance Diet", which recommended a diet with protein from gelatin, proved that some diets could be hazardous.

Isocaloric replacement of ultraprocessed foods was associated with greater weight loss in the POUNDS Lost trial

Higher intake of ultraprocessed foods (UPFs) is associated with obesity. We examined whether replacing UPFs (NOVA 4) with minimally processed foods and culinary ingredients (NOVA 1 + 2) was associated with differential weight change in this secondary prospective analysis of the Preventing Overweight Using Novel Dietary Strategies (POUNDS) Lost trial.

Prevalence of Distal Symmetrical Polyneuropathy by Diabetes Prevention Program Treatment Group, Diabetes Status, Duration of Diabetes, and Cumulative Glycemic Exposure

Abstract P348: Weight Loss of Machine Learning Identified Metabolic Subtypes in Response to Dietary Interventions

Introduction: Metabolic syndrome is a constellation of metabolic risk factors. However, various combinations of metabolic disorders may exhibit distinct responses to weight loss interventions. Objective: To identify metabolic subtypes using the machine learning method and assess their associations with weight loss response to dietary interventions. Methods: The study includes 645 participants from the POUNDS Lost trial. Five criteria for metabolic syndrome were used as the grouping factors. Hierarchical clustering was performed with an 8:2 train/test ratio. Results: Three metabolic subtypes were identified and validated among the POUNDS Lost participants. Cluster 1 was characterized by high proportions of central obesity and high blood pressure but low triglycerides; Cluster 2 showed central obesity with relatively low blood pressure; Cluster 3 had the lowest level of central obesity and blood pressure but the highest triglycerides level. Changes in body weight varied significantly across clusters (p=0.003 at 6 months and p< 0.001 at 2 years). At 6 months, adjusted least-square mean (SE) weights were: -6.5 (0.8) kg in cluster 1, -5.4 (0.6) kg in cluster 2, and -4.2 (0.7) kg in cluster 3. Participants regained weight after 6 months, but the difference across the clusters persisted: -5.5 (1.0) kg in Cluster 1, -3.1 (0.8) kg in Cluster 2, and -1.7 (0.8) kg in Cluster 3. Conclusion: We identified 3 metabolic subtypes that predict different responses to dietary weight loss interventions, which may contribute to subtype-specific precision medicine for obesity prevention and management.

Abstract MP28: Declines in Plasma Levels of Nonnutritive Sweetener Erythritol Are Related to Two-Year Improvements in Atherosclerotic Cardiovascular Disease Risk Estimates Among Adults With Overweight and Obesity

Background: A potential adverse relationship between the consumption of low-calorie sweeteners and cardiovascular disease (CVD) risk has been proposed. High levels of circulating erythritol, a sugar alcohol (polyol) used as one of the non-nutritive sweeteners, have been recently linked to increased risks of major adverse cardiovascular events. However, associations of temporal changes in plasma erythritol and other polyols with cardiometabolic risk remain unclear. Hypothesis: We tested whether changes in plasma levels of non-nutritive sweetener erythritol and other polyols in response to weight-loss dietary interventions were associated with improved atherosclerotic cardiovascular disease (ASCVD) risk estimates and atherogenic lipoproteins among adults with overweight and obesity. Methods: This study included 804 adults (mean BMI: 32.7 [SD 3.9] kg/m 2 ) without diabetes or unstable CVD at baseline who participated in a 2-year intervention of weight-loss diets, the POUNDS Lost trial. Metabolomic profiling was performed to measure plasma erythritol and its precursor erythronate, other sugar alcohols, and low-calorie sweeteners at baseline and 6 months after randomization. The primary outcome was the change in 10-year ASCVD risk scores calculated by the validated pooled cohort equations. Two-year changes in lipid profiles and cholesterol [Chol] in lipoprotein subfractions defined by the presence or absence of apolipoprotein CIII (apoCIII) were analyzed as secondary outcomes. Results: The mean estimated value of the 10-year ASCVD risk was 4.0% at baseline; 16% of the participants were at intermediate or high ASCVD risk (score ≥7.5%). Higher levels of erythritol (per 1 SD increment: β 1.1% [SE 0.2%], p <.0001) and erythronate (β 1.3% [0.2%], p <.0001), as well as other sugar alcohols, such as mannitol-sorbitol, myoinositol, arabitol-xylitol ( p <.0001 for all), and low-calorie sweetener saccharin ( p = 0.02), but not acesulfame ( p =0.8), were related to a higher ASCVD risk at baseline after adjusting for BMI. There was large variability in the changes in metabolite levels across participants; greater decreases in erythritol in response to the interventions were significantly related to greater reductions in ASCVD risk estimates at 6 months (per 1 SD reduction: β -0.2% [SE 0.1%]; p =0.023) and at 2 years (β -0.3% [0.1%]; p = 0.015) after adjusting for covariates, including BMI, the initial metabolite levels, and baseline ASCVD risk. The 6-month decrease in erythritol was associated with long-term (2-year) improvements in atherogenic lipids, including Chol in VLDL+LDL with apoCIII ( p <0.05). Conclusions: Higher plasma levels of erythritol and other sugar alcohols were associated with greater 10-year ASCVD risk scores among adults with overweight and obesity. Weight-loss diet-induced decreases in erythritol levels were related to improved ASCVD risk and atherogenic lipid profiles.

Changes in bile acid subtypes and improvements in lipid metabolism and atherosclerotic cardiovascular disease risk: the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial

Distinct circulating bile acid (BA) subtypes may play roles in regulating lipid homeostasis and atherosclerosis. We investigated whether changes in circulating BA subtypes induced by weight-loss dietary interventions were associated with improved lipid profiles and atherosclerotic cardiovascular disease (ASCVD) risk estimates. This study included adults with overweight or obesity (n=536) who participated in a randomized weight-loss diet intervention trial. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 months after weight-loss diet interventions. The ASCVD risk estimates were calculated by the validated equations. At baseline, higher levels of specific BA subtypes were related to higher levels of atherogenic VLDL lipid subtypes and ASCVD risk estimates. Weight-loss diet-induced decreases in primary BAs were related to larger reductions of triglycerides and total cholesterol (every 1-SD decrease of glycocholate, glycochenodeoxycholate, or taurochenodeoxycholate was related to β [SE] –3.3 [1.3], –3.4 [1.3], or –3.8 [1.3] mg/dl, respectively; PFDR <0.05 for all). Greater decreases in specific secondary BA subtypes were also associated with improved lipid metabolism at 6 months; there was β –4.0 [1.1] mg/dl per 1-SD decrease of glycoursodeoxycholate (PFDR=0.003) for changes in LDL cholesterol. We found significant interactions (Pinteraction <0.05) between dietary fat intake and changes in BA subtypes on changes in ASCVD risk estimates; decreases in primary and secondary BAs (such as conjugated cholate or deoxycholate) were significantly associated with improved ASCVD risk after consuming a high-fat diet but not after a low-fat diet. Decreases in distinct BA subtypes were associated with improved lipid profiles and ASCVD risk estimates, highlighting the importance of changes in circulating BA subtypes as significant factors linked to improved lipid metabolism and ASCVD risk estimates in response to weight-loss dietary interventions. Habitual dietary fat intake may modify the associations of changes in BAs with ASCVD risk.

Circulating MicroRNA-19 and cardiovascular risk reduction in response to weight-loss diets

Objective MicroRNA-19 (miR-19) plays a critical role in cardiac development and cardiovascular disease (CVD). We examined whether change in circulating miR-19 was associated with change in CVD risk during weight loss. Methods This study included 509 participants with overweight or obesity from the 24-month weight-loss diet intervention study (the POUNDS Lost trial) and with available data on circulating miR-19a-3p and miR-19b-3p at baseline and 6 months. The primary outcome for this analysis was the change in atherosclerotic CVD (ASCVD) risk at 6 and 24 months, which estimates the 10-year probability of hard ASCVD events. Secondary outcomes were the changes in ASCVD risk score components. Results Circulating miR-19a-3p and miR-19b-3p levels significantly decreased during the initial 6-month dietary intervention period (P=0.008, 0.0004, respectively). We found that a greater decrease in miR-19a-3p or miR-19b-3p was related to a greater reduction in ASCVD risk (β[SE]=0.33 [0.13], P=0.01 for miR-19a-3p; β[SE]=0.3 [0.12], P=0.017 for miR-19b-3p) over 6 months, independent of concurrent weight loss. Moreover, we found significant interactions between change in miR-19 and sleep disturbance on change in ASCVD risk over 24 months of intervention (P interaction=0.01 and 0.008 for miR-19a-3p and miR-19b-3p, respectively). Participants with a greater decrease in miR-19 without sleep disturbance had a greater reduction of ASCVD risk than those with slight/moderate/great amounts of sleep disturbance. In addition, change in physical activity significantly modified the associations between change in miR-19 and change in ASCVD risk over 24 months (P interaction= 0.006 and 0.004 for miR-19a-3p and miR-19b-3p, respectively). A greater decrease in miR-19 was significantly associated with a greater reduction in ASCVD risk among participants with an increase in physical activity, while non-significant inverse associations were observed among those without an increase in physical activity. Conclusions In conclusion, decreased circulating miR-19 levels during dietary weight-loss interventions were related to a significant reduction in ASCVD risk, and these associations were more evident in people with no sleep disturbance or increase in physical activity. Trial registration ClinicalTrials.gov NCT00072995.

BrayObesity

Commentary on: The fructose survival hypothesis as a mechanism for unifying the various obesity hypotheses

The author declared no conflict of interest.

DNA Methylation at ABCG1 and Long-term Changes in Adiposity and Fat Distribution in Response to Dietary Interventions: The POUNDS Lost Trial

OBJECTIVE: To examine whether participants with different levels of diabetes-related DNA methylation at ABCG1 might respond differently to dietary weight loss interventions with long-term changes in adiposity and body fat distribution. RESEARCH DESIGN AND METHODS: The current study included overweight/obese participants from the POUNDS Lost trial. Blood levels of regional DNA methylation at ABCG1 were profiled by high-resolution methylC-capture sequencing at baseline among 673 participants, of whom 598 were followed up at 6 months and 543 at 2 years. Two-year changes in adiposity and computed tomography-measured body fat distribution were calculated. RESULTS: Regional DNA methylation at ABCG1 showed significantly different associations with long-term changes in body weight and waist circumference at 6 months and 2 years in dietary interventions varying in protein intake (interaction P < 0.05 for all). Among participants assigned to an average-protein (15%) diet, lower baseline regional DNA methylation at ABCG1 was associated with greater reductions in body weight and waist circumference at 6 months and 2 years, whereas opposite associations were found among those assigned to a high-protein (25%) diet. Similar interaction patterns were also observed for body fat distribution, including visceral adipose tissue, subcutaneous adipose tissue, deep subcutaneous adipose tissue, and total adipose tissue at 6 months and 2 years (interaction P < 0.05 for all). CONCLUSIONS: Baseline DNA methylation at ABCG1 interacted with dietary protein intake on long-term decreases in adiposity and body fat distribution. Participants with lower methylation at ABCG1 benefitted more in long-term reductions in body weight, waist circumference, and body fat distribution when consuming an average-protein diet.

QiNutrients

Varying dietary protein and fat targets yields ~3-kg weight loss with no difference between diets.

The POUNDS Lost trial is a 2-year clinical trial testing the effects of dietary interventions on weight loss. This study included 811 adults with overweight or obesity who were randomized to one of four diets that contained either 15% or 25% protein and 20% or 40% fat in a 2 × 2 factorial design. By 2 years, participants on average lost from 2.9 to 3.6 kg in body weight in the four intervention arms, while no significant difference was observed across the intervention arms. In POUNDS Lost, we performed a series of ancillary studies to detect intrinsic factors particular to genomic, epigenomic, and metabolomic markers that may modulate changes in weight and other cardiometabolic traits in response to the weight-loss dietary interventions. Genomic variants identified from genome-wide association studies (GWASs) on obesity, type 2 diabetes, glucose and lipid metabolisms, gut microbiome, and dietary intakes have been found to interact with dietary macronutrients (fat, protein, and carbohydrates) in relation to weight loss and changes of body composition and cardiometabolic traits. In addition, we recently investigated epigenomic modifications, particularly blood DNA methylation and circulating microRNAs (miRNAs). We reported DNA methylation levels at NFATC2IP, CPT1A, TXNIP, and LINC00319 were related to weight loss or changes of glucose, lipids, and blood pressure; we also reported thrifty miRNA expression as a significant epigenomic marker related to changes in insulin sensitivity and adiposity. Our studies have also highlighted the importance of temporal changes in novel metabolomic signatures for gut microbiota, bile acids, and amino acids as predictors for achievement of successful weight loss outcomes. Moreover, our studies indicate that biochemical, behavioral, and psychosocial factors such as physical activity, sleep disturbance, and appetite may also modulate metabolic changes during dietary interventions. This review summarized our major findings in the POUNDS Lost trial, which provided preliminary evidence supporting the development of precision diet interventions for obesity management.