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We evaluated the effect of diets low in energy density (1 kcal/g) and high in either potatoes (Potato) or pulses (Bean) on blood glucose control in participants with insulin resistance. We hypothesized that the Potato and Bean diets would have equivalent effects. This was an 8-week randomized, parallel design, controlled feeding study comparing Potato and Bean diets (50-55% carbohydrate, 30-35% fat, 15-20% protein). Equivalence was prespecified as the mean change in the blood glucose concentration for Potato that was within ±20% of the Bean diet. Thirty-six participants (age: 18-60 years, body mass index: 25-40 kg/m

Exercise is a first-line treatment for type 2 diabetes and preserves β-cell function by hitherto unknown mechanisms. We postulated that proteins from contracting skeletal muscle may act as cellular signals to regulate pancreatic β-cell function. We employed electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatment of β-cells with EPS-conditioned media (EPS-CM) enhanced glucose-stimulated insulin secretion (GSIS). Transcriptomics and subsequent targeted validation revealed Growth Differentiation Factor 15 (GDF15) as a central component of the skeletal muscle secretome. Exposure to recombinant GDF15 enhanced GSIS in cells, islets, and mice. GDF15 enhanced GSIS by upregulating the insulin secretion pathway in β-cells, which was abrogated in the presence of a GDF15 neutralizing antibody. The effect of GDF15 on GSIS was also observed in islets from GFRAL-deficient mice. Circulating GDF15 was incrementally elevated in patients with pre- and type 2 diabetes and positively associated with C-peptide in humans with overweight/obesity. Six weeks of high intensity exercise training increased circulating GDF15 concentrations, which positively correlated with improvements in β-cell function in patients with type 2 diabetes. Taken together, GDF15 can function as a contraction-induced protein that enhances GSIS through activating the canonical signaling pathway in a GFRAL-independent manner.

SummarySleep loss typically imposes negative effects on animal health. However, humans with a rare genetic mutation in thedec2gene (dec2P384R) present an exception; these individuals sleep less without the usual effects associated with sleep deprivation. Thus, it has been suggested that thedec2P384Rmutation activates compensatory mechanisms that allows these individuals to thrive with less sleep. To test this directly, we used aDrosophilamodel to study the effects of thedec2P384Rmutation on animal health. Expression of humandec2P384Rin fly sleep neurons was sufficient to mimic the short sleep phenotype and, remarkably,dec2P384Rmutants lived significantly longer with improved health despite sleeping less. The improved physiological effects were enabled, in part, by enhanced mitochondrial fitness and upregulation of multiple stress response pathways. Moreover, we provide evidence that upregulation of pro-health pathways also contributes to the short sleep phenotype, and this phenomenon may extend to other pro-longevity models.

Precipitated by chronic psychological stress, immune system dysregulation, and a hyperinflammatory state, the sequelae of postacute COVID-19 (long COVID) include depression and new-onset diabetes. We hypothesize that exercise counters the neuropsychiatric and endocrine sequelae of long COVID by inducing the release of circulating factors that mediate the anti-inflammatory response, support brain homeostasis, and increase insulin sensitivity.

This consensus statement is an update of the 2010 American College of Sports Medicine position stand on exercise and type 2 diabetes. Since then, a substantial amount of research on select topics in exercise in individuals of various ages with type 2 diabetes has been published while diabetes prevalence has continued to expand worldwide. This consensus statement provides a brief summary of the current evidence and extends and updates the prior recommendations. The document has been expanded to include physical activity, a broader, more comprehensive definition of human movement than planned exercise, and reducing sedentary time. Various types of physical activity enhance health and glycemic management in people with type 2 diabetes, including flexibility and balance exercise, and the importance of each recommended type or mode are discussed. In general, the 2018 Physical Activity Guidelines for Americans apply to all individuals with type 2 diabetes, with a few exceptions and modifications. People with type 2 diabetes should engage in physical activity regularly and be encouraged to reduce sedentary time and break up sitting time with frequent activity breaks. Any activities undertaken with acute and chronic health complications related to diabetes may require accommodations to ensure safe and effective participation. Other topics addressed are exercise timing to maximize its glucose-lowering effects and barriers to and inequities in physical activity adoption and maintenance.

BACKGROUND: Obesity is a disease that may involve disrupted connectivity of brain networks. Bariatric surgery is an effective treatment for obesity, and the positive effects on obesity-related conditions may be enhanced by exercise. Herein, we aimed to investigate the possible synergistic effects of Roux-en-Y Gastric Bypass (RYGB) and exercise training on brain functional networks. METHODS: Thirty women eligible for bariatric surgery were randomly assigned to a Roux-en-Y gastric bypass (RYGB: n = 15, age = 41.0 ± 7.3 years) or RYGB plus Exercise Training (RYGB + ET: n = 15, age = 41.9 ± 7.2 years). Clinical, laboratory, and brain functional connectivity parameters were assessed at baseline, and 3 (POST3) and 9 months (POST9) after surgery. The 6-month, three-times-a-week, exercise intervention (resistance plus aerobic exercise) was initiated 3 months post-surgery (for RYGB + ET). RESULTS: Exercise superimposed on bariatric surgery (RYGB + ET) increased connectivity between hypothalamus and sensorial regions (seed-to-voxel analyses of hypothalamic connectivity), and decreased default mode network (DMN) and posterior salience (pSAL) network connectivity (ROI-to-ROI analyses of brain networks connectivity) when compared to RYGB alone (all p-FDR < 0.05). Increases in basal ganglia (BG) network connectivity were only observed in the exercised training group (within-group analyses). CONCLUSION: Exercise training is an important component in the management of post-bariatric patients and may improve the hypothalamic connectivity and brain functional networks that are involved in controlling food intake. TRIAL REGISTRATION: Clinicaltrial.gov: NCT02441361.

Background The breath print is a quantitative measurement of molecules in exhaled breath and represents a new frontier for biomarker identification. It is unknown whether this state-of-the-art, noninvasive method can detect malnutrition. We hypothesize that individuals with malnutrition will present with a distinguishable breath print. Methods We conducted a retrospective chart review on patients with previously analyzed breath samples to identify malnutrition. Breath was analyzed by selected-ion flow-tube mass spectrometry. Registered dietitians conducted a retrospective chart review to collect malnutrition diagnosis and nutritional status indicators. Patients were categorized into one of four groups: pulmonary arterial hypertension (PAH), PAH with malnutrition (PAH-Mal), Control, and Control with malnutrition, based on malnutrition diagnosis present in the patient's chart. Principle component analysis was conducted to characterize the breath print. A logistic regression model with forward selection was used to detect the best breath predictor combination of malnutrition. Results 74 subjects met inclusion criteria (PAH:52; PAH-Mal:10; Control:10; Control-Mal:2). 1-octene (PAH-Mal 5.1±1.2, PAH 12.5±11.2; p = 0.005) and ammonia (PAH-Mal 14.6±15.8, PAH 56.2±64.2; p = 0.013) were reduced in PAH-Mal compared to PAH. The combination of 1-octene (p = 0.010) and 3-methylhexane (p = 0.045) distinguished malnutrition in PAH (ROC AUC: 0.8549). Conclusions This proof-of-concept study provides the first evidence that the breath print is altered in malnutrition. Larger, prospective studies are needed to validate these results and establish whether breath analysis may be a useful tool to screen for malnutrition in the clinical setting. Clinical relevancy statement Early identification and intervention combats malnutrition. However, malnutrition screening practices are hindered by a lack of a malnutrition biomarker. The breath print describes the molecules released in the exhaled breath and is a novel "tissue" to identify biomarkers of disease. This report identifies that the breath print is altered in patients with malnutrition and implicates potential for its use as a malnutrition screening biomarker. This article is protected by copyright. All rights reserved.

OBJECTIVE The aim of this study was to investigate the long-term effects of medical and surgical treatments of type 2 diabetes mellitus (T2DM) on patient-reported outcomes (PROs). BACKGROUND Robust data on PROs from randomized trials comparing medical and surgical treatments for T2DM are lacking. METHODS The Surgical Treatment And Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial showed that 5 years after randomization, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) were superior to intensive medical therapy (IMT) alone in achieving glycemic control in patients with T2DM and obesity. A subset of 104 patients participating in the STAMPEDE trial were administered two generic health-related quality of life (QoL) questionnaires (RAND-36 and EQ-5D-3L) and a diabetes-specific instrument at baseline, and then on an annual basis up to 5 years after randomization. RESULTS On longitudinal analysis, RYGB and SG significantly improved the domains of physical functioning, general health perception, energy/fatigue, and diabetes-related QoL compared with IMT group. In the IMT group, none of the QoL components in the generic questionnaires improved significantly from baseline. No significant long-term differences were observed among the study groups in measures of psychological and social aspects of QoL. On multivariable analysis, independent factors associated with improved general health perception at long-term included baseline general health (P < 0.001), insulin independence at 5 years (P = 0.005), RYGB versus IMT (P = 0.005), and SG versus IMT (P = 0.034). Favorable changes following RYGB and SG were comparable. CONCLUSIONS In patients with T2DM, metabolic surgery is associated with long-term favorable changes in certain PROs compared with IMT, mainly on physical health and diabetes-related domains. Psychosocial well-being warrants greater attention after metabolic surgery.

Introduction Patients with type 2 diabetes experience resolution of hyperglycemia within days after Roux-en-Y gastric bypass (RYGB) surgery. This is attributed, in part, to enhanced secretion of hindgut factors following exclusion of the gastric remnant and proximal intestine during surgery. However, evidence of the mechanisms of remission remain limited due to the challenges of metabolic evaluation during the early postoperative period. The purpose of this investigation was to determine the role of foregut exclusion in the resolution of type 2 diabetes after RYGB. Methods Patients with type 2 diabetes (n = 15) undergoing RYGB had a gastrostomy tube (G-tube) placed in their gastric remnant at time of surgery. Patients were randomized to receive a mixed meal tolerance test via oral or G-tube feeding immediately prior to and 2 weeks after surgery in a repeated measures crossover design. Plasma glucose, insulin, C-peptide, incretin responses, and indices of meal-stimulated insulin secretion and sensitivity were determined. Results Body weight, fat mass, fasting glucose and insulin, and circulating lipids were significantly decreased 2 weeks after surgery. The glycemic response to feeding was reduced as a function of total area under the curve but not after adjustment for the reduction in fasting glucose. Oral feeding significantly enhanced insulin and incretin secretion after RYGB, which was entirely ablated by G-tube feeding. Conclusion Foregut exclusion accounts for the rise in incretin and insulin secretion but may not fully explain the early improvements in glucose metabolism after RYGB surgery.

Introduction: Obstructive sleep apnea (OSA) is a prevalent sleep disorder with high type 2 diabetes (T2D) risk. OSA therapy includes positive airway pressure (PAP) treatment, which resolves breathing events but modestly improves metabolic health. Metformin is recommended for T2D prevention but is not advocated in patients with OSA. Our pilot study evaluated the effects of metformin on glucose metabolism and mitochondrial function in OSA patients. Methods: Sixteen adults (50.5±1.6 years, BMI: 36.4±0.8 kg/m2) with OSA (apnea hypopnea index: 53.2±21.1 events/hour) were randomized to receive placebo (n=8) or metformin (n=8) treatment along with PAP for 3 months in a double-blind parallel-group design. Whole body and adipose tissue-specific insulin sensitivity (IS) was determined by oral glucose tolerance test (OGTT) . Skeletal muscle mitochondrial function was determined by high-resolution respirometry using biopsies obtained at baseline and after 3 months of treatment. Results: Change in whole body IS (Matsuda index) was not different in metformin or placebo treated groups (p=0.46) . However, improved acute phase responses during OGTT - glucose uptake (p=0.02) , insulin release (p=0.03) , and suppressed lipolysis (p=0.03) were observed with metformin treatment relative to control. Increased skeletal muscle mitochondrial function was evident with metformin relative to control. Specifically, metformin increased complex I phosphorylation and complex IV electron transfer capacity. Conclusion: Metformin treatment improves acute phase IS and insulin suppression of lipolysis in OSA patients. Strikingly, metformin improved skeletal muscle mitochondrial function independent of changes in second phase glucose disposal and BMI, indicating improved tissue metabolic function. These data suggest that in patients with OSA, improvement in tissue level metabolic function may precede changes in whole-body IS and metformin may improve metabolism. Disclosure E.R.M.Zunica: None. E.C.Heintz: None. R.C.Hebert: None. M.C.Tanksley: None. E.C.Mader: None. J.P.Kirwan: None. C.L.Axelrod: None. P.Singh: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK123456789) ;National Institute of General Medical Sciences (GM123456789)

Introduction: Obesity is the primary determinant of nonalcoholic fatty liver disease (NAFLD) . Interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR) , may serve as effective therapies for NAFLD. The purpose of this study was to compare the effects of Roux-en-Y gastric bypass surgery (RYGB) to CR on hepatic function in mice with obesity and NAFLD. Methods: 6-week-old male C57BL/6J mice were fed a two-choice chow/high-fat diet (HFD) to promote diet-induced obesity. At 16 weeks of age, mice were randomized to (1) sham surgery (Sham) , (2) RYGB, or (3) sham + weight-matched calorie restriction to RYGB (WM) . Mice were euthanized at 36 weeks for determination of NAFLD/NASH and hepatic function. Body weight/composition and food intake were measured weekly during the treatment period. ANCOVA-adjusted energy expenditure (EE) was determined 3 and 17 weeks after treatment. Hepatic lipid content and NAFLD scores were determined from H&E-stained tissue sections. Hepatic enzymes and glycogen content were determined by ELISA. Results: RYGB & WM achieved a similar reduction in body weight relative to baseline. RYGB decreased adiposity to a greater extent than WM relative to baseline and Sham (-4.4±0.6 vs. -1.3±0.6 Δg, P Conclusions: RYGB and WM improve hepatic function and decrease the severity of NAFLD through shared and discrete mechanisms of action. RYGB decreases hepatic lipid content to a greater extent than WM independent of food intake, indicating that evading the expected metabolic adaptation in EE after weight loss likely accounts for the additive hepatic benefit of RYGB. Disclosure C. L. Axelrod: None. I. M. Langohr: None. W. S. Dantas: None. R. Townsend: None. V. L. Albaugh: None. J. P. Kirwan: None. H. Berthoud: None. Funding National Institutes of Health (U54GM104940)

Reductions in β-cell number and function contribute to the onset type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) surgery can resolve T2D within days of operation, indicating a weight-independent mechanism of glycemic control. We hypothesized that RYGB normalizes glucose homeostasis by restoring β-cell structure and function. Male Zucker Diabetic Fatty (fa/fa; ZDF) rats were randomized to sham surgery (n = 16), RYGB surgery (n = 16), or pair feeding (n = 16). Age-matched lean (fa/+) rats (n = 8) were included as a secondary control. Postprandial metabolism was assessed by oral glucose tolerance testing before and 27 days after surgery. Fasting and postprandial plasma GLP-1 was determined by mixed meal tolerance testing. Fasting plasma glucagon was also measured. β-cell function was determined in isolated islets by a glucose-stimulated insulin secretion assay. Insulin and glucagon positive areas were evaluated in pancreatic sections by immunohistochemistry. RYGB reduced body weight (P < 0.05) and improved glucose tolerance (P < 0.05) compared with sham surgery. RYGB reduced fasting glucose compared with both sham (P < 0.01) and pair-fed controls (P < 0.01). Postprandial GLP-1 (P < 0.05) was elevated after RYGB compared with sham surgery. RYGB islets stimulated with 20 mM glucose had higher insulin secretion than both sham and pair-fed controls (P < 0.01) and did not differ from lean controls. Insulin content was greater after RYGB compared with the sham (P < 0.05) and pair-fed (P < 0.05) controls. RYGB improves insulin secretion and pancreatic islet function, which may contribute to the remission of type 2 diabetes following bariatric surgery. NEW & NOTEWORTHY The onset and progression of type 2 diabetes (T2D) results from failure to secrete sufficient amounts of insulin to overcome peripheral insulin resistance. Here, we demonstrate that Roux-en-Y gastric bypass (RYGB) restores islet function and morphology compared to sham and pair-fed controls in ZDF rats. The improvements in islet function were largely attributable to enhanced insulin content and secretory function in response to glucose stimulation.

Bariatric surgery improves cardiovascular health, which might be partly ascribed to beneficial alterations in the autonomic nervous system. However, it is currently unknown whether benefits from surgery on cardiac autonomic regulation in post-bariatric patients can be further improved by adjuvant therapies, namely exercise. We investigated the effects of a 6-month exercise training program on cardiac autonomic responses in women undergoing bariatric surgery. Sixty-two women eligible for bariatric surgery were randomly allocated to either standard of care (control) or an exercise training intervention. At baseline (PRE) and 3 (POST3) and 9 (POST9) months after surgery, we assessed chronotropic response to exercise (CR%; i.e., percentage change in heart rate from rest to peak exercise) and heart rate recovery (HRR30s, HRR60s, and HRR120s; i.e., decay of heart rate at 30, 60, and 120 s post exercise) after a maximal exercise test. Between-group absolute changes revealed higher CR% (Δ = 8.56%, CI95% 0.22–19.90, P = 0.04), HRR30s (Δ = 12.98 beat/min, CI95% 4.29–21.67, P = 0.01), HRR60s (Δ = 22.95 beat/min, CI95% 11.72–34.18, P = 0.01), and HRR120s (Δ = 34.54 beat/min, CI95% 19.91–49.17, P < 0.01) in the exercised vs. non-exercised group. Our findings demonstrate that exercise training enhanced the benefits of bariatric surgery on cardiac autonomic regulation. These results highlight the relevance of exercise training as a treatment for post-bariatric patients, ensuring optimal cardiovascular outcomes.

BACKGROUND: Metabolic surgery has beneficial metabolic effects, including remission of type 2 diabetes. We hypothesized that duodenojejunal bypass (DJB) surgery can protect against development of type 1 diabetes (T1D) by enhancing regulation of cellular and molecular pathways that control glucose homeostasis. METHODS: BBDP/Wor rats, which are prone to develop spontaneous autoimmune T1D, underwent loop DJB (n=15) or sham (n=15) surgery at a median age of 41 days, before development of diabetes. At T1D diagnosis, a subcutaneous insulin pellet was implanted, oral glucose tolerance test was performed 21 days later, and tissues were collected 25 days after onset of T1D. Pancreas and liver tissues were assessed by histology and RT-qPCR. Fecal microbiota composition was analyzed by 16S V4 sequencing. RESULTS: Postoperatively, DJB rats weighed less than sham rats (287.8 vs 329.9 g, P=0.04). In both groups, 14 of 15 rats developed T1D, at similar age of onset (87 days in DJB vs 81 days in sham, P=0.17). There was no difference in oral glucose tolerance, fasting and stimulated plasma insulin and c-peptide levels, and immunohistochemical analysis of insulin positive cells in the pancreas. DJB rats needed 1.3±0.4 insulin implants vs 1.9±0.5 in sham rats (P=0.002). Fasting and glucose stimulated glucagon-like peptide 1 (GLP-1) secretion was elevated after DJB surgery. DJB rats had reduced markers of metabolic stress in liver. After DJB, the fecal microbiome changed significantly, including increases in Akkermansia and Ruminococcus, while the changes were minimal in sham rats. CONCLUSION: DJB does not protect against autoimmune T1D in BBDP/Wor rats, but reduces the need for exogenous insulin and facilitates other metabolic benefits including weight loss, increased GLP-1 secretion, reduced hepatic stress, and altered gut microbiome.

OBJECTIVE The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium is to assess the durability and longer-term effectiveness of metabolic surgery compared with medical/lifestyle management in patients with type 2 diabetes (NCT02328599). RESEARCH DESIGN AND METHODS A total of 316 patients with type 2 diabetes previously randomly assigned to surgery (N = 195) or medical/lifestyle therapy (N = 121) in the STAMPEDE, TRIABETES, SLIMM-T2D, and CROSSROADS trials were enrolled into this prospective observational cohort. The primary outcome was the rate of diabetes remission (hemoglobin A1c [HbA1c] ≤6.5% for 3 months without usual glucose-lowering therapy) at 3 years. Secondary outcomes included glycemic control, body weight, biomarkers, and comorbidity reduction. RESULTS Three-year data were available for 256 patients with mean 50 ± 8.3 years of age, BMI 36.5 ± 3.6 kg/m2, and duration of diabetes 8.8 ± 5.7 years. Diabetes remission was achieved in more participants following surgery than medical/lifestyle intervention (60 of 160 [37.5%] vs. 2 of 76 [2.6%], respectively; P < 0.001). Reductions in HbA1c (Δ = −1.9 ± 2.0 vs. −0.1 ± 2.0%; P < 0.001), fasting plasma glucose (Δ = −52 [−105, −5] vs. −12 [−48, 26] mg/dL; P < 0.001), and BMI (Δ = −8.0 ± 3.6 vs. −1.8 ± 2.9 kg/m2; P < 0.001) were also greater after surgery. The percentages of patients using medications to control diabetes, hypertension, and dyslipidemia were all lower after surgery (P < 0.001). CONCLUSIONS Three-year follow-up of the largest cohort of randomized patients followed to date demonstrates that metabolic/bariatric surgery is more effective and durable than medical/lifestyle intervention in remission of type 2 diabetes, including among individuals with class I obesity, for whom surgery is not widely used.

AIMS: Long-term data from randomized clinical trials comparing metabolic (bariatric) surgery vs. a medical/lifestyle intervention for treatment of patients with obesity/overweight and type 2 diabetes (T2D) are lacking. The Alliance of Randomized Trials of Medicine vs. Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) is a consortium of four randomized trials designed to compare long-term efficacy and safety of surgery vs. medical/lifestyle therapy on diabetes control and clinical outcomes. MATERIALS AND METHODS: Patients with T2D and BMI of 27–45 kg/m(2) who were previously randomized to metabolic surgery (Roux-en-Y gastric bypass, adjustable gastric band, or sleeve gastrectomy) vs. medical/lifestyle intervention in the STAMPEDE, SLIMM-T2D, TRIABETES, or CROSSROADS trials have been enrolled in ARMMS-T2D for observational follow-up. The primary outcome is change in HbA(1c) after a minimum 7 years of follow-up, with additional analyses to determine rates of diabetes remission and relapse, as well as cardiovascular and renal endpoints. RESULTS: A total of 302 patients (192 surgical, 110 medical/lifestyle) previously randomized in the four parent studies were eligible for participation in the ARMMS-T2D observational study. Participant demographics were 71% Caucasian, 27% African-American, and 68% female. At baseline, age=50±8 yrs, BMI=36.5±3.5 kg/m(2), duration of diabetes=8.8±5.6 yrs, HbA(1c)=8.6±1.6 %, and fasting glucose=168±64 mg/dl. More than 35% of patients had a BMI

Soybean products have nutrients, dietary fiber, and phytoalexins beneficial for cardiovascular and overall health. Despite their high consumption in Asian populations, their safety in Western diets is debated. We conducted a dose-escalating clinical trial of the safety and tolerability of soybean products in eight older adults (70–85 years) with obesity. Whole green soybean pods grown under controlled conditions were processed to flour (WGS) at the United States Department of Agriculture using common cooking techniques such as slicing and heat treatment. WGS incorporated into food products was consumed at 10 g, 20 g, and 30 g/day for one week at each dose. The gastrointestinal outcomes, clinical biomarkers, and adverse events were evaluated. We explored the stimulation of phytoalexin (glyceollin) production in live viable soybean seeds (LSS-G). We compared the compositions of WGS and LSS-G with commercial soybean flour and its fermented and enzymatically hydrolyzed forms. We found that although 30 g WSG was well-tolerated, and it made participants feel full. Our processing produced glyceollins (267 µg/g) in LSS-G. Processing soybean flour decreased the iron content, but reduced the oligosaccharides, which could attenuate flatulence. Providing soybean flour at

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet-induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.Eighty-week-old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function.BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1-ubiquitin binding and LC3II, P 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P 0.0001) while limiting ER stress (decreased PERK signalling, P 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase-3/9 activation, all P 0.001), and muscle protein degradation (decreased 14-kDa actin fragment insoluble/soluble ratio, P 0.001).Mitochondrial uncoupling by agents such as BAM15 may mitigate age-related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.

The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients ( n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients ( n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients ( P=0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT ( P=0.01, R 2=0.489 and P=0.03, R 2=0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration ( P

Summary Introduction The incidence of chronic kidney disease (CKD) has increased in recent years. CKD is associated with obesity, type 2 diabetes, and cardiovascular disease, although the mechanism remains unclear. Elevated soluble form of the receptor for advanced glycation end products ( RAGE) is related to proinflammatory signaling pathways that may promote diabetic nephropathy and vascular dysfunction. Because lifestyle modification reduces systematic inflammation in adults with obesity and hyperglycaemia, the hypothesis that exercise plus caloric restriction would lower soluble RAGE in adults with CKD was tested in this study. Methods Eight adults (n = 6 females; age: 56.3 ± 2.8 y; BMI: 43.7 ± 2.2 kg/m2; 2‐h OGTT glucose: 215 ± 9.8 mg/dL; eGFR: 49.6 ± 3.3 mL/min/1.73 m2) were enrolled in a 12‐week pilot lifestyle intervention (supervised aerobic exercise [5 d/wk, up to 60 min/d at approximately 65%‐85% HRmax] plus low‐fat dietary counseling). Body composition (DXA), aerobic fitness (VO2max), insulin sensitivity (120 min 75 g OGTT; Matsuda Index), plasma levels of soluble RAGE and fetuin‐A were measured before and after the intervention. Results Exercise reduced body weight, fasting glucose, and fetuin‐A as well as increased VO2max, glucose tolerance, and insulin sensitivity (all P < .05). Lifestyle intervention decreased plasma soluble RAGE (pre: 1018.1 ± 163 vs post: 810.6 ± 119.6 ng/mL; P = .02), and the decrease was associated with a lower 2‐hour blood glucose (r = 0.76, P = .03) and with increased insulin sensitivity (r = −0.90, P < .01). Conclusions Exercise and caloric restriction are effective at lowering soluble RAGE in relation to glucose regulation in patients with CKD.

We aimed to characterize the plasma metabolome of chronic thromboembolic pulmonary hypertension patients using a high-throughput unbiased omics approach. We collected fasting plasma from a peripheral vein in 33 operable chronic thromboembolic pulmonary hypertension patients, 31 healthy controls, and 21 idiopathic pulmonary arterial hypertension patients matched for age, gender, and body mass index. Metabolomic analysis was performed using an untargeted approach (Metabolon Inc. Durham, NC). Of the total of 862 metabolites identified, 362 were different in chronic thromboembolic pulmonary hypertension compared to controls: 178 were higher and 184 were lower. Compared to idiopathic pulmonary arterial hypertension, 147 metabolites were different in chronic thromboembolic pulmonary hypertension: 45 were higher and 102 were lower. The plasma metabolome allowed us to distinguish subjects with chronic thromboembolic pulmonary hypertension and healthy controls with a predictive accuracy of 89%, and chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension with 80% accuracy. Compared to idiopathic pulmonary arterial hypertension and healthy controls, chronic thromboembolic pulmonary hypertension patients had higher fatty acids and glycerol; while acyl cholines and lysophospholipids were lower. Compared to healthy controls, both idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients had increased acyl carnitines, beta-hydroxybutyrate, amino sugars and modified amino acids and nucleosides. The plasma global metabolomic profile of chronic thromboembolic pulmonary hypertension suggests aberrant lipid metabolism characterized by increased lipolysis, fatty acid oxidation, and ketogenesis, concomitant with reduced acyl choline and phospholipid moieties. Future research should investigate the pathogenetic and therapeutic potential of modulating lipid metabolism in chronic thromboembolic pulmonary hypertension.

Mitochondria are essential to the onset and progression of cancer through energy production, reactive oxygen species regulation, and macromolecule synthesis. Genetic and functional adaptations of mitochondria to the tumor environment drive proliferative and metastatic potential. The advent of DNA and RNA sequencing removed critical barriers to the evaluation of genetic mediators of tumorigenesis. However, to date, methodological approaches to evaluate tumor mitochondrial function remain elusive and require technical proficiency limiting the feasibility, ultimately diminishing diagnostic and prognostic value in both experimental and clinical settings. Here, we outline a simple and rapid method to quantify rates of oxidative phosphorylation (OXPHOS) and electron transfer (ET) capacity in freshly excised solid tumor homogenates using high-resolution respirometry. The protocol can be reproducibly applied across species and tumor types as well as adapted to evaluate a diversity of mitochondrial ET pathways. Using this protocol, we demonstrate that mice bearing a luminal B mammary cancer exhibit defective nicotinamide adenine dinucleotide-linked respiration and reliance on succinate to generate adenosine triphosphate via OXPHOS.

OBJECTIVE: Metabolically healthy obesity (MHO) is often defined as the absence of metabolic syndrome in the presence of obesity. However, phenotypic features of MHO are unclear. Insulin sensitivity in MHO was cross-sectionally compared with metabolically unhealthy obesity (MUO) and a reference group of young healthy participants without obesity. METHODS: Sedentary adults (n = 96) undergoing anthropometric, blood chemistries, maximal aerobic capacity, and euglycemic-hyperinsulinemic clamp measurements were classified by BMI (

Triple negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype with limited treatment options. Obesity and insulin resistance are associated with a worse prognosis in those with TNBC. Moringa oleifera (moringa) is a tropical edible plant used for both food and medicinal purposes and found to have anti-obesity and anti-cancer effects in vitro and in preclinical models. The anti-cancer effects of moringa seed extract alone and in combination with chemotherapy were evaluated in immunocompromised female mice with diet-induced obesity bearing MDA-MB-231-derived xenograft tumors. Moringa supplementation protected against high-fat diet- and chemotherapy-induced increases in fasting glucose and improved insulin sensitivity. Moringa supplementation alone did not attenuate tumor growth relative to chemotherapy alone, and in combination worsened tumor progression. Moringa supplementation alone reduced angiogenesis, but this effect was abrogated in combination with chemotherapy. Moringa supplementation may be an effective strategy to improve metabolic health in mice with obesity and TNBC and reduce angiogenesis in tumors, but may have a negative interaction when used as a concurrent complementary therapy. Caution should be taken when considering the consumption of moringa seed extracts while receiving chemotherapy for breast cancer treatment. Further investigations of alternative timings of moringa therapy are warranted.

Mutations in Valosin Containing Protein (VCP) are associated with several degenerative diseases, including multisystem proteinopathy (MSP-1) and amyotrophic lateral sclerosis. However, patients with VCP mutations vary widely in their pathology and clinical penetrance, making it difficult to devise effective treatment strategies. A deeper understanding of how each mutation affects VCP function could enhance the prediction of clinical outcomes and design of personalized treatment options. The power of a genetically tractable model organism coupled with well-established in vivo assays and a relatively short life cycle make Drosophila an attractive system to study VCP disease pathogenesis. Using CRISPR/Cas9, we have generated individual Drosophila knock-in mutants that include nine hereditary VCP disease mutations. Our models display many hallmarks of VCP-mediated degeneration, including progressive decline in mobility, protein aggregate accumulation and defects in lysosomal and mitochondrial function. We also made some novel and unexpected findings, including nuclear morphology defects and sex-specific phenotypic differences in several mutants. Taken together, the Drosophila VCP disease models generated in this study will be useful for studying the etiology of individual VCP patient mutations and testing potential genetic and/or pharmacological therapies., Summary: We generated a collection of nine Drosophila knock-in models that mimic VCP-related diseases and revealed novel pathologies, including sex-dependent effects and laminopathies.

The extent to which the benefits of bariatric surgery may be maintained by lifestyle changes after surgery is unclear. Our hypothesis is that exercise may sustain some metabolic benefits and counteract some of the adverse effects of surgery. In this review, we present findings supporting the proposition that exercise is key to improving overall health in patients after bariatric surgery.

Background and aims A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial. Methods 19 healthy adults (age:28.4 ± 1.7 years; BMI:22.7 ± 0.3 kg/m2) received an overnight intravenous infusion of lipid (20% Intralipid) or saline followed by a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity using a randomized crossover design. Skeletal muscle biopsies were obtained after the overnight lipid infusion to evaluate activation of mitochondrial dynamics proteins, ex-vivo mitochondrial membrane potential, ex-vivo oxidative phosphorylation and electron transfer capacity, and mitochondrial ultrastructure. Results Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P = 0.003 and P = 0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P = 0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P = 0.011), the number of dilated cristae, and the presence of autophagic vesicles without altering mitochondrial number or respiratory capacity. Additionally, lipid infusion suppressed peripheral glucose disposal (P = 0.004) and hepatic insulin sensitivity (P = 0.014). Conclusions These findings indicate that activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. Targeting mitochondrial dynamics and quality control represents a promising new pharmacological approach for treating insulin resistance and type 2 diabetes. Clinical trial registration NCT02697201 , ClinicalTrials.gov

Many adults receive inadequate sleep, which elevates obesity and type 2 diabetes risk and may hinder benefits of calorie restriction (CR). We hypothesized that short sleepers would experience less weight loss and diminished glycemic benefits compared to adequate sleepers during CR. We performed secondary analyses in participants randomized to 25% CR in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy- Phase 2 (CALERIE 2) trial. Body weight, dual-energy x-ray absorptiometry-measured body composition, fasting glucose, insulin, and HOMA-IR were assessed at baseline, 12, and 24 months. Self-reported sleep duration identified participants with stable sleep as short (≤7 hrs, n=45) or adequate sleepers (>7 hrs, n=65). Sex, BMI, weight, and race-adjusted linear mixed models identified differences over time and between sleepers. Short and adequate sleepers had similar body weight and composition values at all timepoints and experienced equivalent CR-induced reductions over time. Baseline HOMA-IR (1.2 vs. 1.0; P=0.047) was higher in short sleepers, with trends noted for glucose (81.7 vs. 83.5 mg/dL; P=0.093) and insulin (5.7 vs. 4.9 µU/mL; P=0.077). Both phenotypes demonstrated enhanced glycemic control relative to baseline at 12 and 24 months. While there were no 12-month differences in absolute glycemic values between sleepers, initial differences re-emerged at 24 months, with higher HOMA-IR (0.9 vs. 0.7; P=0.01) and insulin concentrations (4.3 vs. 3.4 µU/mL; P Disclosure K. K. Hoddy: None. P. Singh: None. J. L. Dorling: None. R. A. Beyl: None. J. P. Kirwan: None. K. Huffman: None. S. B. Racette: None. S. Das: None. C. K. Martin: Advisory Panel; Self; EHE Health, Board Member; Self; NaturallySlim, Other Relationship; Self; ABGIL, Academy of Nutrition and Dietetics, Research Support; Self; American Society for Nutrition, Leona M. and Harry B. Helmsley Charitable Trust, Lilly, National Institutes of Health, Patient-Centered Outcomes Research Institute, U. S. Department of Agriculture, WW. Funding National Institute on Aging (U01AG022132, U01AG020478, U01AG020487, U01AG020480, R01AG060499, U24AG047121, U24AG047121); Agricultural Research Service (1950-51000-071-01S); American Heart Association (20POST35210907); National Institute of Diabetes and Digestive and Kidney Diseases (5P30DK07247615); National Institute of General Medical Sciences (U54GM104940)

There is limited Level-1 evidence from well-powered randomized controlled trials (RCTs) examining improved glycemic control after metabolic surgery in patients with type 2 diabetes (T2D) and obesity. ARMMS-T2D is a multi-center consortium conducting a follow-up study of 4 merged RCTs in 256 patients with baseline Class 1-3 obesity and T2D, randomly assigned to metabolic surgery (MS;Roux-en-Y gastric bypass, sleeve gastrectomy, or gastric banding) or intensive Medical/Lifestyle Intervention (MLI). Three years after randomization, T2D remission rates were higher after MS than MLI (37.5%, 60/160 vs. 2.6%, 2/76, respectively, P

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.

The cancer anorexia-cachexia syndrome (CACS) is a common, debilitating condition with limited therapeutic options. The defining feature of CACS is weight loss, which suggests a state of negative energy balance. It is unclear whether this net reduction in energy is due solely to anorexia or if a combination of anorexia and increased energy expenditure (EE) occurs. To address this question, we induced lung cancer in mice and measured changes in food intake, EE, and body composition. Mice with CACS developed reductions in food intake, spontaneous activity, and EE. There was severe atrophy and markers of metabolic dysfunction in the adipose and skeletal muscle tissues as compared to mice without CACS and pair-fed wild-type mice. We used anamorelin fumarate (Ana), a ghrelin receptor agonist, alone or in combination ActRIIB-Fc, a ligand trap for TGF-β/activin family members, to reverse anorexia and skeletal muscle atrophy, respectively. Ana effectively increased food intake and the combination of drugs increased lean mass, restored spontaneous activity, and improved overall survival. These beneficial effects were limited to female mice. Our findings suggest that multimodal, gender-specific, therapies are needed to reverse CACS.

Exercise seems to enhance the beneficial effect of bariatric surgery (RYGB) on insulin resistance. We hypothesized that skeletal muscle extracellular matrix (ECM) remodeling may underly these benefits. Women were randomized to either a combined aerobic and resistance exercise training program following RYGB or standard of care (RYGB). Insulin sensitivity was assessed by OGTT. Muscle biopsies were obtained at baseline, and 3 and 9 months after surgery and subjected to comprehensive phenotyping, transcriptome profiling, molecular pathway identification and validation in vitro. Exercise training improved insulin sensitivity beyond surgery alone (e.g., Matsuda index - RYGB: +123% vs. RYGB + ET: +325%; P ≤ 0.0001). ECM remodeling was reduced by surgery alone, with an additive benefit of surgery and exercise training (e.g., collagen I - RYGB: -41% vs. RYGB + ET: -76%; P ≤ 0.0001). Exercise and RYGB had an additive effect on enhancing insulin sensitivity, but surgery alone did not resolve insulin resistance and ECM remodeling. We identified candidates modulated by exercise training that may become therapeutic targets for treating insulin resistance, in particular, the transforming growth factor-beta 1/SMAD 2/3 pathway and its antagonist follistatin. Exercise-induced increases in insulin sensitivity after bariatric surgery are at least partially mediated by muscle extracellular matrix remodeling.

Background Muscle atrophy and strength loss are common adverse outcomes following bariatric surgery. This randomized, controlled trial investigated the effects of exercise training on bariatric surgery‐induced loss of muscle mass and function. Additionally, we investigated the effects of the intervention on molecular and histological mediators of muscle remodelling. Methods Eighty women with obesity were randomly assigned to a Roux‐en‐Y gastric bypass (RYGB: n = 40, age = 42 ± 8 years) or RYGB plus exercise training group (RYGB + ET: n = 40, age = 38 ± 7 years). Clinical and laboratory parameters were assessed at baseline, and 3 (POST3) and 9 months (POST9) after surgery. The 6 month, three‐times‐a‐week, exercise intervention (resistance plus aerobic exercise) was initiated 3 months post‐surgery (for RYGB + ET). A healthy, lean, age‐matched control group was recruited to provide reference values for selected variables. Results Surgery resulted in a similar (P = 0.66) reduction in lower‐limb muscle strength in RYGB and RYGB+ET (−26% vs. −31%), which was rescued to baseline values in RYGB + ET (P = 0.21 vs. baseline) but not in RYGB (P 0.05 vs. baseline) but not RYGB (P > 0.01 vs. baseline). RYGB + ET showed greater Type I (5187 vs. 3898 μm2, P