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Low-glycemic index diets and exercise independently improve glucose tolerance and reduce diabetes risk. However, the combined effect of a low-glycemic index diet and exercise on inflammation and glucose metabolism is not known. Therefore, we randomized 28 insulin-resistant adults (age: 66 ± 1 y; BMI: 34.2 ± 0.7 kg · m(-2)) to a 12-wk, low (LGI = 40) or high- (HGI = 80) glycemic index diet plus aerobic exercise (5 d · wk(-1), 60 min · d(-1), 80-85% heart rate(max)) intervention. All food and fluids were provided during the study. Inflammation was assessed from cytokine (TNFα and IL-6) secretion using peripheral blood mononuclear cells (MNC) stimulated overnight with LPS. Glycemic response was determined following ingestion of a 75-g glucose solution. Fasting blood samples were collected for additional cytokine [TNFα, IL-6, and monocyte chemoattractant protein 1 (MCP-1)] analysis. Both interventions decreased BMI (P < 0.001), fasting plasma glucose (P = 0.01), and insulin (P = 0.02). The glycemic response was reduced only in the LGI group (P = 0.04). Plasma and MNC-derived TNFα secretion were reduced in the LGI group (P = 0.02) but increased in the HGI group (P = 0.02). Secretion of IL-6 from MNC and plasma IL-6 and MCP-1 concentrations were reduced in the LGI group. The change in MNC-derived TNFα (r = 0.43; P = 0.04) and plasma MCP-1 (r = 0.44; P = 0.04) correlated with decreases in the glycemic response. These data highlight the importance of diet composition in the treatment and prevention of inflammation and hyperglycemia. A low-glycemic index diet has antiinflammatory and antidiabetogenic effects when combined with exercise in older, obese prediabetics. [ABSTRACT FROM AUTHOR]

Objective: Restoration of insulin secretion is critical for the treatment of type 2 diabetes. Exercise and diet can alter glucose-induced insulin responses, but whether this is due to changes in beta-cell function per se is not clear. The mechanisms by which lifestyle intervention may modify insulin secretion in type 2 diabetes have also not been examined but may involve the incretin axis.Research Design and Methods: Twenty-nine older, obese (aged 65 +/- 1 years; BMI 33.6 +/- 1.0 kg/m(2)) subjects, including individuals with newly diagnosed type 2 diabetes (obese-type 2 diabetic) and individuals with normal glucose tolerance (obese-NGT), underwent 3 months of nutritional counseling and exercise training. beta-Cell function (oral glucose-induced insulin secretion corrected for insulin resistance assessed by hyperinsulinemic-euglycemic clamps) and the role of glucose-dependent insulinotropic polypeptide (GIP) were examined.Results: After exercise and diet-induced weight loss (-5.0 +/- 0.7 kg), oral glucose-induced insulin secretion was increased in the obese-type 2 diabetic group and decreased in the obese-NGT group (both P < 0.05). When corrected for alterations in insulin resistance, the change in insulin secretion remained significant only in the obese-type 2 diabetic group (1.23 +/- 0.26 vs. 2.04 +/- 0.46 arbitrary units; P < 0.01). Changes in insulin secretion were directly related to the GIP responses to oral glucose (r = 0.64, P = 0.005), which were augmented in the obese-type 2 diabetic group and only moderately suppressed in the obese-NGT group.Conclusions: After lifestyle-induced weight loss, improvements in oral glucose-induced insulin secretion in older, obese, nondiabetic subjects seem to be largely dependent on improved insulin sensitivity. However, in older obese diabetic patients, improved insulin secretion is a consequence of elevated beta-cell function. We demonstrate for the first time that changes in insulin secretion after lifestyle intervention may be mediated via alterations in GIP secretion from intestinal K-cells. [ABSTRACT FROM AUTHOR]

Context: Hyperglycemia resolves quickly after bariatric surgery, but the underlying mechanism and the most effective type of surgery remains unclear.Objective: To examine glucose metabolism and beta-cell function in patients with type 2 diabetes mellitus (T2DM) after two types of bariatric intervention; Roux-en-Y gastric bypass (RYGB) and gastric restrictive (GR) surgery.Design: Prospective, nonrandomized, repeated-measures, 4-week, longitudinal clinical trial.Patients: In all, 16 T2DM patients (9 males and 7 females, 52+/-14 years, 47+/-9 kg m(-2), HbA1c 7.2+/-1.1%) undergoing either RYGB (N=9) or GR (N=7) surgery.Outcome Measures: Glucose, insulin secretion, insulin sensitivity at baseline, and 1 and 4 weeks post-surgery, using hyperglycemic clamps and C-peptide modeling kinetics; glucose, insulin secretion and gut-peptide responses to mixed meal tolerance test (MMTT) at baseline and 4 weeks post-surgery.Results: At 1 week post-surgery, both groups experienced a similar weight loss and reduction in fasting glucose (P<0.01). However, insulin sensitivity increased only after RYGB, (P<0.05). At 4 weeks post-surgery, weight loss remained similar for both groups, but fasting glucose was normalized only after RYGB (95+/-3 mg 100 ml(-1)). Insulin sensitivity improved after RYGB (P<0.01) and did not change with GR, whereas the disposition index remained unchanged after RYGB and increased 30% after GR (P=0.10). The MMTT elicited a robust increase in insulin secretion, glucagon-like peptide-1 (GLP-1) levels and beta-cell sensitivity to glucose only after RYGB (P<0.05).Conclusion: RYGB provides a more rapid improvement in glucose regulation compared with GR. This improvement is accompanied by enhanced insulin sensitivity and beta-cell responsiveness to glucose, in part because of an incretin effect. [ABSTRACT FROM AUTHOR]

Background: The prevalence of insulin resistance, metabolic syndrome, and cardiovascular disease is greatest in older obese patients, and effective evidence-based treatment strategies are lacking.Methods: A prospective controlled study was conducted on 24 older (65.5 +/- 5.0 years) obese (body mass index, 34.3 +/- 5.2 kg/m(2)) adults with clinically diagnosed metabolic syndrome. We examined the effect of exercise alone (EX) or exercise combined with moderate caloric restriction (-500 kcal, EX + CR) on metabolic and cardiovascular risk factors. Measures of insulin sensitivity assessed by euglycemic hyperinsulinemic clamp and by oral glucose tolerance test, lipid profiles, blood pressure, body composition, abdominal fat, and aerobic capacity were all obtained before and after the interventions.Results: Both groups experienced significant weight loss, but the reduction was greater in the EX + CR group than in the EX group (-6.8 +/- 2.7 kg vs -3.7 +/- 3.4 kg, respectively, p = .02). Both interventions improved insulin sensitivity (2.4 +/- 2.4 mg/kg FFM/min and 1.4 +/- 1.7 mg/kgFFM/min, respectively, p < .001) and indices of metabolic syndrome (systolic/diastolic blood pressure, waist circumference, glucose, and triglycerides; p < .05). High-density lipoprotein levels remained unchanged. Total abdominal, subcutaneous, and visceral fat; aerobic capacity; and total and low-density lipoprotein cholesterol were also improved. With the exception of weight loss and subcutaneous fat, there was no difference in the magnitude of improvement between the interventions.Conclusion: These data suggest that exercise alone is an effective nonpharmacological treatment strategy for insulin resistance, metabolic syndrome, and cardiovascular disease risk factors in older obese adults. [ABSTRACT FROM AUTHOR]

Objective: Women with gestational diabetes mellitus (GDM) demonstrate chronic and progressive insulin resistance and a markedly increased risk of converting to type 2 diabetes after pregnancy. However, the cellular mechanisms underlying this insulin resistance are unknown.Research Design and Methods: We investigated the progression of insulin resistance in nine obese women with GDM during late pregnancy (30-36 weeks) and 1 year postpartum. Skeletal muscle biopsies were obtained at each visit, and insulin resistance was determined by the hyperinsulinemic-euglycemic clamp technique.Results: Insulin resistance was not significantly improved in GDM women (4.1 +/- 0.4 vs. 5.8 +/- 1.1 10(-2) mg x kg FFM x min(-1)/microU x ml(-1)). Subjects did not experience significant weight loss postpartum. Body weight, fat mass, fasting glucose, and plasma tumor necrosis factor (TNF)-alpha remained higher 1 year postpartum than seen in previously studied normal glucose-tolerant women. Skeletal muscle TNF-alpha mRNA was elevated five- to sixfold in GDM women and remained higher 1 year postpartum. While levels of insulin receptor (IR), IR substrate (IRS)-1, and p85 alpha improved postpartum, insulin-stimulated IR tyrosine phosphorylation and receptor tyrosine kinase activity did not significantly improve postpartum in GDM. The levels of (312)Ser-IRS-1 also did not improve postpartum and correlated with TNF-alpha mRNA (r(2) = 0.19, P < 0.03), consistent with a state of subclinical inflammation and chronic skeletal muscle insulin resistance.Conclusions: These results suggest the mechanisms underlying chronic insulin resistance in GDM women may be driven by increased inflammation that impinges on the IR and IRS-1 signaling cascade in skeletal muscle. These findings have important implications for the health of GDM women during subsequent pregnancies and their risk for progression to type 2 diabetes. [ABSTRACT FROM AUTHOR]

Historically, insulin resistance during pregnancy has been ascribed to increased production of placental hormones and cortisol. The purpose of this study was to test this hypothesis by correlating the longitudinal changes in insulin sensitivity during pregnancy with changes in placental hormones, cortisol, leptin, and tumor necrosis factor (TNF)-alpha. Insulin resistance was assessed in 15 women (5 with gestational diabetes mellitus [GDM] and 10 with normal glucose tolerance) using the euglycemic-hyperinsulinemic clamp procedure, before pregnancy (pregravid) and during early (12-14 weeks) and late (34-36 weeks) gestation. Body composition, plasma TNF-alpha, leptin, cortisol, and reproductive hormones (human chorionic gonadotropin, estradiol, progesterone, human placental lactogen, and prolactin) were measured in conjunction with the clamps. Placental TNF-alpha was measured in vitro using dually perfused human placental cotyledon from five additional subjects. Compared with pregravid, insulin resistance was evident during late pregnancy in all women (12.4 +/- 1.2 vs. 8.1 +/- 0.8 10(-2) mg. kg(-1) fat-free mass. min(-1). microU(-1). ml(-1)). TNF-alpha, leptin, cortisol, all reproductive hormones, and fat mass were increased in late pregnancy (P < 0.001). In vitro, most of the placental TNF-alpha (94%) was released into the maternal circulation; 6% was released to the fetal side. During late pregnancy, TNF-alpha was inversely correlated with insulin sensitivity (r = -0.69, P < 0.006). Furthermore, among all of the hormonal changes measured in this study, the change in TNF-alpha from pregravid to late pregnancy was the only significant predictor of the change in insulin sensitivity (r = -0.60, P < 0.02). The placental reproductive hormones and cortisol did not correlate with insulin sensitivity in late pregnancy. Multivariate stepwise regression analysis revealed that TNF-alpha was the most significant independent predictor of insulin sensitivity (r = -0.67, P < 0.0001), even after adjustment for fat mass by covariance (r = 0.46, P < 0.01). These observations challenge the view that the classical reproductive hormones are the primary mediators of change in insulin sensitivity during gestation and provide the basis for including TNF-alpha in a new paradigm to explain insulin resistance in pregnancy. [ABSTRACT FROM AUTHOR]

Objective: We examined whether selected indexes of insulin sensitivity derived from an oral glucose tolerance test (IS(OGTT)) or fasting glucose/insulin levels (IS(QUICKI) and IS(HOMA)) can be used to predict insulin sensitivity in women before and during pregnancy.Research Design and Methods: A 2-h euglycemic-hyperinsulinemic clamp (5 mmol/l glucose, 40 mU. m(-2). min(-1) insulin) and a 120-min oral glucose tolerance test (75 g load pregravid, 100 g pregnant) were repeated on 15 women (10 with normal glucose tolerance [NGT] and 5 with gestational diabetes mellitus [GDM]) pregravid and during both early (12-14 weeks) and late (34-36 weeks) pregnancy. An index of insulin sensitivity derived from the clamp (IS(CLAMP)) was obtained from glucose infusion rates adjusted for change in fat-free mass and endogenous glucose production measured using [6,6(-2)H(2)]glucose.Results: Univariate analysis using combined groups and periods of pregnancy resulted in significant correlations between IS(CLAMP) and IS(OGTT) (r(2) = 0.74, P < 0.0001), IS(QUICKI) (r(2) = 0.64, P < 0.0001), and IS(HOMA) (r(2) = 0.53, P < 0.0001). The IS(OGTT) provided a significantly better correlation (P < 0.0001) than either IS(QUICKI) or IS(HOMA.) Multivariate analysis showed a significant group effect (P < 0.0003) on the prediction model, and separate equations were developed for the NGT (r(2) = 0.64, P < 0.0001) and GDM (r(2) = 0.85, P < 0.0001) groups. When subdivided by period of pregnancy, the correlation between IS(CLAMP) and IS(OGTT) pregravid was r(2) = 0.63 (P = 0.0002), during early pregnancy was r(2) = 0.80 (P < 0.0001), and during late pregnancy was r(2) = 0.64 (P = 0.0002).Conclusions: Estimates of insulin sensitivity from the IS(OGTT) during pregnancy were significantly better than from fasting glucose and insulin values. However, separate prediction equations are necessary for pregnant women with NGT and women with GDM. [ABSTRACT FROM AUTHOR]

Background: It has been shown that basal metabolic rate (BMR) decreases with age. The extent to which some of the decrease can be reversed by exercise in older men and women is unclear. Resistance exercise has been shown to significantly increase muscle mass in older individuals, and because muscle is a highly active metabolic tissue there is potential to increase BMR as a secondary outcome to the training adaptation.Methods: Twelve healthy men aged 59-77 years performed single-leg knee extension exercise (right and left leg) and bench press lifts (16 sets, 10 reps/set with timed recovery between sets) at 75% of the individual's 3RM. Subjects only performed the concentric phase of the lift. BMR was measured on two separate occasions, once after a nonexercise control period and again 48 hrs after a bout of resistance exercise.Results: BMR was significantly increased (p < .006) 48 hrs after exercise (EX) compared to control (CON) (284.0 +/- 34.0 vs 274.9 +/- 34.0 kJ/hr, respectively). Calculated over a 24-hour period, the energy expenditure corresponded to 1570 +/- 193 and 1627 +/- 193 kcal/24 hr (p < .0002) for the CON and EX measures, respectively. VO2 (L/min) was higher (p < .0002) 48 hrs after the EX bout compared to 48 hrs post-CON (0.232 +/- 0.03 vs 0.225 +/- 0.03 L/min, respectively).Conclusion: We conclude that in healthy 59-77-year-old men, an acute bout of resistance exercise causes a sustained increase in BMR that persists for up to 48 hours after exercise. [ABSTRACT FROM AUTHOR]

Objective: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective procedures to treat and manage type 2 diabetes (T2D). However, the underlying metabolic adaptations that mediate improvements in glucose homeostasis remain largely elusive. The purpose of this study was to identify metabolic signatures associated with biochemical resolution of T2D after medical therapy (MT) or bariatric surgery., Research Design and Methods: Plasma samples from 90 patients (age 49.9 ± 7.6 years; 57.7% female) randomly assigned to MT (n = 30), RYGB (n = 30), or SG (n = 30) were retrospectively subjected to untargeted metabolomic analysis using ultra performance liquid chromatography with tandem mass spectrometry at baseline and 24 months of treatment. Phenotypic importance was determined by supervised machine learning. Associations between change in glucose homeostasis and circulating metabolites were assessed using a linear mixed effects model., Results: The circulating metabolome was dramatically remodeled after SG and RYGB, with largely overlapping signatures after MT. Compared with MT, SG and RYGB profoundly enhanced the concentration of metabolites associated with lipid and amino acid signaling, while limiting xenobiotic metabolites, a function of decreased medication use. Random forest analysis revealed 2-hydroxydecanoate as having selective importance to RYGB and as the most distinguishing feature between MT, SG, and RYGB. To this end, change in 2-hydroxydecanoate correlated with reductions in fasting glucose after RYGB but not SG or MT., Conclusions: We identified a novel metabolomic fingerprint characterizing the longer-term adaptations to MT, RYGB, and SG. Notably, the metabolomic profiles of RYGB and SG procedures were distinct, indicating equivalent weight loss may be achieved by divergent effects on metabolism., (© 2024 by the American Diabetes Association.)

Microbial challenge in-use studies are performed to evaluate the potential for microbial proliferation in preservative-free single-dose biological products after first puncture and potential accidental contamination during dose preparation (e.g., reconstitution or dilution) and storage. These studies, in addition to physicochemical in-use stability assessments, are used as part of product registration to define in-use hold times in Prescribing Information and in the pharmacy manual in the case of clinical products. There are no formal guidance documents describing regulator expectations on how to conduct microbial challenge in-use studies and interpret microbial data to assign in-use storage hold times. In lieu of guidance, US Food and Drug Administration (FDA) regulators have authored publications and presentations describing regulator expectations. Insufficient or unavailable microbial challenge data can result in shortened in-use hold times, thus microbial challenge data enables flexibility for health care providers (HCPs) and patients while ensuring patient safety. A cross-industry/FDA in-use microbial working group was formed through the Innovation & Quality (IQ) Consortium to gain alignment among industry practice and regulator expectations. The working group assessed regulatory guidance, current industry practice via a blinded survey of IQ Consortium member companies, and scientific rationale to align on recommendations for experimental design, execution of microbial challenge in-use studies, and a decision tree for microbial data interpretation to assign in-use hold times. Besides the study execution and data interpretation, additional considerations are discussed including the use of platform data for clinical stage products, closed system transfer devices (CSTDs), transport of dose solutions, long infusion times, and the use of USP <797> by HCPs for preparing sterile drugs for administration. The recommendations provided in this article will help streamline biological product development, ensure consistency on assignment of in-use hold times in biological product labels across industry, and provide maximum allowable flexibility to HCPs and patients while ensuring patient safety., (© PDA, Inc. 2024.)

The popularity of e-cigarettes (vaping) has soared, creating a public health crisis among teens and young adults. Chronic vaping can induce gut inflammation and reduce intestinal barrier function through the production of the proinflammatory molecule hydrogen sulfide (H 2 S). This is particularly concerning for people with HIV (PWH) as they already face impaired immune function and are at a higher risk for metabolic dysregulation, diabetes, and chronic liver disease. Furthermore, PWH experience unhealthy behaviors, making it crucial to understand the systemic metabolic dysregulation and pathophysiological mechanisms associated with vaping in this population. Here, we employed liquid chromatography-mass spectrometry (LC-MS)-based metabolomics to investigate the upper respiratory, circulation, and gut metabolic profiles of PWH who vape (n = 7) and smoke combustible tobacco/marijuana (n = 6) compared to control participants who did not vape or smoke (n = 10). This hypothesis-generating exploratory study revealed systemic alterations in purine, neurotransmitter, and vitamin B metabolisms and tissue-specific changes in inflammatory pathways and cryptic sulfur cycling associated with vaping and combustible tobacco/marijuana smoking in PWH. In addition, this study provides the first link between microbial-derived metabolite 2,3-dihydroxypropane-1-sulfonate (DHPS) and vaping/smoking (tobacco and marijuana)-induced metabolic dyshomeostasis in the gut. These findings highlight the importance of identifying the full biological and clinical significance of the physiological changes and risks associated with vaping.

Background: Bioenergetic remodeling of core energy metabolism is essential to the initiation, survival, and progression of cancer cells through exergonic supply of adenosine triphosphate (ATP) and metabolic intermediates, as well as control of redox homeostasis. Mitochondria are evolutionarily conserved organelles that mediate cell survival by conferring energetic plasticity and adaptive potential. Mitochondrial ATP synthesis is coupled to the oxidation of a variety of substrates generated through diverse metabolic pathways. As such, inhibition of the mitochondrial bioenergetic system by restricting metabolite availability, direct inhibition of the respiratory Complexes, altering organelle structure, or coupling efficiency may restrict carcinogenic potential and cancer progression., Scope of Review: Here, we review the role of bioenergetics as the principal conductor of energetic functions and carcinogenesis while highlighting the therapeutic potential of targeting mitochondrial functions., Major Conclusions: Mitochondrial bioenergetics significantly contribute to cancer initiation and survival. As a result, therapies designed to limit oxidative efficiency may reduce tumor burden and enhance the efficacy of currently available antineoplastic agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Mitochondria are essential for survival and as such, impairments in organelle homeostasis significantly accelerate age-related morbidity and mortality. Here, we determined the contribution of bioenergetic efficiency to life span and health span in Drosophila melanogaster utilizing the mitochondrial uncoupler BAM15. Life span was determined in flies fed a normal diet (ND) or high fat diet (HFD) supplemented with vehicle or BAM15. Locomotor function was determined by negative geotaxis assay in middle-aged flies fed vehicle or BAM15 under ND or HFD conditions. Redox capacity (high-resolution respirometry/fluorometry), citrate synthase (enzyme activity), mtDNA content (qPCR), gene expression (qPCR), and protein expression (western blot) were assessed in flight muscle homogenates of middle-aged flies fed vehicle or BAM15 ND. The molar ratio of H 2 O 2 and O 2 (H 2 O 2 :O 2 ) in a defined respiratory state was calculated as a measure of redox balance. BAM15 extended life span by 9% on ND and 25% on HFD and improved locomotor activity by 125% on ND and 53% on HFD. Additionally, BAM15 enhanced oxidative phosphorylation capacity supported by pyruvate + malate, proline, and glycerol 3-phosphate. Concurrently, BAM15 enhanced the mitochondrial H 2 O 2 production rate, reverse electron flow from mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) to Complex I, mGPDH, and Complex I without altering the H 2 O 2 :O 2 ratio. BAM15 upregulated transcriptional signatures associated with mitochondrial function and fitness as well as antioxidant defense. BAM15-mediated restriction of bioenergetic efficiency prolongs life span and health span in Drosophila fed a ND or HFD. Improvements in life span and health span in ND were supported by synergistic enhancement of muscular redox capacity., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Importance: Randomized clinical trials of bariatric surgery have been limited in size, type of surgical procedure, and follow-up duration., Objective: To determine long-term glycemic control and safety of bariatric surgery compared with medical/lifestyle management of type 2 diabetes., Design, Setting, and Participants: ARMMS-T2D (Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes) is a pooled analysis from 4 US single-center randomized trials conducted between May 2007 and August 2013, with observational follow-up through July 2022., Intervention: Participants were originally randomized to undergo either medical/lifestyle management or 1 of the following 3 bariatric surgical procedures: Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding., Main Outcome and Measures: The primary outcome was change in hemoglobin A1c (HbA1c) from baseline to 7 years for all participants. Data are reported for up to 12 years., Results: A total of 262 of 305 eligible participants (86%) enrolled in long-term follow-up for this pooled analysis. The mean (SD) age of participants was 49.9 (8.3) years, mean (SD) body mass index was 36.4 (3.5), 68.3% were women, 31% were Black, and 67.2% were White. During follow-up, 25% of participants randomized to undergo medical/lifestyle management underwent bariatric surgery. The median follow-up was 11 years. At 7 years, HbA1c decreased by 0.2% (95% CI, -0.5% to 0.2%), from a baseline of 8.2%, in the medical/lifestyle group and by 1.6% (95% CI, -1.8% to -1.3%), from a baseline of 8.7%, in the bariatric surgery group. The between-group difference was -1.4% (95% CI, -1.8% to -1.0%; P < .001) at 7 years and -1.1% (95% CI, -1.7% to -0.5%; P = .002) at 12 years. Fewer antidiabetes medications were used in the bariatric surgery group. Diabetes remission was greater after bariatric surgery (6.2% in the medical/lifestyle group vs 18.2% in the bariatric surgery group; P = .02) at 7 years and at 12 years (0.0% in the medical/lifestyle group vs 12.7% in the bariatric surgery group; P < .001). There were 4 deaths (2.2%), 2 in each group, and no differences in major cardiovascular adverse events. Anemia, fractures, and gastrointestinal adverse events were more common after bariatric surgery., Conclusion and Relevance: After 7 to 12 years of follow-up, individuals originally randomized to undergo bariatric surgery compared with medical/lifestyle intervention had superior glycemic control with less diabetes medication use and higher rates of diabetes remission., Trial Registration: ClinicalTrials.gov Identifier: NCT02328599.

Obstructive sleep apnea (OSA) is associated with increased risk for diabetes, and standard treatment with positive airway pressure (PAP) device shows inconsistent effects on glucose metabolism. Metformin is known to treat and prevent diabetes, but its effects on skeletal muscle mitochondrial function are not completely understood. Here, we evaluate the effects of metformin on glucose metabolism and skeletal muscle mitochondrial function in patients with OSA. Sixteen adults with obesity (50.9 ± 6.7 years, BMI: 36.5 ± 2.9 kg/m 2 ) and moderate-to-severe OSA were provided with PAP treatment and randomized to 3 months of placebo (n = 8) or metformin (n = 8) treatment in a double-blind parallel-group design. Whole body glucose metabolism was determined by oral glucose tolerance test. A skeletal muscle biopsy was obtained to evaluate mitochondrial respiratory capacity and expression of proteins related to mitochondrial dynamics and energy metabolism. Whole body insulin-sensitivity (Matsuda index) did not change in metformin or placebo treated groups. However, metformin treatment prevented increases in insulin release relative to placebo during follow-up. Insulin area under the curve (AUC) and insulin to glucose AUC ratio increased in placebo but remained unchanged with metformin. Furthermore, metformin treatment improved skeletal muscle mitochondrial respiratory capacity and dynamics relative to placebo. Metformin treatment prevented the decline in whole body glucose homeostasis and skeletal muscle mitochondrial function in patients with moderate to severe OSA. Patients with OSA may benefit from the addition of metformin to prevent diabetes., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Aim: Determine the ketogenic response (β-hydroxybutyrate, a surrogate of hepatic ketogenesis) to a controlled lipid overload in humans., Methods: In total, nineteen young, healthy adults (age: 28.4 ± 1.7 years; BMI: 22.7 ± 0.3 kg/m 2 ) received either a 12 h overnight lipid infusion or saline in a randomized, crossover design. Plasma ketones and inflammatory markers were quantified by colorimetric and multiplex assays. Hepatic and peripheral insulin sensitivity was assessed by the hyperinsulinemic-euglycemic clamp. Skeletal muscle biopsies were obtained to quantify gene expression related to ketone body metabolism and inflammation., Results: By design, the lipid overload-induced hepatic (50%, p < 0.001) and peripheral insulin resistance (73%, p < 0.01) in healthy adults. Ketones increased with hyperlipidemia and were subsequently reduced with hyperinsulinemia during the clamp procedure (Saline: Basal = 0.22 mM, Insulin = 0.07 mM; Lipid: Basal = 0.78 mM, Insulin = 0.51 mM; 2-way ANOVA: Lipid p < 0.001, Insulin p < 0.001, Interaction p = 0.07). In the saline control condition, ketones did not correlate with hepatic or peripheral insulin sensitivity. Conversely, in the lipid condition, ketones were positively correlated with hepatic insulin sensitivity (r = 0.59, p < 0.01), but inversely related to peripheral insulin sensitivity (r = -0.64, p < 0.01). Hyperlipidemia increased plasma inflammatory markers, but did not impact skeletal muscle inflammatory gene expression. Gene expression related to ketone and fatty acid metabolism in skeletal muscle increased in response to hyperlipidemia., Conclusion: This work provides important insight into the role of ketones in human health and suggests that ketone body metabolism is altered at the onset of lipid-induced insulin resistance., (© 2023 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Objective: Obesity is a driver of non-alcoholic fatty liver disease (NAFLD), and interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR), may serve as effective therapies. This study compared the effects of Roux-en-Y gastric bypass surgery (RYGB) and CR on hepatic function in mice with obesity and NAFLD., Methods: C57BL/6J mice were fed a high-fat diet to promote obesity. At 16 weeks of age, mice were randomized to sham surgery (sham), RYGB, or CR weight matched to RYGB (WM). Body weight/composition, food intake, and energy expenditure (EE) were measured throughout treatment. Liver histopathology was evaluated from H&E-stained sections. Hepatic enzymes and glycogen content were determined by ELISA. Transcriptional signatures were revealed via RNA sequencing., Results: RYGB reduced hepatic lipid content and adiposity while increasing EE and lean body mass relative to WM. Hepatic glycogen and bile acid content were increased after RYGB relative to sham and WM. RYGB activated enterohepatic signaling and genes regulating hepatic lipid homeostasis., Conclusions: RYGB improved whole-body composition and hepatic lipid homeostasis to a greater extent than CR in mice. RYGB was associated with discrete remodeling of the hepatic transcriptome, suggesting that surgery may be mechanistically additive to CR., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Background: The obesity pandemic has worsened global disease burden, including type 2 diabetes, cardiovascular disease, and cancer. Metabolic/bariatric surgery (MBS) is the most effective and durable obesity treatment, but the mechanisms underlying its long-term weight loss efficacy remain unclear. MBS drives substrate oxidation that has been linked to improvements in metabolic function and improved glycemic control that are potentially mediated by mitochondria-a primary site of energy production. As such, augmentation of intestinal mitochondrial function may drive processes underlying the systemic metabolic benefits of MBS. Herein, we applied a highly sensitive technique to evaluate intestinal mitochondrial function ex vivo in a mouse model of MBS., Methods: Mice were randomized to surgery, sham, or non-operative control. A simplified model of MBS, ileal interposition, was performed by interposition of a 2-cm segment of terminal ileum into the proximal bowel 5 mm from the ligament of Treitz. After a four-week recovery period, intestinal mucosa of duodenum, jejunum, ileum, and interposed ileum were assayed for determination of mitochondrial respiratory function. Citrate synthase activity was measured as a marker of mitochondrial content., Results: Ileal interposition was well tolerated and associated with modest body weight loss and transient hypophagia relative to controls. Mitochondrial capacity declined in the native duodenum and jejunum of animals following ileal interposition relative to controls, although respiration remained unchanged in these segments. Similarly, ileal interposition lowered citrate synthase activity in the duodenum and jejunum following relative to controls but ileal function remained constant across all groups., Conclusion: Ileal interposition decreases mitochondrial volume in the proximal intestinal mucosa of mice. This change in concentration with preserved respiration suggests a global mucosal response to segment specific nutrition signals in the distal bowel. Future studies are required to understand the causes underlying these mitochondrial changes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sarcopenic obesity, or the loss of muscle mass and function associated with excess adiposity, is a largely untreatable medical condition associated with diminished quality of life and increased risk of mortality. To date, it remains somewhat paradoxical and mechanistically undefined as to why a subset of adults with obesity develop muscular decline, an anabolic stimulus generally associated with retention of lean mass. Here, we review evidence surrounding the definition, etiology, and treatment of sarcopenic obesity with an emphasis on emerging regulatory nodes with therapeutic potential. We review the available clinical evidence largely focused on diet, lifestyle, and behavioral interventions to improve quality of life in patients with sarcopenic obesity. Based upon available evidence, relieving consequences of energy burden, such as oxidative stress, myosteatosis, and/or mitochondrial dysfunction, is a promising area for therapeutic development in the treatment and management of sarcopenic obesity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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 used electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatment of β-cells with EPS-conditioned medium 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 or 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., Article Highlights: Exercise improves glucose-stimulated insulin secretion through direct interorgan communication. Contracting skeletal muscle releases growth differentiation factor 15 (GDF15), which is required to synergistically enhance glucose-stimulated insulin secretion. GDF15 enhances glucose-stimulated insulin secretion by activating the canonical insulin release pathway. Increased levels of circulating GDF15 after exercise training are related to improvements in β-cell function in patients with type 2 diabetes., (© 2023 by the American Diabetes Association.)

Background: Relative energy deficiency in sport (RED-S) as a consequence of athlete malnutrition remains a prominent issue. However, it remains underrecognized, in part due to the perceived outward health of athletes. The Eat2Win app was designed to combat RED-S and athlete malnutrition by providing education, behavior modification, and direct communication with expert sports dietitians to athletes and sport professionals (professionals who work with athletes, eg, sport coaches and athletic trainers)., Objective: The purpose of this formative research was to gain critical insight on motivators and barriers to optimal nutritional intake from both the athletes' and sport professionals' perspectives. Additionally, since these 2 groups represent the primary end users of an app aimed at improving athlete nutrition and reducing the risk of RED-S, a secondary objective was to gain insight on the preferences and perceptions of app-based educational content and functionality., Methods: An electronic survey was developed by an interdisciplinary team of experts. Survey questions were established based upon prevailing literature, professional dietetic field experience, and app design considerations to obtain respondent knowledge on key sports nutrition topics along with motivations and barriers to meal choices. Additionally, the survey included questions about the development of an integrative, clinician-support app aimed at addressing RED-S. These questions included preferences for educational content, modes of in-app information, and communication delivery for the target population (app end users: athletes and sport professionals). The survey was distributed through Research Electronic Data Capture (REDCap) to athletes and sport professionals using targeted email, social media, and community engagement campaigns. The electronic survey was available from May 4 to August 2, 2022., Results: Survey respondents (n=1352) included athletes and professionals who work with athletes from a variety of settings, like high school, collegiate, professional, and club sports. Respondents reported high interest in 8 core sports nutrition topics. The preferred modes of information and communication delivery were visual formats (eg, videos and infographics) and in-app alerts (eg, direct messaging and meal reminders). Only athlete respondents were asked about motivators and barriers that influence meal choices. "Health" and "sports performance" were the highest scoring motivators, while the highest scoring barriers were "cost of food," "easy access to unhealthy food," and "time to cook or prepare food." Notably, survey respondents provided positive feedback and interest using a novel function of the app: real-time meal feedback through food photography., Conclusions: The Eat2Win app is designed to combat RED-S and athlete malnutrition. Results from this study provide critical information on end-user opinions and preferences and will be used to further develop the Eat2Win app. Future research will aim to determine whether the Eat2Win app can prevent RED-S and the risk of athlete malnutrition to improve both health and performance., (©Jacob T Mey, Christine A Karpinski, Shengping Yang, Joseph D Madere, Tavis Piattoly, Ronnie Harper, John P Kirwan. Originally published in JMIR Formative Research (https://formative.jmir.org), 26.07.2023.)

Objective: To collect qualitative data on approaches that can potentially reduce barriers to, and create strategies for, increasing SARS-CoV-2 testing uptake in underserved Black communities in Louisiana., Methods: A series of eight focus groups, including 41 participants, were conducted in primarily Black communities. The Nominal Group Technique (NGT) was used to determine perceptions of COVID-19 as a disease, access to testing, and barriers limiting testing uptake., Results: Common barriers to SARS-CoV-2 testing were identified as lack of transportation, misinformation/lack of information, lack of time/long wait times, fear of the test being uncomfortable and/or testing positive, the cost of testing, and lack of computer/smartphone/internet. The most impactful approaches identified to increase testing uptake included providing testing within the local communities; testing specifically in heavily traveled areas such as supermarkets, churches, schools, and so forth; providing incentives; engaging local celebrities; and providing information to the community through health fairs, or through churches and schools. The strategies that were deemed to be the easiest to implement revolved around communication about testing, with suggested strategies involving churches, local celebrities or expert leaders, social media, text messages, public service announcements, post cards, or putting up signs in neighborhoods. Providing transportation to testing sites, providing incentives, and bringing the testing to neighborhoods and schools were also identified as easy to implement strategies., Conclusions: Several strategies to increase testing uptake were identified in this population. These strategies need to be tested for effectiveness in real-world settings using experimental and observational study designs., (© 2023 The Authors. American Journal of Human Biology published by Wiley Periodicals LLC.)

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis., Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms., Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options., Registration: NCT05172024., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Helen Chu reported consulting for Merck, GSK, Pfizer, Ellume, Janssen, Vindico CME, and the Bill and Melinda Gates Foundation, and receiving research support from Gates Ventures, Ellume, and Sanofi Pasteur. She also serves as a co-investigator on studies funded by Pfizer, Novavax, and GSK. Maged Costantine reported receiving grant support for work not related to RECOVER work/publications from Baxter International and Siemens Healthcare and personal consulting fees not related to this paper from Progenity, Quidel Ortho, and Siemens Healthcare. Kristine Erlandson reported research funding from Gilead Sciences and consulting payments from Gilead Sciences, Merck, and ViiV Pharmaceuticals, all paid to the University of Colorado. Emily Gallagher reported consulting for Novartis, Flare Therapeutics and Seagen. Edward Gardner reported research support (clinical trials) from Gilead Sciences, ViiV Healthcare, and Cepheid. Jason Goldman reported research support from Gilead, Eli Lilly and Regeneron; grants from Gilead, Merck (BARDA); personal fees for consulting from Gilead, Eli Lilly; and non-financial support from Adaptive Biotechnologies and Labcorp/Monogram Biosciences outside the submitted work. Timothy Heinrich reported grant support from Merck Inc. and consulting fees from Roche. Rachel Hess reported serving as Data Safety Monitoring Board member for Astellas Pharmaceuticals unrelated to the current work. Leora Horwitz reported being a member of the National Academy of Medicine Committee on the Long-Term Health Effects Stemming from COVID-19 and Implications for the Social Security Administration. Priscilla Hsue reported receiving honoraria from Gilead and Merck unrelated to study topic, receiving study drug from Regeneron unrelated to study topic, and receiving a research grant from Novartis. Judith James reported OMRF has licensed her IP to Progentec Biosciences, has received grant support from Progentec Biosciences, and serves on Advisory Committees to Glaxo Smith Klein, Merck and Novartis. Arthur Kim reports providing educational materials to Clinical Care Options and UpToDate and serving on a Data Safety Monitoring board for Kintor Pharmaceuticals, Ltd. Bruce Levy reported serving as a consultant for AstraZeneca, Entrinsic Biosciences, Gossamer Bio and Nocion Therapeutics and receiving research support from Amgen, Genentech, GlaxoSmithKline, Pieris Pharmaceuticals, SRA and Sanofi unrelated to the current work. Vincent Marconi reported receiving grants from NIH during the conduct of the study and grants from NIH, Veteran Affairs, and Centers for Disease Control and Prevention; grants, personal fees, nonfinancial support, and other from Lilly and Gilead; grants and personal fees from ViiV; and nonfinancial support from Bayer outside the submitted work. Grace McComsey reported serving as consultant for Merck, Gilead, ViiV, Janssen and have received research support from Pfizer, Vanda, Genentech, Roche, Redhill and Cognivue. Torri Metz reported being a site PI and a participant in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She also reported being a site PI for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Janet Mullington reported support for investigator-initiated research by "Open Medicine Foundation and the Patient-Led Research Collaborative" Princess Ogbogu reported research support from Astrazeneca, GSK, Blueprint medical; advisory board for Astrazeneca, GSK, Sanofi, Kalvista; and consulting for Astrazeneca, GSK Sairam Parthasarathy reported research funding to Institution from Sergey Brin foundation of COVID and Long-COVID research. Michael Peluso reported consulting fees from Gilead Sciences and AstraZeneca, and service on data safety monitoring board for American Gene Technologies. Sean Quigley reported service on speaker Board for Servier, Alnylam, Agios; service on advisory board for Recordati, Alexion. Franz Rischard reported research support from NIH/NHLBI, United Therapeutics, Acceleron/Merck, Janssen, Insmed, Aerovate, and Bayer; and consulting/advisory compensation from Acceleron and Bayer. Nadine Rouphael reported being a consultant for ICON and EMMES as a safety consultant for clinical trials; service on the advisory boards for Moderna; funds to institution from Sanofi, Lilly, Merck, Quidel and Pfizer. PJ Utz reported stock ownership of Gilead and PI of biomarker studies for Pfizer STOP-PASC paxlovid trial Juan Wisnivesky received receiving consulting honorarium from Sanofi, Banook, Prospero, PPD and Atea and research grants from Sanofi, Regeneron, Axella, and Arnold Consultants., (Copyright: © 2023 Horwitz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals., Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections., Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling., Exposure: SARS-CoV-2 infection., Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds)., Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months., Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Background and Objective: The effect of exercise training on whole-body insulin sensitivity has not been systematically summarized. We aimed to summarize the data from randomized controlled trials evaluating the effect of exercise training on insulin action, in adults., Subjects: MEDLINE, EMBASE, and CENTRAL databases were searched until January 2021. Randomized controlled trials lasting ≥4 weeks, including adults, and evaluating the effect of exercise on insulin-stimulated glucose disposal measured using the hyperinsulinemic euglycemic clamp, were included., Methods: Three reviewers extracted summary data from published trials. The primary outcome was insulin-stimulated glucose disposal. Standardized weighted mean differences (SMD) in glucose disposal between intervention and control were compared. The PEDro scale was used to assess risk of bias., Results: We included 25 trials (36 interventions, N = 851). Exercise increased insulin-stimulated glucose disposal relative to control, SMD = 0.52 (95% confidence interval [CI]: 0.39, 0.65; p < 0.001; I 2  = 47%) without significantly suppressing hepatic glucose production. In trials without isotopic tracers, exercise increased glucose disposal (SMD = 0.63; 95% CI: 0.48, 0.77; p < 0.001, I 2  = 55%). In trials with isotopic tracers, exercise increased glucose disposal only when tracers were added to the exogenous glucose used for clamping (SMD = 0.34; 95% CI: 0.03, 0.66, p = 0.034. I 2  = 0%). In a meta-regression model including aerobic exercise, weight change, and tracer technique, only percent weight change explained between trial heterogeneity (β = 0.069; 95% CI: 0.005, 0.013). The PEDro rating indicated relatively low risk of bias (5.8 ± 0.22)., Conclusions: Exercise training for at least four weeks significantly increases insulin-stimulated glucose disposal. Weight loss maximizes the effect and may be needed to improve hepatic insulin sensitivity. Differences in tracer methodology contribute to divergent outcomes and should be considered when assessing conclusions from research examining the effect of exercise on insulin action., Registration: PROSPERO (CRD42019124381)., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

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 <30 g/day may be prudent for overall health and to prevent the exclusion of other food groups and nutrients in older adults with obesity.

Bariatric surgery improves glucose homeostasis and glycemic control in patients with type 2 diabetes. Over the past 20 years, a breadth of studies has been conducted in humans and rodents aimed to identify the regulatory nodes responsible for surgical remission of type 2 diabetes. The review herein discusses central mechanisms of type 2 diabetes remission associated with weight loss and surgical modification of the gastrointestinal tract., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Type 2 diabetes is a systemic, multifactorial disease that is a leading cause of morbidity and mortality globally. Despite a rise in the number of available medications and treatments available for management, exercise remains a first-line prevention and intervention strategy due to established safety, efficacy, and tolerability in the general population. Herein we review the predisposing risk factors for, prevention, pathophysiology, and treatment of type 2 diabetes. We emphasize key cellular and molecular adaptive processes that provide insight into our evolving understanding of how, when, and what types of exercise may improve glycemic control. © 2023 American Physiological Society. Compr Physiol 13:1-27, 2023., (Copyright © 2023 American Physiological Society. All rights reserved.)

The expansive and rapid spread of the SARS-CoV-2 virus has resulted in a global pandemic of COVID-19 infection and disease. Though initially perceived to be acute in nature, many patients report persistent and recurrent symptoms beyond the infectious period. Emerging as a new epidemic, "long-COVID", or post-acute sequelae of coronavirus disease (PASC), has substantially altered the lives of millions of people globally. Symptoms of both COVID-19 and PASC are individual, but share commonality to established respiratory viruses, which include but are not limited to chest pain, shortness of breath, fatigue, along with adverse metabolic and pulmonary health effects. Nutrition plays a critical role in immune function and metabolic health and thus is implicated in reducing risk or severity of symptoms for both COVID-19 and PASC. However, despite the impact of nutrition on these key physiological functions related to COVID-19 and PASC, the precise role of nutrition in COVID-19 infection and PASC onset or severity remains to be elucidated. This narrative review will discuss established and emerging nutrition approaches that may play a role in COVID-19 and PASC, with references to the established nutrition and clinical practice guidelines that should remain the primary resources for patients and practitioners.

Innovation in pharmaceutical therapeutics is critical for the treatment of serious diseases with unmet medical need. To accelerate the approval of these innovative treatments, regulatory agencies throughout the world are increasingly adopting the use of expedited pathways and collaborative regulatory reviews. These pathways are primarily driven by promising clinical results but become challenging for Chemistry, Manufacturing, and Controls (CMC) information in regulatory submissions. Condensed and shifting timelines present constraints that require new approaches to the management of regulatory filings. This article emphasizes technological advances that have the potential to tackle the underlying inefficiencies in the regulatory filing eco-system. Structured content and data management (SCDM) is highlighted as a foundation for technologies that can ease the burden on both sponsors and regulators by streamlining data usage in regulatory submissions. Re-mapping of information technology infrastructure will improve the usability of data by moving away from document-based filings towards electronic data libraries. Although the inefficiencies of the current regulatory filing eco-system are more evident for products that are filed using expedited pathways, it is envisioned that the more widespread adoption of SCDM, across standard filing and review processes, will improve overall efficiency and speed in the compilation and review of regulatory submissions., Competing Interests: Competing interestsJill Beierle, Marquerita Algorri, Marisol Cortés, Nina S. Cauchon, Andrew Lennard, J. Paul Kirwan, Shirley Oghamian, and Michael J. Abernathy reports financial support which was provided by Amgen Inc., (© The Author(s) 2023.)

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 2 ) with insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] >2) were enrolled. Body weight was measured, and subjects underwent a mixed meal tolerance test at baseline and after 8 weeks. Intent-to-treat (ITT) and completer analyses were conducted. Equivalence between the two diets in the area under the curve for serum glucose was attained within ±10%, but the reduction from baseline was not statistically significant. For the Bean diet, insulin (area under the response curve: -2136.3 ± 955.5 mg/[dL∙min], P  = .03) and HOMA-IR (-1.4 ± 0.6, P  = .02) were lower compared with baseline. ITT and completer analyses were similar, except that HOMA-IR was also reduced by the Potato diet (-1.3 ± 0.6, P  < .05). Compliance with the diets was 87-88%, and body weight was reduced in both diets (Potato: -5.6% ± 0.6%; Bean: -4.1% ± 0.6%, P  < .001) with no significant difference between the two diets. Potato and Bean diets low in energy density were equally effective in reducing insulin resistance and promoting weight loss in individuals with impaired blood glucose control. Clinical Trial: The trial was registered with ClinicalTrials.gov Identifier: NCT04203238.

Breast cancer is a common and deadly disease that causes tremendous physical, emotional, and financial burden on patients and society. Early-stage breast cancer and less aggressive subtypes have promising prognosis for patients, but in aggressive subtypes, and as cancers progress, treatment options and responses diminish, dramatically decreasing survival. Plants are nutritionally rich and biologically diverse organisms containing thousands of metabolites, some of which have chemopreventive, therapeutic, and sensitizing properties, providing a rich source for drug discovery. In this study we review the current landscape of breast cancer with a central focus on the potential role of phytochemicals for treatment, management, and disease prevention. We discuss the relevance of phytochemical targeting of mitochondria for improved anti-breast cancer efficacy. We highlight current applications of phytochemicals and derivative structures that display anti-cancer properties and modulate cancer mitochondria, while describing future applicability and identifying areas of promise.

Hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and a leading cause of cancer-related death globally. HCC is associated with an indolent clinical presentation, resulting in frequent advanced stage diagnoses where surgical resection or transplant therapies are not an option and medical therapies are largely ineffective at improving survival. As such, there is a critical need to identify and enhance primary prevention strategies to mitigate HCC-related morbidity and mortality. Obesity is an independent risk factor for the onset and progression of HCC. Furthermore, obesity is a leading cause of nonalcoholic steatohepatitis (NASH), the fasting growing etiological factor of HCC. Herein, we review evolving clinical and mechanistic associations between obesity and hepatocarcinogenesis with an emphasis on the therapeutic efficacy of prevailing lifestyle/behavioral, medical, and surgical treatment strategies for weight reduction and NASH reversal.

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., (© 2022. The Author(s).)

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., (© 2022 by the American Diabetes Association.)

Aims: Long-term data from randomized clinical trials comparing metabolic (bariatric) surgery versus 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 versus medical/lifestyle therapy on diabetes control and clinical outcomes., Materials and Methods: Patients with T2D and body mass index (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) versus 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 glycated haemoglobin 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: In total, 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% white, 27% African-American and 68% female. At baseline: age, 50 ± 8 years; BMI, 36.5 ± 3.5 kg/m 2 ; duration of diabetes, 8.8 ± 5.6 years; glycated haemoglobin, 8.6% ± 1.6%; and fasting glucose, 168 ± 64 mg/dl. More than 35% of patients had a BMI <35 kg/m 2 ., Conclusions: ARMMS-T2D will provide the largest body of long-term, level 1 evidence to inform clinical decision-making regarding the comparative durability, efficacy and safety of metabolic surgery relative to a medical/lifestyle intervention among patients with T2D, including those with milder class I obesity or mere overweight., (© 2022 John Wiley & Sons Ltd.)

Background: 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., Methods: 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., Results: 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)., Conclusions: 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., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

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., (Copyright © 2022 by the American College of Sports Medicine.)

The SARS-CoV-2 pandemic continues to rage around the world. At the same time, despite strong public health measures and high vaccination rates in some countries, a post-COVID-19 syndrome has emerged which lacks a clear definition, prevalence, or etiology. However, fatigue, dyspnea, brain fog, and lack of smell and/or taste are often characteristic of patients with this syndrome. These are evident more than a month after infection, and are labeled as Post-Acute Sequelae of CoV-2 (PASC) or commonly referred to as long-COVID. Metabolic dysfunction (i.e., obesity, insulin resistance, and diabetes mellitus) is a predisposing risk factor for severe acute COVID-19, and there is emerging evidence that this factor plus a chronic inflammatory state may predispose to PASC. In this article, we explore the potential pathogenic metabolic mechanisms that could underly both severe acute COVID-19 and PASC, and then consider how these might be targeted for future therapeutic approaches., Competing Interests: PS, JK, CR No competing interests declared, (© 2022, Scherer et al.)