Plasma glucose and HbA1c concentrations below the diagnostic threshold for diabetes have been achieved in people with type 2 diabetes (T2DM) in three clinical settings: with intensive weight-management programs that induce > 10-15 kg bodyweight loss, following bariatric surgery, and during treatment with highly effective glucose- and weight-lowering medications. The current consensus definition of T2DM remission excludes a status of absence of diabetes achieved with concomitant use of glucose- and weight-lowering medications. However, since these treatments can safely achieve HbA1c and plasma glucose concentrations lower than the ones currently used to define remission, we propose to consider a separate category of diabetes remission mainly achieved and maintained with pharmacological treatment. Our arguments are based on: (1) the similar endocrine mechanisms associated with bariatric surgery and use of GLP-1 receptor agonists or GIP/GLP-1 dual receptor agonists, (2) the lack of evidence that the effects of near-normoglycemic states achieved with lifestyle, surgery or glucose- and weight-lowering medications on long-term complications differ and (3) the frequent use of these medications in conjunction with both lifestyle interventions and following bariatric surgery. With this proposal, we aim to invite further discussion towards expanding the current narrow definition of T2D remission to include remission during treatment with newer highly effective glucose- and weight-lowering medications.

The Lancet Diabetes & Endocrinology Commission undertook the complex task of addressing limitations in existing definitions and classification of obesity. Its consensus framework moves beyond body mass index (BMI) toward direct or surrogate measures of excess adiposity and distinguishes "clinical obesity" (excess adiposity plus objective organ/system dysfunction or functional limitation attributable to adiposity) from "preclinical obesity" (excess adiposity without such evidence). The Endocrine Society (ES) recognizes the substantial effort and expertise underlying this work and its intent to improve diagnostic precision and therefore provides an independent appraisal of the framework's conceptual coherence, empirical support, operational feasibility, and implications for coverage, equity, and clinical implementation. The shift away from BMI-only screening is supported by evidence that central adiposity and fat distribution better predict cardiometabolic risk than BMI alone. Validation studies (All of Us; UK Biobank) demonstrate elevated risk among individuals classified with "preclinical" obesity and even higher risk among those with "clinical" obesity, underscoring the importance of safeguards against undertreatment in the preclinical state. At the same time, lack of standardized anthropometric measurement protocols, increased resource utilization, limited distinction between subcutaneous and visceral fat depots, and insufficient data regarding the long-term implications of obesity-related disease absence prompted the ES to pause before fully endorsing the Commission's consensus. Accordingly, we outline an evaluation framework addressing available evidence, feasibility, coverage and equity considerations, and clinical impact. We advocate harmonization with established staging systems (EOSS, EASO), explicit measurement protocols, age-, sex-, and ancestry-specific thresholds, integration of mental health and patient-reported outcomes, and policies that prevent unintended care restrictions. The Commission's reframing represents a meaningful conceptual advance; broader adoption will require practical and equitable implementation.

OBJECTIVE:To describe the impact of nutrient-stimulated hormone (NuSH) therapies on weight loss by bariatric surgery type, diabetes status, and timing of initial NuSH prescription. METHODS:Retrospective study of 1638 adults who underwent bariatric surgery at a single academic medical center between 2015 and 2022. Baseline demographics, NuSH therapy prescriptions, and follow-up weights were obtained from electronic health records. We calculated percent total weight loss (%TWL) over time using linear mixed models. RESULTS:Patients who underwent Roux-en-Y gastric bypass (RYGB) had greater %TWL compared to those who underwent sleeve gastrectomy (SG). Those without diabetes had greater %TWL compared to those with diabetes. At 72 months, adjusted average %TWL was highest in patients who received NuSH prescriptions both before and after surgery (22.7%, 95% CI: 17.9-27.5), followed by those with prescriptions only after surgery (19.9%, 95% CI: 18.3-21.4) and those without prescriptions (19.6%, 95% CI: 18.1-21.2). The greatest %TWL was seen in patients who had prescriptions within 6 months after surgery. CONCLUSION:Individuals who underwent RYGB and who did not have diabetes had the highest %TWL. Receiving a NuSH prescription both before and after surgery and early NuSH initiation were associated with the greatest %TWL.

Importance:Despite the current enthusiasm for anti-obesity medications, there is a critical need for effective lifestyle interventions that can be broadly implemented. Objective:To assess the effectiveness of REWIND, an obesity and diabetes treatment program. Design:Prospective cohort study. Setting:Virtual, community-based weight management program. Participants:Two-hundred and nineteen participants, BMI ≥ 30 kg/m2, with and without type 2 diabetes (T2D). Intervention:Three phases: "induction" with meal replacement diet to promote ≥ 15% weight loss; "transition" to everyday foods; and "maintenance" to prevent weight regain. REWIND leveraged teams including community leaders, media personalities, nationally recognized athletes and participants, to disseminate information, and foster belonging, commitment, and resilience. Main Outcomes:The co-primary outcomes were the change in weight at 6-, 12-, and 18 months. Secondary outcomes were the proportion of patients achieving ≥ 5%, 10%, 15%, and 20% weight loss at 6, 12, and 18 months, and remission rates in T2D at 6-, 12-, and 18-month, respectively. Results:Two hundred and nineteen participants (mean age 49.1 [SD 10.5] years), 37% men, 12% Black, 26% with T2D. Weight decreased from: 114.4 (20.8) kg to 96.1 (18.4) kg at 6 months, to 98.5 (18.1) kg at 12 months, and to 101.1 (20.5) kg at 18 months. Weight loss percentages at 6, 12, and 18 months were ≥ 5%: 95%, 91%, 84%; ≥ 10%: 79%, 72%, 67%; ≥ 15%: 58%, 46%, 47%; and ≥ 20%: 24%, 25%, 22%. Diabetes remission was achieved by 52% and 43% of participants with T2D at 12- and 18-month, respectively. Limitations:Single geographic region. Weight was self-reported. Conclusion:A virtual community-based program for individuals with obesity and T2D facilitated substantial weight loss and T2D remission. This model has the potential for wide-scale implementation in diverse settings.

Obesity is a chronic, relapsing condition with severe health risks and a huge economic burden. Effective interventions for severe obesity include bariatric or metabolic surgery and high-intensity medical management involving lifestyle changes and pharmacotherapy. This article summarizes the debate between Drs. Schauer and Rothberg at the June 2024 Endocrine Society meeting regarding the optimal approach to managing obesity, exploring mechanisms, outcomes, safety, quality-of-life, and cost-effectiveness. Metabolic surgery results in substantial and sustained weight loss, improvements in comorbidities such as type 2 diabetes, and reduced mortality, and it is cost-effective. However, it carries risks associated with surgery and long-term complications, and its high upfront costs limit its scalability. Conversely, high-intensity medical management, which includes comprehensive lifestyle interventions and pharmacotherapy, leads to meaningful, though sometimes less substantial, weight loss and health improvements. The latter approach prioritizes behavioral changes and is cost-effective but requires patient adherence and faces challenges with medication side effects and costs. Both interventions offer substantial health benefits; the choice between them should consider individual patient needs, health status, target weight loss, and personal preferences. Metabolic surgery may be more suitable for individuals with severe obesity or when comorbidities are inadequately controlled, whereas medical management may be more suited to patients with less severe obesity and those preferring nonsurgical options. Future research should investigate the combined effects of surgery and medical management and enhance access to and affordability of these treatments. A multidisciplinary, personalized approach will likely yield the best outcomes in managing this complex health issue.

While dual-energy X-ray absorptiometry (DEXA) is the gold standard for measuring lean body weight (LBW), computed tomography (CT) provides muscle composition and distribution metrics that can refine LBW for better weight-based dosing. We explored how existing computed tomography (CT) images could be utilized to better estimate LBW. Sixty-three adult patients (71.4

Obesity significantly influences drug pharmacokinetics (PK), which challenges optimal dosing. This study examines the effects of diet-and-exercise-induced weight loss on key drug-metabolizing enzymes and gastric emptying in patients with obesity, who frequently require medications for comorbidities. Participants followed a structured weight management program promoting weight loss over 3-6 months and were not concomitantly on potential CYP inducers or inhibitors. Using a drug cocktail of acetaminophen, caffeine, omeprazole, and midazolam, we assessed UGT1A1, CYP1A2, CYP2C19, and CYP3A4 enzyme activities before and after weight loss, respectively, by measuring parent and metabolite concentrations. The time to maximum acetaminophen plasma concentrations reflected the gastric emptying time. PK profiles were compared across two phases: baseline (Phase 1) and post-weight loss (Phase 2). Twenty-four participants enrolled, 21 completed Phase 1 and 12 completed both phases. Statistically significant (N = 12, P < .05) gains in CYP2C19 and CYP3A4 activity were observed after weight loss of 7.6% to 26.2%, with a median [25th, 75th percentile] increase in activity of 90.5 [15.0, 194.3] % and 43.0 [7.5, 68.0] %, respectively. A 2- or 3-h single plasma sample-based ratio of the metabolite to parent concentration strongly correlated with the respective AUC ratio for the drug metabolism phenotype (N = 21). Our findings provide provisional data for evaluation of the effects of non-pharmacologically and non-surgically induced weight loss on gastric emptying and drug metabolism for future physiologically based PK models. Development of mechanistic models to optimize drug dosing in obesity are necessary since weight and body composition shifts are expected with emerging new treatments.

BACKGROUND:Little is known about motivation for weight loss and barriers to weight loss among patients with idiopathic intracranial hypertension (IIH). Such information is crucial for developing tailored weight management recommendations and novel interventions. METHODS:We administered a survey to patients with IIH presenting to neuro-ophthalmology clinics at The University of Michigan Kellogg Eye Center (Michigan, USA) and St. Thomas' Hospital (London, England). Participants rated importance and motivation to lose weight (1-10 scale; 10 = extremely important/motivated). Facilitators and barriers to weight loss were assessed using open-ended survey questions informed by motivational interviewing methodology. Open-ended responses were coded by 2 team members independently using a modified grounded theory approach. Demographic data were extracted from medical records. Descriptive statistics were used to analyze quantitative responses. RESULTS:Of the 221 (43 Michigan and 178 London) patients with IIH ( Table 1 ), most were female (n = 40 [93.0%] Michigan and n = 167 [94.9%] London). The majority of patients in the United States were White (n = 35 [81.4%] Michigan), and the plurality were Black in the United Kingdom (n = 67 [37.6%] London]) with a mean (SD) BMI of 38.9 kg/m 2 (10.6 kg/m 2 ) Michigan and 37.5 kg/m 2 (7.7 kg/m 2 ) London. Participants' mean (SD) level of importance to lose weight was 8.5 (2.2) (8.1 [2.3] Michigan and 8.8 [2.1] London), but their mean (SD) level of motivation to lose weight was 7.2 (2.2) (6.8 [2.4] Michigan and 7.4 [2.1] London). Nine themes emerged from the 992 open-ended coded survey responses grouped into 3 actionable categories: self-efficacy, professional resources (weight loss tools, diet, physical activity level, mental health, and physical health), and external factors (physical/environmental conditions, social influences, and time constraints). Most responses (55.6%; n = 551) were about barriers to weight loss. Lack of self-efficacy was the most discussed single barrier (N = 126; 22.9% total, 28.9% Michigan, and 20.4% London) and facilitator (N = 77; 17.5% total, 15.9% Michigan, and 18.7% London) to weight loss. Other common barriers were related to physical activity level (N = 79; 14.3% total, 13.2% Michigan, and 14.8% London) and diet (N = 79; 14.3% total, 9.4% Michigan, and 16.3% London). Commonly reported facilitators included improvements in physical activity level (N = 73; 16.6% total, 18.5% Michigan, and 15.1% London) and dietary changes (N = 76; 17.2% total, 16.4% Michigan, and 17.9% London). CONCLUSIONS:Patients with IIH believe weight loss is important. Self-efficacy was the single most mentioned important patient-identified barrier or facilitator of weight loss, but professional resource needs and external factors vary widely at the individual level. These factors should be assessed to guide selection of weight loss interventions that are tailored to individual patients with IIH.

OBJECTIVE:Optimal weight loss involves decreasing adipose tissue while preserving lean muscle mass. Identifying molecular mediators that preserve lean muscle mass is therefore a clinically important goal. We have shown that circulating, postprandial FGF19 levels are lower in patients with obesity and decrease further with comorbidities such as type 2 diabetes and MASLD. Preclinical studies have shown that FGF15 (mouse ortholog of human FGF19) is necessary to protect against lean muscle mass loss following metabolic surgery-induced weight loss in a mouse model of diet-induced obesity. We evaluated if non-surgical weight loss interventions also lead to increased systemic levels of FGF19 and whether FGF19 levels are predictive of lean muscle mass following rapid weight loss in human subjects with obesity. RESEARCH DESIGN AND METHODS:Weight loss was induced in 176 subjects with obesity via a very low-energy diet, VLED (800 kcal/d) in the form of total liquid meal replacement for 3-4 months. We measured plasma FGF19 levels at baseline and following VLED-induced weight loss. Multiple linear regression was performed to assess if FGF19 levels were predictive of lean mass at baseline (obesity) and following VLED. RESULTS:Postprandial levels of FGF19 increased significantly following VLED-weight loss. Multiple linear regression analysis showed that baseline (obesity) FGF19 levels, but not post VLED FGF19 levels, significantly predicted the percent of lean muscle mass after VLED-induced weight loss, while controlling for age, sex, and the baseline percent lean mass. CONCLUSION:These data identify gut-muscle communication and FGF19 as a potentially important mediator of the preservation of lean muscle mass during rapid weight loss.

The concept of type 2 diabetes remission is evolving rapidly, and gaining wide public and professional interest, following demonstration that with substantial intentional weight loss almost nine in ten people with type 2 diabetes can reduce their HbA 1c level below the diagnostic criterion (48 mmol/mol [6.5%]) without glucose-lowering medications, and improve all features of the metabolic syndrome. Pursuing nomoglycaemia with older drugs was dangerous because of the risk of side effects and hypoglycaemia, so the conventional treatment target was an HbA 1c concentration of 53 mmol/mol (7%), meaning that diabetes was still present and allowing disease progression. Newer agents may achieve a normal HbA 1c safely and, by analogy with treatments that send cancers or inflammatory diseases into remission, this might also be considered remission. However, although modern glucagon-like peptide-1 receptor agonists and related medications are highly effective for weight loss and glycaemic improvement, and generally safe, many people do not want to take drugs indefinitely, and their cost means that they are not available across much of the world. Therefore, there are strong reasons to explore and research dietary approaches for the treatment of type 2 diabetes. All interventions that achieve sustained weight loss of >10–15 kg improve HbA 1c , potentially resulting in remission if sufficient beta cell capacity can be preserved or restored, which occurs with loss of the ectopic fat in liver and pancreas that is found with type 2 diabetes. Remission is most likely with type 2 diabetes of short duration, lower HbA 1c and a low requirement for glucose-lowering medications. Relapse is likely with weight regain and among those with a poor beta cell reserve. On current evidence, effective weight management should be provided to all people with type 2 diabetes as soon as possible after diagnosis (or even earlier, at the stage of prediabetes, defined in Europe, Australasia, Canada [and most of the world] as ≥42 and <48 mmol/mol [≥6.0 and <6.5%], and in the USA as HbA1c ≥39 and <48 mmol/mol [≥5.7 and <6.5%]). Raising awareness among people with type 2 diabetes and their healthcare providers that remission is possible will enable earlier intervention. Weight loss of >10 kg and remission lasting 1–2 years may also delay vascular complications, although more evidence is needed. The greatest challenge for research is to improve long-term weight loss maintenance, defining cost-effective approaches tailored to the preferences and needs of people living with type 2 diabetes. Graphical Abstract

Fibroblast growth factor 15/19 (FGF15/19, mouse/human ortholog) is expressed in the ileal enterocytes of the small intestine and released postprandially in response to bile acid absorption. Previous reports of FGF15-/- mice have limited our understanding of gut-specific FGF15's role in metabolism. Therefore, we studied the role of endogenous gut-derived FGF15 in bile acid, cholesterol, glucose, and energy balance. We found that circulating levels of FGF19 were reduced in individuals with obesity and comorbidities, such as type 2 diabetes and metabolic dysfunction-associated fatty liver disease. Gene expression analysis of ileal FGF15-positive cells revealed differential expression during the obesogenic state. We fed standard chow or a high-fat metabolic dysfunction-associated steatohepatitis-inducing diet to control and intestine-derived FGF15-knockout (FGF15INT-KO) mice. Control and FGF15INT-KO mice gained similar body weight and adiposity and did not show genotype-specific differences in glucose, mixed meal, pyruvate, and glycerol tolerance. FGF15INT-KO mice had increased systemic bile acid levels but decreased cholesterol levels, pointing to a primary role for gut-derived FGF15 in regulating bile acid and cholesterol metabolism when exposed to obesogenic diet. These studies show that intestinal FGF15 plays a specific role in bile acid and cholesterol metabolism regulation but is not essential for energy and glucose balance.

AbstractChronological age has been the standard for quantifying the aging process. While it is simple to quantify it cannot fully discern the biological variability of aging between individuals. The growing body of interest in this variability of human aging has led to the introduction of new biomarkers to operationalize biological age. The inclusion of body composition may provide additional value to biological aging as a prediction and estimation factor of individual health outcomes. Diagnostic images based on radiomic techniques such as Computed Tomography contain an untapped wealth of patient‐specific data that remain inaccessible to healthcare providers. These images are beneficial for collecting information from body composition that adds precision and granularity when compared to traditional measures. This information can subsequently be aggregated to construct models for changes in the human body associated with aging. In addition, aging leads to a natural decline in the best parameter of drug dosing in older adults, glomerular filtration rate. Since the conventional models of kidney function are correlated with age and body composition, the radiomic biomarkers representing age‐related changes in body composition may also serve as potential new imaging biomarkers of kidney function for personalized dosing. Our review introduces potential radiomic biomarkers as measures of body composition change targeting the aging processes. As a functional example, we have hypothesized an age‐related model of radiomics as a covariate of kidney function to improve personalized dosing. Future research focusing on evaluating this hypothesis in human subject studies is acknowledged.

Abstract Disclosure: J.M. Eichstaedt: None. R. Sochocki: None. D. Khatib: None. N. Miller: None. V.A. Diwadkar: None. P. Burghardt: None. A.E. Rothberg: None. J.A. Stanley: None. Poor weight loss maintenance (WLM) following dietary intervention has been associated with poor top-down inhibitory control. The neurobiological mechanisms are not fully understood; it is not clear if changes to inhibitory control are specific to the presence of appetitive food cues. The dorsal anterior cingulate cortex (dACC) is central to inhibitory control and can be conceptualized selectively withholding ‘prepotent’ motor responses. This is driven by highly integrated glutamatergic and GABAergic neurotransmission. Temporal changes in glutamate, reflecting shifts in glutamate neurotransmission, can be detected under distinct processes or task conditions using [1]H fMRS. We investigated differences in dACC glutamate under task conditions with or without inhibitory motor control, utilizing neutral Squares and Food/Non-food stimuli, and their association with weight loss. Data were acquired from 13 individuals with obesity following dietary intervention resulting in 10% weight loss (5F; mean age: 50.1±5.2yrs). A visually-guided motor tapping task was used requiring participants to respond to stimuli under two modes, “Non-Selective” (motor responses to 100% of trials) and “Selective” (withholding responses on 20% of trials - involving both motor control and inhibition), and under two stimuli types (Squares and appetitive Food/Non-Food cues). Glutamate modulation changes (relative to the total signal) were assessed across stimuli type (independent of task mode) using repeated measures generalizing estimating equations (GEE) approach (SAS GENMOD). The correlation between glutamate during the Selective mode with food/non-food stimuli and percentage of weight lost during the dietary intervention was also assessed. The stimuli model term was not significant (χ2=3.50, p=0.174), but post hoc analysis indicated significantly increased glutamate during the Squares (z=-1.99, p=0.046), but not the Food/Non-food (z=-1.39, p=0.163) relative to baseline. A trending correlation between decreasing dACC glutamate modulation (Selective mode, Food/Non-Food) and decreasing percentage of weight lost during the intervention was observed (R2=0.274, F(1,11)=4.15, p=0.07). This suggests that the presence of appetitive food cues leads to a non-significant change in the dACC glutamate modulation independent of inhibitory or motor alone responses. The potential correlation between dACC glutamate modulation and weight loss provides preliminary support that appetitive food cues influence inhibitory control and the extent of the influences may be related to one’s ability to maintain weight loss. These results could provide greater understanding of the neurobiological mechanisms underlying top-down inhibitory processes influenced by affect and difficulties with weight loss and maintenance, potentially fueling better treatment for successful long-term WLM in obesity. Presentation: 6/1/2024

Poor top-down inhibitory control and its association to weight loss maintenance is poorly understood. The dorsal anterior cingulate cortex (dACC) is central to inhibitory control that is driven by the interplay of glutamatergic/GABAergic neurotransmission. 1H fMRS can assess changes in glutamate driven by task condition, illuminating neurobiological mechanisms. Here, we present preliminary evidence of dACC glutamate modulation being impacted by emotionally valanced food cues during inhibitory control and its association with weight loss ability in individuals with obesity.

Abstract Background Virtual care offers many potential advantages over traditional in‐person care for people with chronic diseases including obesity. Before the COVID‐19 pandemic, virtual care was not broadly implemented because of regulatory, legal, and reimbursement barriers. Objective To evaluate the impact of the transition from an entirely in‐person format to a virtual format during the COVID‐19 pandemic on retention and weight reduction in a 2‐year, structured, intensive behavioral weight management program for people with moderate to severe obesity. Methods Retrospective cohort study of 1313 program participants stratified according to the phase of the program during which the transition to virtual visits occurred. Results Age, sex, and baseline weight were independent predictors of program retention. Transition to virtual visits was associated with greater 2‐year program retention. Retention but not mode of program delivery was associated with reduction in weight at 2‐year. Conclusions Transition from in‐person to virtual program delivery improved retention and by doing so, indirectly improved weight loss at 2 years. Telemedicine has the potential to overcome many of the limitations associated with traditional in‐person weight loss interventions. Clinical Trial Registration This research was reviewed and approved by the University of Michigan Institutional Review Board and registered on ClinicalTrials.gov (NCT02043457). All participants provided written informed consent.