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Amanda Sheehan,1 Mary Elizabeth Patti1,2 1Research Division, Joslin Diabetes Center, Boston, MA, USA; 2Harvard Medical School, Boston, MA, USACorrespondence: Mary Elizabeth PattiResearch Division, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USATel +1 617-309-1966Fax +1 617-309-2593Email Mary.elizabeth.patti@joslin.harvard.eduContext: Post-bariatric hypoglycemia (PBH) is an increasingly encountered complication of upper gastrointestinal surgery; the prevalence of this condition is anticipated to rise given yearly increases in bariatric surgical procedures. While PBH is incompletely understood, there is a growing body of research describing the associated factors, mechanisms, and treatment approaches for this condition.Evidence Acquisition: Data are integrated and summarized from studies of individuals affected by PBH and hypoglycemia following upper gastrointestinal surgery obtained from PubMed searches (1990– 2020).Evidence Synthesis: Information addressing etiology, incidence/prevalence, clinical characteristics, assessment, and treatment were reviewed and synthesized for the practicing physician. Literature reports were supplemented by clinical experience as indicated, when published data were not available.Conclusion: PBH can be life-altering and severe for a subset of individuals. Given the chronic nature of this condition, and sequelae of both acute and recurrent episodes, increasing provider awareness of both the condition and associated risk factors is critical for assessment, prompt diagnosis, treatment, and preoperative identification of individuals at risk.Keywords: hypoglycemia, post-bariatric hypoglycemia, upper gastrointestinal surgery, bariatric surgery

Background Addiction treatment and harm reduction services reduce risks of death and re-infection among patients with injection drug use-associated infective endocarditis (IDU-IE), but these are not offered at many hospitals. Among hospitalized patients with IDU-IE at the two tertiary-care hospitals in the Canadian Maritimes, we aimed to identify (1) the availability of opioid agonist treatment (OAT) and sterile drug injecting equipment, and (2) indicators of potential unmet addiction care needs. Methods Retrospective review of IDU-IE hospitalizations at Queen Elizabeth II Health Sciences Centre (Halifax, Nova Scotia) and the Saint John Regional Hospital (Saint John, New Brunswick), October 2015 -March 2017. In Halifax, there are no addiction medicine providers on staff; in Saint John, infectious diseases physicians also practice addiction medicine. Inclusion criteria were: (1) probable or definite IE as defined by the modified Duke criteria; and (2) injection drug use within the prior 3 months. Results We identified 38 hospitalizations (21 in Halifax and 17 in Saint John), for 30 unique patients. Among patients with IDU-IE and untreated opioid use disorder, OAT was offered to 36% (5/14) of patients in Halifax and 100% (6/6) of patients in Saint John. Once it was offered, most patients at both sites initiated OAT and planned to continue it after discharge. In Halifax, no patients were offered sterile injecting equipment, and during five hospitalizations staff confiscated patients’ own equipment. In Saint John, four patients were offered (and one was provided) injecting equipment in hospital, and during two hospitalizations staff confiscated patients’ own equipment. Concerns regarding undertreated pain or opioid withdrawal were documented during 66% (25/38) of hospitalizations, and in-hospital illicit or non-medical drug use during 32% (12/38). Two patients at each site (11%; 4/38) had self-directed discharges against medical advice. Conclusions Patients with IDU-IE in the Canadian Maritimes have unequal access to evidence-based addiction care depending on where they are hospitalized, which differs from the community-based standard of care. Indicators of potential unmet addiction care needs in hospital were common.

High-density oligonucleotide arrays were used to compare gene expression of rat hearts from control, untreated diabetic, and diabetic groups treated with islet cell transplantation (ICT), protein kinase C (PKC)beta inhibitor ruboxistaurin, or ACE inhibitor captopril. Among the 376 genes that were differentially expressed between untreated diabetic and control hearts included key metabolic enzymes that account for the decreased glucose and increased free fatty acid utilization in the diabetic heart. ICT or insulin replacements reversed these gene changes with normalization of hyperglycemia, dyslipidemia, and cardiac PKC activation in diabetic rats. Surprisingly, both ruboxistaurin and ACE inhibitors improved the metabolic gene profile (confirmed by real-time RT-PCR and protein analysis) and ameliorated PKC activity in diabetic hearts without altering circulating metabolites. Functional assessments using Langendorff preparations and (13)C nuclear magnetic resonance spectroscopy showed a 36% decrease in glucose utilization and an impairment in diastolic function in diabetic rat hearts, which were normalized by all three treatments. In cardiomyocytes, PKC inhibition attenuated fatty acid-induced increases in the metabolic genes PDK4 and UCP3 and also prevented fatty acid-mediated inhibition of basal and insulin-stimulated glucose oxidation. Thus, PKCbeta or ACE inhibitors may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium. [ABSTRACT FROM AUTHOR]

Background: Obesity and hypercholesterolemia have been associated with better responses to ICIs in NSCLC, while type 2 diabetes (T2D) has been associated with a worse response. However, the association between glucose levels and outcomes remains unknown. This study investigated the impact of mean baseline glucose levels, T2D, dyslipidemia, and obesity on overall survival (OS) in NSCLC patients undergoing ICI therapy., Methods: A multicenter retrospective cohort study was conducted using data from three medical centers, with locally advanced or metastatic NSCLC patients receiving ICI, regardless of treatment line or concurrent therapy. Random venous glucose levels within 4 weeks prior to ICI initiation, BMI, history of dyslipidemia, and T2D, along with OS, were assessed. Patients with BMI < 18.5 were excluded., Results: Among 438 patients, those with the highest quartile of baseline glucose levels had significantly shorter OS compared to those in the lowest quartile (HR, 1.53; 95 % CI, 1.08 - 2.15; p-value = 0.016). This association remind consistent after adjusting for steroid use, diabetes, performance status and glucose-lowering medication use. These effects were consistently observed in subsets of patients treated with ICI monotherapy and with PD-L1 TPS ≥ 1 %., Conclusion: Higher mean baseline glucose levels correlated with shorter survival in patients with NSCLC treated with ICIs. The divergent effects of individual metabolic syndrome components on ICI response in patients with NSCLC underscore the complexity of metabolic influences on treatment outcomes., 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 Elsevier B.V. All rights reserved.)

Hypoglycemia in the absence of diabetes is often multifactorial and challenging to diagnose definitively. We present a case report and an expanded series of adult females with reactive hypoglycemia who were diagnosed with Ehlers-Danlos syndrome (EDS). These patients exhibited predominantly postprandial hypoglycemia, with some fasting and activity-induced episodes. Clinical findings included autonomic dysfunction, gastrointestinal symptoms, and joint hypermobility. Interventions focused on medical nutrition therapy, continuous glucose monitoring, and, in some cases, medication. Many patients continued to experience hypoglycemic episodes despite treatment. Key learning points include the potential association between hypermobile EDS and hypoglycemia, the importance of confirming the Whipple triad, and the need for multidisciplinary management. This case series highlights the need for further research into the prevalence and pathophysiology of hypoglycemia in EDS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Food insecurity has been linked to higher rates of obesity. It has also been shown to diminish the effectiveness of weight loss strategies, including intensive lifestyle interventions. One essential component of food insecurity is having a geospatial disadvantage in access to healthy, affordable food, such as living within a food desert. This study aims to determine if food insecurity also impacts weight loss and nutritional outcomes in patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG)., Methods: Clinical outcomes of patients who underwent RYGB or SG at Cleveland Clinic or affiliate regional hospitals in the United States from 2010 to 2018 were collected. Modified Retail Food Environmental Index (mRFEI) data was collected from the Center for Disease Control and merged with patient census tract data, allowing the patient cohort to be divided into those living in areas identified as food secure (mRFEI > 10%), food swamps (mRFEI = 1-10%), or food deserts (mRFEI = 0). Postoperative weight change was evaluated with quadratic growth mixture models and stratified by surgery type., Results: A total of 5097 patients were included in this study cohort, including 3424 patients who underwent RYGB and 1673 who underwent SG. The median duration of follow-up was 2.3 years (IQR 0.89-3.6 years). Food security status was not associated with postoperative weight change (RYGB p = 0.73, SG p = 0.60), weight loss nadir (RYGB p = 0.60, SG p = 0.79), or weight regain (RYGB p = 0.93, SG p = 0.85). Deficiencies in nutritional markers at 1-2 years after surgery were also not significantly different between food security groups., Conclusion: Despite the established relationship between food insecurity and obesity, food insecurity does not negatively impact weight loss or nutritional outcomes following RYGB or SG, demonstrating metabolic surgery as a powerful and equitable tool for treating obesity., Level of Evidence: IV., (© 2024. The Author(s).)

BACKGROUNDBariatric surgery is a potent therapeutic approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1-3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin.METHODSTo identify mediators of disordered metabolism in PBH, we analyzed the plasma metabolome in the fasting state and 30 and 120 minutes after mixed meal in 3 groups: PBH (n = 13), asymptomatic post-Roux-en-Y gastric bypass (post-RYGB) (n = 10), and nonsurgical controls (n = 8).RESULTSIn the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone β-hydroxybutyrate were increased by 30%-80% in PBH versus asymptomatic. Conversely, multiple amino acids (branched-chain amino acids, tryptophan) and polyunsaturated lipids were reduced by 20%-50% in PBH versus asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced 2- to 10-fold in PBH in the fasting state. Postprandially, plasma serotonin was uniquely increased 1.9-fold in PBH versus asymptomatic post-RYGB. In mice, serotonin administration lowered glucose and increased plasma insulin and GLP-1. Moreover, serotonin-induced hypoglycemia in mice was blocked by the nonspecific serotonin receptor antagonist cyproheptadine and the specific serotonin receptor 2 antagonist ketanserin.CONCLUSIONTogether these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a potential therapeutic target.FUNDINGNational Institutes of Health (NIH) grant R01-DK121995, NIH grant P30-DK036836 (Diabetes Research Center grant, Joslin Diabetes Center), and Fundação de Amparo à Pesquisa do Estado de São Paulo grant 2018/22111-2.

Background: Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration., Methods: In this study, 382 infants born at 24 +0 -27 +6  weeks' gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks' postmenstrual age. The secondary outcomes are BPD at 36 weeks' postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24 +0 to 25 +6  weeks or 26 +0 to 27 +6  weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR)., Discussion: This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24 +0 -27 +6  weeks' gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks' postmenstrual age of life., Trial Registration: ClinicalTrials.gov NCT05711966. Registered on February 3, 2023., (© 2024. The Author(s).)

Objective: Bariatric surgery, a highly effective treatment for obesity and associated comorbidities, may improve cognition and brain volume in parallel with cardiometabolic function. However, some post-bariatric individuals develop post-bariatric hypoglycemia (PBH), which can be frequent and severe. The impact of recurrent hypoglycemia on cognition in PBH is unknown. The objective of this study was to determine whether individuals with PBH display reduced cognitive function compared with postsurgical counterparts without hypoglycemia., Methods: Fourteen adults with a history of Roux-en-Y gastric bypass with hypoglycemia (PBH+, n = 7) or without PBH (PBH-, n = 7) completed assessments of memory, executive function, attention, and psychomotor speed., Results: PBH+ individuals displayed significantly decreased performance in category fluency (p < 0.01), category switching (p < 0.01), and category switching accuracy (p < 0.01), compared with PBH- individuals. Performance in the first (p = 0.03) and third intervals (p = 0.045) of verbal fluency was significantly lower in PBH+ individuals versus PBH- individuals. All other assessments did not differ., Conclusions: PBH+ individuals may be at greater risk for cognitive impairment compared with PBH- individuals, as suggested by impaired semantic processing and cognitive flexibility, as well as greater difficulty initiating and sustaining word retrieval., (© 2023 The Obesity Society.)

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.

Importance: Youth-onset type 2 diabetes (T2D) has a more aggressive phenotype than adult-onset T2D, including rapid loss of glycemic control and increased complication risk., Objective: To identify associations of growth hormone mediators with glycemic failure, beta cell function, and insulin sensitivity in youth-onset T2D., Design, Setting, and Participants: This post hoc secondary analysis of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomized clinical trial, which enrolled participants from July 2004 to February 2009, included 398 participants from 15 university-affiliated medical centers with available plasma samples from baseline and 36 months. Participants were youths aged 10 to 17 years with a duration of T2D of less than 2 years who were randomized to metformin, metformin plus lifestyle intervention, or metformin plus rosiglitazone. Participants were followed up for a mean (SD) of 3.9 (1.5) years during the trial, ending in 2011. Statistical analysis was performed from August 2022 to November 2023., Exposure: Plasma insulin-like growth factor-1 (IGF-1), growth hormone receptor (GHR), and insulin-like growth factor binding protein 1 (IGFBP-1)., Main Outcomes and Measures: Main outcomes were (1) loss of glycemic control during the TODAY study, defined as hemoglobin A1c (HbA1c) level of 8% or more for 6 months or inability to wean from insulin therapy, and (2) baseline and 36-month measures of glycemia (fasting glucose, HbA1c), insulin sensitivity (1/fasting C-peptide), high-molecular-weight adiponectin, and beta cell function (C-peptide index, C-peptide oral disposition index)., Results: This analysis included 398 participants (mean [SD] age, 13.9 [2.0] years; 248 girls [62%]; 166 Hispanic participants [42%]; 134 non-Hispanic Black participants [34%], and 84 non-Hispanic White participants [21%]). A greater increase in IGF-1 level between baseline and 36 months was associated with lower odds of glycemic failure (odds ratio [OR], 0.995 [95% CI, 0.991-0.997]; P < .001) and higher C-peptide index per 100-ng/mL increase in IGF-1 (β [SE], 0.015 [0.003]; P < .001). A greater increase in log2 GHR level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.75 [95% CI, 1.05-2.99]; P = .04) and lower C-peptide index (β [SE], -0.02 [0.006]; P < .001). A greater increase in log2 IGFBP-1 level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.37 [95% CI, 1.09-1.74]; P = .007) and higher high-molecular-weight adiponectin (β [SE], 431 [156]; P = .007)., Conclusions and Relevance: This study suggests that changes in plasma growth hormone mediators are associated with loss of glycemic control in youth-onset T2D, with IGF-1 associated with lower risk and GHR and IGFBP-1 associated with increased risk., Trial Registration: ClinicalTrials.gov Identifier: NCT00081328.

Background: An increasing number of individuals with type 1 diabetes (T1D) manage glycemia with insulin pumps containing short-acting insulin. If insulin delivery is interrupted for even a few hours due to pump or infusion site malfunction, the resulting insulin deficiency can rapidly initiate ketogenesis and diabetic ketoacidosis (DKA)., Methods: To detect an event of accidental cessation of insulin delivery, we propose the design of ketone-based alert system (K-AS). This system relies on an extended Kalman filter based on plasma 3-beta-hydroxybutyrate (BOHB) measurements to estimate the disturbance acting on the insulin infusion/injection input. The alert system is based on a novel physiological model capable of simulating the ketone body turnover in response to a change in plasma insulin levels. Simulated plasma BOHB levels were compared with plasma BOHB levels available in the literature. We evaluated the performance of the K-AS on 10 in silico subjects using the S2014 UVA/Padova simulator for two different scenarios., Results: The K-AS achieves an average detection time of 84 and 55.5 minutes in fasting and postprandial conditions, respectively, which compares favorably and improves against a detection time of 193 and 120 minutes, respectively, based on the current guidelines., Conclusions: The K-AS leverages the rapid rate of increase of plasma BOHB to achieve short detection time in order to prevent BOHB levels from rising to dangerous levels, without any false-positive alarms. Moreover, the proposed novel insulin-BOHB model will allow us to understand the efficacy of treatment without compromising patient safety., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.J.D. reports licensed IP to Insulet, Roche, and Dexcom. L.M.L. reports grant support to her institution from NIH, JDRF, Helmsley Charitable Trust, Eli Lilly and Company, Insulet, Dexcom, and Boehringer Ingelheim; she receives consulting fees unrelated to the current report from NovoNordisk, Roche, Dexcom, Insulet, Boehringer Ingelheim, Medtronic, Laxmi, Vertex, and Provention. M.-E.P. reports receiving grant support, provided to her institution, from NIH, Helmsley Charitable Trust, Chan Zuckerberg Foundation, and Dexcom, patents related to hypoglycemia and pump therapy for hypoglycemia, and advisory board fees unrelated to the current report from Fractyl. E.M.A is currently with University of Trento, Italy, and this work was done when she was with Harvard University. F.J.D is currently with Brown University, USA, and this work was done when he was with Harvard University.

Aim: To determine whether continuous glucose monitoring (CGM) can reduce hypoglycaemia in patients with post-bariatric hypoglycaemia (PBH)., Materials and Methods: In an open-label, nonrandomized, pre-post design with sequential assignment, CGM data were collected in 22 individuals with PBH in two sequential phases: (i) masked (no access to sensor glucose or alarms); and (ii) unmasked (access to sensor glucose and alarms for low or rapidly declining sensor glucose). Twelve participants wore the Dexcom G4 device for a total of 28 days, while 10 wore the Dexcom G6 device for a total of 20 days., Results: Participants with PBH spent a lower percentage of time in hypoglycaemia over 24 hours with unmasked versus masked CGM (<3.3 mM/L, or <60 mg/dL: median [median absolute deviation {MAD}] 0.7 [0.8]% vs. 1.4 [1.7]%, P = 0.03; <3.9 mM/L, or <70 mg/dL: median [MAD] 2.9 [2.5]% vs. 4.7 [4.8]%; P = 0.04), with similar trends overnight. Sensor glucose data from the unmasked phase showed a greater percentage of time spent between 3.9 and 10 mM/L (70-180 mg/dL) (median [MAD] 94.8 [3.9]% vs. 90.8 [5.2]%; P = 0.004) and lower glycaemic variability over 24 hours (median [MAD] mean amplitude of glycaemic excursion 4.1 [0.98] vs. 4.4 [0.99] mM/L; P = 0.04). During the day, participants also spent a greater percentage of time in normoglycaemia with unmasked CGM (median [MAD] 94.2 [4.8]% vs. 90.9 [6.2]%; P = 0.005), largely due to a reduction in hyperglycaemia (>10 mM/L, or 180 mg/dL: median [MAD] 1.9 [2.2]% vs. 3.9 [3.6]%; P = 0.02)., Conclusions: Real-time CGM data and alarms are associated with reductions in low sensor glucose, elevated sensor glucose, and glycaemic variability. This suggests CGM allows patients to detect hyperglycaemic peaks and imminent hypoglycaemia, allowing dietary modification and self-treatment to reduce hypoglycaemia. The use of CGM devices may improve safety in PBH, particularly for patients with hypoglycaemia unawareness., (© 2023 John Wiley & Sons Ltd.)

Adipogenesis is key to maintaining organism-wide energy balance and healthy metabolic phenotype, making it critical to thoroughly comprehend its molecular regulation in humans. By single-nuclei RNA-sequencing (snRNA-seq) of over 20,000 differentiating white and brown preadipocytes, we constructed a high-resolution temporal transcriptional landscape of human white and brown adipogenesis. White and brown preadipocytes were isolated from a single individual's neck region, thereby eliminating inter-subject variability across two distinct lineages. These preadipocytes were also immortalized to allow for controlled, in vitro differentiation, allowing sampling of distinct cellular states across the spectrum of adipogenic progression. Pseudotemporal cellular ordering revealed the dynamics of ECM remodeling during early adipogenesis, and lipogenic/thermogenic response during late white/brown adipogenesis. Comparison with adipogenic regulation in murine models Identified several novel transcription factors as potential targets for adipogenic/thermogenic drivers in humans. Among these novel candidates, we explored the role of TRPS1 in adipocyte differentiation and showed that its knockdown impairs white adipogenesis in vitro. Key adipogenic and lipogenic markers revealed in our analysis were applied to analyze publicly available scRNA-seq datasets; these confirmed unique cell maturation features in recently discovered murine preadipocytes, and revealed inhibition of adipogenic expansion in humans with obesity. Overall, our study presents a comprehensive molecular description of both white and brown adipogenesis in humans and provides an important resource for future studies of adipose tissue development and function in both health and metabolic disease state., 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 GmbH.. All rights reserved.)

Background: The estimation of available active insulin remains a limitation of automated insulin delivery systems. Currently, insulin pumps calculate active insulin using mathematical decay curves, while quantitative measurements of insulin would explicitly provide person-specific PK insulin dynamics to assess remaining active insulin more accurately, permitting more effective glucose control., Methods: We performed the first clinical evaluation of an insulin immunosensor chip, providing near real-time measurements of insulin levels. In this study, we sought to determine the accuracy of the novel insulin sensor and assess its therapeutic risk and benefit by presenting a new tool developed to indicate the potential therapeutic consequences arising from inaccurate insulin measurements., Results: Nine adult participants with type-1 diabetes completed the study. The change from baseline in immunosensor-measured insulin levels was compared with values obtained by standard enzyme-linked immunosorbant assay (ELISA) after preprandial injection of insulin. The point-of-care quantification of insulin levels revealed similar temporal trends as those from the laboratory insulin ELISA. The results showed that 70% of the paired immunosensor-reference values were concordant, which suggests that the patient could take action safely based on insulin concentration obtained by the novel sensor., Conclusions: This proposed technology and preliminary feasibility evaluation show encouraging results for near real-time evaluation of insulin levels, with the potential to improve diabetes management. Real-time measurements of insulin provide person-specific insulin dynamics that could be used to make more informed decisions regarding insulin dosing, thus helping to prevent hypoglycemia and improve diabetes outcomes.

Background: Clinical decision support systems that incorporate information from frequent insulin measurements to enhance individualized diabetes management remain an unmet goal. The development of a disposable insulin strip for fast decentralized point-of-care detection replacing the current centralized lab-based methods used in clinical practice would be highly desirable to improve the establishment of individual insulin absorption patterns and algorithm modeling processes., Methods: We carried out the development and optimization of a novel decentralized disposable insulin electrochemical sensor focusing on obtaining high analytical and operational performance toward achieving a true point-of-care insulin testing device for clinical on-site application., Results: Our novel insulin immunosensor demonstrated an attractive performance and efficient user-friendly operation by providing high sensitivity capability to detect endogenous and analog insulin with a limit of detection of 30.2 pM (4.3 µiU/mL), rapid time-to-result, stability toward remote site application, and scalable low-cost fabrication with an estimated cost-of-goods for disposable consumables of below $5, capable of near real-time insulin detection in a microliter (≤10 µL) sample droplet of undiluted serum within 30 minutes., Conclusions: The results obtained in the optimization and characterization of our novel insulin sensor illustrate its suitability for its potential application in remote clinical environments for frequent insulin monitoring. Future work will test the insulin sensor in a clinical research setting to assess its efficacy in individuals with type 1 diabetes.

The plastic accumulation and its degradation into microplastics is an environmental issue not only for their ubiquity, but also for the release of intrinsic chemicals, such as phthalates (PAEs), non-phthalate plasticizers (NPPs), and bisphenols (BPs), which may reach body organs and tissues, and act as endocrine disruptors. Monitoring plastic additives in biological matrices, such as blood, may help in deriving relationships between human exposure and health outcomes. In this work, the profile of PAEs, NPPs and BPs was determined in Sicilian women's blood with different ages (20-60 years) and interpreted by chemometrics. PAEs (DiBP and DEPH), NPPs (DEHT and DEHA), BPA and BPS were at higher frequencies and greater levels in women's blood and varied in relation to age. According to statistical analysis, younger females' blood had higher contents of plasticizers than older women, probably due to a more frequent use of higher quantities of plastic products in daily life., 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 Elsevier B.V. All rights reserved.)

Background/purpose: Litter size is a biological variable that strongly influences adult physiology in rodents. Despite evidence from previous decades and recent studies highlighting its major impact on metabolism, information about litter size is currently underreported in the scientific literature. Here, we urge that this important biological variable should be explicitly stated in research articles., Results/conclusion: Below, we briefly describe the scientific evidence supporting the impact of litter size on adult physiology and outline a series of recommendations and guidelines to be implemented by investigators, funding agencies, editors in scientific journals, and animal suppliers to fill this important gap., Competing Interests: Conflicts of interest None declared., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Although promising therapeutics are in the pipeline, bariatric surgery (also known as metabolic surgery) remains our most effective strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Of the many available options, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are currently the most widely used procedures. RYGB and VSG have very different anatomical restructuring but both surgeries are effective, to varying degrees, at inducing weight loss and T2DM remission. Both weight loss-dependent and weight loss-independent alterations in multiple tissues (such as the intestine, liver, pancreas, adipose tissue and skeletal muscle) yield net improvements in insulin resistance, insulin secretion and insulin-independent glucose metabolism. In a subset of patients, post-bariatric hypoglycaemia can develop months to years after surgery, potentially reflecting the extreme effects of potent glucose reduction after surgery. This Review addresses the effects of bariatric surgery on glucose regulation and the potential mechanisms responsible for both the resolution of T2DM and the induction of hypoglycaemia., (© 2022. Springer Nature Limited.)

Purpose of Review: This manuscript provides a review of post-bariatric hypoglycemia (PBH) with a special focus on the role of the registered dietitian-nutritionist (RDN) and medical nutrition therapy (MNT) recommendations as foundational for management., Recent Findings: As the number of bariatric surgeries rises yearly, with 256,000 performed in 2019, PBH is an increasingly encountered late complication. Following Roux-en-Y (RYGB) or vertical sleeve gastrectomy (VSG), about 1/3 of patients report symptoms suggestive of at least mild postprandial hypoglycemia, with severe and/or medically confirmed hypoglycemia in 1-10%. Anatomical alterations, changes in GLP1 and other intestinally derived hormones, excessive insulin response, reduced insulin clearance, impaired counterregulatory hormone response to hypoglycemia, and other factors contribute to PBH. MNT is the cornerstone of multidisciplinary treatment, with utilization of personal continuous glucose monitoring to improve safety when possible. While many individuals require pharmacotherapy, there are no currently approved medications for PBH. Increasing awareness and identification of individuals at risk for or with PBH is critical given the potential impact on safety, nutrition, and quality of life. A team-based approach involving the individual, the RDN, and other clinicians is essential in providing ongoing assessment and individualization of MNT in the long-term management of PBH., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Canonical growth hormone (GH)-dependent signaling is essential for growth and counterregulatory responses to hypoglycemia, but also may contribute to glucose homeostasis (even in the absence of hypoglycemia) via its impact on metabolism of carbohydrates, lipids and proteins, body composition, and cardiovascular risk profile. The aim of this review is to summarize recent data implicating GH action in metabolic control, including both IGF-1-dependent and -independent pathways, and its potential role as target for T2D therapy., Recent Findings: Experimental blockade of the GHR can modulate glucose metabolism. Moreover, the soluble form of the GH receptor (GHR, or GHBP) was recently identified as a mediator of improvement in glycemic control in patients with T2D randomized to bariatric surgery vs. medical therapy. Reductions in GHR were accompanied by increases in plasma GH, but unchanged levels of both total and free IGF-1. Likewise, hepatic GHR expression is reduced following both RYGB and VSG in rodents. Emerging data indicate that GH signaling is important for regulation of long-term glucose metabolism in T2D. Future studies will be required to dissect tissue-specific GH signaling and sensitivity and their contributions to systemic glucose metabolism., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II is an extremely rare autosomal recessive inborn error of fatty acid beta oxidation and branched-chain amino acids, secondary to mutations in the genes encoding the electron transfer flavoproteins A and B (ETFs; ETFA or ETFB) or ETF dehydrogenase (ETFDH). The clinical manifestation of MADD are heterogeneous, from severe neonatal forms to mild late-onset forms., Case Presentation: We report the case of a preterm newborn who died a few days after birth for a severe picture of untreatable metabolic acidosis. The diagnosis of neonatal onset MADD was suggested on the basis of clinical features displaying congenital abnormalities and confirmed by the results of expanded newborn screening, which arrived the day the newborn died. Molecular genetic test revealed a homozygous indel variant c.606 + 1 &#95;606 + 2insT in the ETFDH gene, localized in a canonical splite site. This variant, segregated from the two heterozygous parents, is not present in the general population frequency database and has never been reported in the literature., Discussion and Conclusion: Recently introduced Expanded Newborn Screening is very important for a timely diagnosis of Inherited Metabolic Disorders like MADD. In some cases which are the most severe, diagnosis may arrive after symptoms are already present or may be the neonate already died. This stress the importance of collecting all possible samples to give parents a proper diagnosis and a genetic counselling for future pregnacies., (© 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.)

Decentralized sensing of analytes in remote locations is today a reality. However, the number of measurable analytes remains limited, mainly due to the requirement for time-consuming successive standard additions calibration used to address matrix effects and resulting in greatly delayed results, along with more complex and costly operation. This is particularly challenging in commonly used immunoassays of key biomarkers that typically require from 60 to 90 min for quantitation based on two standard additions, hence hindering their implementation for rapid and routine diagnostic applications, such as decentralized point-of-care (POC) insulin testing. In this work we have developed and demonstrated the theoretical framework for establishing a universal slope for direct calibration-free POC insulin immunoassays in serum samples using an electrochemical biosensor (developed originally for extended calibration by standard additions). The universal slope is presented as an averaged slope constant, relying on 68 standard additions-based insulin determinations in human sera. This new quantitative analysis approach offers reliable sample measurement without successive standard additions, leading to a dramatically simplified and faster assay (30 min vs 90 min when using 2 standard additions) and greatly reduced costs, without compromising the analytical performance while significantly reducing the analyses costs. The substantial improvements associated with the new universal slope concept have been demonstrated successfully for calibration-free measurements of serum insulin in 30 samples from individuals with type 1 diabetes using meticulous statistical analysis, supporting the prospects of applying this immunoassay protocol to routine decentralized POC insulin testing.

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.)

The ability to continuously monitor the concentration of specific molecules in the body is a long-sought goal of biomedical research. For this purpose, interstitial fluid (ISF) was proposed as the ideal target biofluid because its composition can rapidly equilibrate with that of systemic blood, allowing the assessment of molecular concentrations that reflect full-body physiology. In the past, continuous monitoring in ISF was enabled by microneedle sensor arrays. Yet, benchmark microneedle sensors can only detect molecules that undergo redox reactions, which limits the ability to sense metabolites, biomarkers, and therapeutics that are not redox-active. To overcome this barrier, here, we expand the scope of these devices by demonstrating the first use of microneedle-supported electrochemical, aptamer-based (E-AB) sensors. This platform achieves molecular recognition based on affinity interactions, vastly expanding the scope of molecules that can be sensed. We report the fabrication of microneedle E-AB sensor arrays and a method to regenerate them for multiple uses. In addition, we demonstrate continuous molecular measurements using these sensors in flow systems in vitro using single and multiplexed microneedle array configurations. Translation of the platform to in vivo measurements is possible as we demonstrate with a first E-AB measurement in the ISF of a rodent. The encouraging results reported in this work should serve as the basis for future translation of microneedle E-AB sensor arrays to biomedical research in preclinical animal models.

Aims: The aim of this study was to examine the hypothesis that pramlintide would reduce hypoglycaemia by slowing gastric emptying and reducing postprandial glucagon secretion, thus limiting postprandial glycaemic excursions and insulin secretion, and thus to determine the efficacy of pramlintide on frequency and severity of hypoglycaemia in post-bariatric hypoglycaemia (PBH)., Materials and Methods: Participants with PBH following gastric bypass were recruited from outpatient clinics at the Joslin Diabetes Center, Boston, Massachusetts for an open-label study of pramlintide efficacy over 8 weeks. Twenty-three participants were assessed for eligibility, 20 participants had at least one pramlintide dose, and 14 completed the study. A mixed-meal tolerance test (MMTT) was performed at baseline and after 8 weeks of subcutaneous pramlintide with a sequential dose increase to a maximum of 120 micrograms (mean 69 ± 32 mcg) three times daily. The primary endpoint was change in glucose excursions during the MMTT. Secondary measures included MMTT insulin response, satiety and dumping score, percentage time with sensor glucose (SG) <3.9 mM, and number of days with minimum SG <3 mM, during masked continuous glucose monitoring., Results: There were no differences in MMTT glucose, glucagon or insulin between baseline and post treatment. We observed no significant change in satiety or dumping scores. The overall frequency of low SG values did not change, although there was substantial inter-individual variability., Conclusions: In PBH, pramlintide does not modulate glycaemic or insulin responses, satiety, or dumping scores during an MMTT and does not impact glycaemic excursions or decrease low SG levels in the outpatient setting., (© 2022 John Wiley & Sons Ltd.)

Introduction: With the increasing performance of bariatric surgery, rare complications are becoming prevalent. We review the diagnosis and treatment of dysautonomia after bariatric surgery and the limited treatment options available. We summarize the suggested mechanisms and explain why a complete understanding of the etiology has yet to be determined., Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was performed., Results: Of 448 studies identified in the literature search, 4 studies were reviewed, describing 87 patients diagnosed with dysautonomia. We present a patient who developed severe dysautonomia following conversion of sleeve gastrectomy to gastric bypass., Conclusion: Treatment needs to focus on optimizing nutrition, avoiding hypoglycemia, and optimizing volume status., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we investigated epigenetic control of systemic metabolism by bromodomain-containing proteins (Brds), which are transcriptional regulators binding to acetylated histone, in both intestinal cells and mice treated with the bromodomain inhibitor JQ-1. In vivo treatment with JQ-1 resulted in hyperglycemia and severe glucose intolerance. Whole-body or tissue-specific insulin sensitivity was not altered by JQ-1; however, JQ-1 treatment reduced insulin secretion during both in vivo glucose tolerance testing and ex vivo incubation of isolated islets. JQ-1 also inhibited expression of fibroblast growth factor (FGF) 15 in the ileum and decreased FGF receptor 4-related signaling in the liver. These adverse metabolic effects of Brd4 inhibition were fully reversed by in vivo overexpression of FGF19, with normalization of hyperglycemia. At a cellular level, we demonstrate Brd4 binds to the promoter region of FGF19 in human intestinal cells; Brd inhibition by JQ-1 reduces FGF19 promoter binding and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum and FGF signaling in the liver and a contributor to the gut-liver axis and systemic glucose metabolism., (© 2022 by the American Diabetes Association.)

Purpose of Review: The purpose of the current review is to summarize findings from the most recent and impactful studies which investigated human and mouse adipose tissue transcriptomes at a single-cell level. We provide perspective about the potential importance of data derived from these single-cell technologies in improving our understanding of the adipose organ and metabolic disease and likely future directions of this approach., Recent Findings: The majority of single-cell or single-nuclei studies of the adipose organ so far have focused on investigating the stromal-vascular fraction (SVF) of mouse subcutaneous and intraabdominal white and interscapular brown fat depots. Few studies have also evaluated the impact of additional factors as drivers of adipose phenotypes, such as high-fat diet-induced obesity, adolescence, aging, and cold exposure. Recent studies have also investigated human cell lines and human fat biopsies across a range of body mass index (BMI) and in response to insulin resistance or T2D. These studies have identified numerous previously unexplored subpopulations of adipocyte progenitors, immune cells, and mature adipocytes in both mice and men. Single-cell and single-nuclei technologies have brought an explosion of data that have advanced our understanding of the adipose organ in health and disease. However, we are still at the dawn of achieving a complete and comprehensive map of the mouse and human adipose organ. Multi-modal single-cell approaches to identify both anatomic localization of specific cellular populations and epigenetic mechanisms responsible for observed transcriptomic patterns are underway and will likely provide an even deeper understanding of the adipose organ in response to health and disease., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Single-cell RNA sequencing (scRNA-seq) enables molecular characterization of complex biological tissues at high resolution. The requirement of single-cell extraction, however, makes it challenging for profiling tissues such as adipose tissue, for which collection of intact single adipocytes is complicated by their fragile nature. For such tissues, single-nucleus extraction is often much more efficient and therefore single-nucleus RNA sequencing (snRNA-seq) presents an alternative to scRNA-seq. However, nuclear transcripts represent only a fraction of the transcriptome in a single cell, with snRNA-seq marked with inherent transcript enrichment and detection biases. Therefore, snRNA-seq may be inadequate for mapping important transcriptional signatures in adipose tissue. In this study, we compare the transcriptomic landscape of single nuclei isolated from preadipocytes and mature adipocytes across human white and brown adipocyte lineages, with whole-cell transcriptome. We show that snRNA-seq is capable of identifying the broad cell types present in scRNA-seq at all states of adipogenesis. However, we also explore how and why the nuclear transcriptome is biased and limited, as well as how it can be advantageous. We robustly characterize the enrichment of nuclear-localized transcripts and adipogenic regulatory lncRNAs in snRNA-seq, while also providing a detailed understanding for the preferential detection of long genes upon using this technique. To remove such technical detection biases, we propose a normalization strategy for a more accurate comparison of nuclear and cellular data. Finally, we show successful integration of scRNA-seq and snRNA-seq data sets with existing bioinformatic tools. Overall, our results illustrate the applicability of snRNA-seq for the characterization of cellular diversity in the adipose tissue., (© 2022 Gupta et al.; Published by Cold Spring Harbor Laboratory Press.)

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR's mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT01073020., (© 2021. The Author(s).)

Background: Postbariatric hypoglycemia (PBH) can be a devastating complication for which current therapies are often incompletely effective. More information is needed regarding frequency, incidence, and risk factors for PBH., Objectives: To examine hypoglycemia symptoms following Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) and baseline and in-study risk factors., Setting: Multicenter, at 10 US hospitals in 6 geographically diverse clinical centers., Methods: A prospective, longitudinal cohort study of adults undergoing RYGB or LAGB as part of clinical care between 2006 and 2009 were recruited and followed until January 31, 2015, with baseline and annual postoperative research assessments. We analyzed baseline prevalence and post-operative incidence and frequency of self-reported hypoglycemia symptoms as well as potential preoperative risk factors., Results: In all groups, postoperative prevalence of hypoglycemia symptoms was 38.5%. Symptom prevalence increased postoperatively from 2.8%-36.4% after RYGB in patients without preoperative diabetes (T2D), with similar patterns in prediabetes (4.9%-29.1%). Individuals with T2D had higher baseline hypoglycemia symptoms (28.9%), increasing after RYGB (57.9%). Hypoglycemia symptoms were lower after LAGB, with 39.1% reported hypoglycemia symptoms at only 1 postoperative visit with few (4.0%) having persistent symptoms at 6 or more annual visits. Timing of symptoms was not restricted to the postprandial state. Symptoms of severe hypoglycemia were reported in 2.6-3.6% after RYGB. The dominant risk factor for postoperative symptoms was preoperative symptoms; additionally, baseline selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitor use was also associated with increased risk in multivariable analysis. Weight loss and regain were not related to hypoglycemia symptom reporting., Conclusion: Hypoglycemia symptoms increase over time after RYGB, particularly in patients without diabetes. In a small percentage, symptoms can be persistent or severe and require hospitalization. Preoperative hypoglycemia symptoms and SSRI/SNRI use in RYGB patients without diabetes is associated with increased risk of symptoms., (Copyright © 2021. Published by Elsevier Inc.)