An open-label 16-week study of liraglutide in adolescents with obesity post-sleeve gastrectomy.

BACKGROUND: Up to 50% of adolescents who undergo metabolic and bariatric surgery (MBS) have obesity 3 years post-MBS, placing them at continued risk for the consequences of obesity. OBJECTIVES: We conducted an open-label, 16-week pilot study of liraglutide in adolescents with obesity after sleeve gastrectomy (SG) to investigate liraglutide effects on weight and body mass index (BMI) post-SG. METHODS: Adolescents aged 12-20.99 years with obesity and a history of SG ≥1 year prior were enrolled. Liraglutide was initiated at 0.6 mg/day, escalated weekly to a maximum of 3 mg/day, with treatment duration 16 weeks. Fasting laboratory assessments and an oral glucose tolerance test were performed at baseline and end-treatment. RESULTS: A total of 43 participants were screened, 34 initiated liraglutide (baseline BMI 41.2 ± 7.7 kg/m2), and 31 (91%) attended the end-treatment visit. BMI decreased by 4.3% (p < 0.001) with liraglutide. Adolescents who had poor initial response to SG (<20% BMI reduction at BMI nadir) had less weight loss with liraglutide. Fasting glucose and haemoglobin A1C concentrations significantly decreased. There were no serious treatment-emergent adverse events reported. CONCLUSIONS: Liraglutide treatment was feasible and associated with a BMI reduction of 4.3% in adolescents who had previously undergone SG, quantitatively similar to results obtained in adolescents with obesity who have not undergone MBS.

Brain dopamine responses to ultra-processed milkshakes are highly variable and not significantly related to adiposity in humans.

Ultra-processed foods high in fat and sugar may be addictive, in part, due to their purported ability to induce an exaggerated postingestive brain dopamine response akin to drugs of abuse. Using standard [11C]raclopride positron emission tomography (PET) displacement methods used to measure brain dopamine responses to addictive drugs, we measured postingestive striatal dopamine responses to an ultra-processed milkshake high in fat and sugar in 50 young, healthy adults over a wide body mass index range (BMI 20-45 kg/m2). Surprisingly, milkshake consumption did not result in significant postingestive dopamine response in the striatum (p=0.62) nor any striatal subregion (p>0.33) and the highly variable interindividual responses were not significantly related to adiposity (BMI: r=0.076, p=0.51; %body fat: r=0.16, p=0.28). Thus, postingestive striatal dopamine responses to an ultra-processed milkshake were likely substantially smaller than many addictive drugs and below the limits of detection using standard PET methods.

Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.

BACKGROUND: Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Magnetic resonance imaging functional imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using cardiac magnetic resonance imaging functional imaging, we evaluated peripheral and coronary endothelial artery structure and function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings. METHODS: Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate. RESULTS: Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P=0.04) and impaired endothelial function: coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells. CONCLUSIONS: Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308.

Recipe for Heart Health: A Randomized Crossover Trial on Cardiometabolic Effects of Extra Virgin Olive Oil Within a Whole-Food Plant-Based Vegan Diet.

BACKGROUND: Whole-food, plant-based vegan diets, low in oils, and Mediterranean diets, rich in extra virgin olive oil (EVOO), reduce cardiovascular disease risk factors. Optimal quantity of dietary fat, particularly EVOO, is unclear. METHODS AND RESULTS: In a randomized crossover trial with weekly cooking classes, adults with ≥5% cardiovascular disease risk followed a high (4 tablespoons/day) to low (<1 teaspoon/day) or low to high EVOO whole-food, plant-based diet for 4 weeks each, separated by a 1-week washout. The primary outcome was difference in low-density lipoprotein cholesterol (LDL-C) from baseline. Secondary measures were changes in additional cardiometabolic markers. Linear mixed models assessed changes from baseline between phases, with age, sex, and body weight change as covariates. In 40 participants, fat intake comprised 48% and 32% of energy during high and low EVOO phases, respectively. Both diets resulted in comparable reductions in LDL-C, total cholesterol, apolipoprotein B, high-density lipoprotein cholesterol, glucose, and high-sensitivity C-reactive protein (all P<0.05). With diet-sequence interactions for LDL-C, differences were detected between diets by diet order (mean±SEM high to low: Δ-12.7[5.9] mg/dL, P=0.04 versus low to high: Δ+15.8[6.8] mg/dL, P=0.02). Similarly, low to high order led to increased glucose, total cholesterol, and high-density lipoprotein cholesterol (all P<0.05). Over period 1, LDL-C reductions were -25.5(5.1) post-low versus -16.7(4.2) mg/dL post-high EVOO, P=0.162, which diminished over period 2. CONCLUSIONS: Both plant-based diet patterns improved cardiometabolic risk profiles compared with baseline diets, with more pronounced decreases in LDL-C after the low EVOO diet. Addition of EVOO after following a low intake pattern may impede further lipid reductions. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04828447.

Prediction of resting energy expenditure for adolescents with severe obesity: A multi-centre analysis.

BACKGROUND AND OBJECTIVES: Resting energy expenditure (REE) assessments can help inform clinical treatment decisions in adolescents with elevated body mass index (BMI), but current equations are suboptimal for severe obesity. We developed a predictive REE equation for youth with severe obesity and obesity-related comorbidities and compared results to previously published predictive equations. METHODS: Data from indirect calorimetry, clinical measures, and body composition per Dual x-ray absorptiometry (DXA) were collected from five sites. Data were randomly divided into development (N = 438) and validation (N = 118) cohorts. A predictive equation was developed using Elastic Net regression, using sex, race, ethnicity, weight, height, BMI percent of the 95th%ile (BMIp95), waist circumference, hip circumference, waist/hip ratio, age, Tanner stage, fat and fat-free mass. This equation was verified in the validation cohort and compared with 11 prior equations. RESULTS: Data from the total cohort (n = 556, age 15 ± 1.7 years, 77% female, BMIp95 3.3 ± 0.94) were utilized. The best fit equation was REE = -2048 + 18.17 × (Height in cm) - 2.57 × (Weight in kg) + 7.88 × (BMIp95) + 189 × (1 = male, 0 = female), R2 = 0.466, and mean bias of 23 kcal/day. CONCLUSION: This new equation provides an updated REE prediction that accounts for severe obesity and metabolic complications frequently observed in contemporary youth.

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.

BACKGROUND: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD). OBJECTIVE: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG). METHODS: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity. RESULTS: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups. CONCLUSIONS: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease. TRIAL REGISTRATION: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022.

Reevaluating First-line Therapies in Youth-Onset Type 2 Diabetes.

The prevalence of youth-onset type 2 diabetes is growing worldwide and current first-line treatment with metformin and intensive behavior and lifestyle changes are suboptimal in over 50% of youth within 2 years of diagnosis. This perspective article is a call to action for reevaluation of existing strategies and critical appraisal of metformin as first-line therapy in youth-onset type 2 diabetes. Increased attention should be given to novel therapeutics approved in youth, including glucagon-like 1 receptor agonists, sodium glucose cotransporter-2, and sociocultural interventions that will promote diabetes self-management.

Glycemia and Gluconeogenesis With Metformin and Liraglutide: A Randomized Trial in Youth-onset Type 2 Diabetes.

OBJECTIVE: Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and ß-cell function after therapy in AA Y-T2D. METHODS: In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. ß-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test. RESULTS: At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P = .003) but not gluconeogenesis or mSI. CONCLUSION: Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance ß-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.

Estimating insulin sensitivity and ß-cell function from the oral glucose tolerance test: validation of a new insulin sensitivity and secretion (ISS) model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and ß-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes (T2D). Existing methods range in sensitivity, input data, and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new insulin secretion and sensitivity (ISS) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. This model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. This model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including postchallenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had a strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.NEW & NOTEWORTHY The pathogenesis of type 2 diabetes (T2D) is determined by a balance between insulin sensitivity (SI) and ß-cell function (BCF), which can be determined by gold standard direct measurements or estimated by fitting differential equation models to oral glucose tolerance tests (OGTTs). We propose and validate a new differential equation model that is simpler to use than current models and requires less data while maintaining good correlation and agreement with gold standards. Matlab and Python code is freely available.

Striatal dopamine tone is positively associated with body mass index in humans as determined by PET using dual dopamine type-2 receptor antagonist tracers.

The relationship between adiposity and dopamine type-2 receptor binding potential (D2BP) in the human brain has been repeatedly studied for >20 years with highly discrepant results, likely due to variable methodologies and differing study populations. We conducted a controlled inpatient feeding study to measure D2BP in the striatum using positron emission tomography with both [18F]fallypride and [11C]raclopride in pseudo-random order in 54 young adults with a wide range of body mass index (BMI 20-44 kg/m2). Within-subject D2BP measurements using the two tracers were moderately correlated (r=0.47, p<0.001). D2BP was negatively correlated with BMI as measured by [11C]raclopride (r= -0.51; p<0.0001) but not [18F]fallypride (r=-0.01; p=0.92) and these correlation coefficients were significantly different from each other (p<0.001). Given that [18F]fallypride has greater binding affinity to dopamine type-2 receptors than [11C]raclopride, which is more easily displaced by endogenous dopamine, our results suggest that adiposity is positively associated with increased striatal dopamine tone.

Virtual Learning and Youth-Onset Type 2 Diabetes During the COVID-19 Pandemic.

INTRODUCTION: Cases and severity of presentation of youth-onset type 2 diabetes (Y-T2D) increased during the COVID-19 pandemic, yet the potential drivers of this rise remain unknown. During this time public health mandates paused in-person education and limited social interactions, resulting in radical lifestyle changes. We hypothesized that the incidence and severity of presentation of Y-T2D increased during virtual learning amidst the COVID-19 pandemic. MATERIALS AND METHODS: We conducted a single center retrospective chart review to identify all newly diagnosed cases of Y-T2D (n=387) at a pediatric tertiary care center in Washington, DC during three pre-determined learning periods as defined by learning modality in Washington, DC Public Schools: pre-pandemic in-person learning (3/11/2018-3/13/2020), pandemic virtual learning (3/14/2020-8/29/2021), and pandemic in-person learning (8/30/2021-3/10/2022) periods. RESULTS: Incident cases were stable during pre-pandemic in-person learning (3.9 cases/month, 95% CI: 2.8 - 5.4 cases/month), increased to a peak during virtual learning (18.7 cases/month, 95% CI: 15.9 - 22.1 cases/month), and declined with return to in-person learning (4.3 cases/month, 95% CI: 2.8 - 6.8 cases/month). Y-T2D incidence was 16.9 (95% CI: 9.8-29.1, p<0.001) and 5.1-fold higher (95% CI: 2.9-9.1, p<0.001) among non-Hispanic Black and Latinx youth, respectively, throughout the study period. Overall COVID-19 infection rates at diagnosis were low (2.5%) and were not associated with diabetes incidence (p=0.26). DISCUSSION/CONCLUSIONS: This study provides timely insights into an important and modifiable correlate of Y-T2D incidence, its disproportionate impact on underserved communities, and the need to consider the effects on long-term health outcomes and pre-existing healthcare inequities when designing public policy.

One-hour glucose is an earlier marker of dysglycemia than two-hour glucose.

AIMS: The timing of increase in 1-hour PG and its utility as an earlier predictor of both prediabetes (PreDM) and type 2 diabetes (T2D) compared to 2-hour PG (2 h-PG) are unknown. To evaluate the timing of crossing of the 1 h-PG ≥ 155 mg/dl (8.6 mmol/L) for PreDM and 209 mg/dl (11.6 mmol/L) for T2D and respective current 2 h-PG thresholds of 140 mg/dl (7.8 mmol/L) and 200 mg/dl (11.1 mmol/L). METHODS: Secondary analysis of 201 Southwest Native Americans who were followed longitudinally for 6-10 years and had at least 3 OGTTs. RESULTS: We identified a subset of 43 individuals who first developed PreDM by both 1 h-PG and 2 h-PG criteria during the study. For most (32/43,74%), 1 h-PG ≥ 155 mg/dl was observed before 2 h-PG reached 140 mg/dl (median [IQR]: 1.7 [-0.25, 4.59] y; mean ± SEM: 5.3 ± 1.9 y). We also identified a subset of 33 individuals who first developed T2D during the study. For most (25/33, 75%), 1 h-PG reached 209 mg/dl earlier (median 1.0 [-0.56, 2.02] y; mean ± SEM: 1.6 ± 0.8 y) than 2 h-PG reached 200 mg/dl, diagnostic of T2D. CONCLUSIONS: 1 h-PG ≥ 155 mg/dl is an earlier marker of elevated risk for PreDM and T2D than 2 h-PG ≥ 140 mg/dl.

Estimating Insulin Sensitivity and Beta-Cell Function from the Oral Glucose Tolerance Test: Validation of a new Insulin Sensitivity and Secretion (ISS) Model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and beta-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes. Many methods exist, ranging in input data and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic models (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new ISS (Insulin Secretion and Sensitivity) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. The model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. The model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including post-challenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts including individuals at high risk of prediabetes (adult women with a wide range of BMI and adolescents with obesity). The new model had strong correlation with gold-standard estimates from intravenous glucose tolerance tests and hyperinsulinemic-euglycemic clamp. The ISS model has broad clinical applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.

Metabolomic Profiling of an Ultraprocessed Dietary Pattern in a Domiciled Randomized Controlled Crossover Feeding Trial.

BACKGROUND: Objective markers of ultraprocessed foods (UPF) may improve the assessment of UPF intake and provide insight into how UPF influences health. OBJECTIVES: To identify metabolites that differed between dietary patterns (DPs) high in or void of UPF according to Nova classification. METHODS: In a randomized, crossover, controlled-feeding trial (clinicaltrials.govNCT03407053), 20 domiciled healthy participants (mean ± standard deviation: age 31 ± 7 y, body mass index [kg/m2] 22 ± 11.6) consumed ad libitum a UPF-DP (80% UPF) and an unprocessed DP (UN-DP; 0% UPF) for 2 wk each. Metabolites were measured using liquid chromatography with tandem mass spectrometry in ethylenediaminetetraacetic acid plasma, collected at week 2 and 24-h, and spot urine, collected at weeks 1 and 2, of each DP. Linear mixed models, adjusted for energy intake, were used to identify metabolites that differed between DPs. RESULTS: After multiple comparisons correction, 257 out of 993 plasma and 606 out of 1279 24-h urine metabolites differed between UPF-DP and UN-DP. Overall, 21 known and 9 unknown metabolites differed between DPs across all time points and biospecimen types. Six metabolites were higher (4-hydroxy-L-glutamic acid, N-acetylaminooctanoic acid, 2-methoxyhydroquinone sulfate, 4-ethylphenylsulfate, 4-vinylphenol sulfate, and acesulfame) and 14 were lower following the UPF-DP; pimelic acid, was lower in plasma but higher in urine following the UPF-DP. CONCLUSIONS: Consuming a DP high in, compared with 1 void of, UPF has a measurable impact on the short-term human metabolome. Observed differential metabolites could serve as candidate biomarkers of UPF intake or metabolic response in larger samples with varying UPF-DPs. This trial was registered at clinicaltrials.gov as NCT03407053 and NCT03878108.

Childhood Obesity and Cardiovascular Disease Risk.

PURPOSE OF REVIEW: The global epidemic of youth-onset obesity is tightly linked to the rising burden of cardiometabolic disease across the lifespan. While the link between childhood obesity and cardiovascular disease is established, this contemporary review summarizes recent and novel advances in this field that elucidate the mechanisms and impact of this public health issue. RECENT FINDINGS: The review highlights the emerging data supporting the relationship between childhood adverse events, social determinants of health, and systemic and institutional systems as etiological factors. We also provide updates on new screening and treatment approaches including updated nutrition and dietary guidelines and benchmarks for pediatric obesity screening, novel pharmacological agents for pediatric obesity and type 2 diabetes such as glucagon-like 1 peptide receptor agonists, and we discuss the long-term safety and efficacy data on surgical management of pediatric obesity. The global burden of pediatric obesity continues to rise and is associated with accelerated and early vascular aging especially in youth with obesity and type 2 diabetes. Socio-ecological determinants of risk mediate and moderate the relationship of childhood obesity with cardiometabolic disease. Recognizing the importance of neighborhood level influences as etiological factors in the development of cardiovascular disease is critical for designing effective policies and interventions. Novel surgical and pharmacological interventions are effective pediatric weight-loss interventions, but future research is needed to assess whether these agents, within a socio-ecological framework, will be associated with abatement of the pediatric obesity epidemic and related increased cardiovascular disease risk.

The effects of prebiotics on gastrointestinal side effects of metformin in youth: A pilot randomized control trial in youth-onset type 2 diabetes.

Disclosure summary: Dr. Yadav is Chief Scientific Officer and Co-Founder of Postbiotics Inc and has no conflict of interest with this work. All other authors have no conflicts of interest to disclose. Background: Metformin is the only approved first-line oral glucose lowering agent for youth with type 2 diabetes mellitus (Y-T2DM) but often causes gastrointestinal (GI) side effects, which may contribute to reduced treatment adherence and efficacy. Prebiotic intake may reduce metformin's side effects by shifting microbiota composition and activity. Objective: The aims of this study were to determine the feasibility and tolerability of a prebiotic supplement to improve metformin-induced GI symptoms and explore the changes in glycemia and shifts in the microbiota diversity. Methods: In a two-phase pilot clinical trial, we compared, stool frequency and stool form every 1-2 days, and composite lower GI symptoms (weekly) at initiation of daily metformin combined with either a daily prebiotic or a placebo shake in a 1-week randomized double-blind crossover design (Phase 1), followed by a 1-month open-labeled extension (Phase 2). Plasma glycemic markers and stool samples were collected before and after each phase. Results: Six Y-T2DM (17.2 ± 1.7y (mean ± SD), 67% male, BMI (42 ± 9 kg/m2), HbA1c (6.4 ± 0.6%)) completed the intervention. Stool frequency, stool composition, and GI symptom scores did not differ by group or study phase. There were no serious or severe adverse events reported, and no differences in metabolic or glycemic markers. After one week Phase 1metformin/placebo Proteobacteria, Enterobacteriaceae, and Enterobacteriales were identified as candidate biomarkers of metformin effects. Principle coordinate analyses of beta diversity suggested that the metformin/prebiotic intervention was associated with distinct shifts in the microbiome signatures at one week and one month. Conclusion: Administration of a prebiotic fiber supplement during short-term metformin therapy was well tolerated in Y-T2DM and associated with modest shifts in microbial composition. This study provides a proof-of-concept for feasibility exploring prebiotic-metformin-microbiome interactions as a basis for adjunctive metformin therapy. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04209075.

Transitioning care in youth-onset type 1 and type 2 diabetes: a scoping review protocol using the socio-ecological model framework.

INTRODUCTION: The transition from paediatric to adult diabetes care in youth-onset diabetes (type 1 diabetes mellitus, Y-T1DM and type 2 diabetes mellitus, Y-T2DM) is associated with worsening glycaemic control, missed clinical visits, decreased medication adherence and the emergence of cardiometabolic complications. The socio-ecological challenges that influence transitioning to adult diabetes care may be distinct between Y-T1DM and Y-T2DM. The goal of this scoping review is to map the state of the literature on transitioning care in Y-T2DM compared with Y-T1DM and to identify the main sources and types of evidence available. The objectives are : (1) to identify the factors within the socio-ecological framework (individual, relationship, community, societal) associated with transitioning to adult care in Y-T2DM compared with Y- T1DM, and (2) to identify knowledge gaps related to transitioning to adult care. METHODS: The scoping review protocol and reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews guidelines. A systematic search of scientific databases (PubMed, Embase, Cumulative Index to Nursing and Allied Health, Scopus and APA PsycNet will be undertaken for articles between 1 January 1990 and 30 September 2022. Study designs will include peer-reviewed experimental and quasi-experimental published studies without language or country-specific restrictions. We will exclude articles on other diabetes subtypes and will exclude non-peer reviewed articles such as opinion papers, anecdotal reports or supplementary commentaries. ANALYSIS: References will be collated, sorted and extracted using Covidence. Factors associated with transition from paediatric to adult diabetes care in Y-T1DM and Y-T2DM will be identified using the socio-ecological framework and results will be presented in narrative format, tables, and summary graphs. ETHICS AND DISSEMINATION: Ethical approval will not be applicable for this review. TRIAL REGISTRATION NUMBER: https://osf.io/k2pwc.

The Relationship Between Lipoproteins and Insulin Sensitivity in Youth With Obesity and Abnormal Glucose Tolerance.

CONTEXT: Youth with obesity and abnormal glucose tolerance have an increased risk for atherosclerosis but the relative contributions of insulin resistance and hyperglycemia to dyslipidemia and the development of subclinical atherosclerosis are unknown. OBJECTIVE: This work aims to determine the association between insulin resistance, dyslipidemia, and carotid intimal thickness (cIMT) in adolescents with normal and abnormal glucose tolerance. METHODS: An observational cohort study in 155 youth: 44 obese insulin sensitive (OIS; fasting insulin ≤ 20 µM/mL, body mass index [BMI] ≥ 95th percentile), 35 obese insulin resistant (OIR; fasting insulin > 20 µM/mL, BMI ≥ 95th percentile), 34 obese abnormal glucose tolerant (AGT; BMI ≥ 95th percentile), and 42 Lean (BMI 5th-85th percentile). Lipids, lipoprotein particle size and concentration (-P), insulin sensitivity (SI an intravenous glucose test), and CMIT were compared using linear models adjusted for age, race/ethnicity, biological sex, and Tanner stage. Lipid/lipoprotein profile and CMIT were reevaluated in a subset after 2 years. RESULTS: Compared to OIS and Lean, OIR and AGT had elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) but similar total cholesterol and low-density lipoprotein cholesterol (LDL-C). Among OIS, OIR, AGT, lower SI was associated with atherogenic lipids (higher triglycerides, LDL-C, non-HDL-C, and lower HDL-C) and lipoproteins (higher total LDL-P and small HDL-P, and lower large HDL-P). There was a steeper decline in the association of SI with HDL-C and large HDL-P in AGT compared with OIR and OIS. cIMT was comparable across groups and inversely correlated with SI, with no change after 2 years. CONCLUSION: Among youth with obesity, insulin resistance was associated with an atherogenic lipoprotein/lipid profile and cIMT, regardless of glucose tolerance status. Insulin resistance in AGT youth was associated with a shift to smaller HDL-P compared to normoglycemic youth with obesity. Alterations in HDL-P metabolism may be early adverse manifestations of hyperglycemia in youth with obesity.

Dietary sugar restriction reduces hepatic de novo lipogenesis in boys with fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) in children resulting from the obesity epidemic is widespread and increasing. Although the complexities of pediatric NAFLD are recognized, screening and therapies in children remain limited. Moreover, pediatric NAFLD diagnosis fails to consider insulin resistance and metabolic dysfunction as important determinants. In this issue of the JCI, Cohen et al. explored the contribution of dietary factors to the pathogenesis of NAFLD in adolescent boys with biopsy-proven NAFLD and control participants. Notably, dietary sugar restriction over 8 weeks decreased de novo lipogenesis (DNL) and hepatic fat. The change in DNL correlated with changes in insulin and weight, but not with changes in hepatic fat, supporting the relevance of metabolic dysfunction to NAFLD. These results confirm the pathological link between excessive dietary sugar intake and NAFLD in children and support recent recommendations to change the nomenclature of NAFLD to metabolic associated fatty liver disease (MAFLD).

Energy expenditure due to gluconeogenesis in pathological conditions of insulin resistance.

Gluconeogenesis (GNG), the formation of glucose from noncarbohydrate precursors, requires adenosine triphosphate (ATP). Previous studies have estimated the energetic cost of GNG in humans based on theoretical calculations of rates of GNG, moles of oxygen consumption by GNG, and average oxygen consumption. Few human studies have measured the energy expenditure (EE) due to GNG. We estimated EE attributable to GNG in patients with three insulin resistance conditions and high GNG rates (insulin receptor pathogenic variants, lipodystrophy, and type 2 diabetes) and obesity without diabetes. Fractional GNG was measured by incorporation of deuterium from body water into newly formed glucose, endogenous glucose production (EGP) as glucose appearance following administration of [6,6-2H2]glucose, and total GNG as fractional GNG × EGP. EE was measured by indirect calorimetry and compared with predicted EE from the Mifflin St. Jeor equation. EE attributable to GNG was estimated using linear regression after accounting for age and fat-free mass (FFM). EE in patients with insulin resistance was significantly higher than predicted by the Mifflin St. Jeor equation. GNG correlated with resting EE (REE). EE attributable to GNG in patients with insulin resistance was almost one-third of REE, substantially higher than theorized in healthy subjects. Our findings demonstrate that GNG is a significant contributor to EE in insulin-resistant states. Prediction equations may underestimate caloric needs in patients with insulin resistance. Therefore, targeting caloric needs to account for higher EE due to increased GNG should be considered in energy balance studies in patients with insulin resistance.NEW & NOTEWORTHY Gluconeogenesis is an energy-requiring process that is upregulated in diabetes, contributing to hyperglycemia. Previous studies have estimated that gluconeogenesis accounts for less than 10% of resting energy expenditure. This study estimates the energy expenditure attributable to gluconeogenesis in uncommon and severe forms of insulin resistance and common, milder forms of insulin resistance. In these populations, gluconeogenesis accounts for almost one-third of resting energy expenditure, substantially higher than previously theorized in the literature.