Disclosure summaryDr. 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.BackgroundMetformin 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.ObjectiveThe 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.MethodsIn 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.ResultsSix 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.ConclusionAdministration 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 registrationhttps://clinicaltrials.gov/, identifier NCT04209075.
IntroductionThe 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.MethodsThe 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.AnalysisReferences 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 disseminationEthical approval will not be applicable for this review.Trial registration numberhttps://osf.io/k2pwc.
Introduction: Youth-onset type 2 diabetes (Y-T2D) may be associated with accelerated vascular aging, but the tempo and mechanisms are unknown. Non-invasive cardiac MRI coupled with ex-vivo experiments to assess endothelial function are ideal for assessing risk in young adults. Plasma exosomes are pro-inflammatory extra-cellular vesicles that may modulate endothelial dysfunction. Methods: We hypothesized that Y-T2D would have endothelial dysfunction compared to healthy age-matched peers measured by right coronary wall thickness (CWT) and coronary and brachial artery dilation during isometric handgrip exercise using a 3.0 Tesla cardiac MRI. In a subset of 4 Y-T2D, we isolated, characterized, and incubated plasma-derived exosomes in human coronary artery epithelial cells (HCAECs) compared to control cells. Results: Y-T2D (n=14, 40% female, age 19.4±1.3y, BMI 38±9kg/m 2 , mean±SD) compared to peers (n=16, 40% female, age 22.9±2.6 y, BMI 23±3 kg/m 2 ) had higher HbA1c (6.5 ± 1.2 vs 5.0 ± 0.5%), C-reactive protein (6.5±8.3 vs. 3.1±2.0 mg/L), systolic blood pressure (130±14 vs. 114±11 mmHg, all P <0.05) but similar LDL-cholesterol and triglycerides. Y-T2D had greater CWT (1.34±0.13 vs. 1.22±0.13 mm, P =0.02) and impaired arterial dilation (Figure 1A). HCAECs incubated with Y-T2D exosomes induced phenotypic changes of endothelial dysfunction: reduced expression of phosphorylated endothelial nitric oxide synthase (peNOS), increased expression of endothelial membrane ICAM-1 and phosphorylation of pERK(1/2) (Figure 1B). Conclusion: Accelerated vascular aging in Y-T2D was associated with paradoxical exercise-induced coronary artery vasoconstriction and peripheral endothelial dysfunction despite young age and the absence of traditional risk factors such as severe hyperglycemia, frank hypertension, or dyslipidemia. Plasma exosomes should be explored in the pathogenesis of endothelial dysfunction and early vascular aging in Y-T2D.
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