Search

Type 2 diabetes (T2D) rates in children and adolescents are rising globally. T2D is a complex and aggressive disease in children with several comorbidities, high treatment failure rates, and insulin needs within a few years from diagnosis. While myriads of pharmacotherapies are licensed to treat adults with T2D, treatments accessible to children and adolescents have been limited until recently. Metformin is an old drug with multiple beneficial metabolic health effects beyond glycemic control. This review discusses Metformin's origins, its mechanisms of action, and evidence for its use in the pediatric population to treat and prevent T2D. We also explore the evidence for its use as an obesity therapy, which is the primary driver of T2D, and T2D-driven comorbidities. While emerging therapies create new horizons for managing pediatric T2D, Metformin remains an inexpensive and safe part of the treatment plans of many T2D children globally for its beneficial metabolic effects. [ABSTRACT FROM AUTHOR]

Abstract Obesity is a worldwide pandemic representing one of the major challenges that societies face around the globe. Identifying the mechanisms involved in its development and propagation will help the development of preventative and therapeutic strategies that may help control its rising rates. Obesity is associated with chronic low-grade inflammation, and this is believed to be one of the major contributors to the development of insulin resistance, which is an early event in obesity and leads to type 2 diabetes when the pancreas fails to keep up with increased demand for insulin. In this review, we discuss the role of macrophages in mediation of inflammation in obesity in metabolic organs including adipose tissue, skeletal muscle and liver. The presence of immune cells at the interface with metabolic organs modulates both metabolic function and inflammatory responses in these organs, and may provide a potential therapeutic target to modulate metabolic function in obesity.

Pediatric type 2 diabetes mellitus (T2DM) patients are often overweight or obese, yet there are no validated clinical measures of adiposity to stratify cardiometabolic risk in this population. The tri-ponderal mass index (TMI, kg/m3) has recently been reported as a measure of adiposity in children, but there has been no validation of the association of TMI with adiposity in pediatric T2DM. We hypothesized that in children with T2DM, the TMI can serve as a more accurate measure of adiposity when compared to BMI z-score, and that it is associated with components of the metabolic syndrome. This is a cross-sectional secondary data analysis from the Improving Renal Complications in Adolescents with Type 2 Diabetes Through REsearch (iCARE) study (n = 116, age 10.20–17.90 years). Spearman's correlations and multivariable regression were used in the analyses. When compared to DXA, TMI demonstrated significant correlation with total adiposity versus BMI z-score (TMI r = 0.74, p-value < 0.0001; BMI z-score r = − 0.08, p-value 0.403). In regression analyses, TMI was associated with WHtR (B = 35.54, 95% CI 28.81, 42.27, p-value < 0.0001), MAP dipping (B = 1.73, 95% CI 0.12, 3.33, p-value = 0.035), and HDL (B = − 5.83, 95% CI − 10.13, − 1.54, p-value = 0.008). In conclusion, TMI is associated with adiposity and components of the metabolic syndrome in pediatric T2DM patients. [ABSTRACT FROM AUTHOR]

Survivors of Childhood Brain Tumors (SCBT) are at a higher risk of developing cardiovascular disease and type 2 diabetes compared to the general population. Adiposity is an important risk factor for the development of these outcomes, and identifying biomarkers of adiposity may help the stratification of survivors based on their cardiovascular risk or allow for early screening and interventions to improve cardiometabolic outcomes. Leptin is an adipokine that positively correlates with the adipose mass in the general population and is a predictor of adverse cardiometabolic outcomes, yet its association with adiposity in SCBT has not been studied. The aim of this study was to determine if leptin levels are associated with the adipose mass in SCBT, and to define its predictors. This cross-sectional study included 74 SCBT (n = 32 females) with 126 non-cancer controls (n = 59 females). Total adiposity was measured using Bioelectrical Impendence Analysis (BIA) and central adiposity was measured using waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR). We used multivariable linear regression analysis to determine if leptin predicts adiposity in SCBT and adjusted for age, sex, puberty, and cancer status. Leptin correlated strongly with total (p < 0.001) and central (WHR p = 0.001; WHtR p < 0.001) adiposity in SCBT and non-cancer controls. In conclusion, leptin is a potential biomarker for adiposity in SCBT, and further investigation is needed to clarify if leptin is a predictor of future cardiometabolic risk in SCBT. [ABSTRACT FROM AUTHOR]

Summary: Obesity is associated with the production of inflammatory cytokines that are implicated in insulin resistance (IR), and if not addressed, can lead to type 2 diabetes (T2D). The role of the immune system in skeletal muscle (SM) inflammation and insulin sensitivity is not yet well characterized. As SM IR is an important determinant of glycaemia, it is critical that the muscle‐immune phenotype is mapped to help design interventions to target T2D. This systematic review synthesized the evidence for SM macrophage content and phenotype in humans and murine models of obesity, and the association of muscle macrophage content and phenotype with IR. Results were synthesized narratively, as we were unable to conduct a meta‐analysis. We included 28 studies (n=10 human, n=18 murine), and all studies detected macrophage markers in SM. Macrophage content was positively associated with IR. In humans and mice, there was variability in muscle macrophage content and phenotype in obesity. Overall certainty in the evidence was low due to heterogeneity in detection methods and incompleteness of data reporting. Macrophages are detected in human and murine SM in obesity and a positive association between macrophage content and IR is noted; however, the standardization of markers, detection methods, and reporting of study details is warranted to accurately characterize macrophages and improve the potential for creating specific and targeted immune‐based therapies in obesity. [ABSTRACT FROM AUTHOR]

Objectives: The current global rates of obesity and type 2 diabetes are staggering. In order to implement effective management strategies, it is imperative to understand the mechanisms of obesity-induced insulin resistance and diabetes. Macrophage infiltration and inflammation of the adipose tissue in obesity is a well-established paradigm, yet the role of macrophages in muscle inflammation, insulin resistance and diabetes is not adequately studied. In this systematic review, we will examine the evidence for the presence of macrophages in skeletal muscle of obese humans and mice, and will assess the association between muscle macrophages and insulin resistance. We will identify published studies that address muscle macrophage content and phenotype, and its association with insulin resistance. We will search MEDLINE/PubMed, EMBASE, and Web of Science for eligible studies. Grey literature will be searched in ProQuest. Quality assessment will be conducted using the Systematic Review Centre for Laboratory Animal Experimentation risk of bias Tool for animal studies. Results: The findings of this systematic review will shed light on immune-metabolic crosstalk in obesity, and allow the consideration of targeted therapies to modulate muscle macrophages in the treatment and prevention of diabetes. The review will be published in a peer-reviewed journal and presented at conferences. [ABSTRACT FROM AUTHOR]

Objective Endurance exercise training reduces insulin resistance, adipose tissue inflammation and non-alcoholic fatty liver disease (NAFLD), an effect often associated with modest weight loss. Recent studies have indicated that high-intensity interval training (HIIT) lowers blood glucose in individuals with type 2 diabetes independently of weight loss; however, the organs affected and mechanisms mediating the glucose lowering effects are not known. Intense exercise increases phosphorylation and inhibition of acetyl-CoA carboxylase (ACC) by AMP-activated protein kinase (AMPK) in muscle, adipose tissue and liver. AMPK and ACC are key enzymes regulating fatty acid metabolism, liver fat content, adipose tissue inflammation and insulin sensitivity but the importance of this pathway in regulating insulin sensitivity with HIIT is unknown. Methods In the current study, the effects of 6 weeks of HIIT were examined using obese mice with serine–alanine knock-in mutations on the AMPK phosphorylation sites of ACC1 and ACC2 (AccDKI) or wild-type (WT) controls. Results HIIT lowered blood glucose and increased exercise capacity, food intake, basal activity levels, carbohydrate oxidation and liver and adipose tissue insulin sensitivity in HFD-fed WT and AccDKI mice. These changes occurred independently of weight loss or reductions in adiposity, inflammation and liver lipid content. Conclusions These data indicate that HIIT lowers blood glucose levels by improving adipose and liver insulin sensitivity independently of changes in adiposity, adipose tissue inflammation, liver lipid content or AMPK phosphorylation of ACC. [ABSTRACT FROM AUTHOR]

Global rates of type 2 diabetes in children and adolescents have increased significantly over the past three decades. Type 2 diabetes is a relatively new disease in this age group, and there is a dearth of information about how to structure treatment programs to manage its comorbidities and complications. In this paper, we describe the design and implementation of a personalized multidisciplinary, family-centered, pediatric and adolescent type 2 diabetes program at a tertiary pediatric center in Hamilton, Ontario, Canada. We report the process of designing and implementing such a program, and show that this multidisciplinary program led to improvement in glycated hemoglobin (n=17, 8% at baseline versus 6.4% at 1 year, 95% confidence interval (0.1-0.28), P-value <0.0001) and stabilized body mass index, with lowered C-peptide and no change in fitness or metabolic biomarkers of lipid metabolism and liver function. As type 2 diabetes becomes more prevalent in youth, the need for programs that successfully address the complex nature of this disease is central to its management and to mitigate its long-term adverse outcomes. [ABSTRACT FROM AUTHOR]

Obesity is associated with insulin resistance and increased risk for developing type 2 diabetes. Enlarged adipocytes develop resistance to the anti-lipolytic action of insulin. Elevated levels of fatty acids in the plasma and interstitial fluids lead to whole-body insulin resistance by disrupting normal insulin-regulated glucose uptake and glycogen storage in skeletal muscle. A new understanding has been cultivated in the past 5 to 10 years that adipocytes and macrophages (resident or bone marrow-derived) in adipose tissue of obese animals and humans are activated in a pro-inflammatory capacity and secrete insulin resistance-inducing factors. However, only recently have fatty acids themselves been identified as agents that engage toll-like receptors of the innate immunity systems of macrophages, adipocytes and muscle cells to trigger pro-inflammatory responses. This review summarizes our observations that fatty acids evoke the release of pro-inflammatory factors from macrophages that consequently induce insulin resistance in muscle cells. [ABSTRACT FROM AUTHOR]

While children with brain tumors are surviving at record rates, survivors are at risk of cardiovascular disease and type 2 diabetes mellitus; these conditions may be driven by excess body fat. Adiponectin in an adipokine that is inversely associated with the fat mass, and has been linked to cardiometabolic risk stratification in the general population. However, adiponectin's profile and determinants in SCBT have not been established. We tested the hypothesis that high molecular weight (HMW) adiponectin levels, the more biologically active form of adiponectin, were associated with adiposity in SCBT similarly to non-cancer controls. Seventy-four SCBT (n = 32 female) and 126 controls (n = 59 female) who were 5–17 years old were included. Partial correlations and multivariable regression analyses assessed the relationship between HMW adiponectin and adiposity. HMW adiponectin was inversely associated with total and central adiposity (FM%: β − 0.21, 95% CI − 0.15, − 0.08; p value < 0.0001; WHR: β − 0.14, 95% CI − 0.02, − 0.01; p value < 0.0001 ;WHtR: β − 0.21, 95% CI − 0.05, − 0.03; p value < 0.0001). In conclusion, HMW adiponectin is inversely correlated with adiposity in SCBT. Adiponectin may serve as a biomarker of cardiometabolic risk and response to interventions to prevent and manage obesity and its comorbidities in SCBT. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is a worldwide epidemic, and while its etiology is polygenic, the role of environmental contaminant exposure in T2DM pathogenesis is of increasing importance. However, the evidence presented in systematic reviews on the relationship between cadmium exposure and T2DM development is inconsistent. This overview aims to assess existing evidence from systematic reviews linking cadmium exposure to T2DM and select metabolic disorders in humans. Methods: Searches will be conducted in Medline, Embase, Web of Science, GEOBASE, BIOSIS Previews, and Cochrane Database of Systematic Reviews. Two reviewers (J.H and S.T.) will independently complete screening, data abstraction, risk of bias evaluation, and quality assessment. The primary outcome will be the association between cadmium exposure and T2DM prevalence. Secondary outcomes will include prediabetes, obesity, dyslipidemia, hypertension, and non-alcoholic fatty liver disease. We will perform a meta-analysis if two or more studies assess similar populations, utilize analogous methods, have related study designs, and evaluate similar outcomes. Discussion: This overview will assess current evidence from systematic reviews for the association between cadmium exposure and risk of T2DM and other metabolic morbidities. This overview may be helpful for policy-makers and healthcare teams aiming to mitigate T2DM risk in populations at risk of cadmium exposure. Systematic review registration: PROSPERO CRD42019125956 [ABSTRACT FROM AUTHOR]

Background: Approximately 50% of all youth-onset type 2 diabetes mellitus (T2DM) in Canada occurs in Indigenous children. In adults, cardiovascular disease is one of the leading causes of mortality in First Nations communities, and diabetes is a significant contributor to the risk of developing this disorder. The early onset of diabetes may predispose these children to premature cardiovascular disease and influence their longevity and quality of life. As a result, the implementation of culturally tailored obesity and T2DM primary prevention programs is vital. This systematic review aims to assess the effectiveness of existing traditional knowledge-based lifestyle intervention programs on preventing obesity and T2DM in Indigenous children in Canada. Methods: We will conduct database searches in MEDLINE, Embase, PsycINFO, SPORTDiscus, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, and the Cochrane Controlled Register of Trials. We will also conduct grey literature searches of central repository of trials (ClinicalTrials.gov), ProQuest Dissertations, Theses A&I, and Indigenous studies portal research tools. Reviewers will independently review titles, abstracts, and full-text articles retrieved from databases to assess potentially eligible studies, and relevant articles will be assessed for risk of bias and quality. The primary outcomes include the change in body mass index z-scores or a diagnosis of diabetes. The secondary outcomes include the change in measures of adiposity as well as lifestyle and metabolic profiles. A meta-analysis will be performed if two or more studies have used similar study designs, comparable intervention techniques , similar populations and measured similar outcomes. Discussion: This review will provide a summary of current interventions to prevent obesity and T2DM in Indigenous children in Canada and help determine the gaps in the literature so that interventions can be developed to control the surge in pediatric T2DM in Indigenous communities. Systematic review registration: PROSPERO CRD42017072781 [ABSTRACT FROM AUTHOR]

Aims: Pediatric type 2 diabetes mellitus (T2DM) is a relatively new disease with increasing incidence corresponding to the obesity epidemic among youth. It is important for clinicians to have access to high-quality clinical practice guidelines (CPGs) for appropriate management of pediatric patients with T2DM. The objective of this systematic review was to evaluate overall quality of CPGs for the management of pediatric T2DM using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. Methods: We searched MEDLINE, Embase, CINAHL, Trip, National Guideline Clearinghouse, and grey literature to identify eligible CPGs. We also searched the webpages of national and international diabetes and pediatric organizations globally. We included CPGs from national and international diabetes and pediatric associations that were published as standalone guidelines for T2DM in children and adolescents (2–18 years of age). We also included pediatric and adult guidelines for type 1 diabetes if they included a section addressing T2DM management in children and adolescents. We retrieved the two most recent guidelines from each organization when available to assess change in quality over time. We excluded individual studies and systematic reviews that made treatment recommendations as well as CPGs that were developed for a single institution. Results: We included 21 unique CPGs in this systematic review. Of the included guidelines, 12 were developed or updated between 2012 and 2014. Five of all included CPGs were specific to pediatric populations. The analysis revealed that "Rigour of Development" (mean 45%, SD 28.68) and "Editorial Independence" (mean 45%, SD 35.19) were the lowest scoring domains on the AGREE II for the majority of guidelines, whereas "Clarity of Presentation" was the highest scoring domain (mean 72%, SD 18.89). Conclusions: Overall, two thirds of the pediatric T2DM guidelines were moderate to low quality and the remaining third ranked higher in quality. Low quality was especially due to the scores for the "Rigour of Development" domain, which directly measures guideline development methodology. It is important that future guidelines and updates of existing guidelines improve the methodology of development and quality of reporting in order to appropriately guide physicians managing children and adolescents with T2DM. Systematic review registration: PROSPERO CRD42016034187 [ABSTRACT FROM AUTHOR]

To evaluate associations between 24-h ambulatory blood pressure monitor (ABPM) data vs. single casual blood pressure (BP) and albuminuria in youth with type 2 diabetes. A cross-sectional analysis of youth with type 2 diabetes 10–<18 yrs. from the iCARE cohort. Main exposures: daytime HTN (+/− nocturnal), isolated nocturnal HTN and single casual BP. Main outcome: non-orthostatic urine albumin: creatinine ratio (ACR) ≥ 3 mg/mmol and log-transformed urine ACR. Regressions evaluated associations between 1. HTN status based on ABPM and log-transformed urine ACR (continuous) and 2. ABPM-derived BP z-scores and casual BPcentiles and albuminuria status (categorical). Of 281 youth included, 19.6 % had daytime HTN (+/− nocturnal), and 28.5 % isolated nocturnal HTN on 24-h ABPM. In multivariate linear regression, HTN (ABPM) (ß = 0.553; p = 0.001), duration of diabetes (ß = 0.857; p = 0.02), HbA1c (ß = 1.172; p ≤0.0001) and ACEI/ARB use (ß = 3.94; p < 0.0001) were positively associated with log-transformed ACR; (R2 = 0.184). In logistic regression analysis, all ABPM LMS z-scores were positively associated with albuminuria; casual BPcentile was not significant. Youth with type 2 diabetes have high rates of HTN based on 24-ABPM data. ABPM-derived measures of BP are associated with albuminuria. These data support the routine use of ABPM devices to diagnose hypertension in youth with type 2 diabetes. • 24-h ABPMs are recommended for screening in at risk children, but not often used in youth with type 2 diabetes in practice. • Daytime and nocturnal hypertension are common in youth with type 2 diabetes and associated with albuminuria. • Physicians should consider implementing screening with 24-hour ABPMs into routine care of youth living with type 2 diabetes. [ABSTRACT FROM AUTHOR]