Kristen J. Nadeau

Insulin Resistance in Adolescents with Type 1 Diabetes and Its Relationship to Cardiovascular Function

CONTEXT Cardiovascular disease is the major cause of death in adults with diabetes, yet little is specifically known about the effects of type 1 diabetes (T1D) on cardiovascular outcomes in youth. Although insulin resistance (IR) likely contributes to exercise and cardiovascular dysfunction in T2D, IR is not typically considered a contributor in T1D. OBJECTIVE We hypothesized that cardiopulmonary fitness would be reduced in T1D youth in association with IR and cardiovascular dysfunction. DESIGN AND PARTICIPANTS This cross-sectional study at an academic hospital included 12 T1D adolescents compared with 12 nondiabetic controls, similar in age, pubertal stage, activity level, and body mass index. OUTCOME MEASURES Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, intramyocellular lipid by magnetic resonance spectroscopy, and body composition by dual-energy x-ray absorptiometry. RESULTS T1D adolescents had significantly decreased VO(2)peak, peak work rate, and insulin sensitivity compared with nondiabetic adolescents. T1D youth also had reduced vascular reactivity and evidence of diastolic dysfunction and left ventricular hypertrophy. Despite their IR and reduced cardiovascular fitness, T1D youth had paradoxically normal intramyocellular lipid, waist to hip ratio, and serum lipids and high adiponectin levels. In multivariate analysis, IR primarily, and forearm blood flow secondarily, independently predicted VO(2)peak. CONCLUSIONS T1D youth demonstrated IR, impaired functional exercise capacity and cardiovascular dysfunction. The phenotype of IR in T1D youth was unique, suggesting a pathophysiology that is different from T2D, yet may adversely affect long-term cardiovascular outcomes.

Age-related consequences of childhood obesity.

The severity and frequency of childhood obesity has increased significantly over the past three to four decades. The health effects of increased body mass index as a child may significantly impact obese youth as they age. However, many of the long-term outcomes of childhood obesity have yet to be studied. This article examines the currently available longitudinal data evaluating the effects of childhood obesity on adult outcomes. Consequences of obesity include an increased risk of developing the metabolic syndrome, cardiovascular disease, type 2 diabetes and its associated retinal and renal complications, nonalcoholic fatty liver disease, obstructive sleep apnea, polycystic ovarian syndrome, infertility, asthma, orthopedic complications, psychiatric disease, and increased rates of cancer, among others. These disorders can start as early as childhood, and such early onset increases the likelihood of early morbidity and mortality. Being obese as a child also increases the likelihood of being obese as an adult, and obesity in adulthood also leads to obesity-related complications. This review outlines the evidence for childhood obesity as a predictor of adult obesity and obesity-related disorders, thereby emphasizing the importance of early intervention to prevent the onset of obesity in childhood.

Insulin Resistance in Adolescents with Type 2 Diabetes Is Associated with Impaired Exercise Capacity

CONTEXT The incidence of pediatric type 2 diabetes (T2D) is rising, with unclear effects on the cardiovascular system. Cardiopulmonary fitness, a marker of morbidity and mortality, is abnormal in adults with T2D, yet the mechanisms are incompletely understood. OBJECTIVE We hypothesized that cardiopulmonary fitness would be reduced in youth with T2D in association with insulin resistance (IR) and cardiovascular dysfunction. DESIGN, SETTING, AND PARTICIPANTS We conducted a cross-sectional study at an academic hospital that included 14 adolescents (age range, 12-19 yr) with T2D, 13 equally obese adolescents and 12 lean adolescents similar in age, pubertal stage, and activity level. MAIN OUTCOME MEASURES Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, body composition by dual-energy x-ray absorptiometry, intramyocellular lipid by magnetic resonance spectroscopy, and inflammation by serum markers. RESULTS Adolescents with T2D had significantly decreased VO(2)peak and insulin sensitivity, and increased soleus intramyocellular lipid, C-reactive protein, and IL-6 compared to obese or lean adolescents. Adolescents with T2D also had significantly prolonged VO(2)kinetics, decreased work rate, vascular reactivity, and adiponectin, and increased left ventricular mass and fatty acids compared to lean adolescents. In multivariate linear regression analysis, IR primarily, and fasting free fatty acids and forearm blood flow secondarily, were significant independent predictors of VO(2)peak. CONCLUSIONS Given the strong relationship between decreased cardiopulmonary fitness and increased mortality, these findings in children are especially concerning and represent early signs of impaired cardiac function.

Childhood obesity and cardiovascular disease: links and prevention strategies

The prevalence and severity of pediatric obesity have dramatically increased since the late 1980s, raising concerns about a subsequent increase in cardiovascular outcomes. Strong evidence, particularly from autopsy studies, supports the concept that precursors of adult cardiovascular disease (CVD) begin in childhood, and that pediatric obesity has an important influence on overall CVD risk. Lifestyle patterns also begin early and impact CVD risk. In addition, obesity and other CVD risk factors tend to persist over time. However, whether childhood obesity causes adult CVD directly, or does so by persisting as adult obesity, or both, is less clear. Regardless, sufficient data exist to warrant early implementation of both obesity prevention and treatment in youth and adults. In this Review, we examine the evidence supporting the impact of childhood obesity on adult obesity, surrogate markers of CVD, components of the metabolic syndrome, and the development of CVD. We also evaluate how obesity treatment strategies can improve risk factors and, ultimately, adverse clinical outcomes.

Type 2 diabetes in the child and adolescent

Phil Zeitlera, Junfen Fub, Nikhil Tandonc, Kristen Nadeaua, Tatsuhiko Urakamid, Timothy Barrette and David Maahsf aThe Children’s Hospital Colorado, Aurora, CO, USA; bThe Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China; cAll India Institute of Medical Sciences, New Delhi, India; dNihon University School of Medicine, Tokyo, Japan; eBirmingham Children’s Hospital, Birmingham, UK and fThe Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA

Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes

OBJECTIVE Type 2 diabetes increases cardiovascular risk. We examined lipid profiles and inflammatory markers in 699 youth with recent-onset type 2 diabetes in the TODAY clinical trial and compared changes across treatment groups: metformin alone (M), metformin plus rosiglitazone (M+R), and metformin plus intensive lifestyle program (M+L). RESEARCH DESIGN AND METHODS Multiethnic youth with type 2 diabetes received M, M+R, or M+L. Statin drugs were begun for LDL cholesterol (LDL) ≥130 mg/dL or triglycerides ≥300 mg/dL. Lipids, apolipoprotein B (apoB), LDL particle size, high-sensitivity c-reactive protein (hsCRP), homocysteine, plasminogen activator inhibitor-1 (PAI-1), and HbA1c were measured over 36 months or until loss of glycemic control. RESULTS LDL, apoB, triglycerides, and non-HDL cholesterol (HDL) rose over 12 months and then stabilized over the next 24 months. Participants with LDL ≥130 mg/dL or using LDL-lowering therapy increased from 4.5 to 10.7% over 36 months, while 55.9% remained at LDL goal (<100 mg/dL) over that time. Treatment group did not impact LDL, apoB, or non-HDL. Small dense LDL (particle size, ≤0.263 relative flotation rate) was most common in M. Triglycerides were lower in M+L than M, and M+L attenuated the negative effect of hyperglycemia on triglycerides and HDL in females. hsCRP, PAI-1, and homocysteine increased over time. However, hsCRP was lower in M+R compared with M or M+L. CONCLUSIONS Dyslipidemia and chronic inflammation were common in youth with type 2 diabetes and worsened over time. Diabetes treatment, despite some treatment group differences in lipid and inflammatory marker change over time, is generally inadequate to control this worsening risk.

ISPAD Clinical Practice Consensus Guidelines 2014. Type 2 diabetes in the child and adolescent.

Phil Zeitlera, Junfen Fub, Nikhil Tandonc, Kristen Nadeaua, Tatsuhiko Urakamid, Timothy Barrette and David Maahsf aThe Children’s Hospital Colorado, Aurora, CO, USA; bThe Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China; cAll India Institute of Medical Sciences, New Delhi, India; dNihon University School of Medicine, Tokyo, Japan; eBirmingham Children’s Hospital, Birmingham, UK and fThe Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA

Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents.

Abstract:  The presence of fatty liver per ultrasound and liver‐associated enzymes were measured in a select cohort of youth with both obesity and insulin resistance, and the effect of metformin on these parameters evaluated. Fifty obese, multiethnic, insulin‐resistant adolescents (mean age 15.1 yr, mean body mass index 39.8 kg/m2) were randomized to receive lifestyle recommendations plus either twice per day doses of 850 mg of metformin or placebo. Fasting and post‐glucose challenge biochemistries and liver ultrasounds were compared at baseline and 6 months. The prevalence of fatty liver was 74%, elevated alanine aminotransferase (ALT) 14%, aspartate aminotransferase (AST) 14%, and gamma‐glutamyl transferase (GGT) 17%. Fatty liver was mild in 23%, moderate in 31%, and severe in 46%. Fatty liver was more common in male and Hispanic subjects and elevated ALT more common in Hispanic subjects. Subjects with fatty liver appeared more insulin resistant (higher fasting insulin and triglycerides, lower high‐density lipoprotein cholesterol) and had higher ALT and AST. At 6 months, mean ALT, GGT, and fasting insulin improved significantly in all subjects. Fatty liver prevalence (p < 0.04), severity (p < 0.04), and fasting insulin (p < 0.025) improved significantly with metformin compared to placebo. Non‐alcoholic fatty liver disease (NAFLD) occurs with a high prevalence and severity in obese, insulin‐resistant adolescents. While metformin plus lifestyle intervention appears promising, defining NAFLD therapies capable of preventing fibrosis and cirrhosis requires further study.

Cardiovascular Disease Risk Factors in Youth With Diabetes Mellitus A Scientific Statement From the American Heart Association

The rates of both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are increasing in youth.1 In the past 10 years, guidelines for the identification and management of cardiovascular disease (CVD) risk factors in youth with diabetes mellitus have been published by multiple professional organizations, including the American Diabetes Association (ADA),2,3 the American Heart Association (AHA),4,5 the American Academy of Pediatrics,6 the International Society of Pediatric and Adolescent Diabetes (ISPAD),7 and the Pediatric Cardiovascular Risk Reduction Initiative.8 This scientific statement summarizes and interprets these guidelines and new developments in the field in the past decade and outlines future research and clinical needs to improve cardiovascular health and risk factor management in youth with diabetes mellitus. Additional goals for this statement are to increase awareness of CVD risk factors and their identification, prevention, and treatment and to improve cardiovascular health in youth with diabetes mellitus by encouraging advancement in research and clinical care, including understanding and implementing current CVD guidelines. Improving cardiovascular health in youth with diabetes mellitus has important public health implications; therefore, this statement aims to reach healthcare providers in diabetes mellitus, cardiology, and related fields. (Note: The sections within this scientific statement are organized by diabetes mellitus type, when possible, with brief summary statements concluding each section. Multiple definitions for CVD are used in the cited articles. Readers of this statement should include risk factors, surrogate markers, and end-organ damage under this umbrella term of CVD.) ### Type 1 Diabetes Mellitus Multiple studies document an increase of 2% to 5% annually in the incidence of T1DM worldwide.9 The SEARCH for Diabetes in Youth (SEARCH) study estimated that there were 166 018 to 179 388 youth with T1DM in the United States in 2010.1 Worldwide, rates of T1DM differ …

The metabolic syndrome and nonalcoholic fatty liver disease in children.

Purpose of review Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in pediatric-age individuals, in parallel with increasing obesity, and can lead to liver inflammation, fibrosis, and even cirrhosis. NAFLD appears tightly linked with features of the metabolic syndrome (MetS). This review aims to reconsider the clinical presentation, laboratory and pathologic assessment, and treatment of NAFLD, with a focus on its relationship with the MetS. Recent findings NAFLD occurs with a high prevalence and severity in obese, insulin-resistant adolescents, especially Hispanic males. Pediatric NAFLD may improve with lifestyle therapy and agents that improve insulin sensitivity. In youth, NAFLD appears tightly correlated with components of the MetS, especially visceral fat, which appears to predict fibrosis as well as liver fat. In addition, noninvasive techniques such as transient elastography may help provide data on fibrosis in youth with NAFLD and avoid biopsy. Summary The close association between NAFLD and the MetS supports screening for other comorbidities associated with the MetS. Further research is urgently required to best identify effective therapies to prevent and treat NAFLD, but its close association with MetS argues for a focus on strategies designed to improve insulin resistance and components of the MetS.