Mitochondrial Function in Pediatric Obesity

The prevalence of pediatric obesity is increasing at an unprecedented rate. Obese children are at risk for the development of insulin resistance, relative insulin deficiency and type 2 diabetes mellitus. However, the cause of insulin resistance remains an area of scientific interest. The study of type 2 diabetes in children is limited by the lack of a non-invasive method to evaluate insulin resistance. Recent studies have suggested that mitochondrial dysfunction is associated with, and perhaps predictive of insulin resistance in adult relatives of individuals with type 2 diabetes. Mitochondria generate energy in muscle tissue through the production of ATP, and are important in the metabolism of both glucose and fat. This study evaluates a novel, non invasive, safe method for predicting insulin resistance and diabetes in children using a magnetic resonance imaging (MRI) based technique to measure mitochondrial function. We propose to investigate mitochondrial function and glucose metabolism in obese and non-obese children in early, mid and late puberty. Analyses will be conducted to investigate the presence of mitochondrial dysfunction in obese children, to evaluate the contribution of mitochondrial dysfunction to insulin resistance, and to determine the contribution of pubertal status to mitochondrial dysfunction and insulin resistance. The successful completion of this study would provide evidence to support the hypothesis that mitochondrial dysfunction plays a role in insulin resistance and diabetes in children. In addition, it would provide a new technique for the prediction of disease states and perhaps lead to the development of preventative therapeutics for insulin resistance and type 2 diabetes in children.

We hypothesize that mitochondrial dysfunction will mirror the progression of insulin resistance and precede and predict abnormal glucose metabolism in a population with pediatric obesity

Study Overview

• Status: Unknown
• Conditions: Obesity; Insulin Resistance

Detailed Description

Aim I: A cross sectional study to evaluate baseline mitochondrial function in obese children compared to non-obese children. Determine whether children with pediatric obesity have impaired mitochondrial function based on 31P magnetic resonance spectroscopy when compared to healthy non-obese control children.Examine the relationship between mitochondrial function and insulin resistance in obese and non-obese children. Determine the impact of pubertal stage on mitochondrial function in obese and non-obese children.

Aim II:A prospective evaluation to determine in a longitudinal cohort study the timing and relationship of mitochondrial dysfunction to the development of insulin resistance in prepubertal/early pubertal obese children compared to prepubertal/early pubertal non-obese children. Determine in a longitudinal cohort study if obese children with mitochondrial dysfunction develop greater insulin resistance and/or impaired glucose tolerance at an earlier time point. Evaluate the relationship of obesity, timing of puberty and related changes in hormone levels to mitochondrial function and the development of insulin resistance and/or impaired glucose tolerance in longitudinal analyses.

• Study Type: Observational
• Enrollment (Anticipated): 110

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Healthy and obese children from clinical practices and the local community

Description

Inclusion Criteria:

1. Girls and boys ages 8 to 18 years old
2. Non-obese cohort: body mass index less than 75th percentile for age
3. Obese cohort: body mass index more than 95th percentile for age

Exclusion Criteria:

1. Underlying medical problem with potential to affect growth, pubertal development or glucose homeostasis
2. Chronic medical therapy with glucocorticoids, growth hormone, estrogen, progesterone, testosterone, or other medications with the potential to alter growth, pubertal development or glucose homeostasis within the proceeding 6 months
3. Personal history of diabetes
4. Family history of diabetes in first degree relative
5. Inability to have MRI scan performed due to metal prosthesis or implant

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
1. Controls; Healthy children ages 8 to 18 years
2. Obese childrens; Obese children, ages 8 to 18 years

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Determine whether children with pediatric obesity have impaired mitochondrial function based on 31P magnetic resonance spectroscopy when compared to healthy non-obese control children	4 years
Examine the relationship between mitochondrial function and insulin resistance in obese and non-obese children	four years

Secondary Outcome Measures

Outcome Measure	Time Frame
Determine the impact of pubertal stage, dietary intake, activity recall, inflammatory markers and metabolic markers on mitochondrial function in obese and non-obese children	four years
Evaluate the relationship of obesity, timing of puberty and related changes in hormone levels to mitochondrial function and the development of insulin resistance and/or impaired glucose tolerance in longitudinal analyses	four years

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Boston Children's Hospital; Lawson Wilkins Pediatric Endocrine Society
• Investigators: Principal Investigator: Amy D Fleischman, MD, MMSc, Massachusetts General Hospital

Publications and helpful links

General Publications

• Fleischman A, Kron M, Systrom DM, Hrovat M, Grinspoon SK. Mitochondrial function and insulin resistance in overweight and normal-weight children. J Clin Endocrinol Metab. 2009 Dec;94(12):4923-30. doi: 10.1210/jc.2009-1590. Epub 2009 Oct 21.
• Fleischman A, Makimura H, Stanley TL, McCarthy MA, Kron M, Sun N, Chuzi S, Hrovat MI, Systrom DM, Grinspoon SK. Skeletal muscle phosphocreatine recovery after submaximal exercise in children and young and middle-aged adults. J Clin Endocrinol Metab. 2010 Sep;95(9):E69-74. doi: 10.1210/jc.2010-0527. Epub 2010 Jun 16.
• McCormack SE, McCarthy MA, Farilla L, Hrovat MI, Systrom DM, Grinspoon SK, Fleischman A. Skeletal muscle mitochondrial function is associated with longitudinal growth velocity in children and adolescents. J Clin Endocrinol Metab. 2011 Oct;96(10):E1612-8. doi: 10.1210/jc.2011-1218. Epub 2011 Aug 10.

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): August 1, 2011
• Study Completion (Anticipated): October 1, 2012

Study Registration Dates

• First Submitted: December 18, 2007
• First Submitted That Met QC Criteria: December 18, 2007
• First Posted (Estimate): December 20, 2007

Study Record Updates

• Last Update Posted (Estimate): April 30, 2012
• Last Update Submitted That Met QC Criteria: April 27, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: Diabetes; Obesity; Insulin resistance; Children; Mitochondrial Function
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Hyperinsulinism; Obesity; Pediatric Obesity; Insulin Resistance
• Other Study ID Numbers: 1K23DK080658 (U.S. NIH Grant/Contract); 2006p001067, Partners IRB; 575, MIT IRB