Study to Investigate the Pathophysiology of Type 2 Diabetes in Youth

The purpose of the study is to determine the role of beta-cell function and insulin resistance in the development of impaired glucose tolerance (IGT) and type 2 diabetes in children and adolescents who have an increased risk of developing type 2 diabetes due to overweight/obesity or a family history of overweight/obesity, diabetes and/or impaired fasting glucose. It is hypothesized that: 1)Obese adolescents with IGT will be more insulin resistant than obese adolescents with NGT. Insulin resistance will be the best predictor of changes in glucose tolerance status., 2)Beta cell function will be impaired in obese adolescents with IGT compared to obese adolescents with NGT., 3)Obese adolescents with IGT will present with greater intramyocellular, intrahepatic and visceral fat than obese adolescents with NGT. Furthermore, obese adolescents with IGT will have larger adipocytes, while having significantly fewer adipocytes compared to obese adolescents with NGT. Obese adolescents with IGT will also have altered expression of key genes related to insulin resistance., and 4)Abnormalities in endothelial function as manifested by low FMD and PAT are already present in obese adolescents with IGT and are linked to insulin resistance.

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome; Insulin Resistance; Childhood Obesity; Impaired Glucose Tolerance; Pre-diabetes

Detailed Description

Type 2 diabetes is a serious and common chronic disease affecting an estimated 6.6% of the U.S. population 20 to 74 years of age. Among children, type 2 diabetes has previously been reported to account for 2% to 3% of all patients with diabetes mellitus. Recent studies, however, indicate that the prevalence of this disorder is increasing in the pediatric population. This phenomenon parallels the increased prevalence of obesity in children and adolescents, particularly in African-American and Hispanic ethnic groups. Despite the wealth of knowledge concerning the epidemiology, pathophysiology and treatment of type 2 diabetes in adults, we know little about the disease in children.Paralleling the rise in childhood obesity and type 2 diabetes is an increase in the metabolic syndrome in youth. The metabolic syndrome, also known as "Syndrome X," is characterized by hypertension, type 2 diabetes, dyslipidemia and obesity. This syndrome was first described in 1966 by Camus and again by Reaven in 1988. Cook et al. showed that the metabolic syndrome is already present in 6.8% of 12-19 year-olds with a BMI between the 85th and 95th percentiles, and in 28.7% of those with a BMI greater than the 95th percentile. In addition, recent studies from our group suggest that risk factors for type 2 diabetes and the metabolic syndrome are already present in overweight children and adolescents. As the degree of obesity worsens, the prevalence of these risk factors greatly increase.Overweight and obese adolescents with NGT and with IGT will be recruited. Progression from NGT to IGT and from IGT to type 2 diabetes will be assessed by annual oral glucose tolerance tests (OGTT). Comprehensive metabolic assessments will be employed to examine within and between group differences in insulin action and beta-cell function at baseline and during the follow-up.

• Study Type: Observational
• Enrollment (Actual): 255

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • 47 College Street

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 22 years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Children and Adolscents seen at the Yale Pediatric Obesity Clinic.

Description

Inclusion Criteria:

• Lean (not overweight or obese) will be defined as a body mass index (BMI) (kg/m2) less than the 85th percentile specific for age and gender, overweight will be defined as a BMI between the 85th and 95th percentiles, and obesity will be defined as a BMI greater than the 95th percentile1. Following the oral glucose tolerance test (OGTT, 75 gm) (HIC #11190), children will be classified as normal glucose tolerant if plasma glucose at two hours is <140 mg/dl and as impaired glucose tolerant if plasma glucose is ≥140 mg/dl. To enter the study all children and adults must be in good general health, have a normal medical history and physical exam, and have no endocrinopathies (normal thyroid function test) or other diseases that might affect glucose metabolism.
• Eligibility will be determined by a comprehensive family and medical history and physical examination prior to enrollment in the study. Tanner stage of pubic breast and gonadal development will be determined by physical examination and by measurements of estradiol, testosterone and IGF1 as biochemical markers of pubertal development.

Exclusion Criteria:

• Medications that are known to alter glucose or insulin metabolism, such as oral steroids, or certain psychiatric medications, such as Celexa, Lithium and Paxil. Children and adults will be excluded from participating in the PAT test if they have a latex allergy. Lean subjects must have at least one parent, grandparent or sibling with overweight/obesity (BMI >25), type 2 diabetes, and/or impaired fasting glucose (IFG) (fasting glucose >100 mg/dl). A fasting plasma glucose level will be obtained via finger stick in parents of potential volunteers in whom status of diabetes or IFG is unknown. Exclusion criteria also include known diabetes or taking any medication that alters liver function and blood pressure. Youth on chronic anti-inflammatory medications or who consume alcohol are also excluded.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
glucose tolerance	glucose tolerance status as determined by oral glucose tolerance test - fasting and 2 hour glucoses	baseline and follow up
insulin resistance	insulin resistance as measured during oral glucose tolerance test by WBISI	baseline and follow up
hepatic fat content and abdominal fat ratio	hepatic fat content and abdominal fat ratio measured by liver mri and abdominal mri	baseline and follow up

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Sonia Caprio, M.D., Yale University

Publications and helpful links

General Publications

• Berry D, Savoye M, Melkus G, Grey M. An intervention for multiethnic obese parents and overweight children. Appl Nurs Res. 2007 May;20(2):63-71. doi: 10.1016/j.apnr.2006.01.007.
• McCartney CR, Blank SK, Prendergast KA, Chhabra S, Eagleson CA, Helm KD, Yoo R, Chang RJ, Foster CM, Caprio S, Marshall JC. Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls. J Clin Endocrinol Metab. 2007 Feb;92(2):430-6. doi: 10.1210/jc.2006-2002. Epub 2006 Nov 21.
• Trico D, Prinsen H, Giannini C, de Graaf R, Juchem C, Li F, Caprio S, Santoro N, Herzog RI. Elevated alpha-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents. J Clin Endocrinol Metab. 2017 Jul 1;102(7):2473-2481. doi: 10.1210/jc.2017-00475.
• D'Adamo E, Northrup V, Weiss R, Santoro N, Pierpont B, Savoye M, O'Malley G, Caprio S. Ethnic differences in lipoprotein subclasses in obese adolescents: importance of liver and intraabdominal fat accretion. Am J Clin Nutr. 2010 Sep;92(3):500-8. doi: 10.3945/ajcn.2010.29270. Epub 2010 Jun 23.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2001
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: September 25, 2007
• First Submitted That Met QC Criteria: September 25, 2007
• First Posted (Estimate): September 27, 2007

Study Record Updates

• Last Update Posted (Actual): January 18, 2018
• Last Update Submitted That Met QC Criteria: January 16, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Childhood Obesity; Metabolic Syndrome; insulin resistance; Pre-Diabetes; Impaired Glucose Tolerance; Non Alcoholic Fatty Liver Disease; High Molecular Weight Adiponectin; Hypoadiponectinemia
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Hyperinsulinism; Hyperglycemia; Obesity; Diabetes Mellitus; Metabolic Syndrome; Pediatric Obesity; Prediabetic State; Glucose Intolerance; Insulin Resistance
• Other Study ID Numbers: 0102012241; R01HD040787 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO