Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes

Type 2 Diabetes (T2D) in obese youth is often preceded by a prediabetic state called: Impaired Glucose Tolerance (IGT), which is associated with a pre-existing defect in insulin secretion. This study intends to determine if genetic factors are associated with defects in insulin secretion, the incretin system and hepatic insulin resistance in obese adolescents. The long-term goal of this study is to generate information on both the genetics as well as the pathophysiology of Type 2 Diabetes in Youth, which ultimately might guide the investigators towards better preventive and treatment avenues.

Study Overview

• Status: Completed
• Conditions: T2D; IGT - Impaired Glucose Tolerance
• Intervention / Treatment: Diagnostic test: Oral Glucose Tolerance Test; Diagnostic test: Hyperglycemic Clamp; Diagnostic test: Isoglycemic Intravenous Glucose Test; Diagnostic test: Hyperinsulinemic Euglycemic Clamp and 2H20

Detailed Description

The Specific Aims of this study are:

Aim 1a. To delineate the effects of TCF7L2 rs7903146 on functional Beta-Cell Capacity in obese adolescents with Impaired Glucose Tolerance (IGT) and pre-IGT.

Aim 1b. To determine if the risk genotype in TCF7L2 is associated with worsening in beta cell function longitudinally, thereby affecting changes in glucose tolerance.

Aim 2. To examine the functional effect of the rs7903146 variant in the TCF7L2 gene on a) incretin effect in obese adolescents with IGT and pre-IGT.

Aim 3. To determine the functional effects of TCF7L2 rs7903146 SNP on hepatic glucose fluxes in obese adolescents with IGT and pre-IGT.

• Study Type: Observational
• Enrollment (Actual): 100

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Subjects will be selected from the Yale Pediatric Obesity Clinic or from the existing cohort of subjects who have had Oral Glucose Tolerance Tests and genotyping. Subjects will be Pre IGT and IGT adolescents 12-18 years old with either the CC or TT genotype. 50 CC pre IGT/IGT obese patients and 50 TT pre IGT/IGT obese patients will be rectruited.

Description

Inclusion Criteria:

• Good general health, taking no medication on a chronic basis;
• Age 12 to 18 yrs, in puberty (girls and boys: Tanner stage II - IV),
• BMI (BMI >85th%) indicating obesity,
• Girls who are menstruating must have a negative pregnancy test during the study and, when possible, be in the follicular phase during infusion study visits (The follicular phase will be identified according to the last menstrual period record and/or according to the oral contraceptive assumption schedule. The investigators will not perform ovulation testing or hormonal assays);
• Subject must have normal liver and kidney function, amylase and lipase levels.
• Pre-IGT or IGT
• TT or CC genotype.

Exclusion Criteria:

• Baseline creatinine >1.0 mg;
• Pregnancy;
• Presence of endocrinopathies (e.g. Cushing syndrome);
• Cardiac, renal or pulmonary or other chronic illness;
• Adolescents with psychiatric disorder or with substance abuse history and taking the drugs that affect glucose metabolism, such as any form of steroids, antipsychotics, progesterone preparations, and others.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
CC Genotype; Subjects who have not already been tested previously will be tested for the TCF7L2 genotype to determine if they are TT or CC. An anticipated 50 obese CC adolescents with IGT or pre-IGT with similar age, pubertal stage, ethnicity and Body Mass Index (BMI) will enrolled. Subjects will undergo Oral Glucose Tolerance Test, Hyperglycemic Clamp, Isoglycemic Intravenous Glucose Test IsoG IVGT and Hyperinsulinemic Euglycemic Clamp and 2H20.	Diagnostic test: Oral Glucose Tolerance Test; The oral glucose tolerance test (OGTT) measures the body's ability to use a type of sugar, called glucose, that is the body's main source of energy. An OGTT can be used to diagnose prediabetes and diabetes.; Other Names: OGTT; Diagnostic test: Hyperglycemic Clamp; Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.; Other Names: Infusion Study; Diagnostic test: Isoglycemic Intravenous Glucose Test; Test which exposes pancreas to blood glucose levels matched to the ones obtained at the OGTT.; Other Names: IsoG IVGT; Diagnostic test: Hyperinsulinemic Euglycemic Clamp and 2H20; Test is used to assess insulin effects on hepatic glucose production.; Other Names: E Clamp with labeled water
TT Genotype; Subjects who have not already been tested previously will be tested for the TCF7L2 genotype to determine if they are TT or CC. An anticipated 50 TT subjects will be enrolled in this group. An anticipated 50 obese TT adolescents with IGT or pre-IGT with similar age, pubertal stage, ethnicity and Body Mass Index (BMI) will be enrolled. Subjects will undergo Oral Glucose Tolerance Test, Hyperglycemic Clamp, Isoglycemic Intravenous Glucose Test IsoG IVGT and Hyperinsulinemic Euglycemic Clamp and 2H20	Diagnostic test: Oral Glucose Tolerance Test; The oral glucose tolerance test (OGTT) measures the body's ability to use a type of sugar, called glucose, that is the body's main source of energy. An OGTT can be used to diagnose prediabetes and diabetes.; Other Names: OGTT; Diagnostic test: Hyperglycemic Clamp; Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.; Other Names: Infusion Study; Diagnostic test: Isoglycemic Intravenous Glucose Test; Test which exposes pancreas to blood glucose levels matched to the ones obtained at the OGTT.; Other Names: IsoG IVGT; Diagnostic test: Hyperinsulinemic Euglycemic Clamp and 2H20; Test is used to assess insulin effects on hepatic glucose production.; Other Names: E Clamp with labeled water

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose tolerance status	An oral glucose tolerance test will be performed to assess glucose tolerance status to determine if subjects are pre-IGT or IGT	Baseline
Genotype	DNA screening to measure whether subject is CC or TT genotype	Baseline
Beta cell capacity	AIRmax stimulation test during the hyperglycemic clamp to ascertain the maximal acute insulin response (AIR) to arginine, which is a measure of functional beta cell capacity.	Baseline
Incretin effect	Subjects will undergo the IsoIVGT test with GLP-1 measurements to measure the incretin effect	3weeks to 1 month post Baseline testing
Beta cell function (longitudinally)	The AIRmax stimulation test during the hyperglycemic clamp will be repeated at 2 years to determine if genotype TCF7L2 contributes to worsening in beta cell function longitudinally	2 years post Baseline
Hepatic glucose fluxes	Measurements from the Hyperinsulinemic Euglycemic Clamp/ 2H20 Study will be used to assess insulin effects on hepatic glucose production and glycerol kinetics isotopes and the deuterium enrichment at carbons 2 and 5 (C2 and C5) of plasma glucose providing information on glucose fluxes	2 months post baseline testing

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Sonia Caprio, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Actual): August 31, 2021
• Study Completion (Actual): August 12, 2022

Study Registration Dates

• First Submitted: March 22, 2017
• First Submitted That Met QC Criteria: June 21, 2017
• First Posted (Actual): June 22, 2017

Study Record Updates

• Last Update Posted (Estimate): February 23, 2023
• Last Update Submitted That Met QC Criteria: February 22, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperglycemia; Prediabetic State; Glucose Intolerance
• Other Study ID Numbers: 2000020183; 1R01DK111038-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No