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Completed

NCT Number: NCT03195400

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.

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Key information

Conditions

IGT - Impaired Glucose Tolerance Glucose Intolerance Glucose Metabolism Disorders Hyperglycemia Metabolic Diseases Nutritional and Metabolic Diseases T2D

Age range

12 year–18 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Yale University

New Haven, Connecticut, 06510, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Oral glucose tolerance test

Diagnostic 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

Hyperglycemic Clamp

Diagnostic Test

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

Isoglycemic Intravenous Glucose Test

Diagnostic Test

Test which exposes pancreas to blood glucose levels matched to the ones obtained at the OGTT.

Other names: IsoG IVGT

Hyperinsulinemic Euglycemic Clamp and 2H20

Diagnostic Test

Test is used to assess insulin effects on hepatic glucose production.

Other names: E Clamp with labeled water

Primary outcomes

  1. Glucose tolerance status

    Time frame: Baseline

    An oral glucose tolerance test will be performed to assess glucose tolerance status to determine if subjects are pre-IGT or IGT

  2. Genotype

    Time frame: Baseline

    DNA screening to measure whether subject is CC or TT genotype

  3. Beta cell capacity

    Time frame: Baseline

    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.

  4. Incretin effect

    Time frame: 3weeks to 1 month post Baseline testing

    Subjects will undergo the IsoIVGT test with GLP-1 measurements to measure the incretin effect

  5. Beta cell function (longitudinally)

    Time frame: 2 years post Baseline

    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

  6. Hepatic glucose fluxes

    Time frame: 2 months post baseline testing

    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

Sponsors and collaborators

Lead sponsor

Yale University

Other

Collaborators

  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Registry information

Important dates

Study start
2017
Primary completion
2021
Study completion
2022
First posted
Jun 22, 2017
Registry last updated
Feb 23, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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