Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes

NCT ID: NCT03195400

Last Updated: 2023-02-23

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

100 participants

Study Classification

OBSERVATIONAL

Study Start Date

2017-03-01

Study Completion Date

2022-08-12

Brief Summary

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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.

Detailed Description

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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.

Conditions

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IGT - Impaired Glucose Tolerance T2D

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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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.

Oral Glucose Tolerance Test

Intervention Type 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.

Hyperglycemic Clamp

Intervention Type DIAGNOSTIC_TEST

Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.

Isoglycemic Intravenous Glucose Test

Intervention Type DIAGNOSTIC_TEST

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

Hyperinsulinemic Euglycemic Clamp and 2H20

Intervention Type DIAGNOSTIC_TEST

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

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

Oral Glucose Tolerance Test

Intervention Type 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.

Hyperglycemic Clamp

Intervention Type DIAGNOSTIC_TEST

Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.

Isoglycemic Intravenous Glucose Test

Intervention Type DIAGNOSTIC_TEST

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

Hyperinsulinemic Euglycemic Clamp and 2H20

Intervention Type DIAGNOSTIC_TEST

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

Interventions

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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.

Intervention Type 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.

Intervention Type DIAGNOSTIC_TEST

Isoglycemic Intravenous Glucose Test

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

Intervention Type DIAGNOSTIC_TEST

Hyperinsulinemic Euglycemic Clamp and 2H20

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

Intervention Type DIAGNOSTIC_TEST

Other Intervention Names

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OGTT Infusion Study IsoG IVGT E Clamp with labeled water

Eligibility Criteria

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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.
Minimum Eligible Age

12 Years

Maximum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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

NIH

Sponsor Role collaborator

Yale University

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Sonia Caprio, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

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Yale University

New Haven, Connecticut, United States

Site Status

Countries

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United States

Other Identifiers

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1R01DK111038-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2000020183

Identifier Type: -

Identifier Source: org_study_id

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