Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes

NCT03195400 | Completed DMC

• 2 other identifiers: 20000201831R01DK111038-01A1
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

IGT - Impaired Glucose Tolerance; T2D

Outcome Measures

Primary Outcomes (6)

• 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

Study Arms (2)

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; Diagnostic Test: Hyperglycemic Clamp; Diagnostic Test: Isoglycemic Intravenous Glucose Test; Diagnostic Test: Hyperinsulinemic Euglycemic Clamp and 2H20

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; Diagnostic Test: Hyperglycemic Clamp; Diagnostic Test: Isoglycemic Intravenous Glucose Test; Diagnostic Test: Hyperinsulinemic Euglycemic Clamp and 2H20

Interventions

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.

Also known as: OGTT

CC Genotype; TT Genotype

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.

Also known as: Infusion Study

CC Genotype; TT Genotype

Isoglycemic Intravenous Glucose Test DIAGNOSTIC_TEST

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

Also known as: IsoG IVGT

CC Genotype; TT Genotype

Hyperinsulinemic Euglycemic Clamp and 2H20 DIAGNOSTIC_TEST

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

Also known as: E Clamp with labeled water

CC Genotype; TT Genotype

Eligibility Criteria

• Age: 12 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• 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.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Yale University: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Yale University

New Haven, Connecticut, 06510, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

DNA will be extracted from whole blood with the use of a Flexigene Kit (Qiagen) and genotyping will be performed using a matrix assisted based laser desorption-ionization time of flight mass spectrometry on the MassARRAY platform (Sequenom). DNA sample is obtained with fasting samples during the OGTT.

MeSH Terms

Conditions

Glucose Intolerance

Interventions

Glucose Tolerance Test

Condition Hierarchy (Ancestors)

Hyperglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Endocrine; Investigative Techniques

Study Officials

• Sonia Caprio, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 22, 2017
• First Posted: June 22, 2017
• Study Start: March 1, 2017
• Primary Completion: August 31, 2021
• Study Completion: August 12, 2022
• Last Updated: February 23, 2023

Record last verified: 2023-02

Locations

US (1)