Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes

Yale University

Status: Completed

Conditions: T2D; IGT - Impaired Glucose Tolerance

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

Study type: Observational

Funder types: Other; NIH

Identifiers

NCT03195400

1R01DK111038-01A1 (U.S. NIH Grant/Contract)

2000020183

Details and patient eligibility

About

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.

Full 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.

Enrollment: 100 patients

Sex: All

Ages: 12 to 18 years old

Volunteers: No Healthy Volunteers

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.

Trial design

100 participants in 2 patient groups

CC Genotype

Description:

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.

Treatment:

Diagnostic Test: Oral Glucose Tolerance Test

Diagnostic Test: Hyperglycemic Clamp

Diagnostic Test: Hyperinsulinemic Euglycemic Clamp and 2H20

Diagnostic Test: Isoglycemic Intravenous Glucose Test

TT Genotype

Description:

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

Treatment:

Diagnostic Test: Oral Glucose Tolerance Test

Diagnostic Test: Hyperglycemic Clamp

Diagnostic Test: Hyperinsulinemic Euglycemic Clamp and 2H20

Diagnostic Test: Isoglycemic Intravenous Glucose Test