Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes

Study Overview
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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.

Official Title
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Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes

Conditions
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IGT - Impaired Glucose Tolerance, T2D

Intervention / Treatment
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* Diagnostic Test: Oral Glucose Tolerance Test
* Diagnostic Test: Hyperglycemic Clamp
* Diagnostic Test: Isoglycemic Intravenous Glucose Test
* Diagnostic Test: Hyperinsulinemic Euglycemic Clamp and 2H20


Participation Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CC Genotype<br>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<br>* 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.<br>* Other names: OGTT;Diagnostic Test: Hyperglycemic Clamp<br>* Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.<br>* Other names: Infusion Study;Diagnostic Test: Isoglycemic Intravenous Glucose Test<br>* Test which exposes pancreas to blood glucose levels matched to the ones obtained at the OGTT.<br>* Other names: IsoG IVGT;Diagnostic Test: Hyperinsulinemic Euglycemic Clamp and 2H20<br>* Test is used to assess insulin effects on hepatic glucose production.<br>* Other names: E Clamp with labeled water;|
| TT Genotype<br>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<br>* 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.<br>* Other names: OGTT;Diagnostic Test: Hyperglycemic Clamp<br>* Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.<br>* Other names: Infusion Study;Diagnostic Test: Isoglycemic Intravenous Glucose Test<br>* Test which exposes pancreas to blood glucose levels matched to the ones obtained at the OGTT.<br>* Other names: IsoG IVGT;Diagnostic Test: Hyperinsulinemic Euglycemic Clamp and 2H20<br>* Test is used to assess insulin effects on hepatic glucose production.<br>* Other names: E Clamp with labeled water;|

What is the study measuring?
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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 |