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Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes

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ClinicalTrials.gov Identifier: NCT03195400
Recruitment Status : Recruiting
First Posted : June 22, 2017
Last Update Posted : June 4, 2019
Sponsor:
Information provided by (Responsible Party):
Yale University

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.

Condition or disease Intervention/treatment
IGT - Impaired Glucose Tolerance T2D Diagnostic Test: Oral Glucose Tolerance Test Diagnostic Test: Hyperglycemic Clamp Diagnostic Test: Isoglycemic Intravenous Glucose Test Diagnostic Test: Hyperinsulinemic Euglycemic Clamp and 2H20

Detailed 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.


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Study Type : Observational
Estimated Enrollment : 100 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes
Actual Study Start Date : March 1, 2017
Estimated Primary Completion Date : August 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prediabetes

Group/Cohort Intervention/treatment
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
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 Name: OGTT

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.
Other Name: Infusion Study

Diagnostic Test: Isoglycemic Intravenous Glucose Test
Test which exposes pancreas to blood glucose levels matched to the ones obtained at the OGTT.
Other Name: IsoG IVGT

Diagnostic Test: Hyperinsulinemic Euglycemic Clamp and 2H20
Test is used to assess insulin effects on hepatic glucose production.
Other Name: E Clamp with labeled water

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
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 Name: OGTT

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.
Other Name: Infusion Study

Diagnostic Test: Isoglycemic Intravenous Glucose Test
Test which exposes pancreas to blood glucose levels matched to the ones obtained at the OGTT.
Other Name: IsoG IVGT

Diagnostic Test: Hyperinsulinemic Euglycemic Clamp and 2H20
Test is used to assess insulin effects on hepatic glucose production.
Other Name: E Clamp with labeled water




Primary Outcome Measures :
  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


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.


Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03195400


Contacts
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Contact: Bridget Pierpont, MA 203-485-2942 bridget.pierpont@yale.edu
Contact: Mary Savoye, RD, CDE 203-737-4384 mary.savoye@yale.edu

Locations
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United States, Connecticut
Yale University Recruiting
New Haven, Connecticut, United States, 06510
Contact: Bridget Pierpont, M.A.    203-785-2942    bridget.pierpont@yale.edu   
Principal Investigator: Sonia Caprio, M.D.         
Sponsors and Collaborators
Yale University
Investigators
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Principal Investigator: Sonia Caprio, MD Yale University

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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT03195400     History of Changes
Other Study ID Numbers: 2000020183
First Posted: June 22, 2017    Key Record Dates
Last Update Posted: June 4, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Prediabetic State
Glucose Intolerance
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperglycemia