Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes

• ClinicalTrials.gov Identifier: NCT03195400
• Recruitment Status: Active, not recruiting
• First Posted: June 22, 2017
• Last Update Posted: April 16, 2020
• Sponsor: Yale University
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Yale University

Tracking Information

• First Submitted Date: March 22, 2017
• First Posted Date: June 22, 2017
• Last Update Posted Date: April 16, 2020
• Actual Study Start Date: March 1, 2017
• Estimated Primary Completion Date: August 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 21, 2017)

• 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
• Genotype [ Time Frame: Baseline ]
  DNA screening to measure whether subject is CC or TT genotype
• 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.
• 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
• 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
• 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

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes
• Official Title: Pathogenesis of Youth Onset Type 2 Diabetes and Prediabetes
• 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.

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.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

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.

• 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.

Condition

• IGT - Impaired Glucose Tolerance
• T2D

Intervention

• 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

Study Groups/Cohorts

• 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.
  Interventions:

  • 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
  Interventions:

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 21, 2017): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2021
• Estimated Primary Completion Date: August 31, 2021 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03195400
• Other Study ID Numbers: 2000020183; 1R01DK111038-01A1 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Yale University
• Study Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Sonia Caprio, MD; Yale University

• PRS Account: Yale University
• Verification Date: April 2020