Impaired Glucose Tolerance, Obesity, Type 2 Diabetes Mellitus
Conditions
Keywords
Childhood and Adolescent Obesity, Metabolic phenotype, Impaired Glucose Tolerance, Type 2 Diabetes Mellitus, Insulin Sensitivity, Insulin Resistance, Abdominal fat partitioning, Impaired Glucose Tolerance (IGT), Type 2 Diabetes Mellitus (T2DM)
Brief summary
The purpose of the study is to determine whether treatment of children and adolescents with Impaired Glucose Tolerance (IGT) with rosiglitazone will lead to improvements in insulin sensitivity and glucose tolerance.
Detailed description
Impaired Glucose Tolerance (IGT) is a prelude to diabetes, which is increasing in prevalence in obese children and adolescents with marked obesity. This condition tends to progress to Type 2 Diabetes Mellitus (T2DM) at an alarmingly rapid tempo. The increased prevalence of childhood and adolescent obesity and greater risk of IGT, and progression to diabetes, in this population set the stage for a series of studies aimed at understanding the metabolic phenotype and natural history of pre-diabetes in obese youth. The investigators found that obese children and adolescents with IGT are characterized by marked insulin resistance related to altered lipid partitioning, favoring lipid deposition in the visceral and intramyocellular compartment. Furthermore, the investigators found an impairment of the acute insulin response in these youngsters. Follow-up revealed a rapid deterioration from IGT to frank diabetes. Based on these studies, there is a strong rationale for changing the balance between visceral and subcutaneous fat and muscle lipid content in a more favorable pattern in order to improve insulin sensitivity. The primary objective of this study is to determine, in a group of ethnically diverse children and adolescents with IGT, whether treatment with rosiglitazone leads to improvements in insulin sensitivity and glucose tolerance. Secondary objectives are to determine whether rosiglitazone is safe and well tolerated.
Interventions
DRUGRosiglitazone
2mg to begin then 4mg, twice daily for 4 months
DRUGPlacebo
Subject receives placebo.
Sponsors
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Good general health * Aged 10 to 18 yrs (females: Tanner stage II-V;and males:testes size\>6ml) * IGT based on 2-hr plasma glucose\>140mg/dl and \<200mg/dl during an OGTT.
Exclusion criteria
* Baseline creatinine\>1.0mg * AST and ALT\>2.5 ULN * Anemia (Hct\<30) * Pregnancy (females must have a negative urine pregnancy test during the study) * Cardiac or pulmonary or other significant chronic illness * Plans to increase the frequency or intensity of a regular exercise program * Psychiatric disorder or substance abuse of anorexic agents.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change From Baseline in Whole-body Insulin Sensitivity | 4 months | This describes the percent changes in insulin sensitivity. Insulin sensitivity was expressed as whole body insulin sensitivity index (WBISI) which is based on the values of insulin (microunits per milliliter) and glucose (milligrams per deciliter) obtained from the OGTT and the corresponding fasting values.The formula is: WBISI=10.000/square root of (fasting glucose x fasting insulin)x(mean glucose x mean insulin). |
| Mean Percent Change in Visceral-to-subcutaneous Abdominal Fat | 4 months | This describes the percent changes of the ratio between visceral and subcutaneous abdominal fat. |
| Percentage of Subjects Who Converted Impaired Glucose Tolerance (IGT) to Normal Glucose Tolerance (NGT) | 4 months | This refers to the number of subjects that converted from IGT to NGT. NGT is defined as fasting glucose lower than 100 mg/dl and 2 hours glucose lower than 140 mg/dl. IGT is defined as 2 hours glucose higher than 140 mg/dl. |
| Mean Percent Change From Baseline in Hepatic Fat Fraction (HFF) | 4 months | It refers to the percent changes of hepatic fat content. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change From Baseline in Adiponectin | 4 months | This refers to the changes of adiponectin levels. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from a multi-ethnic cohort of obese children and adolescents drawn from the Pediatric Obesity Clinic at Yale-New Haven Hospital.
Pre-assignment details
Obese children and adolescents with positive risk factors for Type 2 Diabetes (T2DM) were screened by using a standard oral glucose tolerance test (OCTT).
Participants by arm
| Arm | Count |
|---|---|
| Active Arm (Rosiglitazone) Subject undergoes ogtt, hyperinsulinemic-euglycemic clamp, abdominal and liver MRI, NMR and DEXA scan. Subject then receives Rosiglitazone. Subjects are followed every 2 weeks. Imaging repeated at 2 months. 12 week follow up. And then all tests are repeated at 4 months.
Rosiglitazone : 2mg to begin then 4mg, twice daily for 4 months | 12 |
| Inactive Arm (Placebo) Subject has ogtt, hyperinsulinemic-euglycemic clamp, abdominal and liver MRI, DEXA, NMR. Subject is randomized (double-blind) to placebo. Is followed every 2 weeks, repeats imaging at 2 months, is seen at 12 weeks and then repeats all tests at 2 months.
Placebo : Subject receives placebo. | 9 |
| Total | 21 |
Baseline characteristics
| Characteristic | Active Arm (Rosiglitazone) | Inactive Arm (Placebo) | Total |
|---|---|---|---|
| Age Continuous | 12.8 years STANDARD_DEVIATION 1.6 | 13.9 years STANDARD_DEVIATION 2 | 13.0 years STANDARD_DEVIATION 2 |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 9 |
| serious Total, serious adverse events | 0 / 12 | 0 / 9 |
Outcome results
Primary
Mean Percent Change From Baseline in Hepatic Fat Fraction (HFF)
It refers to the percent changes of hepatic fat content.
Time frame: 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Arm (Rosiglitazone) | Mean Percent Change From Baseline in Hepatic Fat Fraction (HFF) | 2.7 percentage of change from baseline | Standard Deviation 107 |
| Inactive Arm (Placebo) | Mean Percent Change From Baseline in Hepatic Fat Fraction (HFF) | 81 percentage of change from baseline | Standard Deviation 267 |
Primary
Mean Percent Change From Baseline in Whole-body Insulin Sensitivity
This describes the percent changes in insulin sensitivity. Insulin sensitivity was expressed as whole body insulin sensitivity index (WBISI) which is based on the values of insulin (microunits per milliliter) and glucose (milligrams per deciliter) obtained from the OGTT and the corresponding fasting values.The formula is: WBISI=10.000/square root of (fasting glucose x fasting insulin)x(mean glucose x mean insulin).
Time frame: 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Arm (Rosiglitazone) | Mean Percent Change From Baseline in Whole-body Insulin Sensitivity | 87.4 percentage of change from baseline | Standard Deviation 77 |
| Inactive Arm (Placebo) | Mean Percent Change From Baseline in Whole-body Insulin Sensitivity | 63.1 percentage of change from baseline | Standard Deviation 61.6 |
Primary
Mean Percent Change in Visceral-to-subcutaneous Abdominal Fat
This describes the percent changes of the ratio between visceral and subcutaneous abdominal fat.
Time frame: 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Arm (Rosiglitazone) | Mean Percent Change in Visceral-to-subcutaneous Abdominal Fat | -7.3 percentage of change from baseline | Standard Deviation 23.1 |
| Inactive Arm (Placebo) | Mean Percent Change in Visceral-to-subcutaneous Abdominal Fat | 8.9 percentage of change from baseline | Standard Deviation 22.6 |
Primary
Percentage of Subjects Who Converted Impaired Glucose Tolerance (IGT) to Normal Glucose Tolerance (NGT)
This refers to the number of subjects that converted from IGT to NGT. NGT is defined as fasting glucose lower than 100 mg/dl and 2 hours glucose lower than 140 mg/dl. IGT is defined as 2 hours glucose higher than 140 mg/dl.
Time frame: 4 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Arm (Rosiglitazone) | Percentage of Subjects Who Converted Impaired Glucose Tolerance (IGT) to Normal Glucose Tolerance (NGT) | 58 percentage of participants |
| Inactive Arm (Placebo) | Percentage of Subjects Who Converted Impaired Glucose Tolerance (IGT) to Normal Glucose Tolerance (NGT) | 44 percentage of participants |
Secondary
Mean Percent Change From Baseline in Adiponectin
This refers to the changes of adiponectin levels.
Time frame: 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Arm (Rosiglitazone) | Mean Percent Change From Baseline in Adiponectin | 79.3 percentage of change from baseline | Standard Deviation 78.2 |
| Inactive Arm (Placebo) | Mean Percent Change From Baseline in Adiponectin | 19.8 percentage of change from baseline | Standard Deviation 52.8 |