Type 2 Diabetes
Conditions
Keywords
Pioglitazone, Type 2 diabetes, Insulin sensitivity, Healthy adults, Thiazolidinediones, Pharmacogenetics
Brief summary
The purpose of this study is to determine predictors of response to pioglitazone, an anti-diabetic medication. The investigators know from randomized clinical trials that some 30% of patients do not respond to this type of medication. There is presently no way to identify this group of patients leading to unnecessary drug exposure and medication costs.
Detailed description
In phase I, subjects who are eligible based on height and weight and general health information will sign informed consent. In phase II, subjects will be screened to ensure that they fit the inclusion/exclusion criteria, including an oral glucose tolerance test. Other blood tests will be performed to check complete blood count, lipids, liver functions and electrolytes. Qualifying volunteers will enter phase III, which will consist of outpatient radioimaging and body composition, metabolic testing (intravenous glucose tolerance test), and tissue biopsies. Blood will also be drawn for genetic testing and for microarray studies of leukocytes. Written medication information and instructions for pioglitazone, discharge instructions and satisfaction surveys following the tissue biopsy procedures will be given to subjects during the study. During phase IV, subjects will begin pioglitazone therapy. Every 4 weeks throughout the drug intervention, glycemic control, lipoprotein profile, and weight will be monitored. After 12 weeks of pioglitazone therapy, the X-ray and magnetic resonance (MR) measurements of body composition, the biopsies and the metabolic tests performed during phase III will be repeated (phase V), and blood will be drawn for microarray studies of leukocytes. Thereafter, subjects will have the option to be enrolled in a 10 week, behavioral weight loss program (phase VI). Following the 10-week weight loss program, a few outcome measurements will be repeated (phase VII). Throughout the study, Women of Child Bearing Potential (WCBP) will have human human chorionic gonadotrophin (HCG) urine pregnancy tests. Pregnancy tests will only be performed on Women of childbearing potential, meaning women who are pre-menopausal and who have not had surgical sterilization. Women who have not had a hysterectomy or tubal ligation at least six months prior to signing informed consent or have been postmenopausal for at least one year, will be instructed to practice one of the following methods of birth control throughout the study: oral, transdermal, or implantable hormonal contraceptives, intrauterine device, diaphragm plus spermicide, condom plus spermicide, or abstinence. Pioglitazone may reduce the effectiveness of some hormonal types of contraceptives. Women using hormonal methods of birth control will be advised to use a barrier method as well. Female subjects are informed to notify the investigators immediately if they think they might have become pregnant during the study. Participants who are eligible have 10 visits over an approximate 15-week period. Participants can choose to participate in an optional weight management program for an additional 10 weeks after treatment and before their final visit.
Interventions
DRUGPioglitazone
30 mg tablet once daily for 4 weeks, then increased to 45 mg once daily for an additional 8 weeks. Total dosage period is 12 weeks.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Maryland, Baltimore
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
35 Years to 64 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 35-64 * BMI: ≥ 25 and ≤ 40
Exclusion criteria
* Pregnancy as determined by urine pregnancy test Breast-feeding, or planning to become pregnant during the study * Physical dimensions exceeding the limits of any equipment used * Stage III or greater congestive heart failure * Symptomatic peripheral vascular disease * Stroke * Severe hypertension (\>170/100 mmHg) * Anemia (Hgb and Hct \< normal reference range) * Receiving treatment for thyroid, pituitary, kidney or liver disease (except controlled thyroid hormone replacement) * History of diabetes (as told by doctor, or taking diabetic medications Fasting glucose value diagnostic for diabetes 2-h oral glucose tolerance test diagnostic for diabetes * Rheumatoid arthritis * History of wrist, hip or leg fracture after the age of 45 * History of kidney stones * Medications that the investigator judges will make interpretation of the results difficult or increase the risk of participation (e.g. anticoagulants) * Any disease or condition that the investigator judges will affect bone metabolism or make interpretation of the results difficult or increase the risk of participation (e.g. anemia, cardiac decompensation, intolerance to pioglitazone, lidocaine, or other agents used)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Insulin Resistance | 12 weeks | Change in insulin resistance was calculated as change (end of treatment minus baseline) in HOMA-IR index (glucose (mg/dL) x insulin (μU/mL)/405) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Genes Determined to be Correlated With Change in Insulin Sensitivity | 12 weeks | Number of genes determined to be correlated with change in insulin sensitivity as determined by HOMA-IR with a p-value below 0.000001 |
Countries
United States
Participant flow
Recruitment details
Recruitment was through advertisements in local publications and bulletin boards in the University of Maryland and Baltimore area. Additional recruitment among the Old Order Amish was through the University of Maryland Amish Research Clinic in Lancaster County, Pennsylvania.
Pre-assignment details
Screening assessments done following informed consent include anthropometry, screening bloodwork, medical history and baseline study assessments. Participants may be excluded prior to start of study drug and/or baseline assessments if they do not meet eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone (Actos) Participants will have metabolism studies to consist of outpatient X-ray and MR measurements of bone density and body composition, metabolic testing (intravenous glucose tolerance test), and muscle and adipose tissue biopsies. Blood will also be drawn for genetic testing and for microarray studies of leukocytes. Upon completion of the above studies, the participant will begin pioglitazone therapy. Every 4 weeks throughout the drug intervention, glycemic control, lipoprotein profile, and weight will be monitored. After 12 weeks of pioglitazone therapy, the X-ray and MR measurements of body composition, the biopsies, microarray studies for leukocytes and the metabolic tests will be repeated.
Pioglitazone: 30 mg tablet once daily for 4 weeks, then increased to 45 mg once daily for an additional 8 weeks. Total dosage period is 12 weeks. | 114 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Baseline Assessment | Adverse Event | 1 |
| Baseline Assessment | Lost to Follow-up | 2 |
| Baseline Assessment | Physician Decision | 3 |
| Baseline Assessment | Withdrawal by Subject | 9 |
| Screening | Lost to Follow-up | 2 |
| Screening | Physician Decision | 5 |
| Screening | Screening failure | 16 |
| Screening | Withdrawal by Subject | 10 |
| Study Treatment | Adverse Event | 2 |
| Study Treatment | Physician Decision | 1 |
| Study Treatment | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Pioglitazone (Actos) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 114 Participants |
| Insulin resistance | 2.74 HOMA-IR index is unitless by definition STANDARD_DEVIATION 1.82 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 106 Participants |
| Sex: Female, Male Female | 64 Participants |
| Sex: Female, Male Male | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 114 |
| other Total, other adverse events | 15 / 114 |
| serious Total, serious adverse events | 2 / 114 |
Outcome results
Primary
Change in Insulin Resistance
Change in insulin resistance was calculated as change (end of treatment minus baseline) in HOMA-IR index (glucose (mg/dL) x insulin (μU/mL)/405)
Time frame: 12 weeks
Population: Included subjects are those who had complete data, including HOMA-IR index at both baseline and after treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone (Actos) | Change in Insulin Resistance | -0.83 HOMA-IR index is unitless by definition | Standard Deviation 1.23 |
Comparison: After the change (end-of-treatment minus baseline) in HOMA-IR index had been calculated for each subject, the change (end-of-treatment minus baseline) in expression of each of approximately 45,000 transcripts contained in a human gene array was calculated. A Pearson correlation p-value was calculated for the correlation between change in gene expression and change in HOMA-IR index, with the purpose of identifying the genes whose expression changed in concert with changes in HOMA-IR index.p-value: <1e-7Genes with p-values below 10^-6
Secondary
Number of Genes Determined to be Correlated With Change in Insulin Sensitivity
Number of genes determined to be correlated with change in insulin sensitivity as determined by HOMA-IR with a p-value below 0.000001
Time frame: 12 weeks
Population: Only subjects who had complete RNAseq (RNA sequencing) data and HOMA-IR were included
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone (Actos) | Number of Genes Determined to be Correlated With Change in Insulin Sensitivity | 7 Genes |