Type 1 Diabetes
Conditions
Keywords
Adolescent, Youth, Diabetes, Insulin Resistance, Cardiovascular, Metformin
Brief summary
Diabetes is increasingly common among youth, forecasting early complications. Type 1 (T1D) cause early heart disease, shortening lifespan despite modern improvements in control of blood sugars and other risk factors for heart disease. Poor insulin action, otherwise known as insulin resistance (IR), is the main factor causing heart disease in type 2 diabetes (T2D), but the cause of increased heart disease in T1D is unclear. IR may contribute to heart disease in T1D as in T2D, as the investigators and others have found the presence of IR in T1D. Much less is known about IR in T1D, but a better understanding of its role in T1D is critical to understanding causes of heart disease in T1D. The investigators long-term goal is to understand the early causes of heart disease in diabetes so that we can prevent it. The investigators unique initial findings suggest that even reasonably well-controlled, normal weight, T1D youth are IR. The IR appears directly related to the heart, blood vessel, and exercise defects, but in a pattern that appears very different from T2D. The goals of this study are to determine the unique heart, blood vessel and insulin sensitivity abnormalities in T1D youth, and determine whether metformin improves these abnormalities. A clear understanding of these factors will help determine the causes, and what treatments could help each abnormality. Hypothesis 1: Metformin will improve insulin function and mitochondrial function in T1D. Hypothesis 2: Metformin will improve vascular and cardiac function in T1D. All measures will be performed twice, before and after a 3-month randomized, placebo-controlled design where subjects are randomized to either metformin or placebo. The independent impact of insulin action as well as glucose levels, BMI, T1D duration, and gender on baseline outcomes and the impact of changes in insulin action, glucose levels and BMI on response to metformin will also be examined to help customize future strategies to prevent heart disease in T1D. This study will advance the field by providing new information about the role of poor insulin action in the heart disease of T1D, and whether improving insulin action in T1D is helpful. If a focus on directly improving insulin action in T1D youth is supported by our studies, the clinical approach to T1D management may significantly change.
Interventions
DRUGMetformin
DRUGPlacebo
Sponsors
American Diabetes Association
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
1. Adolescents 12-21 years of age with type 1 diabetes (defined as having positive antibodies as well as insulin requirement) 2. Willing to consent for participation in study 3. Body Mass Index (BMI) \>5% on growth charts
Exclusion criteria
1. Current use of medications known to affect insulin sensitivity: oral glucocorticoids within 10 days, atypical antipsychotics, immunosuppressant agents, metformin or thiazolidinediones. 2. Currently pregnant or breastfeeding women 3. Use of a thiazolidinedione within 12 weeks 4. Severe illness or Diabetic Ketoacidosis within 60 days 5. Macroalbuminuria 6. Hemoglobin A1c \> 12% 7. Weight \> 136.4 kg or \< 42 kg, BMI \< 5% 8. Creatinine \> 1.2 9. Hemoglobin \< 9 10. Major psychiatric or developmental disorder limiting informed consent 11. Implanted metal devices 12. Inability to tolerate ≥500mg twice a day of metformin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Insulin Sensitivity | Baseline, Month 3 | Hypothesis 1: Metformin will improve insulin function in Type 1 Diabetes. Insulin function will be measured using a euglycemic-hyperinsulinemic clamp procedure at both baseline and after 3 months of treatment. A clamp measures insulin sensitivity. A higher number indicates a better outcome; a lower number indicates a worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in ADP Time Constant | Baseline, Month 3 | Hypothesis 1b: Metformin will improve mitochondrial function in Type 1 Diabetes. 31Phosphorus magnetic resonance spectroscopy (MRS) was used before, during, and after 90 seconds of near-maximal isometric exercise of the calf muscle for post-exercise muscle mitochondrial function. ADP time constant is the time for conversion of ADP → ATP and is a measure of muscle mitochondrial health (energy metabolism). A faster recovery is a better outcome; a slower recovery is a worse outcome. |
| Change in Pulse Wave Velocity (PWV) | Baseline, Month 3 | Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via pulse wave velocity (PWV) by MRI. PWV is a measure of central arterial stiffness. A lower value indicates a better outcome. |
| Change in Mitral Valve E/A Ratio by Echocardiogram | Baseline, Month 3 | Hypothesis 2b: Metformin will improve cardiac function in Type 1 Diabetes by echocardiogram. Mitral Valve E/A ratio is the ratio of early (E) to late (A) ventricular filling velocities. Ideal myocardial tissue relaxation is indicated by a ratio of \>0.8 and \<2.0. |
| Change in Aortic Wall Sheer Stress (WSS) | Baseline, Month 3 | Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via Aortic Wall Sheer Stress (WSS) by MRI. WSS is a measure of central arterial stiffness. A lower value indicates a better outcome. |
| Change in Central Arterial Intimal Medial Thickness (cIMT) | Baseline, Month 3 | Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via central arterial intimal medial (cIMT) thickness by carotid ultrasound. cIMT is a measure used to diagnose the extent of carotid atherosclerotic vascular disease. The test measures the thickness of the inner two layers of the carotid artery-the intima and media. A lower result is a better outcome. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Brachial Artery Distensibility | Baseline, Month 3 | Hypothesis 2a: Metformin will improve peripheral arterial stiffness in Type 1 Diabetes via Dynapulse. Peripheral arterial stiffness is measured by the distensibility of the arterial wall. Increased arterial stiffness results from reduced elasticity of the arterial wall. A higher result is a better outcome. |
Countries
United States
Participant flow
Pre-assignment details
Three (3) enrolled participants decided against participation in the study before randomization occurred.
Participants by arm
| Arm | Count |
|---|---|
| Metformin Metformin will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to placebo.
Metformin | 25 |
| Placebo Placebo will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to metformin.
Placebo | 23 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Metformin |
|---|---|---|---|
| Age, Continuous | 15.9 years STANDARD_DEVIATION 2.7 | 16.6 years STANDARD_DEVIATION 2.5 | 17.3 years STANDARD_DEVIATION 2.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 7 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 41 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 46 Participants | 24 Participants |
| Sex: Female, Male Female | 10 Participants | 24 Participants | 14 Participants |
| Sex: Female, Male Male | 13 Participants | 24 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 23 |
| other Total, other adverse events | 10 / 25 | 2 / 23 |
| serious Total, serious adverse events | 0 / 25 | 0 / 23 |
Outcome results
Primary
Change in Insulin Sensitivity
Hypothesis 1: Metformin will improve insulin function in Type 1 Diabetes. Insulin function will be measured using a euglycemic-hyperinsulinemic clamp procedure at both baseline and after 3 months of treatment. A clamp measures insulin sensitivity. A higher number indicates a better outcome; a lower number indicates a worse outcome.
Time frame: Baseline, Month 3
Population: Metformin group: 1 participant lost to follow-up, 1 IV access problem Placebo group: 2 lost to follow-up, 2 IV access problems
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Change in Insulin Sensitivity | 12.2 (mg/kg/min)/(insulin) | Standard Deviation 3.2 |
| Placebo | Change in Insulin Sensitivity | -2.4 (mg/kg/min)/(insulin) | Standard Deviation 3.6 |
Comparison: Insulin function was defined as M/I (mg/kg/min)/(insulin). Power calculations were based on data from a small study in youth with poorly controlled T1DM, which reported a significant increase in M/I in the 11 participants treated with Metformin. On the basis of the effect size reported in that study, a sample size of 25 per group and an alpha of 0.05 provided us with 93% power to detect a difference of 1 SD in the primary outcome of M/I.p-value: 0.005Regression, Linear
Secondary
Change in ADP Time Constant
Hypothesis 1b: Metformin will improve mitochondrial function in Type 1 Diabetes. 31Phosphorus magnetic resonance spectroscopy (MRS) was used before, during, and after 90 seconds of near-maximal isometric exercise of the calf muscle for post-exercise muscle mitochondrial function. ADP time constant is the time for conversion of ADP → ATP and is a measure of muscle mitochondrial health (energy metabolism). A faster recovery is a better outcome; a slower recovery is a worse outcome.
Time frame: Baseline, Month 3
Population: 22 participants had both pre/post MRS data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metformin | Change in ADP Time Constant | 0.46 seconds (s) |
| Placebo | Change in ADP Time Constant | -0.47 seconds (s) |
p-value: 0.46Regression, Linear
Secondary
Change in Aortic Wall Sheer Stress (WSS)
Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via Aortic Wall Sheer Stress (WSS) by MRI. WSS is a measure of central arterial stiffness. A lower value indicates a better outcome.
Time frame: Baseline, Month 3
Population: Number of participants analyzed differs from participant flow numbers because the institution's MRI scanner was unavailable during replacement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Change in Aortic Wall Sheer Stress (WSS) | -0.3 dyne/cm2 | Standard Deviation 0.4 |
| Placebo | Change in Aortic Wall Sheer Stress (WSS) | 1.5 dyne/cm2 | Standard Deviation 0.5 |
p-value: 0.03Regression, Linear
Secondary
Change in Central Arterial Intimal Medial Thickness (cIMT)
Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via central arterial intimal medial (cIMT) thickness by carotid ultrasound. cIMT is a measure used to diagnose the extent of carotid atherosclerotic vascular disease. The test measures the thickness of the inner two layers of the carotid artery-the intima and media. A lower result is a better outcome.
Time frame: Baseline, Month 3
Population: Metformin: 1 lost to follow-up Placebo: 2 lost to follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Change in Central Arterial Intimal Medial Thickness (cIMT) | -0.04 mm | Standard Deviation 0.01 |
| Placebo | Change in Central Arterial Intimal Medial Thickness (cIMT) | 0.00 mm | Standard Deviation 0.1 |
p-value: 0.04Regression, Linear
Secondary
Change in Mitral Valve E/A Ratio by Echocardiogram
Hypothesis 2b: Metformin will improve cardiac function in Type 1 Diabetes by echocardiogram. Mitral Valve E/A ratio is the ratio of early (E) to late (A) ventricular filling velocities. Ideal myocardial tissue relaxation is indicated by a ratio of \>0.8 and \<2.0.
Time frame: Baseline, Month 3
Population: Metformin: 2 lost to follow-up Placebo: 2 lost to follow-up, 1 echocardiogram not performed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Change in Mitral Valve E/A Ratio by Echocardiogram | 1.55 ratio | Standard Deviation 0.42 |
| Placebo | Change in Mitral Valve E/A Ratio by Echocardiogram | 1.72 ratio | Standard Deviation 0.34 |
p-value: 0.01Regression, Linear
Secondary
Change in Pulse Wave Velocity (PWV)
Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via pulse wave velocity (PWV) by MRI. PWV is a measure of central arterial stiffness. A lower value indicates a better outcome.
Time frame: Baseline, Month 3
Population: Number of participants analyzed differs from participant flow numbers because the institution's MRI scanner was unavailable during replacement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Change in Pulse Wave Velocity (PWV) | -1.1 m/s | Standard Deviation 1.2 |
| Placebo | Change in Pulse Wave Velocity (PWV) | 4.1 m/s | Standard Deviation 1.6 |
p-value: 0.04Regression, Linear
Other Pre-specified
Change in Brachial Artery Distensibility
Hypothesis 2a: Metformin will improve peripheral arterial stiffness in Type 1 Diabetes via Dynapulse. Peripheral arterial stiffness is measured by the distensibility of the arterial wall. Increased arterial stiffness results from reduced elasticity of the arterial wall. A higher result is a better outcome.
Time frame: Baseline, Month 3
Population: Metformin: 1 lost to follow-up Placebo: 2 lost to follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Change in Brachial Artery Distensibility | 0.23 %/mmHg | Standard Deviation 0.19 |
| Placebo | Change in Brachial Artery Distensibility | 0.16 %/mmHg | Standard Deviation 0.2 |
p-value: 0.8Regression, Linear