EMERALD: Effects of Metformin on Cardiovascular Function in Adolescents With Type 1 Diabetes

Effects of Metformin on Cardiovascular Function in Adolescents With Type 1 Diabetes

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.

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