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

American Diabetes Association, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Inclusion Criteria: Adolescents 12-21 years of age with type 1 diabetes (defined as having positive antibodies as well as insulin requirement) Willing to consent for participation in study Body Mass Index (BMI) >5% on growth charts Exclusion Criteria: Current use of medications known to affect insulin sensitivity: oral glucocorticoids within 10 days, atypical antipsychotics, immunosuppressant agents, metformin or thiazolidinediones. Currently pregnant or breastfeeding women Use of a thiazolidinedione within 12 weeks Severe illness or Diabetic Ketoacidosis within 60 days Macroalbuminuria Hemoglobin A1c > 12% Weight > 136.4 kg or < 42 kg, BMI < 5% Creatinine > 1.2 Hemoglobin < 9 Major psychiatric or developmental disorder limiting informed consent Implanted metal devices Inability to tolerate ≥500mg twice a day of metformin

Tommerdahl KL, Baumgartner K, Schafer M, Bjornstad P, Melena I, Hegemann S, Baumgartner AD, Pyle L, Cree-Green M, Truong U, Browne L, Regensteiner JG, Reusch JEB, Nadeau KJ. Impact of Obesity on Measures of Cardiovascular and Kidney Health in Youth With Type 1 Diabetes as Compared With Youth With Type 2 Diabetes. Diabetes Care. 2021 Mar;44(3):795-803. doi: 10.2337/dc20-1879. Epub 2021 Jan 5.

Bjornstad P, Schafer M, Truong U, Cree-Green M, Pyle L, Baumgartner A, Garcia Reyes Y, Maniatis A, Nayak S, Wadwa RP, Browne LP, Reusch JEB, Nadeau KJ. Metformin Improves Insulin Sensitivity and Vascular Health in Youth With Type 1 Diabetes Mellitus. Circulation. 2018 Dec 18;138(25):2895-2907. doi: 10.1161/CIRCULATIONAHA.118.035525.