Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes

Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes

Insulin resistance (IR) is an important contributor to increased cardiovascular disease risk in type 1 diabetes (T1D). The purpose of this study is to measure the effect of metformin on insulin sensitivity, vascular function and compliance, and mitochondrial function in T1D. The long term goal is to identify novel non-glycemic approaches to managing cardiovascular disease risk in T1D. The results of this study may validate a novel approach to T1D treatment that could significantly improve current management of cardiovascular disease risk in this high risk population.

Inclusion Criteria:

• Age 20-59 years of age,
• Type 1 diabetes based on antibody-positivity, rapid persistent conversion to insulin requirement after diagnosis, absent C-peptide, or DKA at diagnosis, or a clinical course consistent with T1D,
• HbA1c 6.0 - 9.5, and
• Willing and able to commit to two 6 week-long periods of blinded medication followed by hyperinsulinemic euglycemic clamp, vascular testing, and muscle biopsies.

Exclusion Criteria:

• Any comorbid condition associated with:

  • inflammation,

  • insulin Resistance, or

  • dyslipidemia including:

    1. cancer,
    2. heart failure,
    3. active or end stage liver disease,
    4. kidney disease, or
    5. rheumatological disease;

• Tobacco use;

• Pregnancy or women who are breastfeeding;

• Steroid use;

• Scheduled strenuous physical activity >3 days a week;

• Angina, known CAD, or any other cardiovascular or pulmonary disease;

• A history of COPD or asthma;

• Presence of systolic blood pressure >190 at rest or >250 with exercise, or diastolic pressure >95 at rest or >105 with exercise;

• Untreated thyroid disease;

• Proteinuria (urine protein >200 mg/dl) or a creatinine > 1.5 mg/dl (males) or 1.4 mg/dL (females), suggestive of severe renal disease;

• Severe Proliferative retinopathy;

• Niacin treatment;

• Administration of experimental agent for T1D within 30 days prior to screening;

• Recent (prior 6 months) or current metformin or thiazolidenedione use;

• Hypoglycemia unawareness or recurrent severe hypoglycemia (no symptoms of hypoglycemia with FSBS<40 and episodes of this severity >1 per week);

• Weight instability (weight change >5% in last 6 months);

• History of any organ transplant, including islet cell transplant;

• Current or prior infection with HIV, hepatitis B or hepatitis C or hepatic -insufficiency (AST or ALT > 2x the upper limits of normal);

• Any condition, medical or otherwise that would, in the opinion of the investigator, prevent complete participation in the study, or that would pose a significant hazard to the subject;

• History of substance abuse within the 12 months prior to screening.