Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Intervention: Metformin; Placebo
Intervention description: Six week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.; Six-week intervention: Study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Intervention MeSH terms: Metformin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 23.0
Sex: All
Minimum age: 25 Years
Maximum age: 59 Years
Healthy volunteers: No
Keywords: Diabetes; Insulin; Metformin; Vascular; Vessels; Type 1

Summary:

      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.
    

Eligibility criteria:

        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.