Clinical trial NCT01813929: Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes
Official title: Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 1 Diabetes
Keywords: Diabetes
Insulin
Metformin
Vascular
Vessels
Type 1
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: US Department of Veterans Affairs
First posted: 2013-03-19
Enrollment: 23
Sex: ALL
Minimum age (years): 25
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp
timeFrame: End of each 6 week intervention period
measure: Flow-mediated Brachial Artery Dilation
timeFrame: End of each 6 week intervention period
Secondary outcomes:
measure: Arterial Stiffness by PWV
timeFrame: End of each 6 week intervention period
measure: Arterial Stiffness by AI@75
timeFrame: End of each 6 week intervention period
measure: Mitochondrial Measures: Oxygen Consumption
timeFrame: End of each 6 week intervention period
measure: Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes
timeFrame: End of each 6 week intervention period
measure: Inflammatory Marker: hsCRP
timeFrame: End of each 6 week intervention period
measure: Heart Rate Variability
timeFrame: End of each 6 week intervention period
measure: Continuous Glucose Monitor Measures of Mean Glucose
timeFrame: Last Week of each 6 Week Intervention Period (over 7 days)
measure: Continuous Glucose Monitor Measures of Hypoglycemia
timeFrame: Last Week of each 6 Week Intervention Period (over 7 days)
measure: Metabolic Markers: Glucagon
timeFrame: End of each 6 week intervention period
measure: Metabolic Markers: Glucose, Triglycerides, Cholesterol
timeFrame: End of each 6 week intervention period
measure: Metabolic Markers: Fatty Acids
timeFrame: End of each 6 week intervention period
measure: Metabolic Markers: Glycerol
timeFrame: End of each 6 week intervention period
measure: Metabolic Markers: Insulin
timeFrame: End of each 6 week intervention period
measure: Metabolic Markers: Lactate
timeFrame: End of each 6 week intervention period
measure: Metabolic Markers: Adiponection
timeFrame: End of each 6 week intervention period
measure: Vascular Markers: Endothelin-1 (pg/ml)
timeFrame: End of each 6 week intervention period
measure: In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed
timeFrame: End of each 6 week intervention period
measure: In Vivo Mitochondrial Function: Time Constants
timeFrame: End of each 6 week intervention period
measure: In Vivo Mitochondrial Function: QMax, VPCr
timeFrame: End of each 6 week intervention period
measure: In Vivo Mitochondrial Function: Oxidative Phosphorylation
timeFrame: End of each 6 week intervention period
measure: In Vivo Mitochondrial Function:AnGly
timeFrame: End of each 6 week intervention period
measure: Cardiac Function
timeFrame: End of each 6 week intervention period
Other outcomes:
measure: Vascular Markers: PAI-1
timeFrame: End of each 6 week intervention period
measure: Vascular Markers: Exploratory
timeFrame: End of each 6 week intervention period
measure: Oxidative Stress Markers
timeFrame: End of each 6 week intervention period
measure: Mitochondrial Measures: Oxidant Generation
timeFrame: End of each 6 week intervention period
measure: Inflammatory Markers: Exploratory
timeFrame: End of each 6 week intervention period
measure: Mitochondrial Oxidant Generation
timeFrame: after each 6 week intervention
Locations:
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
Study officials:
affiliation: University of Colorado, Denver
name: Irene Schauer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: