Effect of Insulin Sensitizer Therapy on Atherothrombotic and Inflammatory Profiles Associated With Insulin Resistance
Individuals with diabetes mellitus (DM) are disproportionately affected by atherothrombotic
disorders, including cardiovascular, cerebrovascular, and peripheral vascular diseases.
Atherothrombotic disease risk and mortality are also increased with metabolic syndrome, a
constellation of risk factors present in more than 34% of adults, even in absence of
diabetes. Yet, large clinical trials of diabetes therapies have shown that conventional
cardiovascular disease (CVD) risk factors, specifically hyperglycemia and hypertension, do
not fully account for increased CVD risk associated with DM.
There may be an etiologic link among insulin resistance, inflammation and thrombotic events.
This study seeks to determine if certain two diabetes medications (the insulin sensitizing
medications) will affect certain biomarkers (or laboratory tests) for CVD in individuals
with untreated DM or impaired fasting glucose.
Patients will be screened for inclusion into this this double-blinded, randomized),
placebo-controlled study. If inclusion criteria are met and exclusion criteria not met,
patients will be enrolled in the the study. Half of the subjects will be randomized (like
the flip of a coin) to take two insulin sensitizing, anti-diabetic drugs pioglitazone
(Actos) and metformin (Glucophage) taken together for three months and the other half of the
subjects will take corresponding placebo (dummy) tablets.
Laboratory measurements will be obtained on the morning(s) following the two in-patient
overnight stays in the Mayo Clinic Clinical Research Unit. The first stay will be at
baseline and the second stay will be 3 months after baseline. Insulin sensitivity will be
measured in the morning following a standardized meal the preceding night, and after an
The changes (from baseline to 3 months) in insulin sensitivity, glycemic control, the lipid
profile, thrombotic markers and inflammatory markers will be determined and compared between
the two arms of the study (placebo versus insulin sensitizing drugs).
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment
Change From Baseline in Insulin Sensitivity as Measured by Glucose Infusion Rate (GIR)
Insulin sensitivity was measured the morning after an overnight fast during an in-patient stay in the Clinical Research Unit & was determined by the mean GIR necessary to maintain euglycemia during a hyperinsulinemic (1.5 mcIU/kg of FFM per minute)-euglycemic (85-95 mg/dL) clamp. The clamp is an 8 hour process where a hand vein is catheterized to collect blood samples and intravenous lines are used to infuse glucose, saline, insulin, phenylalanine and amino acid solutions at at pre-specified times/rates. The mean GIR was calculated as the rate per kilograms of fat-free mass (FFM) during 4 hours of steady-state (hours 4-8 of the 8 hour clamp) reported as micromols/kilogram of FFM per minute. The FFM was measured by dual-energy x-ray absorptiometry (DEXA) scan. Insulin was infused with 5% essential amino acid solution (3mL/kg of FFM/hour) to prevent the insulin-dependent decrease of amino acids during insulin infusion.
Baseline, 3 months
K. Sreekumaran Nair, M.D., Ph.D.
United States: Institutional Review Board
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