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Effect of Insulin Sensitizer Therapy on Atherothrombotic and Inflammatory Profiles Associated With Insulin Resistance

Phase 2
20 Years
Not Enrolling
Type 2 Diabetes, Insulin Resistance, Metabolic Syndrome

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Trial Information

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
overnight fast.

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).

Inclusion Criteria

Inclusion criteria:

- We will study 30 patients with Type 2 Diabetes or impaired fasting glucose (15 men &
15 women) who are > 20 years old.

- Only patients who use lifestyle modification to manage their diabetes and are not on
any oral hypoglycemic agents or insulin will be included.

- We will enroll subjects who have fasting glucose concentration greater than 100 mg/dl
on two consecutive occasions and have a Body Mass Index between 27-36 kg/m^2.

Exclusion Criteria:

- We will exclude patients whose blood glucose is above 180 mg/dl. This will avoid the
need to perform home glucose monitoring and the potential of unblinding the study by
the volunteers.

- Patients taking oral hypoglycemic agents or insulin would be excluded.

- Any diseases such as active cardiovascular disease, liver diseases, kidney failure
(males with serum creatinine >= 1.5mg/dl, females >=1.4 mg/dl), active
endocrinopathies, debilitating chronic disease, anemia, symptoms of undiagnosed
illness, history of alcoholism (alcohol use > 4oz/day) or substance abuse, chronic
neurological diseases including Alzheimer's disease, stroke, etc, myopathies or any
other active disease that may potentially affect the outcome measures.

- Patients on medicines such as beta blockers, corticosteroids, tricyclics,
benzodiazepines, opiates, barbiturates, anticoagulants and any other drugs or
preparations that may affect mitochondrial function will be excluded.

- People allergic to any of the class of drug such as lidocaine will also be excluded.

- People with pacemakers, certain aneurysm clips and claustrophobia will also be
excluded as they cannot undergo magnetic resonance imaging.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Outcome Measure:

Change From Baseline in Insulin Sensitivity as Measured by Glucose Infusion Rate (GIR)

Outcome Description:

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.

Outcome Time Frame:

Baseline, 3 months

Safety Issue:


Principal Investigator

K. Sreekumaran Nair, M.D., Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Institutional Review Board

Study ID:




Start Date:

August 2005

Completion Date:

August 2010

Related Keywords:

  • Type 2 Diabetes
  • Insulin Resistance
  • Metabolic Syndrome
  • Inflammatory cytokine
  • Cardiovascular Disease
  • Thrombotic factors
  • Dyslipidemia
  • Diabetes Mellitus, Type 2
  • Insulin Resistance
  • Metabolic Syndrome X



Mayo Clinic Rochester, Minnesota  55905