Insulin Receptor Substrate 1 (IRS-1) Regulation in Insulin Resistance
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 2; Insulin Resistance
Study type: Interventional
Phase: Phase 1

Summary: 
      The study is being conducted to find out why too much fat in your blood stream may cause
      insulin resistance in your muscles. Insulin is the hormone, produced normally by your body,
      which causes your blood sugar to return to normal after you eat.
    

Detailed description: 
      Insulin resistance in skeletal muscle is an early event in the pathogenesis of type 2
      diabetes, obesity, and other conditions associated with the Metabolic Syndrome. The aim of
      this study is to determine the extent to which the inflammatory response to lipids is present
      in naturally occurring insulin resistance. We will test the hypothesis that skeletal muscle
      from insulin resistant volunteers is characterized by:

        1. Increased concentrations of circulating proinflammatory cytokines without changes in
           cytokine expression in muscle.

        2. Increased inflammatory response in muscle.

        3. Increased infiltration of inflammatory cells into skeletal muscle.

        4. Changes in expression of proteasome genes.

      Forty five subjects will be studied in total. Three groups will be studied. One group will
      consist of 15 patients with type 2 diabetes mellitus The second group will consist of 15 age,
      gender, and body composition matched overweight or obese subjects (27 < BMI <36) with normal
      glucose tolerance. The third group will consist of 15 age and gender matched nonobese control
      subjects (BMI < 27).

      There will be two visits in the study, a screening visit and the study visit. At visit 2 the
      subject will report to the study site having fasted since the night before, discuss the study
      and provide written consent, and provide a history and physical exam. Screening tests include
      a 12-lead resting EKG, complete blood chemistry and complete blood count (CBC), glycated
      hemoglobin (HbA1c), and a lipid profile. If the results of these tests show that the subject
      is eligible to participate in the study, a second visit will be scheduled. On the same day as
      the screening visit, the patient will have an oral glucose tolerance test.

      Within 3 months of the screening visit, the subject will return after an overnight fast for a
      euglycemic clamp study and 2 muscle biopsies. Diabetic subjects will have oral medications
      discontinued for 3 days before study (metformin and thiazolidinedione treatment will be
      excluded). Patients taking insulin will have neutral protamine Hagedorn (NPH) discontinued
      the evening before study, and Glargine will be discontinued the morning and evening on the
      day before study. An antecubital catheter will be placed for infusion of substances.
      Deuterated glucose will be used to determine the rates of basal and insulin stimulated
      glucose uptake. A hand vein will be catheterized and placed in a heated box to arterialize
      venous blood for measurement of arterial glucose concentrations. One hour later, a
      percutaneous biopsy of the vastus lateralis muscle will be performed. Biopsy specimens
      (75-150 mg) will be frozen immediately in liquid nitrogen and stored in liquid nitrogen until
      they are processed. One hour after the muscle biopsy (two hours after the start of deuterated
      glucose), a primed-continuous (80 milliunits (mU)/(m^2 per min)) insulin infusion will be
      started and continued for 120 minutes to quantify the effects of insulin on glucose disposal.
      Throughout the insulin infusion, an infusion of 20% glucose will be adjusted to maintain
      euglycemia. Plasma glucose in the diabetics will be allowed to fall during the insulin
      infusion to euglycemia, where it will be maintained. A second muscle biopsy will be performed
      in the contralateral leg at the conclusion of the insulin infusion.
    

Intervention name(s): Human insulin
Intervention type(s): Drug
Intervention description(s): U100 Humulin at a rate of 80 mU/m^2 surface area per minute one time over 4 hours
Other intervention name(s): Humulin
Intervention MeSH terms: Insulin; Insulin, Globin Zinc
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: diabetes; insulin resistance