Study to Estimate the Effects of Inhaled Versus Intravenous (IV) Infusion of Human Insulin in Subjects With Type 1 Diabetes
Study to Estimate the Effects of Inhaled Versus Intravenous (IV) Infusion of Human Insulin in Subjects With Type 1 Diabetes
University of Pittsburgh Medical Center (UPMC) diabetes research physicians are studying the
 action in muscle tissue of "inhaled" insulin (Exubera®) and "infused" (intravenous or IV)
 insulin on blood sugar control in people with type 1 diabetes. Type 1 diabetics often take
 2-4 shots of insulin every day. Exubera may offer an alternative to these insulin injections.
A dry powder insulin formulation delivered by an aerosol inhaler has been in clinical
 development for use in types 1 and 2 diabetes mellitus (DM) and just recently (1-27-06)
 received approval from the U.S. Food and Drug Administration (FDA) for the clinical treatment
 of diabetes. Administration of insulin without the need for subcutaneous (SC) injection is an
 attractive alternative for patients with diabetes. There are preclinical and clinical data
 that indicate inhalation of insulin results in a more potent effect on glucose disposal and a
 lower fasting glucose than is attained with equivalent dosing of SC or intravenous (IV)
 insulin. The physiological mechanism(s) are unclear, but occur even when matched for
 pharmacokinetics.

 The current proposal seeks primarily to more fully delineate whether there are physiological
 differences in the metabolic effects of inhaled compared to IV infused insulin, giving IV
 insulin to match the pharmacokinetics (PK) achieved with inhaled insulin.

 There are 3 specific aims:

 1. The first aim is to establish a protocol for matching the PK of inhaled insulin with the
 PK of intravenously infused insulin. An infusion algorithm has been developed and will
 be tested and refined in healthy volunteers (n = 3-5), and will be used for the
 physiological studies (aims) outlined below.

 2. The second aim is to perform Positron Emission Tomography (PET) imaging of [18F]-FDG
 uptake by muscle, following administration of a single dose of inhaled compared to
 infused insulin. Volunteers with type 1 DM (n =12) will be studied, serving as his/her
 within-subject control, under each condition of insulin administration.

 In these type 1 diabetes mellitus (type 1 DM) volunteers, we will test the hypothesis
 that a single dose of inhaled versus infused insulin, matched for arterial
 concentrations, causes greater stimulation of muscle glucose uptake.

 3. The third aim is to determine overnight rates of glucose production and plasma glucose
 after a single pre-dinner dose of inhaled compared to IV infused insulin. The same 12
 volunteers studied for Aim 2 will be studied the evening preceding the PET imaging
 studies and will serve as his/her within-subject control, under each condition of
 insulin administration.
Inclusion Criteria:

 -  Ages 18 to 50 years old

 -  Body mass index (BMI) 20 to 27 kg/m2 and a total body weight > 50 kg (110 lbs)

 -  Blood pressure: systolic < 150; diastolic < 95.

 -  Type 1 DM

 -  Have diagnosed diabetes type 1 for a minimum of 12 months prior to study entry

 -  In good general health with no evidence or history of clinically significant
 hematological, renal, endocrine (other than diabetes), pulmonary, gastrointestinal,
 cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug
 allergies, but excluding untreated, asymptomatic, seasonal allergies at time of
 dosing)

 -  Hematocrit (Hct) > 34%

 -  ALT < 60; AST < 60

 -  Alkaline phosphatase (Alk Phos) < 150

 -  Sensitive thyroid-stimulating hormone (sTSH) < 6

 -  Fasting (morning) glucose 100-160 mg/dl

 -  Documented hemoglobin A1c (HbA1c) < 7.5% at time of entry

 -  Triglycerides < 175

 -  Cholesterol < 275

 Exclusion Criteria:

 -  Exclude if unable to master use of the inhalation device after 3 attempts

 -  Exclude if positive urine drug screen

 -  Exclude if any episodes of severe hypoglycemia in the past 3 months

 -  Exclude if pregnant or breastfeeding or unwilling to use an acceptable method of
 non-hormonal contraception from at least 14 days prior to the first dose of Exubera®
 until study is completed.

 -  Exclude if any history of (h/o) asthma or chronic obstructive pulmonary disease (COPD)

 -  Exclude if forced expiratory volume in one second (FEV1) or forced vital capacity
 (FVC) < 70% predicted

 -  Exclude if treatment with an investigational drug within 30 days preceding the first
 dose of trial medication.

 -  Exclude if blood donation of approximately 1 pint (500 mL) within 56 days prior to
 dosing

 -  Exclude if unable or unwilling to comply with the protocol as written

 -  Exclude if any use of tobacco or nicotine containing products within the past 6 months

 -  Exclude if history of regular alcohol consumption exceeding 7 drinks/week for females
 or 14 drinks/week for men (1 drink = 5 ounces of wine or 12 ounces [360 mL] of beer or
 1.5 ounces [45 mL] of hard liquor) within 6 months of screening

 -  Exclude if claustrophobic, any surgical or vascular implants or pacemakers, or any
 metal in the body