Sensor-Augmented Insulin Delivery: Insulin Plus Glucagon Versus Insulin Alone
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus, Type 1
Intervention: Insulin, Asp(B28)-; Glucagon; Placebo
Intervention description: Insulin dosing and frequency calculated by Fading Memory Proportional Derivative algorithm; During incipient hypoglycemia, glucagon was given in an attempt to prevent overt hypoglycemia. Dosing and frequency was calculated by the Fading Memory Proportional Derivative algorithm; Saline solution 0.9%
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Glucagon
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Enrollment: 14.0
Sex: All
Minimum age: 21 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: diabetes; pancreas; beta cell; glucagon; insulin; hypoglycemia

Summary:

      This study aims to test an insulin and glucagon delivery algorithm designed to be used in
      conjunction with a continuous glucose monitoring system. This combined glucose
      sensing/hormone delivery approach is a step on the way to eventual development of an
      artificial (or automated) pancreas. The insulin and glucagon delivery algorithm is based on
      the difference between the current blood glucose and the target glucose (proportional error)
      and the rate of change in blood glucose (derivative error), both adjusted for the recent
      glucose history. This algorithm is called the Fading Memory Proportional-Derivative (FMPD)
      Algorithm. The principal investigator of this study has published previous research regarding
      the use of this algorithm and found it to be well-suited to control blood glucose in type 1
      diabetic animals. The addition of glucagon was helpful; better glycemic control with fewer
      glucose excursions were observed when small intermittent infusions of subcutaneous glucagon
      were given during times of impending low blood sugar (Ward et al. 2008).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age 21-65, history of Type 1 Diabetes Mellitus for > 3 months.

          -  Women:

               -  For women of childbearing potential, a negative urine pregnancy test is required
                  on the first day of the study prior to sensor insertion AND the subject must
                  agree to use contraception prior to and during the study.

               -  For menopausal women or those who have undergone surgical sterilization, no
                  pregnancy test or contraception will be required.

          -  Willingness to attend all clinic visits and participate in two 28-hour studies or one
             9-hour study.

          -  Hemoglobin A1C of 5.0-10%. (Values below 5.0 suggest a severe tendency towards
             hypoglycemia, and values above 10% suggest severely uncontrolled diabetes with risk
             for ketoacidosis.)

          -  Body mass index of 19-35.

        Exclusion Criteria:

          -  Pregnancy, lactation or refusal to use contraception.

          -  Use of any investigational drug during the 30 days prior to screening.

          -  Enrollment or participation in any other research studies 30 days prior to and during
             the entirety of sensor insertion.

          -  Current alcohol abuse, substance abuse, or severe mental illness (as judged by the
             Principal Investigator (PI)).

          -  Any prior cerebrovascular accident or major permanent neurological damage such as
             aphasia, hemiparesis, or dementia.

          -  A history of cerebrovascular disease or cardiovascular disease regardless of the time
             since occurrence.

          -  Coronary artery disease (symptomatic or asymptomatic) as manifested by unstable
             angina, acute coronary syndrome, myocardial infarction or therapeutic coronary
             procedure (e.g., Percutaneous Transluminal Coronary Angioplasty (PTCA), stent
             placement, Coronary Artery By-pass Grafting (CABG)) within the prior 6 months.

          -  Any degree of heart failure (as defined by New York Heart Association)..

          -  Renal insufficiency (serum creatinine of > 2.5).

          -  Current foot or leg ulceration.

          -  Peripheral arterial disease with uncontrolled claudication.

          -  Active uncontrolled malignancy except basal cell or squamous cell skin cancers.

          -  Concurrent illness, other than diabetic mellitus, that is not controlled by a stable
             therapeutic regimen.

          -  Hemoglobin A1C of less than 5.0 or greater than 10%.

          -  A total bilirubin level above 1.5 mg/dl.

          -  Medications: Oral or parenteral corticosteroids (glucocorticoid therapy) are
             exclusions; topical corticosteroids are not.

          -  Any chronic immunosuppressive medication (such as cyclosporine, azathioprine,
             sirolimus, or tacrolimus).

          -  Visual impairment that would prevent reading the display of the Medtronic Guardian®
             Receiver.

          -  Physical impairment that would prevent using the buttons of the Medtronic Guardian®
             Receiver.

          -  Serum Alanine Transaminase (ALT) or Aspartate Transaminase (AST) ≥3x the upper limit
             of normal.

          -  Serum albumin level of < 3.2 g/dl.

          -  Severe anemia as defined by a hematocrit of < 28%.

          -  Severe serum electrolyte abnormality (sodium, potassium, carbon dioxide, chloride).

          -  Cardiac rhythm disturbance characterized by: 2nd or 3rd degree heart block,
             bradycardia of less than 50 bpm (exception of bradycardia in an aerobic athlete),
             tachycardia of greater than 100 bpm, or any arrhythmia judged by the investigator to
             be exclusionary.

          -  A history of Human Immunodeficiency Virus (HIV) infection.

          -  An active hepatitis infection.

          -  Known allergy to any type of insulin

          -  Insulin resistance requiring more than 200 units of insulin per day

          -  Known bleeding disorders or chronic usage of warfarin.

          -  Any known seizure disorder.

          -  Past history of pheochromocytoma or a family history of Multiple Endocrine Neoplasia
             (MEN) 2A, MEN 2B, neurofibromatosis, or von Hippel-Lindau disease.

          -  Hypoglycemic unawareness or chronic hypoglycemia.

          -  A severe hypoglycemic event which required hospitalization within the past two years.

          -  Adrenal insufficiency.

          -  Insulinoma.

          -  Use of both acetaminophen and ascorbic acid.

          -  Impaired mentation or psychiatric diagnoses

          -  Uncontrolled candidiasis.

          -  Any known allergy to glucagon.