Four Way Crossover Closed Loop With Exercise Detection

Subjects will undergo four approximately 84 hour studies. The first day of each study will be
an approximately 12 hour inpatient visit to include activities of daily living and an
exercise period with 2 days spent as an outpatient. The subject will come back to the
research center on the fourth day to complete another approximately 12 hour inpatient visit
to include activities of daily living and an exercise period followed by removal of all
devices. In randomized order, subjects will have glucose controlled using the following
systems: 1) dual-hormone closed-loop system, 2) insulin only closed-loop system, 3)
predictive low glucose suspend system and 4) sensor augmented pump therapy with subject using
their own insulin and insulin pump. Both of the closed-loop system algorithms have an
exercise detection algorithm that uses inputs from a heart rate monitor and accelerometer,
the Zephyrlife BioPatch. After exercise detection, insulin is turned off for the first 30
minutes, the total insulin infusion rate is adjusted by an exercise multiplier, and for the
dual-hormone system, the target glucose for glucagon is increased along with the maximum dose
of glucagon allowed. The predictive low glucose suspend system will utilize the patient's
optimized basal rates, correction factor, and carb ratio. The patient will bolus for meals
and hyperglycemia as usual under PLGS, but will have the additional safety net of the pump
suspending insulin when it predicts a hypoglycemic event. The Dexcom CGM system and the
Tandem t:slim pumps will be used for all three intervention visits.

Subjects will arrive at the CTRC at 7am at the start of intervention visits. Subjects will
eat breakfast, lunch and dinner in the research center. Subjects will eat breakfast at
8:30am. After breakfast, subjects will complete activities of daily living (sitting on a
chair, lying on a bed, washing dishes, sweeping the floor, etc.). Subjects will eat lunch at
12pm. Subjects will exercise for 45 minutes on a treadmill around 2pm. Subjects will eat
dinner at 6pm and be discharged. The subject will then go home for Day 2 and Day 3 and return
on Day 4 to complete another 12 hour inpatient visit with the schedule of activities
identical to Day 1.

Inclusion Criteria:

- Diagnosis of type 1 diabetes mellitus for at least 1 year.

- Physically willing and able to perform 45 min of exercise (as determined by the
investigator after reviewing the subjects activity level)

- Current use of an insulin pump.

- Lives with another person age 18 or older who will be present while subject exercises
at home and that can attend the training on using the system with the subject.

- Lives within 20 miles of OHSU.

- A1C<10%

- Willingness to follow all study procedures, including attending all clinic visits.

- Willingness to sign informed consent and HIPAA documents.

Exclusion Criteria:

- Female of childbearing potential who is pregnant or intending to become pregnant or
breast-feeding, or is not using adequate contraceptive methods. Acceptable
contraception includes birth control pill / patch / vaginal ring, Depo-Provera,
Norplant, an IUD, the double barrier method (the woman uses a diaphragm and spermicide
and the man uses a condom), or abstinence.

- Any cardiovascular disease, defined as a clinically significant EKG abnormality at the
time of screening or any history of: stroke, heart failure, myocardial infarction,
angina pectoris, or coronary arterial bypass graft or angioplasty. Diagnosis of 2nd or
3rd degree heart block or any non-physiological arrhythmia judged by the investigator
to be exclusionary.

- Renal insufficiency (GFR < 60 ml/min, using the MDRD equation as report by the OHSU
laboratory).

- Liver failure, cirrhosis, or any other liver disease that compromises liver function
as determined by the investigator.

- Hematocrit of less than or equal to 34%.

- Hypertensive subjects with systolic blood pressure >= 160 mmHg or diastolic blood
pressure >= 100 mmHg despite treatment or who have treatment-refractory hypertension
(e.g. requiring four or more medications).

- History of severe hypoglycemia during the past 12 months prior to screening visit or
hypoglycemia unawareness as judged by the investigator. Subjects will complete a
hypoglycemia awareness questionnaire. Subjects will be excluded for four or more R
responses.

- Adrenal insufficiency.

- Any active infection.

- Known or suspected abuse of alcohol, narcotics, or illicit drugs.

- Seizure disorder.

- Active foot ulceration.

- Severe peripheral arterial disease characterized by ischemic rest pain or severe
claudication.

- Major surgical operation within 30 days prior to screening.

- Use of an investigational drug within 30 days prior to screening.

- Chronic usage of any immunosuppressive medication (such as cyclosporine, azathioprine,
sirolimus, or tacrolimus).

- Bleeding disorder, treatment with warfarin, or platelet count below 50,000.

- Allergy to aspart insulin.

- Allergy to glucagon.

- Insulin resistance requiring more than 200 units per day.

- Need for uninterrupted treatment of acetaminophen.

- Current administration of oral or parenteral corticosteroids.

- Any life threatening disease, including malignant neoplasms and medical history of
malignant neoplasms within the past 5 years prior to screening (except basal and
squamous cell skin cancer).

- Beta blockers or non-dihydropyridine calcium channel blockers.

- Current use of any medication intended to lower glucose other than insulin (ex. use of
liraglutide).

- Diagnosis of pheochromocytoma, insulinoma, or glucagonoma, personal or family history
of multiple endocrine neoplasia (MEN) 2A, MEN 2B, neurofibromatosis or von
Hippel-Lindau disease.

- History of severe hypersensitivity to milk protein.

- Current use of any medication with strong anticholinergic properties, such as
antihistamines, sleep aids, and antidiarrheal medications.

- Current use of indomethacin.

- Conditions that may result in low levels of releasable glucose in the liver and an
inadequate reversal of hypoglycemia by glucagon such as prolonged fasting, starvation
or chronic hypoglycemia as determined by the investigator.

- A positive response to any of the questions from the Physical Activity Readiness
Questionnaire.

- Any chest discomfort with physical activity, including pain or pressure, or other
types of discomfort.

- Any clinically significant disease or disorder which in the opinion of the
Investigator may jeopardize the subject's safety or compliance with the protocol.