Closed-loop Glucose Control for Automated Management of Type 1 Diabetes

This study investigates the utility of an integrated closed-loop glucose-control system for
regulating BG in type 1 diabetic subjects. The closed-loop system utilizes sub-cutaneous
infusion or insulin and glucagon under the control of a computer algorithm. The only inputs
to the algorithm are the subject weight and BG values measured every five minutes. Subjects
will undergo up to three 27 hour GCRC admissions during which they will consume three
standardized meals. Subject may participate in up to two closed-loop visits (with different
insulin lispro pharmacokinetic parameter settings in the control algorithm) and some subjects
will participate in open-loop visits. During the closed-loop admission BG will be controlled
by the closed-loop system. During the open-loop visit subjects will regulate their own BG in
the usual function using their insulin pumps. A small group of non-diabetic subjects will
undergo a single 27 hour GCRC admission during which they will eat the same standardized
meals. During all admission BG will be measured every 5 minutes and blood will be collected
for measurement of insulin and glucagon levels every 10 minutes. During the closed-loop
admission of diabetic subjects and the single admission of non-diabetic subjects, three
commercially available continuous glucose monitoring devices will be worn. The data from
these devices will later be compared to reference BG data.

Inclusion Criteria (type 1 diabetic subjects):

- Age 18 years or older

- Clinical type 1 diabetes for at least five years

- Otherwise healthy (mild chronic disease allowed if well controlled)

- Diabetes managed using an insulin infusion pump

- Body mass index (BMI) between 20 and 31

- Total daily dose (TDD) of insulin ≤ 1 U/kg and ≤ 100 U/day

- Post-prandial C-peptide < 0.1 nmol/L at 90 minutes in a mixed meal (Sustacal)
tolerance test by the DCCT method

- Hemoglobin A1c less than or equal to 8.5%

- Prescription medication regimen stable for at least 1 month

Inclusion Criteria (non-diabetic subjects):

- Age 18 years or older

- No personal history of diabetes, impaired fasting glucose, or impaired glucose
tolerance

- No personal history of pancreatic disease

- Not taking medication that may affect glucose, insulin, or glucagon dynamics

- Otherwise healthy (mild chronic disease allowed if well controlled)

- Body mass index (BMI) between 20 and 31

- Normal 75 g oral glucose tolerance test (fasting, 1 hour, and 2 hour measurements)

Exclusion Criteria (all subjects):

- Unable to provide informed consent or are unable to comply with study procedures

- Current participation in another clinical trial

- Anemia (HCT or hemoglobin less than normal for sex)

- Elevated alanine aminotransferase (ALT > 3 fold above upper limit of normal)

- Untreated or inadequately treated hyperthyroidism or hypothyroidism (abnormal TSH or
free T4)

- Pregnancy (positive urine HCG), breast feeding, plan to become pregnant in the
immediate future, or sexually active without use of contraception

- Progressive or proliferative diabetic retinopathy (subjects with mild,
non-proliferative background retinopathy or stable disease previously treated with
photocoagulation are not excluded).

- Renal insufficiency (creatinine clearance estimated by Cockcroft-Gault equation of ≤
50 ml/min)

- Any known history or symptoms of coronary artery disease.

- Abnormal EKG

- Congestive heart failure

- History of TIA or stroke within preceding 6 months

- Acute illness or exacerbation of chronic illness at the time of the study procedure

- Change in medication regimen in the 30 days prior to enrollment

- History of seizures

- History of pheochromocytoma

- Abnormal plasma fractionated metanephrines

- History of adrenal disease or tumor

- History of pancreatic tumor, including insulinoma

- History of impaired gastric motility or gastroparesis requiring pharmacological or
surgical treatment

- Current alcohol abuse (> 3 drinks daily) or substance abuse (any use within the last 6
months of illegal drugs)

- Severe mental illness (schizophrenia, bipolar disease, inadequately treated
depression, or any psychiatric hospitalization in the last year)

- Impaired cognition or altered mental status.

- Hypertension (blood pressure > 140/90) at the time of screening

- Use of medications that reduce gastric motility

- Electrically powered implants that might be susceptible to RF interference

- Use non-insulin injectable anti-diabetic medications, inhaled insulin, or oral
anti-diabetic medications

- History of adverse reaction to glucagon (including allergy) besides nausea and
vomiting.

- Established history of latex, adhesive, tape allergy, inadequate venous access,
history of allergy to or intolerance of aspirin.