Exercise Physiology Study

Diabetes mellitus afflicts close to 10% of our population and 5% of those with diabetes have
type 1, which is defined by an absolute deficiency of insulin. The need for managing diabetes
is critical, given the economic burden of this disease, with over $175 billion dollars in
direct health care costs, and almost another $70 billion in indirect costs for disability and
work loss. The personal impact is equally as important for people with this disease, as
diabetes mellitus is the leading cause of blindness, the need for kidney dialysis, and
non-traumatic amputations in the United States. Type 2 diabetes is associated with reduced
insulin sensitivity and the metabolic syndrome, and dietary modification and exercise are
important components in the management of underlying insulin resistance. However, these
lifestyle strategies are also important in type 1 diabetes for many reasons: 1) type 1
diabetes subjects now live into adulthood, when insulin resistance and obesity become factors
for glycemic control, 2) latent autoimmune diabetes of adulthood (LADA) represents a "mixed"
form of autoimmune diabetes where some type 2 diabetes characteristics such as insulin
resistance can exist, and 3) dietary modification and exercise remain effective means for
management of acute hyperglycemia and, in the longer term, HbA1c, potentially reducing the
risk of microvascular complications. Therefore, the need for exercise is still evident in
subjects with type 1 diabetes to maintain good glycemic control and to prevent complications
from developing. However, exercise is challenging for people with T1D to manage. Exercise
causes increased insulin sensitivity along with rapid uptake of glucose by muscle and other
tissues within the body, leading to a sharp decline in glucose levels and hypoglycemia as
shown by other groups as well as ours.

Without adjustments in insulin for exercise, hypoglycemia is common in persons with type 1
diabetes. In a study of 48 individuals with T1D, with no adjustments to insulin, who exercise
for 60 min at a moderate intensity, glucose levels dropped on average by 40%, with 52% of
subjects falling to 70 mg/dL or below. Despite this clear need for insulin adjustments for
exercise, there are no uniform recommendations on how to dose insulin around the time of
exercise. In 2006, the DirecNet Study Group published a study on the impact of suspending
basal insulin at the start of exercise in 40 children with type 1 diabetes on insulin pump
therapy. This intervention significantly reduced hypoglycemia (from 43% to 16%), but much
more commonly resulted in hyperglycemia (increased from 4% to 23%). Schiavon and Cobelli et
al addressed this issue of how to best adjust insulin for exercise using in silico
simulations. Adjusting insulin doses in the in silico environment decreased hypoglycemia from
88% to 16% of patients when a universal adjustment was applied, and to 4% when an individual
adjustment was applied.

The study described within this protocol is designed to disambiguate the impact of exercise
on insulin and non-insulin mediated effects on glycemic control. To achieve this, the
investigators will perform a series of stable glucose tracer studies in which subjects will
be fasting for about 8 hours and will undergo aerobic exercise at a moderate and intense
level for 45 minutes while insulin rates are clamped at a low (subject's basal rate), medium
(basal x 1.5), and high (basal x 3) insulin infusion rate. Subject's basal rates will be
obtained from injected basal insulin amounts, such as NPH/glargine/detemir, or basal rates in
those who use insulin pumps and will be adjusted for the HbA1c, as described in the OHSU AP
system. Di-deuterated glucose (6,6-2H2-glucose) which is not radioactive and which can be
metabolized via usual pathways in the human body will be the stable tracer. Each subject per
arm will undergo 3 10-hour studies while blood glucose, insulin, and glucagon levels are
captured throughout the study, and catecholamine and fatty acid levels are captured during
and just after the exercise period, as outlined below. Glucose tracer levels will be measured
at OHSU through the Bioanalytical Shared Resource/PK core lab, and calculation of rate of
appearance (Ra) and rate of disappearance (Rd) of glucose will be performed by our colleagues
at McGill University using a non-steady state model of glucose dynamics.

The data obtained from this study will inform an updated model of glucose regulation in type
1 diabetes, providing exercise as an input to the model, which will be utilized in a model
predictive control (MPC) system for managing type 1 diabetes. Such a system can be used to
deliver insulin and/or glucagon to manage glycemic changes during and outside of exercise.

Inclusion Criteria:

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

2. Male or female subjects 18 to 45 years of age.

3. Physically willing and able to perform 45 minutes of physical exercise, as determined
by the investigator after reviewing the subject's activity level.

4. A hemoglobin A1c (HbA1c) less than 10%.

5. Willingness to follow all study procedures, including attending all study visits.

6. Willingness to sign informed consent and HIPAA documents.

Exclusion Criteria:

1. Female of childbearing potential who is pregnant, intending to become pregnant,
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.

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

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

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

5. Hematocrit of less than 34%.

6. Hypertension 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).

7. 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 (included in Appendix A). Subjects will be
excluded for four or more 'R' responses.

8. Adrenal insufficiency.

9. Any active infection.

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

11. Seizure disorder.

12. Active foot ulceration.

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

14. Major surgical operation within 30 days prior to screening.

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

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

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

18. Insulin resistance requiring more than 200 units per day.

19. Current administration of oral or parenteral corticosteroids.

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

21. Beta blockers or non-dihydropyridine calcium channel blockers.

22. Current use of any medication intended to lower glucose other than insulin (e.g. use
of liraglutide, exenatide, etc.)

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

24. History of severe hypersensitivity to milk protein.

25. 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.

26. A positive response to any of the questions from the Physical Activity Readiness
Questionnaire with one exception: subject will not be excluded if only a single blood
pressure medication that doesn't impact heart rate is used, and blood pressure is
controlled on the medication (blood pressure is less than 140/90 mmHg). See Appendix
B.

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

28. Any clinically significant disorder which, in the opinion of the investigator, may
jeopardize the subject's safety or compliance with the protocol.