Glucose Counterregulation in Long Standing Type 1 Diabetes

The present protocol is designed to determine whether strict hypoglycemia avoidance by
real-time continuous glucose monitoring (RT-CGM), can restore endogenous glucose production
in response to hypoglycemia in patients with long standing disease. Twelve subjects with long
standing type 1 diabetes complicated by hypoglycemia unawareness underwent assessment of the
endogenous glucose production response to insulin-induced hypoglycemia using paired
hyperinsulinemic eu- and hypoglycemic clamps with stable glucose isotope infusions before and
at 6 and 18 months following initiation of RT-CGM. The primary analysis will be change in the
endogenous glucose production response from before to 6 months following initiation of
RT-CGM, and a secondary analysis will consider the persistence of any change at 18 months.
The clinical significance of any determined changes in the endogenous glucose production
response to insulin-induced hypoglycemia will be determined by comparison to responses
obtained using paired hyperinsulinemic eu- and hypoglycemic clamps on one occasion in a
matched control group of 12 subjects with long-standing type 1 diabetes but no hypoglycemia
unawareness (GROUP 2) and in a matched control group of 12 nondiabetic subjects (GROUP 3).
The Investigator is now ONLY recruiting for GROUP 2.

Enrollment for Group 1 (Hypo-Unaware) and Group 3 (Non-diabetic) is complete.

Hypoglycemia is a major barrier to the achievement of adequate glycemic control for most
patients with insulin-dependent diabetes. Type 1 diabetic patients with absolute insulin
deficiency (C-peptide negative) are at greatest risk for experiencing severe hypoglycemic
events because the near total destruction of insulin producing islet β-cells produces an
associated defect in glucagon secretion from neighboring α-cells. Such patients then depend
on the sympathoadrenal system as a final defense against hypoglycemia, but unfortunately,
recurrent episodes of hypoglycemia blunt sympathoadrenal activation and produce a syndrome of
hypoglycemia unawareness that is associated with a twenty-fold increased risk of
life-threatening hypoglycemia. Without intact islet or sympathoadrenal (especially
epinephrine) responses to hypoglycemia, these patients cannot increase endogenous (primarily
hepatic) glucose production to prevent or correct low blood glucose.

Key Inclusion Criteria for GROUP 2 only (Group 1 and Group 3 are complete)

1. Male and female subjects age 25 to 70 years.

2. Able to provide written informed consent and to comply with the procedures of the
study protocol.

3. Clinical history compatible with type 1 diabetes with disease onset < 40 years of age

4. Insulin-dependent for > 10 years

5. Absent C-peptide (< 0.3 ng/mL).

6. Involvement in intensive diabetes management defined as the use of basal-bolus insulin
analog delivery by multi-dose injection (MDI) or continuous subcutaneous insulin
infusion (CSII) together with self-monitoring of blood glucose values four or more
times daily, without continuous glucose monitoring (CGM), under the direction of an
endocrinologist, diabetologist, or diabetes nurse practitioner with at least 3
clinical evaluations during the previous 12 months.

7. Intact hypoglycemia awareness indicated by a Clarke score of 3 or less. 8. No episodes
of severe hypoglycemia in the past 3 years.

Key Exclusion Criteria for all 3 groups

1. Body mass index (BMI) greater than 30 kg/m2.

2. Insulin requirement of more than 1.0 IU/kg/day.

3. HbA1c greater than 10%.

4. Untreated proliferative diabetic retinopathy.

5. SBP greater than 160 mmHg or DBP greater than 100 mmHg.

6. Glomerular filtration rate (GFR) less than 55 ml/min/1.73 m-squared

7. Positive pregnancy test, presently breast-feeding, or unwillingness to use effective
contraceptive measures for the duration of the study.

8. Baseline hemoglobin less than 11 g/dl in women and less than12 g/dl in men.

9. Severe co-existing cardiac disease

10. Persistent elevation of liver function tests greater than 1.5 upper normal limits

11. Hyperlipidemia despite medical therapy

12. Receiving treatment for a medical condition requiring chronic use of systemic steroids

13. Presence of a seizure disorder not attributable to hypoglycemia.

14. Untreated hypothyroidism, Addisons disease, or Celiac disease.

15. Treatment with any anti-diabetic medication other than insulin within 4 weeks of
enrollment.

16. Use of RT-CGM (continuous glucose monitor) within last 4 weeks.

- Non-diabetic patients do not need to meet any of the glucose criteria.