Adrenergic System in Islet Transplantation

This study is designed to test the hypothesis that α-adrenergic (neural) blockade will
abolish insulin-mediated suppression of C-peptide, attenuating α-cell glucagon secretion
during hypoglycemia, and that β-adrenergic (hormonal) blockade will have no effect. Glucose
counterregulatory responses will be measured during hyperinsulinemic euglycemic-hypoglycemic
clamps on three occasions with randomized, double-blind administration of the α-adrenergic
blocker phentolamine, the β-adrenergic blocker propranolol, or placebo. The demonstration of
neural rather than hormonal regulation of the transplanted islet cell response to
hypoglycemia is critical for understanding the mechanism for protection from hypoglycemia
afforded by intrahepatically transplanted islets.

Glucose counterregulation has not been studied in type 1 diabetic recipients of extrahepatic
islet transplantation. Comparison of glucose counterregulatory responses measured during
hyperinsulinemic euglycemic-hypoglycemic clamps will be compared to those obtained from type
1 diabetic recipients of intrahepatic islet transplantation studied under the placebo
condition above.

Glucose counterregulation has not been directly compared between recipients of intrahepatic
auto- and allo-islet transplantation. Direct comparison of glucose counterregulatory
responses under the same experimental conditions is required to understand whether mechanisms
other than the glucagon response may be important to the reported hypoglycemia affecting
pancreatectomized recipients of islet auto-transplantation.

Inclusion Criteria:

GROUP 1

1. Male and female subjects age 21 to 65 years of age.

2. Subjects who are 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 onset of disease at < 40 years
of age and insulin-dependent for > 10 years at the time of islet transplantation > 6
months before study.

4. Stable islet graft function defined by C-peptide > 0.5 ng/ml and insulin-independent
or insulin-dependent with daily insulin requirement < 0.2 units/kg•d to maintain HbA1c
< 7.0%.

5. Use of standard immunosuppression consisting of tacrolimus with or without sirolimus
or mycophenolic acid. Substitutions of tacrolimus with cyclosporine, and of sirolimus
or mycophenolic acid with azathioprine are permissible if stable for over 3 months.
Prednisone is allowable if no more than 5 mg daily.

Exclusion Criteria:

GROUP 1

1. BMI ≥ 30 kg/m2.

2. Insulin requirement of ≥ 0.2 units/kg•day.

3. HbA1c ≥ 7.0%.

4. Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood
pressure > 100 mmHg.

5. History of cardiovascular disease, including coronary artery, cerebrovascular or
peripheral vascular disease, or current use of β-blocker therapy.

6. Bronchial asthma.

7. Abnormal kidney function: Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73
m2.

8. Abnormal liver function: persistent elevation of liver function tests > 1.5 times the
upper limit of normal.

9. Untreated hypothyroidism, Addison's disease, or Celiac disease.

10. Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men.

11. Presence of a seizure disorder not related to prior severe hypoglycemia.

12. Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent
physiologic dose of hydrocortisone.

13. For female participants of child-bearing potential: Positive pregnancy test, presently
breast-feeding, or unwillingness to use effective contraceptive measures for the
duration of study participation. Oral contraceptives, intra-uterine devices,
Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable
contraceptive methods; condoms used alone are not acceptable.

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

15. Use of any investigational agents within 4 weeks of enrollment.

16. Any medical condition that, in the opinion of the PI, will interfere with the safe
completion of the study

Inclusion Criteria GROUP 2

1. Male and female subjects age 21 to 65 years of age.

2. Subjects who are 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 onset of disease at < 40 years
of age and insulin-dependent for > 10 years at the time of islet transplantation > 6
months before study.

4. Stable islet graft function defined by C-peptide > 0.5 ng/ml and insulin-independent
or insulin-dependent with daily insulin requirement < 0.2 units/kg•d to maintain HbA1c
< 7.0%.

5. Use of standard immunosuppression consisting of tacrolimus with or without sirolimus
or mycophenolic acid. Substitutions of tacrolimus with cyclosporine, and of sirolimus
or mycophenolic acid with azathioprine are permissible if stable for over 3 months.
Prednisone is allowable if no more than 5 mg daily.

Exclusion Criteria:

GROUP 2

1. BMI ≥ 30 kg/m2.

2. Insulin requirement of ≥ 0.2 units/kg•day.

3. HbA1c ≥ 7.0%.

4. Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood
pressure > 100 mmHg.

5. Active cardiovascular disease, including coronary artery, cerebrovascular or
peripheral vascular disease.

6. Abnormal kidney function: eGFR < 60 ml/min/1.73 m2.

7. Abnormal liver function: persistent elevation of liver function tests > 1.5 times the
upper limit of normal.

8. Untreated hypothyroidism, Addison's disease, or Celiac disease.

9. Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men.

10. Presence of a seizure disorder not related to prior severe hypoglycemia.

11. Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent
physiologic dose of hydrocortisone.

12. For female participants of child-bearing potential: Positive pregnancy test, presently
breast-feeding, or unwillingness to use effective contraceptive measures for the
duration of study participation. Oral contraceptives, intra-uterine devices,
Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable
contraceptive methods; condoms used alone are not acceptable.

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

14. Use of any investigational agents within 4 weeks of enrollment.

15. Any medical condition that, in the opinion of the PI, will interfere with the safe
completion of the study

Inclusion Criteria GROUP 3

Patients who meet all of the following criteria are eligible for participation in Group 3
of this study:

1. Male and female subjects age 21 to 65 years of age.

2. Subjects who are able to provide written informed consent and to comply with the
procedures of the study protocol.

3. Clinical history compatible with total pancreatectomy and autologous islet
transplantation > 6 months before study.

4. Stable islet graft function defined by C-peptide > 0.5 ng/ml and insulin-independent
or insulin-dependent with daily insulin requirement < 0.2 units/kg•d to maintain HbA1c
< 7.0%.

Exclusion Criteria:

GROUP 3

1. BMI ≥ 30 kg/m2.

2. Insulin requirement of ≥ 0.2 units/kg•day.

3. HbA1c ≥ 7.0%.

4. Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood
pressure > 100 mmHg.

5. Active cardiovascular disease, including coronary artery, cerebrovascular or
peripheral vascular disease.

6. Abnormal kidney function: eGFR < 60 ml/min/1.73 m2.

7. Abnormal liver function: persistent elevation of liver function tests > 1.5 times the
upper limit of normal.

8. Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men.

9. Presence of a seizure disorder not related to prior severe hypoglycemia.

10. Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent
physiologic dose of hydrocortisone.

11. For female participants of child-bearing potential: Positive pregnancy test, presently
breast-feeding, or unwillingness to use effective contraceptive measures for the
duration of study participation. Oral contraceptives, intra-uterine devices,
Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable
contraceptive methods; condoms used alone are not acceptable.

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

13. Use of any investigational agents within 4 weeks of enrollment.

14. Any medical condition that, in the opinion of the PI, will interfere with the safe
completion of the study