Adrenergic System in Islet Transplantation

• Status: Active, not recruiting
• Trial end date: 2023-12-01
• Target enrollment: 0
• Participant gender: All

Summary

To determine the effect of sympathetic neural and hormonal (epinephrine) input on islet cell hormonal responses to insulin-induced hypoglycemia in type 1 diabetic recipients of intrahepatic islet transplantation. We hypothesize that α-adrenergic (neural) blockage will abolish insulin-mediated suppression of C-peptide, attenuating α-cell glucagon secretion during hypoglycemia, and that β-adrenergic (hormonal) blockage 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.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Pennsylvania
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH)
• Treatments: Adrenergic Agents; Phentolamine; Propranolol

Criteria

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