Adrenergic System in Islet Transplantation

Early Phase 1CompletedNCT03079921

University of Pennsylvania9 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Eligibility

Sex: ALLMin age: 21 YearsMax age: 65 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

C-PEPTIDE Suppression During Hyperinsulinemia Euglycemia.

The primary outcome measures will be the levels of C-peptide during hyperinsulinemia euglycemia.

Time frame: For C-peptide at the 60-90 minute time-point during the hyperinsulinemic euglycemic-hypoglycemic clamp.

GLUCAGON Activation During Hyperinsulinemia Hypoglycemia.

The primary outcome measures will be the levels of glucagon during hyperinsulinemia hypoglycemia.

Time frame: For Glucagon at the 150-180 minute time-point during the hyperinsulinemic euglycemic-hypoglycemic clamp.

Secondary Outcomes

EPINEPHRINE During Hyperinsulinemia Hypoglycemia.

Secondary outcome measures will include levels of epinephrine during hyperinsulinemia hypoglycemia.

Time frame: During metabolic testing in the 150-180 minute time-point of the hyperinsulinemic euglycemic-hypoglycemic clamp.

Rates of ENDOGENOUS GLUCOSE PRODUCTION During Hyperinsulinemia Hypoglycemia.

Secondary outcome measures will include rates of endogenous glucose production during hyperinsulinemia hypoglycemia

Time frame: During metabolic testing in the 150-180 minute time-point of the hyperinsulinemic euglycemic-hypoglycemic clamp.

AUTONOMIC SYMPTOMS During Hyperinsulinemia Hypoglycemia

A questionnaire was administered every 15-30 min during the study to quantitate autonomic symptoms as the sum of scores ranging from 0 (none) to 5 (severe) for each of the following symptoms: anxiety, palpitations, sweating, tremor, hunger, and tingling. (6 symptoms) Total scores range 0 - 30, where higher scores indicate greater autonomic symptoms.

Time frame: The autonomic symptom score was calculated as the mean of scores at the two hypoglycemic time points during the clamp (165 and 180 minutes).

Adrenergic System in Islet Transplantation

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes