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Adrenergic System in Islet Transplantation

Primary Purpose

Type1diabetes, Hypoglycemia, Hypoglycemia Unawareness

Status

Active

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Phentolamine

Propranolol

Placebo

About this trial

This is an interventional basic science trial for Type1diabetes focused on measuring Islet Graft Function, Islet Cell transplantation, Auto-islet transplantation, Intra-hepatic islets, Extra-hepatic islets

Eligibility Criteria

21 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

GROUP 1

Male and female subjects age 21 to 65 years of age.
Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
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.
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%.
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

BMI ≥ 30 kg/m2.
Insulin requirement of ≥ 0.2 units/kg•day.
HbA1c ≥ 7.0%.
Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
History of cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease, or current use of β-blocker therapy.
Bronchial asthma.
Abnormal kidney function: Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2.
Abnormal liver function: persistent elevation of liver function tests > 1.5 times the upper limit of normal.
Untreated hypothyroidism, Addison's disease, or Celiac disease.
Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men.
Presence of a seizure disorder not related to prior severe hypoglycemia.
Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone.
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.
Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
Use of any investigational agents within 4 weeks of enrollment.
Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study

Inclusion Criteria GROUP 2

Male and female subjects age 21 to 65 years of age.
Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
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.
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%.
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

BMI ≥ 30 kg/m2.
Insulin requirement of ≥ 0.2 units/kg•day.
HbA1c ≥ 7.0%.
Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
Active cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease.
Abnormal kidney function: eGFR < 60 ml/min/1.73 m2.
Abnormal liver function: persistent elevation of liver function tests > 1.5 times the upper limit of normal.
Untreated hypothyroidism, Addison's disease, or Celiac disease.
Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men.
Presence of a seizure disorder not related to prior severe hypoglycemia.
Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone.
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.
Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
Use of any investigational agents within 4 weeks of enrollment.
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:

Male and female subjects age 21 to 65 years of age.
Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
Clinical history compatible with total pancreatectomy and autologous islet transplantation > 6 months before study.
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

BMI ≥ 30 kg/m2.
Insulin requirement of ≥ 0.2 units/kg•day.
HbA1c ≥ 7.0%.
Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
Active cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease.
Abnormal kidney function: eGFR < 60 ml/min/1.73 m2.
Abnormal liver function: persistent elevation of liver function tests > 1.5 times the upper limit of normal.
Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men.
Presence of a seizure disorder not related to prior severe hypoglycemia.
Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone.
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.
Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
Use of any investigational agents within 4 weeks of enrollment.
Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study

Sites / Locations

University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Active Comparator

Placebo Comparator

No Intervention

Arm Label

Group 1-Propranolol Intra-hepatic islet

Group 1-Phentolamine Intra-hepatic islet

Group 1- Placebo Intra-hepatic islet

Group 2 - Extra-hepatic islet

Group 3 - Intra-hepatic auto islet

Arm Description

The dose of propranolol will be 0.48 μg/kilogram•minute, which will provide a total dose of 0.10 mg/kg. It will be administered 1 x only via intravenous infusion over 3.5 hours, starting 30 min before conduct of a hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp.

The dose of phentolamine will be 0.95 μg/kg•min, which will provide a total dose of 0.20 mg/kg. It will be administered 1 x only via intravenous infusion over 3.5 hours, starting 30 min before conduct of a hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp.

Placebo in 100mL NSS. Infuse Intravenously at 0.0095 ML/KG/MIN. 1 x only via intravenous infusion over 3.5 hours, starting 30 min before conduct of a hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp.

Hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp only.

Outcomes

Primary Outcome Measures

C-PEPTIDE suppression during hyperinsulinemia euglycemia.

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

GLUCAGON activation during hyperinsulinemia hypoglycemia.

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

Secondary Outcome Measures

EPINEPHRINE during hyperinsulinemia hypoglycemia.

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

Rates of ENDOGENOUS GLUCOSE PRODUCTION during hyperinsulinemia hypoglycemia.

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

AUTONOMIC SYMPTOMS during hyperinsulinemia

Secondary outcome measures will include levels of autonomic symptoms during hyperinsulinemia hypoglycemia. Autonomic symptoms will be measured by answering a short symptoms questionnaire with a level scale of 0-5.

Full Information

NCT ID

NCT03079921

First Posted

February 28, 2017

Last Updated

August 28, 2023

Sponsor

University of Pennsylvania

Collaborators

National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

1. Study Identification

Unique Protocol Identification Number

NCT03079921

Brief Title

Adrenergic System in Islet Transplantation

Official Title

Adrenergic Contribution to Glucose Counterregulation in Islet Transplantation

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

January 20, 2017 (Actual)

Primary Completion Date

April 30, 2019 (Actual)

Study Completion Date

December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Pennsylvania

Collaborators

National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type1diabetes, Hypoglycemia, Hypoglycemia Unawareness, Islet Cell Transplantation

Keywords

Islet Graft Function, Islet Cell transplantation, Auto-islet transplantation, Intra-hepatic islets, Extra-hepatic islets

7. Study Design

Primary Purpose

Basic Science

Study Phase

Early Phase 1

Interventional Study Model

Factorial Assignment

Model Description

This study is a within subject and across group mechanistic design. Islet cell hormonal responses to a hyperinsulinemic euglycemic-hypoglycemic clamp will be assessed in "Group 1" on three occasions with randomized, double-blind administration of the α-adrenergic blocker phentolamine, the β-adrenergic blocker propranolol, or placebo. Responses in "Group 1" under the placebo condition will be used for comparison to those obtained from hyperinsulinemic euglycemic-hypoglycemic clamp testing on one occasion in subjects in each of "Group 2" and "Group 3".

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Conditions of testing for "Group 1" (intra-hepatic islet recipients) will remain double-blind for each subject until their completion of all testing visits, unless for safety concerns, either the PI or Medical Monitor request an unblinding. Groups "2" and "3" will have no masking.

Allocation

Randomized

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group 1-Propranolol Intra-hepatic islet

Arm Type

Active Comparator

Arm Description

Arm Title

Group 1-Phentolamine Intra-hepatic islet

Arm Type

Active Comparator

Arm Description

Arm Title

Group 1- Placebo Intra-hepatic islet

Arm Type

Placebo Comparator

Arm Description

Arm Title

Group 2 - Extra-hepatic islet

Arm Type

No Intervention

Arm Description

Hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp only.

Arm Title

Group 3 - Intra-hepatic auto islet

Arm Type

No Intervention

Arm Description

Hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp only.

Intervention Type

Drug

Intervention Name(s)

Phentolamine

Other Intervention Name(s)

Regitine

Intervention Description

Physiologic receptor blockade (α1-receptor).

Intervention Type

Drug

Intervention Name(s)

Propranolol

Other Intervention Name(s)

Inderal

Intervention Description

Physiologic receptor blockade (β2-receptor).

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Saline, Sodium Chloride Solution

Intervention Description

100mL bag of Normal Saline Solution (NSS).

Primary Outcome Measure Information:

Title

C-PEPTIDE suppression during hyperinsulinemia euglycemia.

Description

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

Time Frame

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

Title

GLUCAGON activation during hyperinsulinemia hypoglycemia.

Description

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 Outcome Measure Information:

Title

EPINEPHRINE during hyperinsulinemia hypoglycemia.

Description

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.

Title

Rates of ENDOGENOUS GLUCOSE PRODUCTION during hyperinsulinemia hypoglycemia.

Description

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.

Title

AUTONOMIC SYMPTOMS during hyperinsulinemia

Description

Time Frame

During metabolic testing; this symptom questionnaire will be asked at the following time points: -15min, -1min, 30min, 60min,75min, 90min,120min, 150min, 165min, 180min.

10. Eligibility

Sex

All

Gender Based

Yes

Gender Eligibility Description

Male or Female at birth.

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: GROUP 1 Male and female subjects age 21 to 65 years of age. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol. 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. 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%. 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 BMI ≥ 30 kg/m2. Insulin requirement of ≥ 0.2 units/kg•day. HbA1c ≥ 7.0%. Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg. History of cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease, or current use of β-blocker therapy. Bronchial asthma. Abnormal kidney function: Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Abnormal liver function: persistent elevation of liver function tests > 1.5 times the upper limit of normal. Untreated hypothyroidism, Addison's disease, or Celiac disease. Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men. Presence of a seizure disorder not related to prior severe hypoglycemia. Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone. 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. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment. Use of any investigational agents within 4 weeks of enrollment. Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study Inclusion Criteria GROUP 2 Male and female subjects age 21 to 65 years of age. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol. 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. 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%. 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 BMI ≥ 30 kg/m2. Insulin requirement of ≥ 0.2 units/kg•day. HbA1c ≥ 7.0%. Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg. Active cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease. Abnormal kidney function: eGFR < 60 ml/min/1.73 m2. Abnormal liver function: persistent elevation of liver function tests > 1.5 times the upper limit of normal. Untreated hypothyroidism, Addison's disease, or Celiac disease. Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men. Presence of a seizure disorder not related to prior severe hypoglycemia. Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone. 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. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment. Use of any investigational agents within 4 weeks of enrollment. 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: Male and female subjects age 21 to 65 years of age. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol. Clinical history compatible with total pancreatectomy and autologous islet transplantation > 6 months before study. 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 BMI ≥ 30 kg/m2. Insulin requirement of ≥ 0.2 units/kg•day. HbA1c ≥ 7.0%. Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg. Active cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease. Abnormal kidney function: eGFR < 60 ml/min/1.73 m2. Abnormal liver function: persistent elevation of liver function tests > 1.5 times the upper limit of normal. Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men. Presence of a seizure disorder not related to prior severe hypoglycemia. Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone. 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. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment. Use of any investigational agents within 4 weeks of enrollment. Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael R Rickels, MD., MS

Organizational Affiliation

Division of Endocrinology, Diabetes & Metabolism, Perelman School of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

It is not yet known if there will be any further plan to make IPD available besides the Informed Consent.

Links:

URL

https://www.med.upenn.edu/apps/faculty/index.php/p32032

Description

Perelman School of Medicine / Faculty Search /Michael Rickels, M.D., M.S.

URL

https://clinicalresearch.itmat.upenn.edu/?_ga=1.86091032.1687586810.1437483178

Description

Research Studies at the University of Pennsylvania

URL

https://www.med.upenn.edu/idom/trials.html

Description

Institute for Diabetes, Obesity and Metabolism Research Studies

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Adrenergic System in Islet Transplantation

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