Adrenergic System in Islet Transplantation

NCT03079921 | Completed Early Phase 1 Results DMC FDA Drug

• 2 other identifiers: 8263862R01DK091331-06
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

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.

Conditions

Type1diabetes; Hypoglycemia; Hypoglycemia Unawareness; Islet Cell Transplantation

Keywords

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

Outcome Measures

Primary Outcomes (2)

• C-PEPTIDE Suppression During Hyperinsulinemia Euglycemia.

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

  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.

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

Secondary Outcomes (3)

• EPINEPHRINE During Hyperinsulinemia Hypoglycemia.

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

• Rates of ENDOGENOUS GLUCOSE PRODUCTION During Hyperinsulinemia Hypoglycemia.

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

• AUTONOMIC SYMPTOMS During Hyperinsulinemia Hypoglycemia

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

Study Arms (5)

Group 1-Propranolol Intra-hepatic islet

ACTIVE COMPARATOR

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.

Drug: Propranolol

Group 1-Phentolamine Intra-hepatic islet

ACTIVE COMPARATOR

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.

Drug: Phentolamine

Group 1- Placebo Intra-hepatic islet

PLACEBO COMPARATOR

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.

Drug: Placebo

Group 2 - Extra-hepatic islet

NO INTERVENTION

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

Group 3 - Intra-hepatic auto islet

NO INTERVENTION

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

Interventions

Phentolamine DRUG

Physiologic receptor blockade (α1-receptor).

Also known as: Regitine

Group 1-Phentolamine Intra-hepatic islet

Propranolol DRUG

Physiologic receptor blockade (β2-receptor).

Also known as: Inderal

Group 1-Propranolol Intra-hepatic islet

Placebo DRUG

100mL bag of Normal Saline Solution (NSS).

Also known as: Saline, Sodium Chloride Solution

Group 1- Placebo Intra-hepatic islet

Eligibility Criteria

• Age: 21 Years - 65 Years
• Gender Eligibility Details: Male or Female at birth.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Pennsylvania: lead
• National Institutes of Health (NIH): collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism

Philadelphia, Pennsylvania, 19104, United States

Location

Related Links

• Perelman School of Medicine / Faculty Search /Michael Rickels, M.D., M.S.
• Research Studies at the University of Pennsylvania
• Institute for Diabetes, Obesity and Metabolism Research Studies

MeSH Terms

Conditions

Hypoglycemia

Interventions

Phentolamine; Propranolol; Sodium Chloride

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Michael Rickels, MD.
• Organization: University of Pennsylvania

rickels@pennmedicine.upenn.edu

215-746-0025

Study Officials

• Michael R Rickels, MD., MS

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Michael R. Rickels, M.D., M.S. Associate Professor of Medicine Division of Endocrinology, Diabetes & Metabolism Director, Translational Research Program Institute for Diabetes, Obesity & Metabolism University of Pennsylvania Perelman School of Medicine

Model Details: 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".

Study Record Dates

• First Submitted: February 28, 2017
• First Posted: March 15, 2017
• Study Start: January 20, 2017
• Primary Completion: April 30, 2019
• Study Completion: December 31, 2025
• Last Updated: April 27, 2026
• Results First Posted: April 27, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)