Adrenergic Blockers for Type 1 Diabetes Post-Islet Transplant

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Pennsylvania

Compensation: Varies

Number of Visits: 3

Duration: 3.5 hours per session, across three sessions

11 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you do not take any anti-diabetic medication other than insulin within 4 weeks of enrollment. If you are on other medications, you may need to stop them before joining the study.

What evidence supports the effectiveness of the drug propranolol for patients with type 1 diabetes post-islet transplant?

Propranolol, a beta-adrenergic blocker, has been shown to prevent hypoglycemic attacks in patients with insulinoma, suggesting it may help manage blood sugar levels. However, it can impair recovery from low blood sugar in people with type 1 diabetes, indicating a need for careful monitoring. ^{1 2 3 4 5}

Is propranolol safe for people with Type 1 Diabetes?

Propranolol, a beta-blocker, can prolong low blood sugar episodes in people with Type 1 Diabetes, making it potentially unsafe for them. It may also cause high blood pressure during low blood sugar events, so a different type of beta-blocker might be a better choice for these patients. ^{1 6 7 8 9}

How does the drug Phentolamine and Propranolol differ from other treatments for Type 1 Diabetes post-islet transplant?

This drug combination is unique because it involves both alpha and beta-adrenergic blockers, which can influence insulin secretion and glucose tolerance. While propranolol, a beta-blocker, can impair recovery from low blood sugar, phentolamine, an alpha-blocker, may help improve glucose tolerance, offering a novel approach to managing blood sugar levels in patients with transplanted islets. ^{1 2 3 10 11}

Research Team

Michael R Rickels, MD., MS

Principal Investigator

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

Eligibility Criteria

This trial is for adults aged 21-65 with type 1 diabetes who have had an islet cell transplant at least 6 months ago. They should be using standard immunosuppression, have stable graft function, and not require high doses of insulin. Women must not be pregnant or breastfeeding and willing to use contraception. Exclusions include severe chronic diseases, uncontrolled hypertension, obesity (BMI ≥30), abnormal organ functions, certain medication uses within the last month, and other conditions that could affect safety.

Inclusion Criteria

I am between 21 and 65 years old.

GROUP 1: Subjects able to provide written informed consent and comply with study protocol

I am using standard immunosuppression medication as directed.

Exclusion Criteria

My kidney function is below normal levels.

I take more than 5 mg of prednisone daily or its equivalent.

You have a body mass index (BMI) of 30 or higher.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo hyperinsulinemic euglycemic-hypoglycemic clamps with administration of α-adrenergic blocker phentolamine, β-adrenergic blocker propranolol, or placebo

3.5 hours per session, across three sessions

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Phentolamine
• Placebo
• Propranolol

Trial Overview The study tests how blocking different parts of the nervous system affects blood sugar control in those who've received a pancreas cell transplant for diabetes. It involves three drugs: phentolamine (α-adrenergic blocker), propranolol (β-adrenergic blocker), and placebo. Participants will undergo glucose clamps under each condition in a randomized double-blind manner to see if these interventions influence their body's response to low blood sugar.

Participant Groups

Group I: Group 1-Propranolol Intra-hepatic islet Active Control 1 Intervention

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.

Group II: Group 2 - Extra-hepatic islet Active Control 1 Intervention

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

Group III: Group 3 - Intra-hepatic auto islet Active Control 1 Intervention

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

Group IV: Group 1-Phentolamine Intra-hepatic islet Active Control 1 Intervention

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.

Group V: Group 1- Placebo Intra-hepatic islet Placebo Group 1 Intervention

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.

Phentolamine is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Regitine for:

• Hypertension
• Pheochromocytoma

Approved in Canada as Phentolamine for:

• Hypertension
• Pheochromocytoma

Approved in European Union as Phentolamine for:

• Hypertension
• Pheochromocytoma

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

In a study of 215 patients with insulin-dependent diabetes, the use of alpha-adrenoblockers led to a reduction in blood sugar levels without needing to increase insulin doses, suggesting they can help manage diabetes more effectively.

In contrast, beta-adrenoblockers worsened diabetes control and did not change growth hormone levels, indicating they are not recommended for patients with diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of alpha and beta receptor blockaders on the degree of glycemia, growth hormone content of blood and catecholamine excretion in insulin-dependent diabetes mellitus]. Alekseeva, GG., Iukhlova, NA.[2016]

References

1. United States pubmed.ncbi.nlm.nih.gov

Oral propranolol and metoprolol both impair glucose recovery from insulin-induced hypoglycemia in insulin-dependent diabetes mellitus. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Prevention of hypoglycemic attacks by propranolol in a patient suffering from insulinoma. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Effects of UK-14,304, noradrenaline, and propranolol on insulin release from transplanted mouse islets. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Preserved sensitivity to beta2-adrenergic receptor agonists in patients with type 1 diabetes mellitus and hypoglycemia unawareness. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

beta-Adrenergic insulin release and adrenergic innervation of mouse pancreatic islets. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Hypertensive crisis caused by hypoglycemia and propranolol. [2013]

7. England pubmed.ncbi.nlm.nih.gov

Comparison of atenolol and propranolol during insulin-induced hypoglycaemia. [2019]

8. Germany pubmed.ncbi.nlm.nih.gov

Adrenergic modulation of glucagon and insulin secretion in obese and lean humans. [2018]

9. England pubmed.ncbi.nlm.nih.gov

The role of the sympathetic system in the control of insulin release in response to hyperglycaemia in conscious calves. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Adrenergic receptor and epinephrine-induced hyperglycemia and glucose tolerance. [2019]

11. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Effect of alpha and beta receptor blockaders on the degree of glycemia, growth hormone content of blood and catecholamine excretion in insulin-dependent diabetes mellitus]. [2016]