Mechanisms of Hypoglycemia Associated Autonomic Failure

January 12, 2021 updated by: Meredith Hawkins, Albert Einstein College of Medicine
Intensive glucose control in type 1 diabetes mellitus (T1DM) is associated with clear health benefits (1). However, despite development of insulin analogs, pump/multi-dose treatment and continuous glucose monitoring, maintaining near-normal glycemia remains an elusive goal for most patients, in large part owing to the risk of hypoglycemia. T1DM patients are susceptible to hypoglycemia due to defective counterregulatory responses (CR) characterized by: 1) deficient glucagon release during impending/early hypoglycemia; 2) additional hypoglycemia-associated autonomic failure (HAAF) and exercise-associated autonomic failure (EAAF) that blunt the sympathoadrenal responses to hypoglycemia following repeated episodes of hypoglycemia or exercise as well as degrading other CR; and 3) hypoglycemia unawareness (HU), lowering the threshold for symptoms that trigger behavioral responses (e.g. eating). Thus, the risk of hypoglycemia in T1DM impedes ideal insulin treatment and leads to defaulting to suboptimal glycemic control (2). There are two approaches that could resolve this important clinical problem: 1) perfection of glucose sensing and insulin and glucagon delivery approaches (bioengineered or cell-based) that mimic normal islet function and precisely regulate glucose continuously, or 2) a drug to enhance or normalize the pattern of CR to hypoglycemia. Despite much research and important advances in the field, neither islet transplantation nor biosensor devices have emerged as viable long-term solutions for the majority of patients (3, 4). Over the past several years, our lab has explored the approach of enhancing CR by examining mechanisms responsible for HAAF/EAAF and searching for potential pharmacological methods to modulate the CR to hypoglycemia (5-11). Our work has led to a paradigm shift in the field of hypoglycemia, exemplified by the novel hypothesis and published experimental data supporting a role for opioid signaling that resulted in the initiation of exploratory clinical trials by other research groups.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

In the prior project period of R01 DK079974, we elucidated the central role played by the opioid signaling system as a mechanism for the development of HAAF/EAAF. We have demonstrated previously that opioid receptor blockade by acute infusion of naloxone during antecedent hypoglycemia can prevent experimentally induced HAAF in nondiabetic and T1DM subjects (JCEM 94:3372-80, 2009; JCEM 96:3424-31, 2011). We have also shown that opioid receptor blockade also abolishes EAAF, and that both effects are regulated by the stress response (hypoglycemia and exercise, respectively). Furthermore, recently we have shown that activation of μ-opioid receptors with IV infusion of morphine reproduces some of the key biochemical and clinical features of HAAF in nondiabetic humans.Taken together, these studies demonstrate that the opioid system plays a central role in hypoglycemia counterregulation and in HAAF.

Study Type

Interventional

Enrollment (Anticipated)

116

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • Bronx, New York, United States, 10461
        • Albert Einstein College of Medicine / General Clinical Research Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 60 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Non-diabetic individuals

Exclusion Criteria:

  • Hypertension
  • Hyperlipidemia
  • Heart disease
  • Cerebrovascular disease
  • Seizures
  • Bleeding disorders

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Healthy
Healthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Drug: naloxone
Administering naloxone on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Names:
  • Narcan
Dietary supplement: fructose
Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Names:
  • Insulin
Behavioral: exercise
Administering exercise on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Drug: Morphine sulfate
Administering morphine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Names:
  • Morphine
Drug: Epinephrine
Administering epinephrine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Names:
  • Adrenalin
EXPERIMENTAL: Type 1 Diabetes
T1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Drug: naloxone
Administering naloxone on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Names:
  • Narcan
Dietary supplement: fructose
Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Names:
  • Insulin
Behavioral: exercise
Administering exercise on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Drug: Morphine sulfate
Administering morphine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Names:
  • Morphine
Drug: Epinephrine
Administering epinephrine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Names:
  • Adrenalin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in the counterregulatory responses to hypoglycemia compared to controls
Time Frame: Measured every 15 minutes at timepoints 0, 15, 30, 45...120 through study completion
Measurements of counterregulatory hormones will be measured throughout the study
Measured every 15 minutes at timepoints 0, 15, 30, 45...120 through study completion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Symptom scores
Time Frame: Measured every 15 minutes at timepoints 0, 15, 30, 45...120 through study completion
Symptoms of hypoglycemia will be taken during the study
Measured every 15 minutes at timepoints 0, 15, 30, 45...120 through study completion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Albert Einstein College of Medicine

Collaborators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 1, 2008

Primary Completion (ANTICIPATED)

August 1, 2022

Study Completion (ANTICIPATED)

August 1, 2022

Study Registration Dates

First Submitted

May 14, 2008

First Submitted That Met QC Criteria

May 14, 2008

First Posted (ESTIMATE)

May 15, 2008

Study Record Updates

Last Update Posted (ACTUAL)

January 14, 2021

Last Update Submitted That Met QC Criteria

January 12, 2021

Last Verified

January 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2012-665
  • R01DK079974 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Diabetes Mellitus

Clinical Trials on naloxone

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Indonesia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe