Mechanisms of Hypoglycemia Associated Autonomic Failure
2 other identifiers
interventional
116
1 country
1
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_2 diabetes-mellitus
Started Mar 2008
Longer than P75 for phase_2 diabetes-mellitus
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
March 1, 2008
CompletedFirst Submitted
Initial submission to the registry
May 14, 2008
CompletedFirst Posted
Study publicly available on registry
May 15, 2008
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 1, 2022
CompletedStudy Completion
Last participant's last visit for all outcomes
August 1, 2022
CompletedJanuary 14, 2021
January 1, 2021
14.4 years
May 14, 2008
January 12, 2021
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Change in the counterregulatory responses to hypoglycemia compared to controls
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 Outcomes (1)
Symptom scores
Measured every 15 minutes at timepoints 0, 15, 30, 45...120 through study completion
Study Arms (2)
Healthy
EXPERIMENTALHealthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Type 1 Diabetes
EXPERIMENTALT1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Interventions
Administering naloxone on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Administering exercise on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Administering morphine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Administering epinephrine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Eligibility Criteria
You may qualify if:
- Non-diabetic individuals
You may not qualify if:
- Hypertension
- Hyperlipidemia
- Heart disease
- Cerebrovascular disease
- Seizures
- Bleeding disorders
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
Albert Einstein College of Medicine / General Clinical Research Center
The Bronx, New York, 10461, United States
Related Publications (2)
Carey M, Gospin R, Goyal A, Tomuta N, Sandu O, Mbanya A, Lontchi-Yimagou E, Hulkower R, Shamoon H, Gabriely I, Hawkins M. Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans. Diabetes. 2017 Nov;66(11):2764-2773. doi: 10.2337/db16-1478. Epub 2017 Aug 31.
PMID: 28860128DERIVEDMilman S, Leu J, Shamoon H, Vele S, Gabriely I. Opioid receptor blockade prevents exercise-associated autonomic failure in humans. Diabetes. 2012 Jun;61(6):1609-15. doi: 10.2337/db11-1622. Epub 2012 Apr 20.
PMID: 22522612DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Meredith Hawkins, M.D., M.S.
Albert Einstein College of Medicine
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- PARTICIPANT, INVESTIGATOR
- Purpose
- BASIC SCIENCE
- Intervention Model
- CROSSOVER
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
May 14, 2008
First Posted
May 15, 2008
Study Start
March 1, 2008
Primary Completion
August 1, 2022
Study Completion
August 1, 2022
Last Updated
January 14, 2021
Record last verified: 2021-01
Data Sharing
- IPD Sharing
- Will not share