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Mechanisms Responsible for Hypoglycemia Associated Autonomic Failure (HAAF)

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ClinicalTrials.gov Identifier: NCT00678145
Recruitment Status : Recruiting
First Posted : May 15, 2008
Last Update Posted : January 18, 2018
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Meredith Hawkins, Albert Einstein College of Medicine, Inc.

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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus Hypoglycemia Autonomic Failure Drug: naloxone Dietary Supplement: fructose Behavioral: exercise Drug: Morphine sulfate Drug: Epinephrine Phase 2

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  (Clinical Trial)
Estimated Enrollment : 116 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Mechanisms of Hypoglycemia Associated Autonomic Failure
Actual Study Start Date : March 2008
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hypoglycemia
U.S. FDA Resources

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 Name: Narcan
Dietary Supplement: fructose
Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Name: 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 Name: Morphine
Drug: Epinephrine
Administering epinephrine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Name: 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 Name: Narcan
Dietary Supplement: fructose
Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Name: 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 Name: Morphine
Drug: Epinephrine
Administering epinephrine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.
Other Name: Adrenalin



Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Non-diabetic individuals
  • Patients with type 1 diabetes mellitus
  • BMI <28
  • No 1st degree relatives with diabetes

Exclusion Criteria:

  • Pregnant or planning to get pregnant women
  • Breast-feeding women
  • Children
  • Subjects taking pain killers (narcotics) or illicit drug users
  • Uncontrolled hyperlipidemia or hypertension
  • Smoking (Greater than 5-6 cigarettes per day)
  • 1st degree relatives with diabetes
  • HIV/AIDS, Liver Problems, Hepatitis
  • Surgeries that include removal of endocrine glands or abnormal thyroid
  • Not enrolled in any other study for at least 1 month
  • Cancer, stroke, Heart attack

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00678145


Contacts
Contact: Tiffany Cheng, B.S. 718-430-2903 tiffany.cheng@einstein.yu.edu

Locations
United States, New York
Albert Einstein College of Medicine / General Clinical Research Center Recruiting
Bronx, New York, United States, 10461
Sponsors and Collaborators
Albert Einstein College of Medicine, Inc.
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
Principal Investigator: Meredith Hawkins, M.D., M.S. Albert Einstein College of Medicine, Inc.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Meredith Hawkins, Principal Investigator, Albert Einstein College of Medicine, Inc.
ClinicalTrials.gov Identifier: NCT00678145     History of Changes
Other Study ID Numbers: 2012-665
R01DK079974 ( U.S. NIH Grant/Contract )
First Posted: May 15, 2008    Key Record Dates
Last Update Posted: January 18, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Meredith Hawkins, Albert Einstein College of Medicine, Inc.:
Diabetes
Hypoglycemia
HAAF
Counterregulation

Additional relevant MeSH terms:
Hypoglycemia
Diabetes Mellitus
Pure Autonomic Failure
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Morphine
Epinephrine
Racepinephrine
Epinephryl borate
Naloxone
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic beta-Agonists
Bronchodilator Agents
Autonomic Agents
Anti-Asthmatic Agents