Mechanisms of Hypoglycemia Associated Autonomic Failure

Intensive glucose control in type 1 diabetes mellitus (T1DM) is associated with clear health benefits. 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. 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. Over the past several years, the Diabetes Research Center laboratory at Albert Einstein College of Medicine 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. The work by the laboratory 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: Terminated
• Conditions: Diabetes Mellitus; Hypoglycemia; Autonomic Failure
• Intervention / Treatment: Drug: naloxone; Dietary supplement: fructose; Behavioral: exercise; Drug: Morphine sulfate; Drug: Epinephrine

Detailed Description

In the prior project period of R01DK079974, the study team elucidated the central role played by the opioid signaling system as a mechanism for the development of HAAF/EAAF. The study team has previously demonstrated 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). The study team has also shown that opioid receptor blockade also abolishes EAAF, and that both effects are regulated by the stress response (hypoglycemia and exercise, respectively). Furthermore, 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.

NOTE: This ClinicalTrials.gov registration does not include the proposed fructose and exercise interventions described within the Arms/Interventions section. These interventions predate the change in PI and official notice of transfer of the NIH-NIDDK grant on February 06, 2014 and were not conducted. Interventions conducted as part of this study include the independent assessments of Epinephrine and Morphine as part of Aim 1 and assessment of intranasal Naloxone as part of Aim 3: Aim 2 of this protocol was not conducted prior to early termination of the study.

It should be noted that information, including summarized Results data for four of the participants associated with the intranasal naloxone intervention were reported as part of a separate study approved by the IRB under a different study number. For these results, please reference NCT03608163 (ID: 2018-9208).

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Non-diabetic individuals

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

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: Adrenaline
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: Adrenaline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endogenous Glucose Production (EGP) Response Rate - Morphine Sulfate Study	EGP response after antecedent morphine administration was assessed in the Morphine Sulfate vs Matched Placebo study. EGP response is a measure of how the body produces glucose from substrates to maintain blood sugar levels, particularly during fasting. Morphine was administered on Day 1 followed by a stepped hypoglycemia clamp (i.e., euglycemia → 90 mg/dl → 80 mg/dl → 70 mg/dl → 60 mg/dl) on Day 2. EGP response rate is reported in milligrams/kilograms/minute (mg/kg/min) and results are summarized and reported by study arm using basic descriptive statistics. Data from the final hour of the 3rd clamp episode were averaged/reported.	Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~7 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.
Endogenous Glucose Production (EGP) Via Glucose Infusion Rate - Naloxone Study	For the Naloxone vs Matched Placebo study, EGP, a measure of the body's production of sugar, was assessed by determining the Glucose Infusion Rate (GIR) an indirect measure of endogenous glucose production, during the first and third hypoglycemic clamp episodes. GIR is reported in cubic centimeters/minute (cc/min) and results are summarized and reported by study arm using basic descriptive statistics.	Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~5 months apart. Data from the five timepoints over the final hour of the 1st and 3rd clamp episodes were averaged/reported.
Endogenous Glucose Production (EGP) Response Rate - Epinephrine Study	EGP response after antecedent epinephrine administration was assessed in the Epinephrine vs Matched Epinephrine study. EGP response, a measure of how the body produces glucose from substrates to maintain blood sugar levels, was assessed during the final hypoglycemic clamp episode. EGP at the major nadir at the 60 mg/dL, during the last 10 minutes of the 3rd clamp episode, is reported in milligrams per kilogram per minute (mg/kg/min) and results are summarized and reported by study arm using basic descriptive statistics. Data from the final hour of the 3rd clamp episode were averaged/reported	Obtained every 15 minutes during the 1st and 3rd 2-hour hypoglycemic episodes (on Day 1 and Day 2), crossover visits up to ~19 months apart. Data from the final hour of the 3rd clamp episode were averaged/reported.
Counterregulatory Response to Hypoglycemia - Morphine Sulfate Study	Counterregulatory response to hypoglycemia was assessed for the Morphine Sulfate study by quantifying peak plasma responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 54 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. Group mean results are summarized for the Morphine Sulfate arm and Matched Placebo arm.	Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~7 months apart.
Counterregulatory Response to Hypoglycemia - Naloxone Study	Counterregulatory response to hypoglycemia was assessed for the Naloxone study by quantifying peak plasma responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 54 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. The second challenge on Day 1 was conducted to assess the impact of the third episode for informational purposes only but was not reported. Group mean results are summarized for the 1st and 3rd episodes in the Naloxone arm and Matched Placebo arm.	Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~5 months apart.
Counterregulatory Response to Hypoglycemia - Epinephrine Study	Counterregulatory response to hypoglycemia was assessed for the Epinephrine study by quantifying peak plasma epinephrine level responses to three episodes of induced hypoglycemia over two days: two, 2-hour episodes of moderate hyper-insulinemic, hypoglycemic clamp studies (target glucose 60 mg/dL), separated by a 2-hour break with a small snack, on Day 1, followed by a third, comparable hypoglycemic episode on Day 2. Group mean results are summarized for the Epinephrine arm and Matched Placebo arm.	Approximately 2 Days following intervention (Day 1 and Day 2), crossover visits up to ~19 months apart.
Hypoglycemic Symptom Scores - Morphine Sulfate Study	Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 8-point Likert scale ranging from 0 = "Not at all" to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.	Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores - Naloxone Study	Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 8-point Likert scale ranging from 0 = "Not at all", to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.	Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported
Hypoglycemic Symptom Scores - Epinephrine Study	Hypoglycemic Symptom Scores were evaluated using the Edinburgh Hypoglycemia Symptom Scale (EHSS). The EHSS is an instrument to evaluate patients' experiences of symptoms in a typical hypoglycemic episode. It is comprised of 11 symptoms within 3 domains: Neuroglycopenic (i.e., confusion, drowsiness, odd behavior, speech difficulty, and incoordination), Autonomic (i.e., sweating, palpitations, shaking, and hunger), and General Malaise (i.e., headaches, nausea); which are evaluated by a 7-point Likert scale ranging from 1 = "Not at all", to 7 = "Very severely." An overall global mean composite score for the 11 symptoms was summed and averaged for each participant during the 3rd hypoglycemic episode on Day 2. Higher scores are indicative of more EHSS symptoms. Group mean values will be reported using basic descriptive statistics.	Obtained at the end of each hypoglycemic episode on Day 2, crossover visits up to ~19 months apart. Summarized mean values for each participant during the 3rd hypoglycemic episode on Day 2 are reported

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptom scores	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

• Sponsor: Albert Einstein College of Medicine
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Meredith Hawkins, M.D., M.S., Albert Einstein College of Medicine

Publications and helpful links

General Publications

• 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.
• Milman 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2008
• Primary Completion (Actual): August 1, 2018
• Study Completion (Actual): August 1, 2018

Study Registration Dates

• First Submitted: May 14, 2008
• First Submitted That Met QC Criteria: May 14, 2008
• First Posted (Estimated): May 15, 2008

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Diabetes; Hypoglycemia; HAAF; Counterregulation
• Additional Relevant MeSH Terms: Endocrine System Diseases; Nervous System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Primary Dysautonomias; Autonomic Nervous System Diseases; Nutritional and Metabolic Diseases; Hypoglycemia; Diabetes Mellitus; Pure Autonomic Failure; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Alkaloids; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Amines; Catechols; Phenols; Benzene Derivatives; Alcohols; Heterocyclic Compounds, 4 or More Rings; Amino Alcohols; Ethanolamines; Sugars; Insulins; Pancreatic Hormones; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Morphine Derivatives; Biogenic Monoamines; Biogenic Amines; Catecholamines; Proinsulin; Hexoses; Monosaccharides; Ketoses; Morphine; Insulin; Epinephrine; Naloxone; Exercise; Fructose
• 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