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Purpose

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.

Conditions

Eligibility

Eligible Ages
Between 21 Years and 60 Years
Eligible Genders
All
Accepts Healthy Volunteers
Yes

Inclusion Criteria

  • Non-diabetic individuals

Exclusion Criteria

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

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Crossover Assignment
Primary Purpose
Basic Science
Masking
Double (Participant, Investigator)

Arm Groups

ArmDescriptionAssigned Intervention
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

More Details

Status
Unknown status
Sponsor
Albert Einstein College of Medicine

Study Contact

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.