Mechanisms of Hypoglycemia Associated Autonomic Failure

Phase 2

• Conditions: Diabetes Mellitus; Autonomic Failure; Hypoglycemia
• Interventions: Drug: naloxone; Dietary Supplement: fructose; Behavioral: exercise; Drug: Morphine sulfate; Drug: Epinephrine

• Registration Number: NCT00678145
• Lead Sponsor: Albert Einstein College of Medicine

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.

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 Timeline

• Study Start: 2008-03
• Study First Submitted: 2008-05-14
• Study First Submitted QC: 2008-05-14
• Study First Posted: 2008-05-15
• Status Verified: 2021-01
• Last Update Submitted: 2021-01-12
• Last Update Posted: 2021-01-14
• Primary Completion: 2022-08
• Study Completion: 2022-08

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 116

Inclusion Criteria

• Non-diabetic individuals

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Exclusion Criteria

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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Type 1 Diabetes	fructose	T1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Healthy	exercise	Healthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Type 1 Diabetes	exercise	T1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Healthy	fructose	Healthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Healthy	naloxone	Healthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Healthy	Morphine sulfate	Healthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Healthy	Epinephrine	Healthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Type 1 Diabetes	naloxone	T1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Type 1 Diabetes	Morphine sulfate	T1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.
Type 1 Diabetes	Epinephrine	T1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.

Primary Outcome Measures

Name	Time	Method
Change in the counterregulatory responses to hypoglycemia compared to controls	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

Name	Time	Method
Symptom scores	Measured every 15 minutes at timepoints 0, 15, 30, 45...120 through study completion	Symptoms of hypoglycemia will be taken during the study

Trial Locations

Locations (1)

Albert Einstein College of Medicine / General Clinical Research Center; 🇺🇸 Bronx, New York, United States