Mechanisms of Hypoglycemia Associated Autonomic Failure

Diabetes Mellitus Clinical Trial

Official title:

Mechanisms of Hypoglycemia Associated Autonomic Failure

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00678145
• Other study ID #: 2012-665
• Secondary ID: R01DK079974
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: March 2008
• Est. completion date: August 2022

Study information

• Verified date: January 2021
• Source: Albert Einstein College of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 116
• Est. completion date: August 2022
• Est. primary completion date: August 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 60 Years

Eligibility

Inclusion Criteria:

• Non-diabetic individuals

Exclusion Criteria:

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

Related Conditions & MeSH terms

• Autonomic Failure
• Diabetes Mellitus
• Hypoglycemia
• Pure Autonomic Failure

Intervention

Drug:
• naloxone
Administering naloxone on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

Dietary Supplement:
• fructose
Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

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.
• Epinephrine
Administering epinephrine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

Locations

Country	Name	City	State
United States	Albert Einstein College of Medicine / General Clinical Research Center	Bronx	New York

Sponsors (3)

Lead Sponsor	Collaborator
Albert Einstein College of Medicine	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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