Mechanisms of Hypoglycemia Associated Autonomic Failure

NCT ID: NCT00678145

Last Updated: 2021-01-14

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 116 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-03-31
• Study Completion Date: 2022-08-31

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.

Conditions

Diabetes Mellitus; Hypoglycemia; Autonomic Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Healthy

Healthy individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.

Group Type: EXPERIMENTAL

naloxone

Intervention Type: DRUG

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

fructose

Intervention Type: DIETARY_SUPPLEMENT

Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

exercise

Intervention Type: BEHAVIORAL

Administering exercise on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

Morphine sulfate

Intervention Type: DRUG

Administering morphine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

Epinephrine

Intervention Type: DRUG

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

Type 1 Diabetes

T1D individuals will receive drug (naloxone, morphine sulfate, epinephrine) and placebo comparator.

Group Type: EXPERIMENTAL

naloxone

Intervention Type: DRUG

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

fructose

Intervention Type: DIETARY_SUPPLEMENT

Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

exercise

Intervention Type: BEHAVIORAL

Administering exercise on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

Morphine sulfate

Intervention Type: DRUG

Administering morphine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

Epinephrine

Intervention Type: DRUG

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

Interventions

naloxone

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

Intervention Type: DRUG

fructose

Administering fructose on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

Intervention Type: DIETARY_SUPPLEMENT

exercise

Administering exercise on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

Intervention Type: BEHAVIORAL

Morphine sulfate

Administering morphine on Day 1, and quantifying the counterregulatory responses to hypoglycemia on Day 2.

Intervention Type: DRUG

Epinephrine

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

Intervention Type: DRUG

Other Intervention Names

Narcan; Insulin; Morphine; Adrenalin

Eligibility Criteria

Inclusion Criteria

• Non-diabetic individuals

Exclusion Criteria

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

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Albert Einstein College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Meredith Hawkins

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Meredith Hawkins, M.D., M.S.

Role: PRINCIPAL_INVESTIGATOR

Albert Einstein College of Medicine

Locations

Albert Einstein College of Medicine / General Clinical Research Center

The Bronx, New York, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 28860128 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 22522612 (View on PubMed)

Other Identifiers

R01DK079974

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2012-665

Identifier Type: -

Identifier Source: org_study_id