Mechanisms of Hypoglycemia Associated Autonomic Failure

Summary

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.

Conditions

• Diabetes Mellitus
• Hypoglycemia
• Autonomic Failure

Interventions

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.

DRUG

Epinephrine

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

Sponsors & Collaborators

• National Institutes of Health (NIH)

  collaborator NIH

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

  collaborator NIH

• Albert Einstein College of Medicine

  lead OTHER

Principal Investigators

• Meredith Hawkins, M.D., M.S. · Albert Einstein College of Medicine

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

CROSSOVER

Eligibility

Min Age

21 Years

Max Age

60 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2008-03-31

Primary Completion

2018-08-31

Completion

2018-08-31

FDA Drug

Yes

Countries

• United States

Study Locations