Mechanisms of Hypoglycemia Associated Autonomic Failure
Status:
Active, not recruiting
Trial end date:
2022-08-01
Target enrollment:
Participant gender:
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.
Phase:
Phase 2
Details
Lead Sponsor:
Albert Einstein College of Medicine Albert Einstein College of Medicine of Yeshiva University
Collaborators:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) National Institutes of Health (NIH)