Mechanisms of Hypoglycemia Associated Autonomic Failure

Autonomic Failure, Diabetes Mellitus, Hypoglycemia

Diabetes, Hypoglycemia, HAAF, Counterregulation

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.

In the prior project period of R01DK079974, the study team elucidated the central role played by the opioid signaling system as a mechanism for the development of HAAF/EAAF. The study team has previously demonstrated 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). The study team has also shown that opioid receptor blockade also abolishes EAAF, and that both effects are regulated by the stress response (hypoglycemia and exercise, respectively). Furthermore, 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. NOTE: This ClinicalTrials.gov registration does not include the proposed fructose and exercise interventions described within the Arms/Interventions section. These interventions predate the change in PI and official notice of transfer of the NIH-NIDDK grant on February 06, 2014 and were not conducted. Interventions conducted as part of this study include the independent assessments of Epinephrine and Morphine as part of Aim 1 and assessment of intranasal Naloxone as part of Aim 3: Aim 2 of this protocol was not conducted prior to early termination of the study. It should be noted that information, including summarized Results data for four of the participants associated with the intranasal naloxone intervention were reported as part of a separate study approved by the IRB under a different study number. For these results, please reference NCT03608163 (ID: 2018-9208).

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