Mechanisms Responsible for Hypoglycemia Associated Autonomic Failure

Conditions:Other Indications, Endocrine, Diabetes
Therapuetic Areas:Endocrinology, Other
Age Range:18 - 55
Start Date:March 2008
End Date:August 2022
Contact:Tiffany Cheng, B.S.

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Mechanisms of Hypoglycemia Associated Autonomic Failure

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.

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.

Inclusion Criteria:

- Non-diabetic individuals

- Patients with type 1 diabetes mellitus

- BMI <28

- No 1st degree relatives with diabetes

Exclusion Criteria:

- Pregnant or planning to get pregnant women

- Breast-feeding women

- Children

- Subjects taking pain killers (narcotics) or illicit drug users

- Uncontrolled hyperlipidemia or hypertension

- Smoking (Greater than 5-6 cigarettes per day)

- 1st degree relatives with diabetes

- HIV/AIDS, Liver Problems, Hepatitis

- Surgeries that include removal of endocrine glands or abnormal thyroid

- Not enrolled in any other study for at least 1 month

- Cancer, stroke, Heart attack
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Bronx, NY
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