Intensive glucose control in type 1 diabetes mellitus (T1DM) is associated with clear health benefits. However, maintaining near-normal glycemia remains an elusive goal for most patients, in large part owing to the risk of low glucose levels (hypoglycemia). T1DM patients are susceptible to hypoglycemia due to defective counterregulatory responses (CR) characterized by: 1) deficient glucagon release during impending 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, 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 suboptimal glycemic control. Our lab has explored a new approach of enhancing CR by translating mechanisms responsible for HAAF/EAAF into potential therapeutics to modulate the CR to hypoglycemia. We have previously demonstrated that HAAF can be prevented in T1DM patients by opioid receptor blockade. Since adrenergic activation has also a modulatory effect on hypoglycemia CR, we thus hypothesize that a common mechanism linking opioidergic and adrenergic systems is responsible for the development of HAAF and EAAF.
Our specific aims are to 1. Examine whether activation of ?-opioid receptors, and/or adrenergic receptors, regulate HAAF in humans, 2. Establish the components of the adrenergic response responsible for modulating HAAF/EAAF and their association with the opioidergic system, and 3. Perform a preliminary clinical trial to examine the efficacy of chronic opioid receptor blockade in preventing HAAF in patients with T1DM. Correction or improvement of hypoglycemia counterregulation and restoring hypoglycemia awareness in patients with T1DM would represent an enormous step forward in the management of these patients, including preventing morbidities or death.

Public Health Relevance

Patients with type 1 diabetes mellitus (T1DM) on intensive insulin treatment suffer from recurrent episodes of low glucose (hypoglycemia), with severe consequences: 1) a tendency to maintain suboptimal glycemic control, which results in increased risk for vascular complications, and 2) recurrent morbidity that is associated with hypoglycemia which may be fatal (6 to 10% of deaths in patients with T1DM are directly related to hypoglycemic events). Hypoglycemia associated autonomic failure (HAAF) represents a defect in the capacity to recover from hypoglycemia after recurrent previous episodes of hypoglycemia, but its mechanism is not established. In this project we propose to elucidate the defect responsible for HAAF in T1DM patients and to explore the possibility of treating patients with a drug that may reverse this defect.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Teff, Karen L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Milman, Sofiya; Leu, James; Shamoon, Harry et al. (2012) Magnitude of exercise-induced *-endorphin response is associated with subsequent development of altered hypoglycemia counterregulation. J Clin Endocrinol Metab 97:623-31
Milman, Sofiya; Leu, James; Shamoon, Harry et al. (2012) Opioid receptor blockade prevents exercise-associated autonomic failure in humans. Diabetes 61:1609-15
Vele, Septimiu; Milman, Sofiya; Shamoon, Harry et al. (2011) Opioid receptor blockade improves hypoglycemia-associated autonomic failure in type 1 diabetes mellitus. J Clin Endocrinol Metab 96:3424-31
Leu, James; Cui, Min-Hui; Shamoon, Harry et al. (2009) Hypoglycemia-associated autonomic failure is prevented by opioid receptor blockade. J Clin Endocrinol Metab 94:3372-80