Novel Approach for the Prevention of Hypoglycemia Associated Autonomic Failure (HAAF)

Type I diabetes affects the body's ability to respond to low blood sugar (hypoglycemia).
Repeated episodes of hypoglycemia may affect an individual's autonomic system, and leads to
hypoglycemia associated autonomic failure (HAAF) in 2/3 of individuals. This study is looking
at healthy, non-diabetic individuals who are susceptible to developing HAAF and their
response to either naloxone nasal spray alone or in combination with diazoxide in improving
their body's ability to respond to episodes of low blood sugar, and in preventing the
development of HAAF.

The body's response to episodes of hypoglycemia is measured using a procedure called a
hypoglycemic clamp; each phase of this study involves three clamp procedures over a period of
2 days. During the clamp procedures, glucose (a sugar) and insulin (a hormone produced in the
pancreas that regulates the amount of glucose in the blood) are infused with an intravenous
catheter, and blood samples are collected periodically throughout the procedure to measure
blood sugar levels and the levels of several hormones, including epinephrine, that are found
in the body and are related to glucose metabolism. The rates of endogenous glucose production
(a measure of the body's production of sugar) will be measured. Additionally, the level of
awareness of hypoglycemia symptoms will be monitored using a standardized questionnaire.

Both hypoglycemia and stress activate the body's opioid system. Recently published data has
shown that blocking opioid receptors with naloxone may increase the body's ability to respond
to hypoglycemia.The body's response to hypoglycemia affects many systems, and acting on
several of these systems may help the body to respond more effectively to episodes of low
blood sugar, and to prevent the development of HAAF. Studies have shown that potassium
channels in the hypothalamus, a part of the brain, have an important role in detecting
hypoglycemia. Diazoxide activates potassium channels in the cells of the brain that respond
to changes in sugar (glucose) that occur in the body, and may also reduce the development of
hypoglycemia associated autonomic failure. Additionally, certain glucose-responsive cells in
the brain have opioid receptors that are combined with potassium channels which may respond
to both diazoxide and naloxone which may work together to more effectively increase the
body's ability to respond to episodes of low blood sugar and prevent HAAF.

Inclusion Criteria:

-Healthy, non-diabetic subjects 21-55 years old

Exclusion Criteria:

- BMI >30kg/m2

- BP >140/90 or <90/60 on more than one occasion (unless determined to be white coat
hypertension)

- Triglycerides >400 mg/dL and/or total cholesterol >300 mg/dL

- Clinically significant liver dysfunction

- Clinically significant kidney dysfunction

- Anemia

- Leukocytosis or leukopenia

- Thrombocytopenia or thrombocytosis

- Positive drug screen for amphetamines, barbiturates, benzodiazepines, cocaine,
methadone, opiates, PCP

- Currently taking beta-blockers or medications that affect counterregulatory response
to hypoglycemia

- Urinalysis: clinically significant abnormalities

- Clinically significant electrolyte abnormalities

- Smoking >7 cigarettes/day

- Heavy alcohol use

- History of chronic conditions (eg, chronic liver disease, cardiovascular disease,
bleeding disorders, cancer, HIV/AIDS, seizures, systemic rheumatologic conditions)

- Surgeries involving endocrine glands

- Pregnancy

- Enrollment in another medication intervention study less than one month prior

- Family history of diabetes or premature cardiac death in first degree relatives

- Allergies to medications given during study

- Uncontrolled psychiatric disorders