The overall objective of this project is to determine if the intranasal administration of naloxone during exercise will be a novel approach to preserve the counterregulatory response to hypoglycemia experienced the next day in patients with type 1 diabetes. Exercise induced autonomic failure contributes to the development of impaired awareness of hypoglycemia. Treatments that blunt the consequences of exercise induced autonomic failure, such as preserving the post-exercise counterregulatory response to hypoglycemia, may improve awareness of hypoglycemia. Naloxone, an opioid antagonist, is an extremely promising agent. In healthy volunteers, intravenous administration of naloxone during exercise preserved the counterregulatory response to hypoglycemia the following day (1). In this study, investigators will extend the clinical applicability by administering intranasal naloxone to individuals with type 1 diabetes. Specifically, the investigators will use a randomized, placebo controlled, crossover design to administer drug or placebo to patients with type 1 diabetes during acute exercise and assess the counterregulatory response to hypoglycemia the following day. The use of intranasal naloxone is a highly innovative aspect of this proposal. Intranasal naloxone translates readily to clinical use and, as demonstrated by the investigators preliminary data, achieves similar plasma drug concentrations as after IV administration.

Inclusion Criteria:

• Type 1 diabetes diagnosed on clinical grounds (history of DKA, use of insulin within 6 months of diagnosis)
• Diabetes duration < 30 years (impaired awareness of hypoglycemia increases with duration so it will be more likely that shorter duration participants will have hypoglycemia awareness) but > 2 years (to ensure that they have lost hypoglycemia induced glucagon secretion as is typical in patients who develop impaired awareness of hypoglycemia)
• Age 18 - 65 years
• Baseline hemoglobin A1C 6.8 - 9.0% (range selected to reduce the risk of hypoglycemia and uncontrolled diabetes in the weeks before the study, both of which may affect the responses to hypoglycemia)
• Awareness of hypoglycemia as verified by Cox questionnaire

Exclusion Criteria:

• History of stroke, seizures (other than those related to hypoglycemia), arrhythmias, active cardiac disease
• History of hypertension or blood pressure > 140/95 mm Hg at screening visit
• Pregnancy or plan to become pregnant during the study period
• Health related limitations in exercise (including but not limited to: angina, uncontrolled asthma, peripheral arterial disease)
• Unwillingness to avoid exercise during the 7 days before each part of the study
• Concomitant medical problems that may prevent the participant from successfully completing the protocol
• Smoking as defined by 2 or more tobacco cigarettes a week
• Daily use of opioids or an opioid antagonist or use in the past two weeks
• Unwillingness to wear a continuous glucose monitor for one week before and one week after each part of the study

3-6 months