Glucose Counterregulation in Long Standing Type 1 Diabetes

Key Inclusion Criteria for intervention GROUP 1 (Long-standing T1D complicated by hypoglycemia unawareness) 1. Male and female subjects aged 25 to 70 years 2. Able to provide written informed consent and to comply with the protocol procedures 3. Clinical history compatible with type 1 diabetes with disease onset \< 40 years of age OR onset ≥ 40 years and documented islet autoimmunity 4. Insulin-dependent for \> 10 years 5. Absent C-peptide (\< 0.3 ng/mL). 6. Involvement in intensive diabetes management defined as self-monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the previous 12 months.) 7. Hypoglycemia unawareness manifested by a Clarke score of 4 or more AND at least one of the following: * HYPO score greater than or equal to the 90th percentile (1047); OR marked glycemic lability defined by a glycemic lability index (LI) score greater than or equal to the 90th percentile (433 mmol/l2/h·wk-1); OR * A composite of a HYPO score greater than or equal to the 75th percentile (423) and a LI greater than or equal to the 75th percentile (329). 8. At least one episode of severe hypoglycemia in the past 12 months defined as an event with symptoms or signs compatible with hypoglycemia in which the subject was unable to treat him/herself and which was associated with either a blood glucose level \< 54 mg/dl \[3.0 mmol/L\] or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration; OR documented \> 5% time spent in the hypoglycemic range (glucose \< 60 mg/dl) by 72-hour blinded CGM. Key Inclusion Criteria for control GROUP 2 (Long-standing T1D with intact hypoglycemia awareness) 1. Male and female subjects aged 25 to 70 years. 2. Able to provide written informed consent and to comply with the procedures of the study protocol. 3. Clinical history compatible with type 1 diabetes with disease onset \< 40 years of age 4. Insulin-dependent for \> 10 years 5. Absent C-peptide (\< 0.3 ng/mL). 6. Involvement in intensive diabetes management defined as the use of basal-bolus insulin analog delivery by multi-dose injection (MDI) or continuous subcutaneous insulin infusion (CSII) together with self-monitoring of blood glucose values four or more times daily, without continuous glucose monitoring (CGM), under the direction of an endocrinologist, diabetologist, or diabetes nurse practitioner with at least 3 clinical evaluations during the previous 12 months. 7. Intact hypoglycemia awareness indicated by a Clarke score of 3 or less. 8. No episodes of severe hypoglycemia in the past 3 years. Key Inclusion Criteria for control GROUP 3 (Non-diabetic controls) 1. Male and female subjects aged 25 to 70 years. 2. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol. 3. No history of diabetes. Key Exclusion Criteria for ALL 3 groups 1. Body mass index (BMI) greater than 38 kg/m2. 2. Insulin requirement of more than 1.0 IU/kg/day. 3. HbA1c greater than 10%. 4. Untreated proliferative diabetic retinopathy. 5. SBP greater than 160 mmHg or DBP greater than 100 mmHg. 6. Glomerular filtration rate (GFR) less than 55 ml/min/1.73 m-squared 7. Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study. 8. Baseline hemoglobin less than 11 g/dl in women and less than12 g/dl in men. 9. Severe co-existing cardiac disease 10. Persistent elevation of liver function tests greater than 1.5 upper normal limits 11. Hyperlipidemia despite medical therapy 12. Receiving treatment for a medical condition requiring chronic use of systemic steroids 13. Presence of a seizure disorder not attributable to hypoglycemia. 14. Untreated hypothyroidism, Addisons disease, or Celiac disease. 15. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment. 16. Use of RT-CGM (continuous glucose monitor) within last 4 weeks. * Non-diabetic patients do not need to meet any of the glucose criteria.