Glucose Counterregulation in Long Standing Type 1 Diabetes

Key Inclusion Criteria for intervention GROUP 1 (Long-standing T1D complicated by hypoglycemia unawareness)

• Male and female subjects aged 25 to 70 years
• Able to provide written informed consent and to comply with the protocol procedures
• Clinical history compatible with type 1 diabetes with disease onset 10 years
• Absent C-peptide ( 5% time spent in the hypoglycemic range (glucose 10 years
• Absent C-peptide (< 0.3 ng/mL).
• 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.
• Intact hypoglycemia awareness indicated by a Clarke score of 3 or less.
• No episodes of severe hypoglycemia in the past 3 years.

Key Inclusion Criteria for control GROUP 3 (Non-diabetic controls)

• Male and female subjects aged 25 to 70 years.
• Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
• No history of diabetes.

Key Exclusion Criteria for ALL 3 groups

• Body mass index (BMI) greater than 38 kg/m2.
• Insulin requirement of more than 1.0 IU/kg/day.
• HbA1c greater than 10%.
• Untreated proliferative diabetic retinopathy.
• SBP greater than 160 mmHg or DBP greater than 100 mmHg.
• Glomerular filtration rate (GFR) less than 55 ml/min/1.73 m-squared
• Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study.
• Baseline hemoglobin less than 11 g/dl in women and less than12 g/dl in men.
• Severe co-existing cardiac disease
• Persistent elevation of liver function tests greater than 1.5 upper normal limits
• Hyperlipidemia despite medical therapy
• Receiving treatment for a medical condition requiring chronic use of systemic steroids
• Presence of a seizure disorder not attributable to hypoglycemia.
• Untreated hypothyroidism, Addisons disease, or Celiac disease.
• Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
• Use of RT-CGM (continuous glucose monitor) within last 4 weeks.
• Non-diabetic patients do not need to meet any of the glucose criteria.