Group 1A) T1DM subjects with severe hypoglycemia unawareness and awaiting islet cell transplantation will be referred by participating islet transplantation centers.

Group 1B) T1DM subjects with severe hypoglycemia unawareness but not awaiting islet cell transplantation will be from the greater New Haven, CT area.

Group 2)T1DM, not optimally controlled and without hypoglycemia unawareness will be from the greater New Haven, CT area.

Group 3) Non-Diabetics from the greater New Haven CT area.

Inclusion Criteria:

• Inclusion Criteria for all subjects:

  • Age 18-49
  • > 85 kg
  • BMI <27female <28 male
  • able to provide written informed consent
  • able to speak and read English fluently
  • must meet Magnetic Resonance safety evaluation

Inclusion criteria for Group 1A:

• T1DM undergoing intensive clinical management and currently on the islet transplant list
• History of severe hypoglycemia

Inclusion criteria for Group 1B:

• T1DM undergoing intensive clinical management
• History of severe hypoglycemia unawareness

Inclusion criteria for Group 2:

• T1DM with poor glycemic control, HbA1c > 8%
• no episodes of hypoglycemia requiring assistance from another person for at least 1 yr, no episodes in last 4 weeks, and hypoglycemia aware

Exclusion Criteria:

Group 1A: (T1DM subjects being considered for islet cell transplantation)

• Detectable c-peptide level
• Untreated proliferative retinopathy
• Creatinine clearance < 65 ml/min/1.73 m2
• Serum creatinine ≥1.5 mg/dL
• Previous pancreas or islet transplant
• Positive pregnancy test, or presently breast-feeding, or failure to follow effective contraceptive measures
• Active infection including hepatitis C, hepatitis B, HIV, or TB (or under treatment for suspected TB ), or subjects with a positive PPD performed within 1 yr. of enrollment, and no history of adequate prophylaxis
• Invasive aspergillus infection within year prior to study entry
• Any history of malignancy except for adequately treated squamous or basal cell carcinoma of the skin
• Active alcohol or substance abuse- includes cigarette smoking (must be abstinent for 6 months)
• History of non-adherence to prescribed regimens
• Psychiatric disorder making the subject not a suitable candidate for transplantation
• Baseline Hgb < 10.5 g/dL in females, or < 13 g/dL in males; lymphopenia (<1,000/μL), or leukopenia (< 3,000 total leukocytes/μL), or an absolute CD4+ count < 500/μL
• History of coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) after transplantation (low-dose aspirin treatment is allowed) or patient with INR >1.5
• Severe co-existing cardiac disease, as determined by referring center
• Baseline liver function tests outside of normal range (an initial liver function test panel with any values >1.5 times normal upper limits will exclude a patient without a re-test; a re-test for any values between normal and 1.5 times normal will be made, and if the values remain elevated above normal, the patient will be excluded), or history of significant liver disease
• Severe unremitting diarrhea or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications
• Addison's disease as determined by clinical history
• Under treatment for a medical condition requiring chronic use of systemic steroids
• Any medical condition or medication that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes

Group 1 B: (T1DM with Severe Hypoglycemia Unawareness not on the Transplant List)

• Detectable C-peptide level
• Serum creatinine ≥1.5 mg/dL
• Positive pregnancy test, or presently breast-feeding, or failure to follow effective contraceptive measures
• Active alcohol or substance abuse- includes cigarette smoking (must be abstinent for 6 months)
• Psychiatric disorder making the subject not a suitable candidate for transplantation
• Baseline Hgb < 10.5 g/dL in females, or < 13 g/dL in males
• Baseline liver function tests outside of normal range (an initial liver function test panel with any values >1.5 times normal upper limits will exclude a patient without a re-test; a re-test for any values between normal and 1.5 times normal will be made, and if the values remain elevated above normal, the patient will be excluded), or history of significant liver disease
• Under treatment for a medical condition requiring chronic use of systemic steroids
• Any medical condition or medication that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes

Group 2: (T1DM control subjects)

• Detectable C-peptide level
• Serum creatinine ≥1.5 mg/dL
• Positive pregnancy test, or presently breast-feeding, or failure to follow effective contraceptive measures
• Any history of malignancy except for adequately treated squamous or basal cell carcinoma of the skin
• Active alcohol or substance abuse- includes cigarette smoking (must be abstinent for 6 months)
• Baseline Hgb < 10.5 g/dL in females, or < 13 g/dL in males Baseline liver function tests outside of normal range (an initial liver function test panel with any values >1.5 times normal upper limits will exclude a patient without a re-test; a re-test for any values between normal and 1.5 times normal will be made, and if the values remain elevated above normal, the patient will be excluded), or history of significant liver disease
• Addison's disease as determined by clinical history
• Under treatment for a medical condition requiring chronic use of systemic steroids
• Any medical condition or medication that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes

Group 3: (Normal Controls)

• FBG > 100 mg/dL
• Serum creatinine ≥1.5 mg/dL
• Positive pregnancy test, or presently breast-feeding, or failure to follow effective contraceptive measures
• Any history of malignancy except for adequately treated squamous or basal cell carcinoma of the skin
• Active alcohol or substance abuse- includes cigarette smoking (must be abstinent for 6 months)
• Baseline Hgb < 10.5 g/dL in females, or < 13 g/dL in males
• Baseline liver function tests outside of normal range (an initial liver function test panel with any values >1.5 times normal upper limits will exclude a patient without a re-test; a re-test for any values between normal and 1.5 times normal will be made, and if the values remain elevated above normal, the patient will be excluded), or history of significant liver disease
• Under treatment for a medical condition requiring chronic use of systemic steroids
• Any medical condition or medication that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes