Adverse Effects of Systemic Hypoglycemia Exposure on Endothelial Function in Humans

Inclusion Criteria:

- Type 2 Diabetes Inclusion Criteria

1. Adult age 21 or older

2. If on 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase reductase therapy, must be on
a stable dose for at least 6 weeks prior to enrollment

3. Diagnosis of type 2 diabetes by a physician as defined by the American Diabetes
Association standard criteria: 1) Fasting Plasma glucose at or above 126 mg/dL 2) a
two-hour value in an oral glucose tolerance test at or above 200 mg/dL, or 3) a
random plasma glucose concentration 200 mg/dL in the presence of symptoms, or 4)
glycosylated hemoglobin greater than or equal to 6.5%.

Score of < 4 using the Gold method for assessing hypoglycemia awareness

Inclusion Criteria for Healthy subjects

1. Adult age 21 or older

2. No evidence of metabolic syndrome or diabetes, hypertension (BP≥140/90), or high
cholesterol (LDL≥160) at the time of screen.

Exclusion Criteria:

1. History of stroke, peripheral arterial disease, or coronary artery disease (as
defined by the presence of at least one coronary stenosis ≥ 40% on angiography or by
confirmed history of myocardial infarction by standard criteria)

2. Evidence of other evident major illness including chronic renal insufficiency(plasma
creatinine > 1.4 for women or 1.5 for men), liver disease (aspartate aminotransferase
or alanine aminotransferase greater than 2.5 x normal), and cancer currently
undergoing therapy or had therapy for cancer within 1 year of enrollment.

3. Pregnancy as determine by urinary pregnancy test

4. Subjects on warfarin, oral anti-thrombin inhibitors, or thienopyridines

5. Subjects who have had changes to dosing of thiazolidinedione, dipeptidyl
peptidase-4 (DPP-4) inhibitor, or metformin therapy within 6 weeks of enrollment.

6. Failed Allen's test in both arms - unable to safely place an arterial line

7. Glucose reading of < 50 mg/dL and/or episodes of symptomatic hypoglycemia requiring
the assistance of another person for recovery in the 2 years prior to enrollment.

8. History of hypoglycemic convulsions

9. Current fluoxetine therapy (known to interfere with neuroendocrine response to
hypoglycemia)

10. Glycosylated hemoglobin over 8.5%

11. On aldosterone antagonist therapy at the time of enrollment

12. On insulin therapy at the time of screening.

13. History of allergy to local anesthetic injection like lidocaine.

14. Age below 21.

Exclusion Criteria for Healthy Subjects:

1. Meet any of the exclusion criteria for diabetic or metabolic syndrome group Meet
criteria for type 2 diabetes or metabolic syndrome

2. On medication for cholesterol or blood pressure.

3. History of allergy to local anesthetic injection like lidocaine.