Adverse Effects of Systemic Hypoglycemia Exposure on Endothelial Function in Humans

Prior work suggests exposure to low glucose levels (hypoglycemia) is associated with increased cardiovascular risk. However, whether there is a causal relationship between cardiovascular events and hypoglycemia remains unclear with conflicting data in the literature. In this study, we plan to study whether acute exposure of patients to clinically relevant (50-60 milligrams/deciliter) levels of hypoglycemia induces or worsens blood vessel endothelial dysfunction- a key 1st step in the development of heart attacks and strokes. This will be determined in humans both with and with type 2 diabetes.


Eligibility Criteria:
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.