Metabolic Causes of Thrombosis in Type 2 Diabetes Mellitus

Currently 75-80% of diabetes mellitus (DM) patients die due to thrombotic causes. Data from
the Centers for Disease Control and Prevention released in 2000 indicated that mortality due
to coronary artery disease is decreasing except in individuals with diabetes. Clearly the
disordered metabolism, which includes abnormal metabolism of fats resulting in higher
triglyceride and free fatty acid blood levels, occurring in diabetes predisposes these
individuals to increased thrombotic events. Unless the underlying mechanisms responsible for
these events can be identified, there will be an unprecedented number of diabetic patients
suffering thrombotic episodes in the next 10 years.

The specific aims of this study are to determine the effects of elevated free fatty acids
and hyperglycemia (high glucose)on endothelial function and thrombolytic balance in patients
with type 2 diabetes, and to determine the effects of increased insulin in this setting.

Inclusion Criteria

- 16 Type 2 diabetic patients age 18 - 60 yrs

- 16 Non-diabetic controls age 18-60 yrs

- Body mass index >20 kg/m2

- Female volunteers of childbearing potential: negative urine pregnancy test

- Volunteers over 40 years old: an ECG with no clinically significant conduction or
ischemic changes.

- For those with type 2 diabetes: HBA1C > 5.5%

- For those with type 2 diabetes: C-peptide >0.2 nmol, If C-peptide is abnormal or
there is a clinical suspicion for type 1 diabetes, MODY or LADA, anti-islet cell and
anti-GAD antibodies will be assessed to establish the diagnosis of type 2 diabetes
vs. type 1/LADA/MODY.

- PT (time) 12.8-14.6 seconds, PTT (time) 25-38 seconds

Exclusion Criteria

- Any current disease condition that alters carbohydrate metabolism (other than type 2
DM) and/or evidence for clinically significant cardiac disease

- Uncontrolled hypertension

- Pregnancy

- Subjects unable to give voluntary informed consent

- Subjects with history of pancreatitis

- Subjects on anticoagulant drugs, anemic, or with known bleeding diseases

- Subjects with history of GI bleeding requiring treatment

- Tobacco Use

- Subjects with history of heparin-induced thrombocytopenia or heparin allergy

- Subjects with severe egg or legume (soybean) allergy

- Abnormal results following screening tests and physical examination that is
clinically significant:

Medical history/Physical Exam Exclusion Criteria

- Fever greater than 38 degrees C at screening or study initiation

- Uncontrolled severe hypertension (i.e., blood pressure greater than 160/100)

- Cardiac Abnormalities (e.g. Heart Failure, Arrhythmia, Cardiomyopathy, ischemic
tachycardia, S-T segment deviations, etc.,) from history or ECG testing in subjects >
40 years old.

- Diagnosed Pneumonia

- Hepatic Failure/Jaundice

- Clinically significant coagulopathy

- Renal Failure

- Acute Cerebrovascular/ Neurological deficit

Screening Laboratory Tests Exclusion Criteria according to protocol