Metabolic Causes of Thrombosis in Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study is to learn more about why patients with diabetes have increased heart attacks, strokes and other illnesses due to blood clots causing blockage of a blood vessel. The proposed protocol will study the separate and combined effects of high glucose and high fats on certain cardiovascular responses in Type 2 DM.

Detailed Description
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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.

Official Title
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Metabolic Causes of Thrombosis in Type 2 Diabetes Mellitus, Question 3

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Procedure: euinsulinemic euglycemic glucose clamp
* Procedure: euinsulinemic hyperglycemic glucose clamp
* Procedure: Hyperinsulinemic euglycemic glucose clamp
* Procedure: Hyperinsulinemic hyperglycemic glucose clamp


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Euinsulinemic (low insulin infusion) Euglycemic (normal blood glucose levels) glucose clamp with lipid (fat) infusion | Procedure: euinsulinemic euglycemic glucose clamp<br>* euinsulinemic euglycemic glucose clamp with lipid infusion 48 ml/hr for 4 hours<br>* Other names: Intralipid;|
| Experimental: 2<br>Euinsulinemic Hyperglycemic (high glucose levels) glucose clamp with lipid infusion | Procedure: euinsulinemic hyperglycemic glucose clamp<br>* euinsulinemic hyperglycemic glucose clamp with lipid infusion at 48 ml/hr for 4 hours<br>* Other names: Intralipid;|
| Experimental: 3<br>Hyperinsulinemic (High dose insulin) euglycemic glucose clamp with lipid infusion | Procedure: Hyperinsulinemic euglycemic glucose clamp<br>* Hyperinsulinemic euglycemic glucose clamp with lipid infusion at 48 ml/hr for 4 hours<br>* Other names: Intralipid;|
| Experimental: 4<br>Hyperinsulinemic hyperglycemic (high glucose level) glucose clamp with lipid infusion | Procedure: Hyperinsulinemic hyperglycemic glucose clamp<br>* Hyperinsulinemic hyperglycemic glucose clamp with lipid infusion at 48 ml/hr for 4 hours<br>* Other names: Intralipid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in flow mediated dilation of brachial artery |  | 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Lipid measures |  | 4hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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endothelial function, fibrinolytic balance