Metabolic Causes of Thrombosis in Type 2 Diabetes - Question 4

Study Overview
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Brief Summary
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Hypoglycemia (low blood glucose level) occurs frequently in intensively treated patients with diabetes. Although hypoglycemia was thought to occur almost exclusively in T1DM, with the advent of improved metabolic control in T2DM, the incidence of hypoglycemia is rising in these patients. Therefore in this application, we will test the novel hypothesis that prior hypoglycemia will result in (cardiovascular complications) during subsequent hypoglycemia.

Detailed Description
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This study will test the hypothesis that 1) hypoglycemia causes a prothrombotic state and defective endothelial function and 2) episodes of repeated hypoglycemia will result in greater impairments of endothelial function and an increased prothrombotic tendency. Preliminary data in healthy men demonstrates that hypoglycemia can dramatically increase PAI-1 levels and the PAI-1 to tPA ratio, thereby creating a prothrombotic state. Whether this also occurs in type 2 DM patients is unknown. Furthermore, the effects of hypoglycemia on endothelial function in T2DM are also unknown.

Official Title
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SCCOR in Hemostatic and Thrombotic Diseases Project 5 - Metabolic Causes of Thrombosis in Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Other: Hyperinsulinemic Hypoglycemic Clamp


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 14 (7 female/ 7 male) Type 2 diabetic patients age 18-60 yrs 14 (7 female/ 7 male) Non-diabetic controls age and weight matched Body mass index >20 kg/m2 Normal results of routine blood test to screen for hepatic, renal, and hematological abnormalities Female volunteers of childbearing potential: negative HCG pregnancy test Volunteers over 40 years old: normal baseline cardiac stress test For those with type 2 diabetes: HBA1C >5.5% For those with type 2 diabetes: diabetes < 20 years For those with type 2 diabetes: C-peptide >0.2 nmol (1.1-4.4 ng/ml). If c-peptide is abnormal or there is a clinical suspicion of type 1 diabetes, MODY, or LADA, Anti-Islet cell (negative) and Glutamic Acid Decarboxylase (GAD) antibody negative (0.0-1.5 U/ml) will be performed Exclusion Criteria Uncontrolled hypertension History of cerebrovascular incidents Pregnancy Subjects unable to give voluntary informed consent Subjects with a recent medical illness Subjects on anticoagulant drugs, anemic, or with known bleeding diseases Tobacco Use Physical Exam Exclusion Criteria Blood Pressure greater than 150/95 Clinically significant Cardiac Abnormalities (e.g. Heart Failure, Arrhythmias, ischemic tachycardia, S-T segment deviations, ect.) from history or from cardiac stress testing Pneumonia Hepatic Failure/Jaundice Renal Failure Acute Cerebrovascular/ Neurological deficit Fever greater than 38.0 C Screening blood tests exclusions 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: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control study then antecedent hypoglycemia study group<br>Day 1 euglycemia, day 2 hypoglycemia Hyperinsulinemic Hypoglycemic Clamp: hyperinsulinemic glucose clamp separated by 8 weeks then participants proceeded to antecedent hypoglycemia study Day 1 hypoglycemia, Day 2 hypoglycemia | Other: Hyperinsulinemic Hypoglycemic Clamp<br>* all participants received (2) hyperinsulinemic glucose clamp studies separated by 8 weeks<br>|
| Active Comparator: Antecedent Hypoglycemic clamp study<br>Day 1 hypoglycemia, day 2 hypoglycemia Hyperinsulinemic Hypoglycemic Clamp: hyperinsulinemic glucose clamp separated by 8 weeks then participants proceeded to control study Day 1 euglycemia, Day 2 hypoglycemia | Other: Hyperinsulinemic Hypoglycemic Clamp<br>* all participants received (2) hyperinsulinemic glucose clamp studies separated by 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Changes in Endothelial Function as Measured by Flow Mediated Dilation by 2D Doppler Ultrasound on Day 2 | A measure of the baseline arterial dilation on day 2 is compared to the post intervention measure of dilation of the brachial artery on Day 2. | baseline on day 2 and  6 hours later at end of glucose clamp period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, Endothelial Function, Fibrinolytic Balance, Hypoglycemia