The Suppression of Toll Like Receptors by Insulin

Study Overview
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Brief Summary
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This study will help us understand the possible beneficial effects of insulin in inflammation. Inflamamtion is considered to be the cause of atherosclerosis and heart disease.

Detailed Description
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Obesity and type 2 diabetes are major health problems in the United States and the world. Both conditions are characterized by increased inflammation and oxidative stress and are associated with increased risk of cardiovascular disease. Our previous work shows that insulin exerts a prompt and powerful anti-inflammatory effect, on circulating blood cells and in plasma in healthy subjects and in critically ill patients. Toll like receptors (TLRs) recognize bacterial and viral products like endotoxin and viruses and are major determinants of the inflammatory response against foreign pathogens. In view of the recent data showing that TLRs recognize a range of molecules and proteins that are not of pathogenic source like saturated lipids and that TLRs are involved in the pathogenesis of atherosclerosis which leads to cardiovascular disease and insulin resistance which leads to type 2 diabetes (DM) we hypothesized that insulin infusion suppresses TLRs expression. Our preliminary data show that insulin infusion for 4 hours reduces the levels of many TLRs and thus might protect from inflammation induced conditions We therefore propose to investigate, in more detail, the effect of infusing different doses of insulin on TLRs mRNA and protein levels and its activity in obese and DM subjects over a longer infusion period and a larger number of subjects in circulating white blood cells and in fat tissue. Also we will be comparing the baseline levels of TLRs and TLRs related proteins as well as their modulation by insulin between normal, obese and DM subjects.

Official Title
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The Suppression of Toll Like Receptors by Insulin

Conditions
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Insulin Resistance

Intervention / Treatment
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* Drug: insulin
* Drug: insulin
* Drug: insulin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Lean Group: Age: 20 to 65 years of age inclusive Sex: male or female Normal fasting plasma glucose (65-100 mg/dl) Normal BMI (20-25) Obese Group: Age: 20 to 65 years of age inclusive Sex: male or female Normal fasting plasma glucose (65-100 mg/dl) BMI> 30 DM Group: Type 2 Diabetes Mellitus Age: 20 to 65 years of age inclusive Sex: male or female BMI >30 Hba1c < 8% If on statins, angiotensin converting enzyme inhibitor, angiotensin receptor blocker or low dose aspirin, should be on a stable dose for one month. EXCLUSION CRITERIA Pregnancy Congestive heart failure Heart Rate <50 beats /minute Sick Sinus Syndrome Second or third degree heart block Blood pressure <80 mm systolic or > 160/100 mmHg Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass surgery or coronary angioplasty) in the previous three months Hepatic disease (transaminase > 3 times normal) Renal impairment (serum creatinine > 1.5) History of drug or alcohol abuse within past one year Participation in any other concurrent clinical trial Potassium (K+) values <3.5 meq/l to > 5.5 meq/l) Any other life-threatening, non-cardiac disease Use of an investigational agent or therapeutic regimen within 30 days of study Type 2 diabetics on thiazolidinediones and/ or insulin Subjects on steroids, NSAIDS or antioxidants Patients taking exenatide or sitaglipin or loop diuretics Anemia (Hemoglobin level less than 12gm/dl in females and 13gm/dl in males) 19)Allergy to lidocaine

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: obese<br>20 obese subjects | Drug: insulin<br>* insulin to be infused at three different rates (2, 3.5 and 5 units/hour)<br>|
| Active Comparator: lean<br>20 lean subjects | Drug: insulin<br>* insulin to be infused at three different rates (2, 3.5 and 5 units/hour)<br>|
| Experimental: type 2 diabetes<br>20 type 2 diabetes | Drug: insulin<br>* insulin to be infused at three different rates (2, 3.5 and 5 units/hour)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Suppression of Toll Like receptors by Insulin | Expression of TLR2, TLR4, TLR7 and TLR9 mRNA in mononuclear cells and adipose tissue | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TLR expression | Basal TLR expression in obese and type 2 diabetic subjects as compared to lean subjects | 0 hours |