The Suppression of Toll Like Receptors by Insulin

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.

INCLUSION CRITERIA

Lean Group:

1. Age: 20 to 65 years of age inclusive

2. Sex: male or female

3. Normal fasting plasma glucose (65-100 mg/dl)

4. Normal BMI (20-25)

Obese Group:

1. Age: 20 to 65 years of age inclusive

2. Sex: male or female

3. Normal fasting plasma glucose (65-100 mg/dl)

4. BMI> 30

DM Group:

1. Type 2 Diabetes Mellitus

2. Age: 20 to 65 years of age inclusive

3. Sex: male or female

4. BMI >30

5. Hba1c < 8%

6. 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

1. Pregnancy

2. Congestive heart failure

3. Heart Rate <50 beats /minute

4. Sick Sinus Syndrome

5. Second or third degree heart block

6. Blood pressure <80 mm systolic or > 160/100 mmHg

7. Coronary event or procedure (myocardial infarction, unstable angina, coronary artery
bypass surgery or coronary angioplasty) in the previous three months

8. Hepatic disease (transaminase > 3 times normal)

9. Renal impairment (serum creatinine > 1.5)

10. History of drug or alcohol abuse within past one year

11. Participation in any other concurrent clinical trial

12. Potassium (K+) values <3.5 meq/l to > 5.5 meq/l)

13. Any other life-threatening, non-cardiac disease

14. Use of an investigational agent or therapeutic regimen within 30 days of study

15. Type 2 diabetics on thiazolidinediones and/ or insulin

16. Subjects on steroids, NSAIDS or antioxidants

17. Patients taking exenatide or sitaglipin or loop diuretics

18. Anemia (Hemoglobin level less than 12gm/dl in females and 13gm/dl in males)
19)Allergy to lidocaine