1. Vascular Effects of Insulin: Implications for Hyperglycemia Management

2. Potential beneficial effects of insulin Dandona P et al. Am J Cardiol. 2007;99(suppl):15B-26. Mechanistic benefits of insulin Vasodilatory + Platelet inhibitory  NO release  cAMP  eNOS Antithrombotic  TF  PAI-1 Glucose lowering Anti-inflammatory  NF-κB  MCP-1  ICAM-1  CRP  IκB Anti-oxidative  ROS Cardioprotective Neuroprotective Antiapoptotic

3. Insulin exerts dose-dependent vasodilatory effect on adenosine-stimulated myocardial blood flow Sundell J et al. Diabetes. 2002;51:1125-30. N = 10 healthy men MBF (mL/g per min) *P < 0.001 vs basal; † P < 0.05 vs saline; ‡ P < 0.05 vs insulin 1 mU * *†*† * †‡  19%  20%

4. P = 0.045 P = 0.018 P = 0.003 P = 0.043 Rest Adenosine MBF (mL/g per min) *1 mU/kg per min IV Lautamäki R et al. Diabetes. 2006:55:511-6. Non-ischemic regionsIschemic regions Insulin infusion improves myocardial blood flow in patients with T2DM and CAD N = 43

5. Insulin reduces myocardial injury and post-ischemic apoptosis in dogs Zhang H-X et al. J Cardiovasc Pharmacol. 2006;48:306-13. *P < 0.05, † P < 0.01 vs vehicle V = vehicle; G = glucose; K = Potassium; I = Insulin Apoptotic index (%) V GK GIK Low- dose I Infarct size/ AAR (%) 12 10 8 6 4 2 0 V GK GIK Low- dose I 24 20 16 12 8 4 0 Infarct sizeApoptosis †† †† * *

6. Insulin improves post-MI cardiac contractile function recovery in dogs Zhang H-X et al. J Cardiovasc Pharmacol. 2006;48:306-13. *P < 0.05, † P < 0.01 vs vehicle Pre-I-10 min50 min1 hr2 hr3 hr4 hr +LVdP/dt max (mm Hg/s) Time GKVGIKLow-I Ischemia Reperfusion 0 1800 2000 2200 2400 2600 † † † † † † * * * *

7. Insulin infusion has anti-inflammatory and profibrinolytic effects Chaudhuri A et al. Circulation. 2004;109:849-54. *P < 0.05 between groups; † Insulin vs control; ‡ Changes vs baseline PAI = plasminogen activator inhibitor Time (hours)  CRP (mg/L) N = 32 with acute STEMI, without hyperglycemia ControlInsulin 7 6 5 4 3 2 1 0 –1–1 02462448 * *  44% † * 25 20 15 10 5 0 –5–5 –10  PAI-1 (ng/ mL ) 02462448  7% ‡  13% ‡

8. Insulin infusion with normoglycemia decreases NF-  B Dandona P et al. J Clin Endocrinol Metab. 2001;86:3257-65. N = 10 with obesity, without diabetes *P < 0.05 vs baseline Intranuclear NF-  B,  from baseline (%) Time (hours) 0246 Dextrose infusionInsulin infusion 0 20 40 60 80 100 120 140 *

9. Intensive insulin reverses impaired platelet response in ACS patients with T2DM Worthley MI et al. J Am Coll Cardiol. 2007;49:304-10. N = 76 SNP = sodium nitroprusside, a nitric oxide (NO) donor Admission blood glucose (mg/dL) r = -0.31 P = 0.007  Platelet response to NO correlates with  BG  Platelet response to NO with intensive IV insulin Platelet SNP response (% inhibition) 100 80 60 40 20 0 090180270360450540630 Time (hours) 012 55 45 35 25 IV insulin sc insulin P = 0.049 vs sc insulin