Vascular Effects of Insulin: Implications for Hyperglycemia Management

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

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

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

Insulin reduces myocardial injury and post-ischemic apoptosis in dogs Zhang H-X et al. J Cardiovasc Pharmacol. 2006;48: *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 (%) V GK GIK Low- dose I Infarct sizeApoptosis †† †† * *

Insulin improves post-MI cardiac contractile function recovery in dogs Zhang H-X et al. J Cardiovasc Pharmacol. 2006;48: *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 † † † † † † * * * *

Insulin infusion has anti-inflammatory and profibrinolytic effects Chaudhuri A et al. Circulation. 2004;109: *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 –1– * *  44% † * –5–5 –10  PAI-1 (ng/ mL )  7% ‡  13% ‡

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

Intensive insulin reverses impaired platelet response in ACS patients with T2DM Worthley MI et al. J Am Coll Cardiol. 2007;49: N = 76 SNP = sodium nitroprusside, a nitric oxide (NO) donor Admission blood glucose (mg/dL) r = P =  Platelet response to NO correlates with  BG  Platelet response to NO with intensive IV insulin Platelet SNP response (% inhibition) Time (hours) IV insulin sc insulin P = vs sc insulin