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 cAMPeNOS

AntithromboticTFPAI-1

Glucose lowering

Anti-inflammatoryNF-κBMCP-1ICAM-1CRPIκB

Anti-oxidative ROS

Cardioprotective Neuroprotective

Antiapoptotic

Insulin exerts dose-dependent vasodilatory effect on adenosine-stimulated myocardial blood flow

Sundell J et al. Diabetes. 2002;51:1125-30.

N = 10 healthy men

0

2

4

6

8

Basal Adenosine +Saline

Adenosine +Insulin 1 mU

Adenosine +Insulin 5 mU

MBF(mL/g

per min)

*P < 0.001 vs basal; †P < 0.05 vs saline; ‡P < 0.05 vs insulin 1 mU

*

*†

*†‡

19%20%

0

1

2

3

4

5

6

7

Fasting Insulin* Fasting Insulin*

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 CADN = 43

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

0V GK GIK Low-

dose I

24

20

16

12

8

4

0

Infarct size Apoptosis

† †

† †

* *

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 min 50 min 1 hr 2 hr 3 hr 4 hr

+LVdP/dtmax (mm Hg/s)

TimeGKV GIK Low-I

Ischemia Reperfusion0

1800

2000

2200

2400

2600

††

†

††

†

* *

* *

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 baselinePAI = plasminogen activator inhibitor

Time (hours)

CRP(mg/L)

N = 32 with acute STEMI, without hyperglycemia

Control Insulin

7

6

5

4

3

2

1

0

–10 2 4 6 24 48

*

*

44%†

*

25

20

15

10

5

0

–5

–10

PAI-1(ng/mL)

0 2 4 6 24 48

7%‡

13%‡

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)

0 2 4 6

Dextrose infusion Insulin infusion

0

20

40

60

80

100

120

140

*

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 = -0.31P = 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

0 90 180 270 360 450 540 630Time (hours)

0 12

55

45

35

25

IV insulin

sc insulin

P = 0.049 vs sc insulin