Inflammatory Markers and Anti- Inflammatory Effects of Insulin

Inflammatory Markers and AntiInflammatory Markers and Anti-- Inflammatory Effects of InsulinInflammatory Effects of Insulin

Paresh Dandona, BSc, MD, DPhil, FRCP, FACP, FACC, FACE

Distinguished Professor of Medicine and Pharmacology School of Medicine and Biomedical SciencesDivision Head, Endocrinology and Metabolism

State University of New York at BuffaloFounder and Medical Director,

Diabetes-Endocrinology Center of Western New York Head, Division of Endocrinology

Kaleida Health/Millard Fillmore Hospital, Buffalo, New York

7/21/2009 1:52 PM [Insert Title Here].ppt

2

Cum

ula

tive

Rat

e of Rec

urr

ent

MI

or

Coro

nar

y D

eath

Lowering CRP Lowering CRP with Statinwith Statin

Therapy is BeneficialTherapy is Beneficial

Follow-up (Years)

0.0 0.5 1.0 1.5 2.0 2.50

1

2

3

4

5

6

% C

V E

vents

at

8 Y

ears

Higher CRP Levels Higher CRP Levels are Associated with are Associated with

Adverse EventsAdverse Events

Adapted from Ridker PM et al. Circulation 2003;107:391-397. | Ridker PM et al. N Engl J Med 2005;352:20-28. Copyright Massachusetts Medical Society. All rights reserved.

CRP <1CRP 1–3

CRP >3

CRP 2 mg/L

CRP <2 mg/L

0.00

0.02

0.04

0.06

0.08

0.10


3Clinical Relevance of Achieved LDLClinical Relevance of Achieved LDL--C and Achieved CRP Combined after Treatment C and Achieved CRP Combined after Treatment

with Statin Therapy: with Statin Therapy: PROVE ITPROVE IT––TIMI 22TIMI 22Rec

urr

ent

MI

or

Coro

nar

y D

eath

(%)

Follow-up (Years)0.0 0.5 1.0 1.5 2.0 2.5

LDL 70 mg/dl, CRP 2 mg/L

LDL 70 mg/dl, CRP <2 mg/LLDL <70 mg/dl, CRP 2 mg/L

LDL <70 mg/dl, CRP <2 mg/L

LDL <70 mg/dl, CRP <1 mg/L

0.00

0.02

0.04

0.06

0.08

0.10

Ridker PM et al. N Engl J Med 2005;352:20-28. Copyright 2005 Massachusetts Medical Society. All rights reserved.


4

JUPITER: Primary endpoint

Years

Cumulative incidence

0.08

0.06

0.04

0.02

0.000 1 2 3 4

Placebo

Rosuvastatin

Ridker PM et al. N Engl J Med. 2008;359:2195-207.

HR 0.56 (0.46-0.69)P < 0.00001


5

JUPITER: MI, stroke, or CV death

Ridker PM et al. N Engl J Med. 2008;359:2195-207.

Placebo

Rosuvastatin

Years


0.08

0.06

0.04

0.02

0.000 1 2 3 4

HR 0.53 (0.40-0.69)P < 0.00001


6

N Rate

Placebo 7832 1.11LDL-C achieved 70 mg/dL 2110 0.91 P < 0.0001LDL-C achieved <70 mg/dL 5606 0.51

Placebo 7832 1.11LDL-C reduction <50% 4181 0.74 P < 0.0001LDL-C reduction 50% 3535 0.47

Placebo 7832 1.11hsCRP achieved 2 mg/L 4305 0.77 P < 0.0001hsCRP achieved <2 mg/L 3411 0.42

Placebo 7832 1.11hsCRP reduction <50% 4143 0.70 P < 0.0001hsCRP reduction 50% 3573 0.51

JUPITER: Clinical events according to magnitude of reduction in LDL-C or hsCRP

Ridker PM et al. Lancet. 2009;373:1175-82.

MI, stroke, admission for UA, arterial revascularization, or CV death

Rosuvastatinbetter

Rosuvastatinworse

0.25 0.5 1.0 2.0 4.0

Hazard ratio (95% CI)


7JUPITER: Importance of achieving dual LDL-C and hsCRP reductionCumulative incidence of MI, stroke, admission for UA, arterial revascularization, or CV death

1 2 3 4Follow-up (years)


0.08

0.06

0.04

0.02

0

Rosuvastatin (LDL-C 70 mg/dL or hsCRP 2 mg/L)

Placebo Rosuvastatin (LDL-C <70 mg/dL and hsCRP <2 mg/L)

Ridker PM et al. Lancet. 2009;373:1175-82.


8Summary of Studies of the Effect of C-Reactive Protein (CRP) Genotype Combination and Apolipoprotein E

Genotype on the Risk of Ischemic Heart Disease (IHD)

Zacho J et al. N Engl J Med 2008;359:1897-1908


9Summary of Studies of the Effect of C-Reactive Protein (CRP) Genotype Combination on the Risk of Ischemic

Cerebrovascular Disease (ICVD)

Zacho J et al. N Engl J Med 2008;359:1897-1908

Effect of Insulin on NEEffect of Insulin on NE--Induced Induced VenoconstrictionVenoconstriction

A B

DC

Grover A, et al. Hypertension. 1995;25:779-784.

A. Normal vein before cuff inflation

C. Constriction induced by norepinephrine

B. The same vein after inflation

D. Attenuation of the norepinephrine effect by insulin

Effect of Insulin on NEEffect of Insulin on NE--Induced Induced Venoconstriction: ControlsVenoconstriction: Controls

Diameter of Vein (%)

Relative to Basal Inflated

Grover A, et al. Hypertension. 1995;25:779-784.

NE (ng/min) NE (100 ng/min) +Insulin (U/min)

Basal

P<0.05

Inflated 12.5 25 50 100 8 16 24 320

20

40

60

80

100

120 100%97%

74%

67%60%

77%80%

87% 97%

Effect of Methylene Blue (MB)Effect of Methylene Blue (MB)

Grover, et al. Hypertension. 1995;25:779-784.

Diameter of Vein (mm)

NE (100 ng/min) NE (100 ng/min) +IN (32 U/min) +MB (0.125 g/min)

NE (100 ng/min) +Insulin (32 U/min)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Mean ±

SEM

Inability of Insulin to Inhibit Platelet Inability of Insulin to Inhibit Platelet Aggregation in DiabeticsAggregation in Diabetics

Dandona P. Presented at :American Diabetes Association 57th Scientific Session; June, 1997. Boston, Mass.

400 nM U46619 Agonist

CD50 of Insulin(µU/mL)

Control IDDM NIDDM0

10

20

30

40

50

60

70

P<0.001

Factor VIII Ulex Europaeus

CD31 EN4

-Actin Negative Control

Aljada A, Dandona P. Metabolism. 2000;49:147-150.

A) A representative standard curve is shown (r2 = 0.99). B) Representative output generated from an experiment where NO production was measured in response to

increasing concentrations of insulin. Current generated by the NO electrode is recorded as a function of time. The concentrations of insulin shown represent cumulative concentrations.

Direct Measurement of NO From HUVECDirect Measurement of NO From HUVEC

B

Basal

50 pA200 sec

1 50 100 500 1000 5000 10,000 50,000Insulin Dose(nM)

Nitric Oxide(nM)

A 200150100500

0 50 100 150 200 250 300Current (pA)

Zeng G, Quon MJ. J Clin Invest. 1996;98:894-898.

A) Western blot showing the induction of eNOS in human aortic endothelial cells by insulin. The induction is observed at 25 U/mL.

B) No i-NOS bands were observed in HAEC induced with different concentrations of insulin even at very high X-ray film exposure.

A)

Insulin

µU/m

L

µU/m

L

µU/m

L

µU/m

L

0 25 100

1000EC N

OS

140 KD-

B) Insulin

µU/m

L

µU/m

L

µU/m

L

µU/m

L

0 25 100

1000

130 kDa-

LPS-

Stim

ulated

Mono

cytes

Induction of eNOS in Induction of eNOS in Endothelial Cells by InsulinEndothelial Cells by Insulin

Adapted from: Aljada A, Dandona P. Metabolism. 2000;49:147-150.

% C

hang

e Fro

m Ba

selin

e eNO

S Pr

otein

Leve

ls0

50

100

150

200

250

300

350

Insulin (U/ml, Mean

SD)0 25 100 1000

*

*

*

*P<0.05

NFNF--B ActivationB Activation

IB Kinases

Cytoplasm

Nucleus

Inflammatory Gene

mRNA

Degradation

NF-B

Cell Membrane

Activation Signals

Inflammatory Proteins

Barnes and Karin. N Engl J Med. 1997;336:1066-1071.

Barnes and Karin. N Engl J Med. 1997;336:1066-1071.

Effects of Glucocorticoids Effects of Glucocorticoids on NFon NF--B ActivationB Activation

Cytokine

Cytoplasm

Coding Sequence

Inflammatory Gene

mRNA

Nucleus

NF-B

Cell Membrane Glucocorticoid Inflammatory

ProteinsCytokine Receptor

Glucocorticoid Receptor

Glucocorticoid Response ElementIB

Gene

Protein

Plasma Insulin and Glucose Concentrations Following Insulin or Plasma Insulin and Glucose Concentrations Following Insulin or Glucose or Saline Infusions*Glucose or Saline Infusions*

*Insulin infusion in 10 obese human subjects.

Adapted from: Dandona P, et al. J Clin Endocrinol Metab. 2001;86:3257-3265.

Time (hours)0 2 4 6

Insuli

n (μU

/mL)

0

5

10

15

20

25

30

35

40

*P<0.05*

*

Insulin InfusionDextrose InfusionSaline Infusion

Time (hours)0 2 4 6

Plas

ma G

lucos

e (mg

/dL)

0102030405060708090

100110


ROS Generation by MNC in Obese Subjects Following ROS Generation by MNC in Obese Subjects Following Insulin or Dextrose or Saline InfusionsInsulin or Dextrose or Saline Infusions


%RO

S Ge

nera

tion

By M

NC

Time (hours)0 2 4 6

0102030405060708090

100110120130140150160

*P<0.05

*

*

*


Relative Expression of p47Relative Expression of p47phoxphox

Subunit Protein LevelsSubunit Protein Levels

Time (hours): 0 2 4 6

Time (hours): 0 2 4 6

p47phox

p47phox

Mean

SE.


Relative Expression of p47phox

Subunit in MNC Following Insulin Infusion (Upper Gel) or Dextrose

Infusion (Lower Gel)

Densitometry

% C

hang

e In p

47ph

oxSu

bunit

Time (hours)0 2 4 6

0

20

40

60

80

100

120

140

160

180

200

*P<0.05

**

Insulin InfusionDextrose Infusion

Relative NFRelative NF--B Binding to DoubleB Binding to Double--Stranded OligonucleotideStranded Oligonucleotide-- Containing NFContaining NF--B DNA Binding Site Following Insulin or Dextrose B DNA Binding Site Following Insulin or Dextrose

InfusionInfusionGel Shift Assay

Insulin Infusion

Dextrose Infusion

Adapted from Dandona P, et al. J Clin Endocrinol Metab. 2001;86:3257-3265.

% C

hang

e In I

ntran

uclea

r NFk

B

Time (hours)0 2 4 6

0

20

40

60

80

100

120

140Insulin InfusionDextrose Infusion

*P<0.05

*

*

Plasma sICAMPlasma sICAM--1 Concentrations Following Insulin or 1 Concentrations Following Insulin or Dextrose or Saline InfusionsDextrose or Saline Infusions

Adapted from Dandona P, et al. J Clin Endocrinol Metab. 2001;86:3257-3265.

% Change in sICAM-1

(ng/mL)

Time (hours)0 2 4 6

50

60

70

80

90

100

110

120

130

140

**


*P<0.05

Plasma MCPPlasma MCP--1 Concentrations Following Insulin or 1 Concentrations Following Insulin or Dextrose or Saline InfusionsDextrose or Saline Infusions

Adapted from Dandona, et al. J Clin Endocrinol Metab. 2001;86:3257-3265.Time (hours)

0 2 4 650

60

70

80

90

100

110

120

130

140

150

160

% C

hang

e In M

CP-1

*P<0.05

*

*


Plasma MMPPlasma MMP--2 and MMP2 and MMP--9 Concentrations 9 Concentrations Following Insulin or Dextrose InfusionsFollowing Insulin or Dextrose Infusions

Dandona P, Aljada A, et al. Diabetes Care. 2003;26:3310-3314.

Time (hours)0 2 4 6

% C

hang

e in M

MP-2

0

20

40

60

80

100

120

140

160

**


*P<0.05

% C

hang

e in M

MP-9

0

20

40

60

80

100

120

140

160

*P<0.05

Time (hours)0 2 4 6

* *


Plasma TF and PAIPlasma TF and PAI--1 Concentrations Following Insulin or 1 Concentrations Following Insulin or Dextrose InfusionsDextrose Infusions

Time (hours)0 2 4 6

% C

hang

e in P

lasma

TF

0

20

40

60

80

100

120

140

160

180

200

**


*P<0.05

% C

hang

e in P

lasma

PAI

-1

0

20

40

60

80

100

120

140

160

180

200

*P<0.05

Time (hours)0 2 4 6

* **


Plasma VEGF Concentrations Following Insulin or Plasma VEGF Concentrations Following Insulin or Dextrose InfusionsDextrose Infusions

% Changein VEGF

0

20

40

60

80

100

120

140

160

Time (hours)0 2 4 6

*P<0.05

* *


Dandona P, Aljada A, et al. Diabetes Care. 2003;26:3310-3314.

Toll-Like Receptors (TLRs) Family

Effect of Insulin Infusion in T2DM onTLR4 Expression

* P < 0.05 by One Way RM ANOVA # P < 0.05 by Two Way RM ANOVA

Hours0 2 4 6

% C

hang

e in

TLR

4 m

RN

A E

xpre

ssio

n

40

60

80

100

120

140 InsulinDextrose

*#

*#

Hours0 2 4 6

% C

hang

e in

TLR

2 m

RN

A E

xpre

ssio

n

60

80

100

120

140

160

InsulinDextrose

*# *

Effect of Insulin Infusion in T2DM onTLR2 Expression


GIKGIK-- MIMI-- GlucoseGlucose

Time (hours)0h 2h 4h 6h 24h 48h

Gluc

ose (

mg/dl

)

40

60

80

100

120

140

160

180

200

220

Control Insulin

GIKGIK-- MIMI-- InsulinInsulin

*p< 0.05, TWANOVA, † p<0.05, paired t-test

Insuli

n (µU

/ml)


20

40

60

80

100

*††

†

††

Control Insulin

GIKGIK-- MIMI-- Plasma CRPPlasma CRP

*p< 0.01, TWANOVA, † p< 0.05, t-testTime (hours)

0h 2h 4h 6h 24h 48h

Incre

ase i

n CRP

(ng/m

l) fro

m ba

selin

e

0

-1000

1000

2000

3000

4000

5000

6000

7000*†

†Control Baseline: 2700ng/ml Insulin Baseline: 3800ng/ml

*p< 0.01, TWANOVA, † p< 0.05, t-test

GIK GIK –– MI Serum Amyloid AMI Serum Amyloid AInc

reas

e in S

AA (n

g/ml) f

rom

base

line

0

10x103

20x103

30x103


*†

†Control Baseline : 12 x 103

Insulin Baseline: 19 x 103

*p< 0.05, TWANOVA

GIKGIK-- MIMI-- Plasma PAIPlasma PAI--11Inc

reas

e in P

AI-1

(ng/m

l) Fro

m Ba

selin

e


-10

0

10

20

*

Control Baseline: 47ng/ml Insulin Baseline: 54 ng/ml

*p< 0.05, TWANOVA, † p<0.05, t-test, ‡ p< 0.05, paired t - test

GIKGIK-- MIMI-- p47p47phoxphox SubunitSubunit

0h 2h 4h 6h 24h 48h0

200

400

600

% In

creas

e in P

47 ph

ox P

rotei

n in M

NC

Time (hours)

*

†

‡

Control Insulin

*p<0.01, Log CK, TWANOVA

GIKGIK-- MIMI-- Inferior Wall CKInferior Wall CKCK

(U/L)

Time (hours)0h 2h 4h 6h 8h 16h 24h 48h

0

500

1000

1500

2000

*

Control Insulin

*p<0.01, Log CKMB, TWANOVA

GIKGIK-- MIMI-- Inferior Wall CKMBInferior Wall CKMBCK

MB (U

/L)

Time (hours)0h 2h 4h 6h 8h 16h 24h 48h

-100

0

100

200

300

400

500

*

Control Insulin

GIKGIK-- MIMI-- Myoglobin

Time (hours)

0h 2h 4h 6h 24h 48h

Cha

nge

in M

yogl

obin

(ng/

ml)

from

bas

elin

e

-300-250-200-150-100-50

050

100150200250300350400

insulin control

*

Time (hours)

0h 2h 4h 6h 24h 48h

Free

Fat

ty A

cids

(mic

rom

ol/l)

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

control Insulin

*

GIKGIK-- MIMI-- FFA

GIK = glucose-insulin-potassium; CABG = coronary artery bypass graft.Visser L et al. Br J Anaesth. 2004;109:849-854.

Effects of Insulin Infusion Clamp on Effects of Insulin Infusion Clamp on Inflammatory Responses During CABGInflammatory Responses During CABG

*†

†

ControlGIK

250

200

150

100

50

0

CR

P (m

g/L)

Baseli

neRep

erfusio

n2-h

Rep

erfus

ionIC

U 6-8 P

MPOD1 6

-8 AM

POD1 6-8

PMPOD2 6

-8 AM

POD2 6-8

PM

Time dependence of CRP production. Data are presented as mean (SEM). *P<0.05 between groups; 2-way ANOVA for repeated measurements with Bonferroni correction; †P<0.05 between groups at separate time points. Note that at some measurement points the error bars are too small to be visible on the scale used.

Admission Glucose Dependent Mortality in the CREATE-ECLA

6.6

8.5

14.0

<126126to

144

>144

Glucose LevelsGlucose LevelsCONTROL(mg/dl)

GIK(mg/dl)

Baseline 162 162

6 hrs 145 187

24hrs 135 160

Estimated 30 day mortality versus Baseline Blood Glucose Level iEstimated 30 day mortality versus Baseline Blood Glucose Level in n

CREATECREATE--ECLAECLA

Estimated 30 Day Mortality versus Baseline Blood Glucose Level

4

5

6

7

8

9

10

11

12

13

14

15

5 5.5 6 6.5 7 7.5 8 8.5 9 9.5 10 10.5 11

Blood Glucose (mmol/L)

Mor

taili

ty (%

)

% mortality = 100 * {1 - 1.03*exp(-0.0167*BG) }

Based on JAMA 1/26/05-Vol 293, No 4, pg 443

30 day mortaility = 13.4% at BG = 187mg/dl

30 day mortaility = 10.8% at BG = 145mg/dl

Chaudhuri A et al: Targeting Glucose in AMI: Has GIK missed the target? (Diabetes Care, 2007)

Hyperglycemia related mortality inHyperglycemia related mortality in CREATE ECLA based CREATE ECLA based on relationship of admission glucose to mortality in on relationship of admission glucose to mortality in

controls.controls.

Control GIK

Time BG*(mg/dl)

% Mortality BG*(mg/dl)

% Mortality

0 162 11.4 162 11.4

6h 145 10.2 187 13.4

24h 135 9.1 160 10.8

Chaudhuri A et al: Targeting Glucose in AMI: Has GIK missed the target? (in press), 2007

Observed vs Estimated Mortality based on blood Observed vs Estimated Mortality based on blood glucose during the 24 hrs in CREATE ECLAglucose during the 24 hrs in CREATE ECLA

02468

101214

Control GIK

ObservedEstimated

9.7% 9.9% 10.0%

12.2%

Chaudhuri A et al: Targeting Glucose in AMI: Has GIK missed the target? (Diabetes Care, 2007

INTENSIVE Study: Intensive Insulin Therapy and Size of INTENSIVE Study: Intensive Insulin Therapy and Size of Infarct as a Visual Endpoint by Cardiac MRIInfarct as a Visual Endpoint by Cardiac MRI

TIMI = thrombolysis in MI; TMPG = TIMI myocardial perfusion grade; STR = ST segment recovery.

RevascularizationI

Inflammatory Markers

Intensive Insulin Therapy (n = 294) BG goal 90-130

Hour 0 Day 6096 hours

Men or Women

35-80 y/oPrimary AWMI

Glucose 140 mg/dL<6 hours of symptoms

TIMI flow, TMPG, STR

Primary Endpoint: Final Myocardial Infarct Size at Day 60 (DE- CMR)

Randomization

Standard Care (n = 294) BG goal <180

MACE : Major Adverse Coronary Events

DE-CMR = Delayed Enhancement Cardiovascular Magnetic Resonance

Time (Hours)-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26

% C

hang

e in

Pla

sma

NO

2/NO

3

60

80

100

120

140

160

180

200

LPS+ SalineLPS+Insulin

Ins/Sal

LPS

*#

*#

*#

*#

Insulin Infusion Suppresses LPS-

Induced Increase in NO2

/NO3

Concentrations



Induced Increase in ROS Generation by PMN

Tim e (H ours)-1 0 1 2 4 6 24

% C

hang

e in

RO

S G

ener

atio

n (P

MN

)

0255075

100125150175200225250275300325350375400

LPS (2ng/Kg)LPS (2ng/Kg)+ Ins



Induced Increase in Plasma TBARS

* P < 0.05 by One Way RM ANOVA # P < 0.05 by Two Way RM ANOVAT im e (H ours)

0 1 2 4 6 24

% C

hang

e in

Pla

sma

TB

AR

S

50

100

150

200

250

300

350

400L P SL P S +In s


Induced

Increase in MIF Concentrations


Time (Hours)0 1 2 4 6 24

% C

hang

e in

MIF

Con

cent

ratio

ns

60

80

100

120

140

160

180

200

220

240

260 EndotoxinEndotoxin+Insulin


Induced

Increase in Myoglobin

Concentrations

* P < 0.05 by One Way RM ANOVA # P < 0.05 by Two Way RM ANOVATime (Hours)

0 1 2 4 6 24

% C

hang

e in

Myo

glob

in C

once

ntra

tions

40

60

80

100

120

140

160

180

200

220

EndotoxinEndotoxin+Insulin


Induced

Increase in FFA Concentrations

* P < 0.05 by One Way RM ANOVA # P < 0.05 by Two Way RM ANOVATim e (H ours)

0 1 2 4 6 24

Pla

sma

FFA

(%

Ch

ange

)

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

340EndotoxinEndotoxin+Insulin

Effect of Low Dose Insulin Infusion in T2DM onAmyloid-

Precursor mRNA Expression in MNC

* P < 0.05 by One Way RM ANOVA # P < 0.05 by Two Way RM ANOVAHours

0 2 4 6

% C

hang

e in

APP

m

RN

A E

xpre

ssio

n

50

60

70

80

90

100

110

120

130

140InsulinDextroseSaline

*#

Effect of Low Dose Insulin Infusion in T2DM onIL4 mRNA Expression in MNC


Infusion time (hours)0 2 4 6

% C

hang

e in

IL-4

mR

NA

Exp

ress

ion

40

60

80

100

120

140 InsulinDextroseSaline

*#

*#

Effect of Low Dose Insulin Infusion in T2DM onADAM-33 Expression in MNC

* P < 0.05 by One Way RM ANOVA # P < 0.05 by Two Way RM ANOVAHours

0 2 4 6

% C

hang

e in

AD

AM

33 m

RN

A E

xpre

ssio

n

50

60

70

80

90

100

110

120

130


*# *


Effect of Low Dose Insulin Infusion in T2DM onCCR2 mRNA Expression in MNC

Hours0 2 4 6

% C

hang

e in

CC

R-2

mR

NA

Exp

ress

ion

40

50

60

70

80

90

100

110

120 InsulinDextrose

*# *#


Infusion time (hours)0 2 4 6

% C

hang

e in

CC

R5

mR

NA

Exp

ress

ion

40

60

80

100

120

140 InsulinDextrose

*# *#

Effect of Low Dose Insulin Infusion in T2DM onCCR5 mRNA Expression in MNC


Effect of Low Dose Insulin Infusion in T2DM onPlasma MCP-1 Concentrations

Hours0 2 4 6

% C

hang

e in

pla

sma

MC

P-1

con

cent

ratio

ns

60

70

80

90

100

110

120


*# *


Effect of Low Dose Insulin Infusion in T2DM onPlasma Eotaxin Concentrations

Hours0 2 4 6

Eota

xin

Con

cent

ratio

ns (%

Cha

nge)

70

75

80

85

90

95

100

105

110

115



Effect of Low Dose Insulin Infusion in T2DM onPlasma RANTES Concentrations

Hours0 2 4 6

Plas

ma

RA

NTE

S C

once

ntra

tions

(ng/

ml)

20

25

30

35

40



Effect of Low Dose Insulin Infusion in T2DM onPlasma MMP-9 Concentrations

Hours0 2 4 6

% C

hang

e in

MM

P-9

Plas

ma

conc

entr

atio

ns

60

70

80

90

100

110


*#

*

Hours0 2 4 6

% C

hang

e in

Pla

sma

NO

2/NO

3

40

50

60

70

80

90

100

110

120

130

140InsulinsalineDextrose

*#

Effect of Low Dose Insulin Infusion in T2DM onPlasma NO2 /NO3 Concentrations


Inflammatory Markers and Anti- Inflammatory Effects of Insulin

Documents

Transcript of Inflammatory Markers and Anti- Inflammatory Effects of Insulin