“ Angiotensin -Insulin Cross Talk” Implications For Insulin Resistance

Sharma Prabhakar MD MBA FACP Sharma Prabhakar MD MBA FACP FASNFASN

Professor and Chief, Nephrology Professor and Chief, Nephrology DivisionDivision

Texas Tech University Health Texas Tech University Health Sciences Center Sciences Center

““Angiotensin-Insulin Angiotensin-Insulin Cross Talk”Cross Talk”

Implications For Insulin Implications For Insulin ResistanceResistance

A True Story A True Story From Bedside to the From Bedside to the

BenchBench

Insulin ResistanceInsulin Resistance Type II diabetesType II diabetes Metabolic syndrome (Obesity, Metabolic syndrome (Obesity,

hyperlipidemia, hypertension, proteinuria)hyperlipidemia, hypertension, proteinuria) Essential hypertension is also an Essential hypertension is also an

insulin resistant state in most patients.insulin resistant state in most patients. RAAS and Angiotensin II is activated in all RAAS and Angiotensin II is activated in all

these states these states Evidence of cross talk at several steps Evidence of cross talk at several steps

between signaling pathways that mediate between signaling pathways that mediate AII and Insulin actions.AII and Insulin actions.

tyrosine phosphorylation

(pY)

(Ser/Thr)1

2

3

45

Angiotensin II Signaling Pathways

The Role of Angiotensin II in The Role of Angiotensin II in Endothelial Dysfunction and AtherosclerosisEndothelial Dysfunction and Atherosclerosis

NADH = nicotinamide adenine dinucleotide; EC = endothelial cell.

Interference With Endothelium-Dependent Vasodilation

Activation of NADHOxidase in EC O2

Generation

OO22

NO

Accumulation of Lipids in Plaques

EC Injury

LOX-1 Receptors LDL Oxidation and Uptake by Macrophages

Angiotensin II

O2Oxidized LDL

Uptake of Oxidized LDL

Formation of Foam Cells

GFRProteinuriaAldosterone releaseGlomerular sclerosis

A II

Atherosclerosis*VasoconstrictionVascular hypertrophyEndothelial dysfunction

LV hypertrophyFibrosisRemodelingApoptosis

Stroke

Death

*Preclinical data.LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate.

Hypertension

Heart FailureMI

Renal Failure

Angiotensin II Plays a Central Role in Organ Damage

Adapted from Willenheimer R et al. Eur Heart J . 1999;20:997–1008; Dahlöf B. J Hum Hypertens. 1995;9(suppl 5):S37–S44; Daugherty A et al. J Clin Invest. 2000;105:1605–1612; Fyhrquist F et al. J Hum Hypertens. 1995;9(suppl 5):S19–S24;Booz GW, Baker KM. Heart Fail Rev. 1998;3:125–130; Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy.17th ed. Whitehouse Station, NJ: Merck Research Laboratories. 1999:1682–1704; Anderson S. Exp Nephrol . 1996;4(suppl 1):34–40;Fogo AB. Am J Kidney Dis. 2000;35:179–188.

ACE Inhibition Versus AT1 ACE Inhibition Versus AT1 Blockade Blockade

in the Renin-Angiotensin Systemin the Renin-Angiotensin System

Kallikrein

Kininogen Angiotensinogen

Renin

Bradykinin Angiotensin I

Inactive Peptides Angiotensin II

ACE

↓ Blood Pressure↓ Vascular Proliferation↓ Oxidative Stress↓ Vascular Inflammation↓ Thrombogenesis

NitricOxide

ACE Inhibitors

ARBs

ARB

AT1

Adapted with permission from Brown NJ, et al. Circulation. 1998;97:1411-1420.

ACE-I

ARB

Inhibitors of RAS and Inhibitors of RAS and antidiabetic effectsantidiabetic effectsStudy Patient

sSamp

le Duration (yrs)

Drugs Results

UKPDS (1998)

HT+T2DM 1,148 9 Captopril vs. atenolol

captopril lowered mean HbA1c (7.0 ± 1.4 vs.7.5 ± 1.4%, p = 0.0044)

CAPP (1999)

HT 10,935

6 Captopril v. conventional Rx

Incidence of new onset diabetes was lower in captopril group (RR 0.86, p = 0.039)

HOPE (2000)

High risk for CVD

9,297 4.5 Ramipril vs. placebo

Fewer patients in the ramipril group had NODM

ALLHAT (2002)

HT + I RF for CVD

33,397

4.9 Lisinopril vs.chlorthalidone vs.amlodipine

NODM at 4 yrs was lower in lisinopril group (8.1 vs. 11.6%, p< 0.001). It was 9.8% in amlodipine group

LIFE (2002)

Ess HT +LVH

9,193 4 Losartan vs. atenolol

NODM lower in losartan group 6 vs. 8 % ( RR0.75, P<0.001

CHARM (2003)

CHF 7,599 3.2 Candesartan vs. placebo

NODM less in cadesartan (6% vs. 7.5%) p<0.02

VALUE (2004)

HT +high risk for CVD

15,245

4.2 Valsartan vs. amlodipine

NODM less in valsartan (13 vs 16%) RR 0.77, p <0.0001)

ASCOT-BPLA (2005)

HT+3 CV risk factors

19,257

5.4 Amlodipine+perindopril vs. atenolol +thiazides

NODM less common in Aml+peri group RR 0.68 , p<0.0001)

RAAS inhibition and RAAS inhibition and antidiabetic effectsantidiabetic effects

Meta-analysis of 10 RCT in 75, 950 pts Meta-analysis of 10 RCT in 75, 950 pts with HT or CHF showed a 22% risk with HT or CHF showed a 22% risk reduction of NODM with ACEi/ARB reduction of NODM with ACEi/ARB therapy after a mean follow up of 4.5 yrstherapy after a mean follow up of 4.5 yrs

(Sheen AJ Diab Metab 2004)(Sheen AJ Diab Metab 2004)

Glycemic indices in diabetic pts were Glycemic indices in diabetic pts were much better in pts treated with ACEi/ARB much better in pts treated with ACEi/ARB vs other anti HTN therapies vs other anti HTN therapies -Pollare et al -Pollare et al NEJM 1989, NEJM 1989,

-UKPDS study, BMJ 1998-UKPDS study, BMJ 1998 --Velasquez MT et al Metabolism 1998Velasquez MT et al Metabolism 1998

Karin et al J Hypertension 2006

NAVIGATOR STUDYNAVIGATOR STUDY

Examine if drugs inhibiting RAS would Examine if drugs inhibiting RAS would reduce the risk of diabetes and reduce the risk of diabetes and cardiovascular events in patients with cardiovascular events in patients with impaired glucose tolerance (IGT).impaired glucose tolerance (IGT).

Double blind randomized 2x2 factorial Double blind randomized 2x2 factorial designdesign

9306 subjects with IGT with CV disease or 9306 subjects with IGT with CV disease or risk factors randomized to receive risk factors randomized to receive valsartan or placebo valsartan or placebo

Median follow up 5 yearsMedian follow up 5 yearsN Engl J Med 2010;362:1477-90.


ResultsResults

Cumulative incidence of Cumulative incidence of development of diabetesdevelopment of diabetes

33.1 % ( valsartan group) vs 36.8% 33.1 % ( valsartan group) vs 36.8% (placebo)(placebo)

HR 0.86, p<0.001HR 0.86, p<0.001

Cardiovascular outcomes Cardiovascular outcomes

14.4% vs. 14.8% HR = 0.96 p=0.4314.4% vs. 14.8% HR = 0.96 p=0.43

N Engl J Med 2010;362:1477-90.


ConclusionsConclusions

Among patients with impaired Among patients with impaired glucose tolerance and cardiovascular glucose tolerance and cardiovascular disease or risk factors, the use of disease or risk factors, the use of valsartan for 5 years, along with valsartan for 5 years, along with lifestyle modification, led to a relative lifestyle modification, led to a relative reduction of 14% in the incidence of reduction of 14% in the incidence of diabetes but did not reduce the rate diabetes but did not reduce the rate of cardiovascular events.of cardiovascular events.

N Engl J Med 2010;362:1477-90.

ZSF ratZSF rat

Obese ZDFxSHHF-fa/faObese ZDFxSHHF-fa/facpcp model was model was developed by crossing lean female Zucker developed by crossing lean female Zucker Diabetic Fatty (ZDF ./fa) and lean male Diabetic Fatty (ZDF ./fa) and lean male Spontaneously Hypertensive Heart Failure Spontaneously Hypertensive Heart Failure (SHHF/Mcc-facp, ./fa) rats.(SHHF/Mcc-facp, ./fa) rats.

Phenotypically normal until 8 weeksPhenotypically normal until 8 weeks Develops progressive obesity, hyperglycemia Develops progressive obesity, hyperglycemia

and hypertension after 8 weeks. Other and hypertension after 8 weeks. Other features are nephropathy, heart failure and features are nephropathy, heart failure and hyperlipidemia.hyperlipidemia.

ZSF1 (8 wks) ZSF1 (20 wks)

Body wt (g) 365±35 695±47*

Systolic BP (mm/Hg) 132±19 176±23*

Diastolic BP (mm/Hg) 88±8 103±11*

Plasma glucose (mg/dL) 126±12 196±22*

Serum creatinine (mg/dl) 0.77±0.19 1.47±0.25*‡

Creatinine Clearance (L/kg/day) 5.72±0.19 1.87±0.43‡

Proteinuria (mg/kg/day) 139±39 534±54* (80% albumin)

Urinary 8-OHdG (ng/day/kg) 746±110 5322±336‡

Total Cholesterol (mg/dL) 276±87 525±121*

Triglycerides (mg/dL) 369±62 1956±254‡

Tubular casts (0-4) 0 3+*

Tubular dilation/ atrophy(0-4) 0 4+*

Glomerular sclerosis(0-4) 0 1+

Arteriolar sclerosis(0-4) 0 4+*

Table 1. Characteristics of ZSF1 rats at 8 Table 1. Characteristics of ZSF1 rats at 8 weeks and 20 weeks.weeks and 20 weeks.

N=12 in each group, * P<0.01 vs. 8 wks ZSF1-8 wk rats, ‡ P<0.001 vs. ZSF1 -8 wk rats

RAAS RAAS inhibition and glycemic inhibition and glycemic control in ZSF rats control in ZSF rats

Syst/DiastSyst/Diast

BP (mm/Hg)BP (mm/Hg)PlasmaPlasma

Glucose Glucose mg/dlmg/dl

HemoglHemoglobin Aobin A1C1C %%

ZSF (8 ZSF (8 wks)wks)

ControlControl

132±99/88±8132±99/88±8 126±12126±12 5.9±1.15.9±1.1


176±23*/176±23*/103±11*103±11*

196±22*196±22* 10.9±2.10.9±2.1*1*


LosartanLosartan

151±11*/151±11*/91±9*91±9*‡‡

154±19*154±19*‡‡ 8.9±1.68.9±1.6‡‡

**

* P<0.01 vs. control ‡ P<0.05 vs. ZSF 20 wks, ‡ P<0.05 vs. ZSF 20 wks,

Effects of losartan therapy on (Effects of losartan therapy on (33H)-2-Deoxy-D-H)-2-Deoxy-D-

glucose uptake by of ZSFglucose uptake by of ZSF1 1 ratrat myoocytesmyoocytes

(3H

)-2

-de

oxy-D

-glu

co

se

up

take

(d

pm

/ g p

rote

in )

0

5

10

15

20

1. C – 30 min

2. L- 30 min

3. C-60 min

4. L-60 min

5. C-90 min

6. L-90 min

7. C.120 min

8. L-120 min

* P<0.05 vs. C. n=6 in both groups

Prabhakar et al JASN 2003 ( abstract)

Effects of angiotensin blockade on insulin secretion in pancreatic cells

Ins

uli

n l

eve

l (n

g /

ml)

0

5

10

15

20

25

30

**

1 Control 2 Captopril 3 Losartan4 Captopril + L=NMMA 5. Losartan + L-NMMA

1 2 3 4 5

* P<0.01 vs. control, n=6 in all grops


Proposed molecular mechanisms of Ang II–induced insulin resistance.

Ser307 phosphorylation inhibitsthe binding of IRS-1 to the

insulin receptor and triggersIRS-1 degradation.

phosphorylation of Ser612 and Ser302 are involved in dissociation of IRS-1 from

the p85 subunit of PI3-K

26S proteasome degradative pathway

Prolonged loss of IRS 1 protein

IRS-1 Phospho-tyrosine IRS-1 Phospho-tyrosine expression in ZSF rat expression in ZSF rat

musclemuscle

Phospho-tyrosine

- Actin

1 2 3 4

1. Obese ZSF 2. Lean ZSF 3. Obese +losartan 4. Positive control


IRS-1 Phospho-serine IRS-1 Phospho-serine expression in ZSF rat expression in ZSF rat

musclemuscle

Phospho-serine

- Actin

1. Lean ZSF 2. Obese ZSF 3. Obese +losartan 4. Positive control

1 2 3 4



Pla

sm

a A

dip

on

ec

tin

le

vel

( g

/ml)

0

2

4

6

#

Characteristics of ZSF rats at 12th week

Lean Obese Obese +Losartan

# P<0.05 vs. lean, N=4 in each group


1.Obese 2. lean 3. Obese 4. + control

+ losartan

Expression of AdipoR2 expression in ZSF rat liver

AdipoR2

*

*P,0.01 vs. lean† P<0.05 vs. lean

†

Inte

nsi

ty (

rela

tive

to l

ean

at

Inte

nsi

ty (

rela

tive

to l

ean

at

sam

e a

ge

sam

e a

ge ))


Lean

Lean

Lean

Lean

Obe

sO

bes

ee

Obe

sO

bes

eeO

bese

Obe

se

+

+

losa

rta

losa

rta

nn

8 8 weeksweeks

12 weeks12 weeks

P-AMPK P-AMPK

IP – IP – AMPKAMPK

Lean

Lean

Lean

Lean

Obe

sO

bes

ee

Obe

sO

bes

eeO

bese

Obe

se

+

+

losa

rta

losa

rta

nnSood et al JASN 20038( abstract)

SUMMARYSUMMARY

Angiotensin inhibition improves Angiotensin inhibition improves insulin resistance by multiple insulin resistance by multiple mechanisms which includemechanisms which include Increased insulin secretion from Increased insulin secretion from

pancreatic isletspancreatic islets Increased IRS tyr phosphorylationIncreased IRS tyr phosphorylation Increased adiponectin receptor Increased adiponectin receptor

signaling signaling Increased AMPK activityIncreased AMPK activity

ANGIOTENSIN INHIBITION

Ser phosphorylation

Tyr phosphorylation

X

Increased secretion

Questions to ponder onQuestions to ponder on

Is the therapeutic benefit of RAAS Is the therapeutic benefit of RAAS inhibition (HTN control, target organ inhibition (HTN control, target organ damage, cardiorenal protection etc) damage, cardiorenal protection etc) partly due to antidiabetic effects?partly due to antidiabetic effects?

Is RAAS activation the basis of systemic Is RAAS activation the basis of systemic hypertension in most patients - even salt hypertension in most patients - even salt retention?retention?

Does HTN and DM represent two clinical Does HTN and DM represent two clinical expressions of RAAS activation ? expressions of RAAS activation ?

Story to be continued…..Story to be continued…..

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“ Angiotensin -Insulin Cross Talk” Implications For Insulin Resistance