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.
NAVIGATOR STUDYNAVIGATOR STUDY
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.
NAVIGATOR STUDYNAVIGATOR STUDY
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
ZSF (20 ZSF (20 wks)wks)
176±23*/176±23*/103±11*103±11*
196±22*196±22* 10.9±2.10.9±2.1*1*
ZSF (20 ZSF (20 wks)wks)
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
Prabhakar et al JASN 2003 ( abstract)
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
Prabhakar et al JASN 2007 ( abstract)
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
Prabhakar et al JASN 2007 ( abstract)
Prabhakar et al JASN 2007 ( abstract)
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
Prabhakar et al JASN 2008 ( abstract)
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 ))
Prabhakar et al JASN 2008 ( abstract)
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…..