Cardiovascular Consequences of Insulin Resistance

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Cardiovascular Consequences of Insulin Resistance

Cardiovascular Consequences of Insulin

Resistance

E. Dale Abel MD, Ph.D., University of Utah

No Disclosures

dale.abel@hmbg.utah.edu


Outline

• Review the Epidemiology of Cardiovascular

Disease in Obesity and Diabetes

• Review Mechanisms that may Increase Heart

Failure Risk in Diabetes

• Experimental Evidence Linking

Hyperinsulinemia with Adverse Cardiovascular

Outcomes

• Discuss the Implications of these Observations

on Therapeutic Strategies in Type 2 Diabetes

Based Upon Tight Metabolic Control


Age-adjusted Percentage of U.S. Adults Who Were Obese

or Who Had Diagnosed Diabetes

Obesity (BMI ≥30 kg/m 2 )

1994

2000

2009

No Data 26.0%

Diabetes

1994

2000

2009

No Data 9.0%

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System

available at http://www.cdc.gov/diabetes/statistics


An Evolutionary Biologists View of the

Type 2 Diabetes and Obesity Epidemic

Dec 11 th , 2003

The Economist


Looking to the Future

Wall- e


Percentage with Diabetes

Number with Diabetes (Millions)

Number and Percentage of U.S. Population with Diagnosed Diabetes,

1958-2009

8

25

7

6

Percentage with Diabetes

Number with Diabetes

20

5

15

4

3

10

2

5

1

0

1958 61 64 67 70 73 76 79 82 85 88 91 94 97 00 03 06 09

Year

0

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System

available at http://www.cdc.gov/diabetes/statistics


Cardiovascular Disease the Leading

Cause of Mortality in Diabetes


Diabetes and Post-MI

Survival in Two Ethnic Groups


Insulin Resistance and Pre-Diabetes

That affects 79 Million Americans Also

Potently Increases the Risk of CVD


IRAS: Number of CVD Risk Factors and

Conversion to Type 2 Diabetes


Insulin Resistance a Characteristic of Type 2 Diabetes

Insulin

Fatty Acids

Glucose


The NeoClassical View of Insulin

Resistance in the Pathogenesis of

Diabetes

The Deadly Octet

Defronzo RA, Diabetes 2009


Cardiovascular targets and actions of insulin

Copyright ©2007 The Endocrine Society Muniyappa, R. et al. Endocr Rev 2007;28:463-491


Insulin Resistance Increases

the Risk for Cardiovascular

Disease and is Associated

with More Adverse

Consequences


Obesity and the risk of heart failure. Kenechiah et al, NEJM 2002;347:305

Based on BMI

at time of

enrollment.

Mean age at

enrollment was

53 years.

Of the patients

who had an

echo near the

time of CHF dx,

most had a

reduced EF.

Obese

Overweight

Normal


Diabetes and Heart Failure:

Current Knowledge


Glycemic Control and Risk of

Development of HF in Diabetes


Heart Failure Is More Common

in Patients With Type 2

Diabetes


Extrinsic

Hyperlipidemia

Increased coronary atherosclerosis

Ischemic heart disease

Volume expansion

Increased Cardiac output

Hypertension

Sleep disordered breathing

Sympathetic activation

Activation of the renin angiotensin system

Increased vascular tone

Decreased NO availability

Insulin Resistance/Hyperinsulinemia

Impaired glucose tolerance/diabetes

Increased triglycerides

Increased FFA

Hypoadiponectinemia

Intrinsic

Altered substrate

metabolism

- Increased FA oxidation

- Decreased glucose

utilization

- Reduced cardiac

efficiency

Oxidative stress

Mitochondrial dysfunction

Apoptosis

Lipotoxicity

Altered Ca 2+ dynamics

Inflammation

Fibrosis

Mechanisms Contributing to Cardiac Dysfunction in Obesity and Diabetes

Abel ED JACC, 2011


Metabolic Signatures of

Diabetic Cardiomyopathy


Substrate Metabolism in the Hearts of ob/ob

and db/db Mice at 8-10 weeks of age

Perfusion conditions: 11mM Glucose, 1mM Palmitate, 1nM Insulin

Mazumder et al.,Diabetes, 2004; Buchanan et al. Endocrinology, 2005


Cardiac Performance and Myocardial Oxygen

Consumption in the Hearts of ob/ob and db/db

Mice at 8-10 weeks of age

Perfusion conditions: 11mM Glucose, 1mM Palmitate, 1nM Insulin

Mazumder et al.,Diabetes, 2004; Buchanan et al. Endocrinology, 2005


Contribution of

Mitochondria to Altered

Energy Metabolism and

Impaired Cardiac

Efficiency in Diabetes


Mechanisms for Myocardial Mitochondrial Dysfunction in Diabetes

Proposed mechanisms:

- Fatty acid-induced mitochondrial uncoupling

- Mitochondrial ROS production

- Mitochondrial proteomic remodeling

- Impaired mitochondrial Ca 2+ -handling

- Altered mitochondrial biogenesis

Diabetes

Mitochondrial dysfunction

Contractile dysfunction

??

??

Hypothetical/underexplored mechanisms:

-Impaired mitochondrial dynamics

-Autophagy

- Mitochondrial O-GlcNAcylation

- Role of mitochondrial subpopulations

- Mitochondrial permeability transition

Bugger H, Abel ED Cardiovascular Res. 2010


FAO

Delivery of Reducing Equivalents

OXPHOS

ROS


Mitochondrial

Dysfunction in Human

Diabetic Cardiomyopathy


Decreased Mitochondrial Function Correlates with Worsening Diabetes

Anderson E, JACC. 2009;54:1891-1898.


ROS Generation is Increased in Mitochondria

from Diabetic Atria

Anderson E, JACC. 2009;54:1891-1898.


Evidence for Increased Oxidative Stress in Diabetic

Atrial Tissue

Anderson E, JACC. 2009;54:1891-1898.


Insulin Resistance and

Diabetic Cardiomyopathy


Insulin Resistance a Characteristic of Type 2 Diabetes

Insulin

Fatty Acids

Glucose


Does Insulin Resistance Exist

in the Heart?


Insulin Signaling

Glucose

Insulin

receptor

PI 3-kinase

IRSs

P

P

Shc

ATP

Grb2 Sos

Ras

Raf

Glucose

Transport

Glucose

Oxidation

GLUT4

vesicle

?

FA Oxidation

PKC

Akt/PKB

Glycogen

synthesis

mTOR

GSK3

Cell

growth

p70S6K

Protein

synthesis

MEK

MAPK

p90rsk MNK1

Gene

expression


Animal Models of Type II Diabetes

The Jackson

Laboratory

4 or 8 week-old male db/db

(C57BL/KsJ-db/db) mice

& homozygous normal

lean (C57BL/KsJ) litter

mates

4 or 8 week-old male ob/ob

(C57BL/J6-ob/ob) mice &

homozygous normal lean

(C57BL/J6) litter mates


Insulin-Stimulated Activation of Akt is

Impaired in ob/ob mouse hearts

Wildtype

ob/ob

p-Akt

t-Akt

Insulin: - + - + - + - +

Mazumder et al.,Diabetes, 2004


Impaired Glucose Uptake

Mazumder et al.,Diabetes, 2004


Genetic Mouse Models of

Insulin Resistance


Insulin and IGF-1 Signaling to Mitochondria

IGF-1

receptor

Insulin

receptor

P

P

ATP

P

IRS1/2

IRS1/2

P

ATP

PI 3-kinase

Increased Mitochondrial Function in

Response to Physiological Cardiac

Hypertrophy by regulating the increase in

PGC-1

Boudina et al, Circulation, 2009

Sena et al, JMCC, 2009

Belke et al, JCI, 2002

Kim et al, Mol Endo 2008

Maintenance of Basal Mitochondrial

Function

Regulation of TCA and FAO protein content

Regulates PPAR and SIRT1 expression

Regulation of Electron Transport Chain

Stoichiometry

KO increases mitochondrial ROS


Complete Loss of Insulin Signaling

Accelerates LV Remodeling

IGF-1

receptor

Insulin

receptor

ATP

IRS1/2

Combined KO of Insulin and IGF1

Receptors Leads to Accelerated Heart

failure

P

P

PI 3-kinase

IRS1/2

P

P

ATP

KO of IRS1/2 Leads to Accelerated

heart failure and increased autophagy

Hu et al, AJP, 2003

McQueen et al, JMCC, 2005

Lautsen et al, MCB, 2007

Sena et al, JMCC, 2009

IR KO increases LV remodeling following

TAC or Isoproterenol-induced LVH

or following Coronary artery ligation


The Story is More Nuanced


Short -Term High Fat Feeding

and Myocardial Insulin

Resistance


Metabolic Consequence of 2-

Weeks of High Fat Feeding

Normal

Chow

HFD

Fasting Insulin

(ng/ml)

0.15±0.03 0.27±0.05*

Triglycerides (mg/dl) 15.0±1.6 16.4±2.2

Free Fatty Acids

(nM)

0.40±0.04 0.41±0.04

Wright JJ et al, Cardiovascular Res. 82:351-60, 2009


Short Term High Fat Feeding Increases Myocardial Fatty

Acid Utilization and Increased Oxygen Consumption

Wright JJ et al, Cardiovascular Res. 82:351-60, 2009


Short Term High Fat Feeding Reduces Myocardial

Glucose Utilization

Wright JJ et al, Cardiovascular Res. 82:351-60, 2009


Short Term High Fat Feeding Impairs Myocardial

Glucose Uptake

Wright JJ et al, Cardiovascular Res. 82:351-60, 2009


But Insulin Signaling is Normal

Wright JJ et al, Cardiovascular Res. 82:351-60, 2009


Impaired Glucose Uptake is Secondary to Impaired

GLUT4 Translocation

Wright JJ et al, Cardiovascular Res. 82:351-60, 2009


Insulin-induced Re-organization of

GLUT4 is Impaired by 2-weeks High Fat Feeding

Ariel Contreras and Adam Wende

n = 4, ** P < 0.01, ## P < 0.05


Generalized Insulin

Resistance Leads to Selective

Insulin Resistance” in the

Heart.

Decreased Insulin Mediated

Glucose Uptake, but with

Intact Proximal Signaling to

Akt and AS160


Decreased Insulin-Mediated Myocardial Glucose

Uptake in Type 2 Diabetes Heart

Iozzo et al, Diabetologia, 45: 1404-1409, 2002


Insulin Signaling in Diabetic

Human Hearts


Comparison of Insulin Signaling in Cardiac and Skeletal

Muscle in Diabetes and Heart Failure

Cook SA et al, Eur Heart J. 31:100-111, 2010


Evidence for Whole Body and Myocardial Insulin Resistance

Cook SA et al, Eur Heart J. 31:100-111, 2010


Proximal Insulin Signaling In Skeletal Muscle is Impaired

Cook SA et al, Eur Heart J. 31:100-111, 2010


Proximal Insulin Signaling In Cardiac Muscle is Increased

Cook SA et al, Eur Heart J. 31:100-111, 2010


Plasma Membrane GLUT4 In Cardiac Muscle is Decreased

Cook SA et al, Eur Heart J. 31:100-111, 2010


WORKING MODEL OF THE METABOLIC CONSEQUENCES OF INSULIN

RESISTANCE IN THE HEART

Increased PM CD36

Hyperinsulinemia

IR

PM Glucose Transporters

Impaired GLUT4

Translocation is Akt

Independent

Increased

TAG Pool

FA- Acyl-CoA

Akt-p

Glycolysis

PPAR- Signaling

Mitochondrion

+

MVO 2

FAO

ROS

Pyruvate

GO

Oxidative damage

H +

ADP

I II

III IV

H + H + H +

H + H +

F 0 F 1 -ATPase

+

+

UCP

ANT

ATP

Cardiomyocyte


Can Hyperinsulinemia be

Driving Some of the Cardiac

Pathologies in Diabetic

Cardiomyopathy?


Transverse Aortic Constriction or Myocyte Stretch

is Associated with Activation of Insulin Signaling

Shimizu I et al, JCI; 120:1506, 2010


Transverse Aortic Constriction Induces Insulin

Generalized Resistance

Shimizu I et al, JCI; 120:1506, 2010


Will Reducing Insulin

Signaling Ameliorate LV

Dysfunction Following TAC?


Heterozygous Reduction of IR Expression

Ameliorates LV Dysfunction following TAC

Shimizu I et al, JCI; 120:1506, 2010


Heterozygous Reduction of IR Expression Ameliorates

Cardiomyocyte Hypertrophy and Tissue Hypoxia

Shimizu I et al, JCI; 120:1506, 2010


Collectively These Data

Suggest that Hyperinsulinemia

May Drive Proximal Signaling

Events That Adversely Impact

Left Ventricular Contractile

Function Particularly in the

Context of Cardiac

Hypertrophy


Intensive Management Does Not Reduce Risk of

Incident Heart Failure

Castagno D et al, Source: American Heart Journal 2011; 162:938-948.e2 (DOI:10.1016/j.ahj.2011.07.030 )


Type 2 Diabetes Therapy

and Cardiovascular Events:

Comparing VADT With Other Trials


Does Tight Metabolic Control

Matter?


YES!

• Reduces Retinopathy

• Reduces Nephropathy

• Reduces Neuropathy

• May Reduce Mortality in Hospitalized

Patients


But Reducing Macrovascular

Complications and Heart

Failure Remains a Challenge


Steno-2: Percentage of Patients at Treatment

Goals at End of Study


Steno-2: Effect of Multifactorial Intervention on

Mortality in

Type 2 Diabetes


Steno-2: Effect of Multifactorial Intervention on

Diabetic Complications


Steno-2: Effect of Multifactorial Intervention on

Various CV Events in

Type 2 Diabetes


UKPDS Results: Tight BP Control


Reduction of CVD Morbidity and

Mortality Remains a Critical Goal in

Managing Subjects with Type 2

Diabetes. Management Goals Must

Involve a Multipronged Reduction of

Multiple Risk Factors. Future Studies

are Required to Determine if Reduction

of Hyperinsulinemia will Lead to

Greater Reductions in Adverse

Cardiovascular Outcomes


The Lab Summer 2011

Jordan Wright - MD PhD Student - University of Michigan


Acknowledgements

•Ichiro Shiojima, Issei Komuro – University of Osaka

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