Insulina e Cuore: dalla Fisiologia alla Fisiopatologia - Giorgino Francesco... · Insulina e Cuore:...

Insulina e Cuore: dalla Fisiologia alla Fisiopatologia

FRANCESCO GIORGINO

DIPARTIMENTO DELL’EMERGENZA E DEI TRAPIANTI DI ORGANI

SEZIONE DI MEDICINA INTERNA, ENDOCRINOLOGIA, ANDROLOGIA E MALATTIE METABOLICHEDiapositiva preparata da FRANCESCO GIORGINO e ceduta alla Società Italiana di Diabetologia.

Per ricevere la versione originale si prega di scrivere a [email protected]

Disclosures

Advisory Boards: AstraZeneca/BMS; Eli Lilly; Roche Diagnostics, Takeda

Consultant: AstraZeneca/BMS; Boehringer Ingelheim; Lifescan; Merck Sharp & Dohme; Novo Nordisk; Sanofi

Research Support: AstraZeneca/BMS; Eli Lilly; Lifescan; Sanofi; Takeda

Diapositiva preparata da FRANCESCO GIORGINO e ceduta alla Società Italiana di Diabetologia.


I. Physiology



Cardiac Actions of Insulin

Iliadis et al., Diabetes Res Clin Pract, 2011



Heart Metabolism

The heart consumes about 10% of whole body energy expenditure for cardiac contraction via:

(1) the cellular uptake of free fatty acids and glucose(2) the catabolism of these substrates by beta-oxidation and glycolysis(3) the entry of the intermediary metabolites in the Krebs cycle(4) the oxidative phosphorylation by the mitochondrial respiratory chain

(Barsotti et al., 2009, Kolwicz et al., 2013).

The principal mediator of energy transformation is adenosine triphosphate (ATP) and ATP levels are essential for the uninterrupted myocardial contraction/relaxation cycle.

The human heart produces and consumes between 3.5 and 5 kg of ATP everyday to sustain pumping (Opie et al., 2004). The way to generate this energy depends on the cardiac environment including coronary flow, blood substrate supply, hormones and nutritional status (Lopaschuk et al., 2007; Stanley et al., 2005; Kodde et al., 2007; Ventura-Clapier et al., 2004).Diapositiva preparata da FRANCESCO GIORGINO e ceduta alla Società Italiana di Diabetologia.


Cardiac Metabolism under Physiological ConditionsI. During Fasting

• The heart prefers to consume long chain fatty acids (LCFAs) – fatty acid breackdown gives more energy thanglucose (e.g. oxidation of one moleculeof palmitic acid produces 129 ATP, while one molecule of glucoseproduces only 36 ATP) (Iliadis et al., 2011).

• Glucose uptake and metabolism are reduced by the increased fatty acid oxidation via the Randle cycle (red lines).

• However, free fatty acid catabolismrequires about 10% more oxygen to produce the same amount of ATP deriving from glucose breakdown (Lopaschuk et al., 2002).

Adapted from Bertrand et al., 2008



Cardiac Metabolism under Physiological ConditionsII. During Postprandial State

Adapted from Bertrand et al., 2008

• Insulin secretion stimulates: GLUT4 translocation, 6-phosphofructo-2-kinase (PFK-2) activation, LCFAs uptake.

• In contrary to glucose, the resultingincrease in intracellular LFCA concentration does not result in the increase in LCFA oxidation, but in the storage of this excess into the intracellular pool of lipids (Dyck et al., 2001).



Regulation of Protein Synthesis by InsulinInsulin

IRS-1

PI3KPDK1PKB/Akt

PIP3

PKB/Akt

TSC2

Rheb

mTOR

4E-BPI

Translation initiation

p70S6KeEF2KeEF2

Translation elongation

Ribosomal biogenesis

S6

GSK3

eIF2B



Insulin and Cardiomyocytes Hypertrophy, Atrophy and Angiogenesis

Insulin

IRS-1

PI3KPDK1PKB/Akt

PIP3

PKB/Akt

Cell growth

GSK3

NFAT

FOXO

Shc

MAPK

Cardiomyocyte hypertrophyalone might have detrimentaleffects. However insulinstimulates VEGF and thereby angiogenesis, restoring the imbalancebetween cardiac hypertrophyand blood perfusion(Walsh et al., 2006; O’Neill et al., 2005).



IRS-1

PI3KPDK1PKB/Akt

PIP3

PKB/Akt

Anti-apoptotic

Bad-BaxCaspase

Insulin and Cardiomyocyte Apoptosis and Survival

NOS

HSP90

Insulin



Insulin and Cardiac Contractility

Insulin augments myocardiac contractility by increasing:

• sarcoplasmic Ca2+ inflow via L channels (Maier et al., 1999) or reverse Na+/Ca2+ exchanger (von Lewinski et al., 2005);

• mRNA expression of both ryanodine receptor (RYR) and Ca2+ pump(SERCa2+-ATPase) of sarcoplasmic reticulum (Teshima et al., 2000);

• cardiomyocyte contraction (Iliadis et al., 2011).



Insulin and Myocardial Blood PressureInsulin has important vascular actions that lead to:• Vasodilation;• Increased blood flow;• Subsequent augmentation of glucose disposal in insulin-target tissues (Bertrand et al., 2008).

Insulin

IRS-1

PI3KPDK1PKB/Akt

PIP3

PKB/Akt

Vasodilation

eNOS

HSP90

Coronary artery endothelium

Produced nitric oxide (NO) isdiffused to vascular smoothmuscle cells (VSMCs), where itactivates soluble guanylylcyclase (sGC) and increasescGMP concentration, whichcauses VSMCs relaxation and vasodilation through Ca2+

decreases (Sundell et al., 2003). Diapositiva preparata da FRANCESCO GIORGINO e ceduta alla Società Italiana di Diabetologia.


II. Pathophysiology



Insulin Action under IschaemiaInsulin signaling and action are greatly altered under myocardial ischaemia (Hue et al., 2002).

Insulin

IRS-1

PI3KPDK1PKB/Akt

PIP3

PKB/Akt

Decrease in phosphorylation of differentdownstream proteins such as p70S6K and GSK-3

IschaemiapH↓

AMPK GLUT4

PFK-2 Glycolysis

FAT/CD36

TSC2/mTOR/p70S6Kand eEF2 pathways

Protein synthesis



Beneficial Insulin Effects During MyocardialIschaemia and Reperfusion

Reduce fatty acid levels

Increase glucose-derived ATP production

Decrease ROS production

Decrease O2 consumption

Increase the ATP production/O2 consumption ratio

Antagonize the detrimental effects of AMPK during reperfusion

Activate cellular survival

Protect from apoptosis

Exert anti-inflammatory properties (↓NFκ, ↓MCP-1, ↓ICAM-1,↓CRP, ↑IκB)

Exert anti-thrombotic properties (↓TF, ↓PAI-1)

Increase blood flow in ischemic myocardial segments




Insulin Signalling and Cardiac Hypertrophy

PI3K/Akt

Embryonic and postnatal growth

Heineke et al., 2006; McMullen et al., 2007; Proud et al., 2004; Samuelsson et al., 2006.

PI3K/AktMAPK

PKC/calcineurin/NFAT

Compensatoryhypertrophy

Chronic stimulation

Angiotensin IIMAPK

PKC/calcineurin/NFAT

Pathologicalhyperthrophy

Chronic stimulation



Diabetes-Induced Alterations in Cardiac Glucose and Fatty Acid Metabolism

Bertrand et al., 2008; Barsotti et al., 2009; Iliadis et al., 2011ACC: Acetyl-CoA carboxylaseCPT1-2:carnitine-palmitoyl-transferases

ACC Decreased glucose uptake

and oxidation. Increased LCFA uptake and

oxidation Increase in LCFA oxidation

not sufficient to prevent lipidaccumulation

Myocardial lipidaccumulation (especiallyceramides) insulin resistance



Proposed Mechanisms of Diabetic Cardiomyopathy




% F

orm

a I

Glic

ogen

o-Si

ntet

asi

30

40

20

50

10

0

Controllo Diabete

*

Basale Insulina Basale Insulina

Attività dellaGlicogeno-Sintetasi

Wang PH et al., Endocrinology, 1999



Fosforilazione Ser473

0

100

200

300

Uni

tàar

bitra

rie

#

* *

Controllo Diabete+-+-Insulina

Fosforilazione Thr308

0

150

200

50

250

100

* §

*Uni

tàar

bitra

rie

Controllo Diabete+-+-Insulina

Akt

Laviola L. et al., Diabetes, 2001



ControlloInsulinaInsulina +-

GSK-3αGSK-3β

0

100

200

300

400

500

- + - +

§

*

GSK-3α

*

§

- + - +GSK-3βDiabete

+-

Uni

tàar

bitr

arie

ControlloInsulina +-

Diabete+- 0

200

400

600

800*

*GSK-3α/βPeptide

Immunoblot anti-fosfo-GSK-3

Uni

tàar

bitr

arie

Insulina - + - +

Immunoblot anti-fosfo-GSK-3

Laviola L. et al., Diabetes, 2001



RecettoreInsulinico

TyrTyr PP

IRS-1Tyr

PI PI 3-P

SubunitàRegolatoria

SubunitàCatalitica

PI 3-Chinasi

Akt

GSK-3

Insulina

Ser473

PDK1

“PDK2”Thr308

GSGSAttiva

PP

Inattiva

Ser P

P P P

Sintesi Glicogeno

GlycogenParticle

Membrana Plasmatica

P



Bornfeldt KE & Tabas ICell Metab 2011



Effetti dell’Insulina sul Sistema VascolareProtezione

Insulina

Cellula Endoteliale

eNOS

NO↓ Aggregazione Piastrinica

↓ Proliferazione Cellulare

↓ Attivazione Macrofagi

VasodilatazioneDiapositiva preparata da FRANCESCO GIORGINO e ceduta alla Società Italiana di Diabetologia.


Effetti dell’Insulina sul Sistema VascolarePotenziale Danno

Insulina

Cellula Muscolare LisciaCellula Endoteliale

↑ Produzione PAI-1↑ Produzione ET-1

↑ Proliferazione CellulareDiapositiva preparata da FRANCESCO GIORGINO e ceduta alla Società Italiana di Diabetologia.


Insulin Receptor

PYPYPYPYPYPY

Shc

MAP Kinase

Grb-2SOS

PI 3-KinaseIRS Proteinsp85p110

Grb-2SOS

eNOS Expression

NO Production

Insulin

Jiang et al, J Clin Invest, 1999

Impaired Vasodilation Normal MitogenesisDiapositiva preparata da FRANCESCO GIORGINO e ceduta alla Società Italiana di Diabetologia.


Insulin Receptor

Selective Insulin Resistance

in T2DMPYPYPYPYPYPY

Insulin

Impaired Glucose Utilization

PI 3-K / Akt

IRS

GLUT4

Glucose Transport

Skeletal Muscle

eNOS

NO Release

Endothelial Dysfunction

SHC

MAP Kinase

PAI-1, ET-1 Secretion

EC / VSMC



Bornfeldt KE & Tabas ICell Metab 2011



Endothelial dysfunction predicts CV events• Hypertensive patients: Perticone F et al, Circulation 104: 191-196, 2001

• CHD patients: Heitzer T et al, Circulation 104: 2673-2678, 2001

Insulin therapy improves endothelial function• Vehkavaara S et al, Arterioscler Thromb Vasc Biol

20: 545-550, 2000• Rask-Madsen C et al, Diabetes 50: 2611, 2001• Gaenzer H et al, Am J Cardiol 15: 431, 2002• Vehkavaara S et al, Arterioscler Thromb Vasc Biol

24: 325-30, 2004

eNOS

ACh

M

Ca 2+

NADPHNO

cGMPGTP

guanylatecyclase

Endothelialcell

Vascular smooth muscle cellDiapositiva preparata da FRANCESCO GIORGINO e ceduta alla Società Italiana di Diabetologia.


‘‘Insulin resistance’’ can mean either defective insulin receptor signaling or overstimulation of insulin receptor pathways caused by hyperinsulinemia.

Relative importance of insulin resistance vs. hyperglycemia.

Systemic risk factors induced by these syndromes vs. direct processes acting at the level of the arterial wall.

Early-to-mid-stage atherogenesis (subendothelial retention of apoB-containing lipoproteins; EC activation; recruitment of monocytes and other inflammatory cells; cholesterol loading of lesional

cells; and VSMC migration to intima) distinct from advanced plaque progression (plaque

necrosis and thinning of a collagenous ‘‘scar’’ overlying the lesion called the fibrous cap).Diapositiva preparata da FRANCESCO GIORGINO e ceduta alla Società Italiana di Diabetologia.


EIRAKO mice (EC-specific IR ko, apoE-/- background) reduced levels of eNOS and endothelin-1 mRNA in ECs and aorta

(Vicent et al., JCI 2003). increased atherosclerosis, decreased eNOS activity, increased VCAM-

1 expression and leukocyte adhesion (Rask-Madsen et al., Cell Metab2010).

Akt1-/, apoE-/- mice increase in aortic atherosclerosis; very large coronary arterial lesions;

increased lesional inflammatory cytokines and decreased p-S1176-eNOS (Fernandez-Hernando C et al., Cell Metab 2006).

IGF-I R masks the antiinflammatory capacity of insulin in VSMCs(Engberding N et al., ATVB 2009)



Macrophage IR ko, apoE-/- background Protection from atherosclerosis (Tabas I et al., Circ Res 2010).

Macrophage IR or IRS-2 ko, apoE-/- background Protection from atherosclerosis (Baumgartl J et al., Cell Metab 2006).

IR KO bone marrow into C57BL6 Ldlr-/- mice fed Western diet Increased apoptosis of macrophages in advanced lesions increased plaque necrosis and potential for rupture (Han S et al., Cell Metab 2006).



0 3 10 0 7.5 10SNP (µg/min) ACh (µg/min)

Normal subjectsT2 DM before insulin glargine TxT2 DM after insulin glargine Tx

Vehkavaara S et al, ATVB, 2004

Forearm Blood Flow Responsesto Intra-Arterial SNP and ACh

in Type 2 Diabetic Patients

Bloo

d flow

(m

l/dl x

min)

0

5

10

15

After 3.5 yrs

0

5

10

15

Bloo

d flow

(m

l/dl x

min)

After 6 m

Bloo

d flow

(m

l/dl x

min)

0

5

10

15

Baseline



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