ppar - whats next

8/7/2019 PPAR - Whats Next

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A Constellation ofComplications

GastropathyGastropathy

AutonomicAutonomicNeuropathyNeuropathy

RenalRenal

DiseaseDiseasePeripheralPeripheral

NeuropathyNeuropathy

Retinopathy/Retinopathy/

MacularMacular

EdemaEdema

HypertensionHypertensionCardiovascularCardiovascular

DiseaseDisease

DyslipidemiaDyslipidemia

PeripheralPeripheral

VascularVascular

DiseaseDisease

ErectileErectile

DysfunctionDysfunction

DiabetesDiabetes


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NormalNormal -cell-cellfunctionfunction

CompensatoryCompensatory

hyperinsulinemiahyperinsulinemia

NormoglycemiaNormoglycemia

Relative insulin deficiencyRelative insulin deficiency

HyperglycemiaHyperglycemia

Type 2 diabetesType 2 diabetes

AbnormalAbnormal -cell-cellfunctionfunction

Diabetes: Dual ImpairmentInsulin Resistance and Impaired b-Cell Function

InsulinInsulin

resistanceresistance


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Insulin Resistance Genetic

Acquired Central obesity

Medications

In 80-90% of type 2 patients

Clusters with metabolic disease syndrome

Associated with increased macrovascular

disease


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IncreasedVisceral Fat

InsulinResistance

EndothelialDysfunction

Modified from Caballero AE. Current Diabetes Reports 2004; 4:237- 246

l Fat, Insulin Resistance and Endothelial Dysf

Cytokines,SubstratesHormones

HyperglycemiaHypertensionDyslipidemia

IL1, IL6, TNF- ,FFA,, PAI-1, RAS,leptin, resistin

Adiponectin

GenesGenes

GeneGeness


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GLITAZONES

PANCREO PROTECTIVE

CARDIO PROTECTIVE

VASCULO PROTECTIVE Macro vascular

Micro vascular

FEW SIDE EFECTS

FIRST LINE ANTI DIABETIC

FIRST LINE ANTI- IGT DRUG


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BETA-CELL PROTECTION

TZDs improve IR, -cell function,increase pancreatic islet cell densityin db/db mice [rosi Finegood DT et al,2001; tro Sreenan S et al 1999]

Tro restored NGT and improved -cell function in IGT patients

[Cavaghan MK et al, 1997]


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BETA-CELL PROTECTION

Tro prevents onset of T2DM inHispanic women with previous h/oGDM [Buchanan TA et al, 2002]

TZDs reduce FFAs, preventlipotoxicity and preserve -cellfunction/mass [Martin G et al, 1998]


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PLEIOTROPIC EFFECTS

PPAR receptors inadipose tissue, skeletalmuscle

Receptors in allvascular cells relevantto atherosclerosis endothelial cells,vascular smooth

muscle cells,monocytes [Plutzky J,2001]


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PLEIOTROPIC EFFECTS

Regulate inflammation, macrophagemetabolism, foam cell formation [MooreKJ et al, 2001]

Regulate lipid uptake, cholesterolefflux, cytokine production inmacrophages [Moore KJ et al, 2001]

Direct antiatherogenic effects of PPAR agonists [Glass CK, 2001]


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PLEIOTROPIC EFFECTS

Enhance insulin sensitivityby reducing FFA levels [SaltielAR et al, 1996]

Down-regulate resistin

[Steppan CL et al, 2001] Alter levels of multiple

resistin-like molecules[Steppan CL et al, 2001]

Stimulate acetyl-CoAcarboxylase activity[Thampy GK et al, 2000]


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MACROVASCULAR PROTECTION

Pio 30 mg/d x 6 m x 53 T2DM patientsreduced carotid IMT by 0.084 0.023 mm[Koshiyama H et al, 2001]

Pio 30 mg/d x 67 overweight T2DM reducedLDL3 mass, improved LDL1, HDL

[LDL 36.2 to 28.0; HDL 1.28 to 1.36 mmol/l].

No change with gliclazide. No change inHDL with metformin [Lawrence JM et al, 2004]


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VASCULAR PROTECTION

TZDs enhance vasorelaxation in smoothmuscle cells [Buchanan TA, 1995]

All 3 TZDs improve hypercoaguability[Parlukar AA, 2001]

Rosi 4 mg bd given to 12 recent T2DMimproves endothelial function and

IR by 60% ascompared to nateglinide

[Pistrosch F, 2004]


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MICROVASCULAR PROTECTION

Reduces urinary albuminexcretion [Bakris GL etal, 1999; Freed M et al,1999]

May prevent progressionof retinopathy: tro androsi inhibit retinalneovascularization byreducing response ofendothelial cells to VEGFin neonatal mice [MurataT et al, 2001]


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GLITAZONES IN NON-DIABETIC

PATIENTS Pio 45 mg x 16 wks to 54 hypertensivesreduced dense LDL, without changing TG, TC,LDL, HDL, blood glucose [5.4 to 5.1 mmol/l][Winkler K et al, 2003]

Rosi 4 mg bd x 16 wks x 24 hypertensivesreduced SBP [138 to 134 mm Hg], DBP [ 85 to80 mm Hg], TG, LDL, HDL, CRP, PAI-1,improved insulin sensitivity. B.P. checked by24 hr ABPM [Raji A, 2003]

Rosi restored normal circadian rhythm in11/12 nondippers


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PPARs

Discovered in 1990s Members of nuclear receptor superfamily

of ligand activated transcription factors

PPAR Isoforms

PPAR alpha chromosome 22q12 Brown adipose tissue, Liver, Kidney, Heart, Brain, Skeletal

muscle

PPAR beta/delta/NUC1 chromosome 6p21

Intestines, Kidney, Liver, Brain

PPAR gamma chromosome 3p25

Adipocytes, Colon, Renal epithelial cells, Monophages andmacrophages, Brain, Retinal Pigment Epithelium

Reiss, A. et. al. Current Medicinal Chemistry2006;13:3227 3238.

Auwerx,J. Diabetologia 1999;42:1033 1049.


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From Activation toExpression

CellMembrane

CellNucleu

ExogenousActivation

PPAR PPA

R

DNA

EndogenousActivation

RXR


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CellMembrane

CellNucleu

DNA

PPAR

Endogenous

Activation

RXR

RXR

PPAR

ExogenousActivation


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CellMembrane

CellNucleu

DNA

Transcription

RXR

PPA

R

ExogenousActivation

EndogenousActivation

RX

R

PPAR


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Important Molecules in AMDImportant Molecules in AMD

and Their Interaction withand Their Interaction with

PPARsPPARs

Herzlich. et.al. PPAR Research 2008;2008(1):389507-389518.


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Roles of PPAR Subtypes

PPAR alpha

Fatty Acid

Metabolism Immunity Atherosclerosis Apoptosis Cholesterol Replication Signal Cascade

PPAR beta

Fatty AcidFatty Acid

MetabolismMetabolism EmbryogenesiEmbryogenesi

ss DiabetesDiabetes CancerCancer ApoptosisApoptosis CellCell

DifferentiationDifferentiation NuclearNuclear

ReceptorReceptor

PPAR gamma

AdipocyteAdipocyte

DifferentiationDifferentiationAtherosclerosisAtherosclerosis InflammationInflammation StarvationStarvation ApoptosisApoptosis DiabetesDiabetes CancerCancer Cell CycleCell Cycle


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Insulin Resistance

Inability of tissues to respond to normal levels of insulin Insulin normally:

Increases muscle and adipocyte glucose uptake (via GLUT-4translocation)

Increases glycogenesis, lipogenesis and other anabolic processess

Decreases glycogenolysis, lipolysis, proteolysis, gluconeogenesis Insulin acts via tetrameric receptor

Tyrosine phosphorylation

IRS-I, various protein kinases/phosphatases, etc

All processes malfunctioning in IR

Receptor phosphorylation, receptor number, GLUT-4, IRS-1phosphorylation, etc, etc

ppar - whats next

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