View
243
Download
0
Category
Preview:
Citation preview
8/7/2019 PPAR - Whats Next
1/22
8/7/2019 PPAR - Whats Next
2/22
A Constellation ofComplications
GastropathyGastropathy
AutonomicAutonomicNeuropathyNeuropathy
RenalRenal
DiseaseDiseasePeripheralPeripheral
NeuropathyNeuropathy
Retinopathy/Retinopathy/
MacularMacular
EdemaEdema
HypertensionHypertensionCardiovascularCardiovascular
DiseaseDisease
DyslipidemiaDyslipidemia
PeripheralPeripheral
VascularVascular
DiseaseDisease
ErectileErectile
DysfunctionDysfunction
DiabetesDiabetes
8/7/2019 PPAR - Whats Next
3/22
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
8/7/2019 PPAR - Whats Next
4/22
Insulin Resistance Genetic
Acquired Central obesity
Medications
In 80-90% of type 2 patients
Clusters with metabolic disease syndrome
Associated with increased macrovascular
disease
8/7/2019 PPAR - Whats Next
5/22
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
8/7/2019 PPAR - Whats Next
6/22
GLITAZONES
PANCREO PROTECTIVE
CARDIO PROTECTIVE
VASCULO PROTECTIVE Macro vascular
Micro vascular
FEW SIDE EFECTS
FIRST LINE ANTI DIABETIC
FIRST LINE ANTI- IGT DRUG
8/7/2019 PPAR - Whats Next
7/22
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]
8/7/2019 PPAR - Whats Next
8/22
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]
8/7/2019 PPAR - Whats Next
9/22
PLEIOTROPIC EFFECTS
PPAR receptors inadipose tissue, skeletalmuscle
Receptors in allvascular cells relevantto atherosclerosis endothelial cells,vascular smooth
muscle cells,monocytes [Plutzky J,2001]
8/7/2019 PPAR - Whats Next
10/22
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]
8/7/2019 PPAR - Whats Next
11/22
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]
8/7/2019 PPAR - Whats Next
12/22
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]
8/7/2019 PPAR - Whats Next
13/22
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]
8/7/2019 PPAR - Whats Next
14/22
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]
8/7/2019 PPAR - Whats Next
15/22
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
8/7/2019 PPAR - Whats Next
16/22
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.
8/7/2019 PPAR - Whats Next
17/22
From Activation toExpression
CellMembrane
CellNucleu
ExogenousActivation
PPAR PPA
R
DNA
EndogenousActivation
RXR
8/7/2019 PPAR - Whats Next
18/22
From Activation toExpression
CellMembrane
CellNucleu
DNA
PPAR
Endogenous
Activation
RXR
RXR
PPAR
ExogenousActivation
8/7/2019 PPAR - Whats Next
19/22
From Activation toExpression
CellMembrane
CellNucleu
DNA
Transcription
RXR
PPA
R
ExogenousActivation
EndogenousActivation
RX
R
PPAR
8/7/2019 PPAR - Whats Next
20/22
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.
8/7/2019 PPAR - Whats Next
21/22
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
8/7/2019 PPAR - Whats Next
22/22
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
Recommended