Insulin Resistance and Cardiovascular Diseases

1
Insulin Resistance and Cardiovascular Diseases
Hyun Ho Shin, M.D. Department of Medicine Samsung
Cheil Hospital Sungkyunkwan Univ. School of
Medicine
2
What to call the syndrome?

• Reaven's Syndrome
• Deadly Quartet
• Insulin Resistance Syndrome
• Syndrome X
• Dysmetabolic Syndrome X
• Multiple Metabolic Syndrome
• Metabolic Syndrome

3
Effects of Insulin on the Vasculature in the
Context of Insulin Resistance
Increased arterial lipid synthesis Increased
connective tissue matrix synthesis Increased
proliferation and migration of arterial smooth
muscle cells and macrophages Increased migration
of endothelial cells Increased LDL receptor
activity in arterial smooth muscle cells and
macrophages Increased PAI - 1 Differential effect
of insulin signaling on MAP kinase versus PI3
kinase
LDL low-density lipoprotein MAP
mitogen-activated protein PAI-1 plasminogen
activator inhibitor1 PI3 kinase
phosphatidylinositol 3 kinase
4
Interaction Between Insulin and the NO System
Sodium Nitroprusside
Acetylcholine
Insulin
L-NMMA
NO
L-ARG
NO
L-ARG
Endothelium
NOS
NOS
Vascular Smooth Muscle
Guanylate Cyclase
cGMP
Vasodilation
Baron, J Invest Med 1996
5
Insulin Potential Atherogenic and
Antiatherogenic Actions in Vascular Cells
Insulin Receptor
Angiotensin II Receptor
Shc
PKC
IRS-1,2
ras raf MEK MAPK
PI 3-Kinase
Nitric Oxide
Atherogenic Vascular Cell Growth Synthesis of
Extracellular Matrix Proteins
Antiatherogenic NO-Mediated Vasodilation


Feener et al, Lancet 1997
6
Insulin Resistance and Heart Disease

• Diabetes
• Hypertension
• Low HDL
• High triglycerides
• Increased number of small dense LDL particles
• Abdominal obesity
• Endothelial dysfunction
• L.V.H.
• Increased PAI-1
• Increased C-reactive protein

7
Interrelation Between Atherosclerosis and Insulin
Resistance
Insulin Resistance
Hyper- insulinemia
Hypertri- glyceridemia
Small, dense LDL
Hypercoagu-lability
Hypertension
Obesity
Low HDL
Diabetes
Atherosclerosis
8
Paris Prospective Study CHD Mortality and
Hyperinsulinemia
3 2 1 0
CHD Mortality (rate per 1,000)
lt 5 5.1-8 8.1-12 12.1-19 gt19
Quintiles of Fasting Plasma Insulin(µU/mL)
Fontbonne, Eschwege. Diabetes Care 199114461.
Mean coronary artery disease (CAD) mortality
rates by fasting plasma insulin quintiles
increased CAD mortality correlated positively
with increased fasting plasma insulin quintiles.
N 7,028 men 943 with impaired glucose
tolerance or diabetes mellitus.
9
Diagnosis of Metabolic Syndrome
Any Three of the Following
Defining risk factor Criteria
Abdominal obesity gt 102 (90) Cm in men gt 88 (80) Cm in women
Higher fasting TG 150 mg/dl
Lower HDL lt 40 mg/dl for men lt 50 mg/dl for women
Higher blood pressure 130 / 85 mmHg
Higher fasting glucose gt 110 mg/dl
NCEP ATP III. JAMA. 20012852486.
10
The metabolic syndrome of insulin resistance
cardiovascular disease
EndothelialDysfunction
Chronic systemicInflammation
Complexdyslipidemia TG, sdLDL HDL
Insulin Resistance
Athero-sclerosis CHD
ReducedFibrinolysis
VisceralObesity
Hypertension
Type 2 Diabetes
11
Behavior That Increases Insulin Resistance

• Lack of exercise
• Aging - loss of muscle mass
• Obesity
• High fat, high carbohydrate diet
• Anxiety
• Depression
• ? blockers, HCTZ, nicotinic acid
• Menopause
• Smoking

12
Interventions That Reduce Insulin Resistance

• Aerobic exercise
• Strength training - increase muscle mass
• Weight loss - decrease adipose tissue
• High fiber, low fat, low sugar diet
• Metformin
• Thiazolidinediones
• Estrogen
• ACE inhibitors alpha blockers

13
Potential role of peroxisome proliferator-activate
d receptor g (PPARg) activating
thiazolidinediones (TZDs) in the vessel wall.
TZDs, through their capacity to activate PPARg,
might--in addition to their metabolic effects on
glucose metabolism and insulin sensitivity--exhibi
t direct anti-atherogenic effects in the vessel
wall, thus potentially reducing the incidence of
cardiovascular events in the high-risk population
of patients with diabetes mellitus. PPRE--PPAR
response elementm RXR--retinoic X receptor.
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Rosiglitazone, SU and metformin have distinct,
complementary actions
Acarbose
I
Sulfonylureas meglitinides
I
I
I
I
I
I
Metformin
sites of rosiglitazone action
17
Rosiglitazone complementary mode of action to
metformin and SU
Sulfonylureas primarily work by increasing
insulin release from the pancreas
Rosiglitazone improves b-cell function a key
factor in disease progression
Rosiglitazone decreases excessive lipolysis and
reduces free fatty acid output
Pancreas
Rosiglitazone decreases excessive hepatic
glucose production
Adiposetissue
Metformin primarily works by reducing glucose
output from the liver
Muscle
Liver
Rosiglitazone directly reduces insulin resistance
a key underlying factor in type 2 diabetes
18
Rosiglitazone improves insulin sensitivity
(euglycemic clamp)
91
Treatment 16 wks
p0.002
0.4
0.35
0.3
0.25
Mean Change from Baseline
(umol glucose/min/kg FFM/mU/L)
0.2
0.15
0.1
p0.988
0.05
0
RSG 4mg bd
Placebo
Error Bars SE
n17
n14
Carey D. Diab Res Clin Pract 2000 50(suppl 1)
P311
19
The metabolic syndrome of insulin resistance
cardiovascular disease
EndothelialDysfunction
Chronic systemicInflammation
Complexdyslipidemia TG, sdLDL HDL
Insulin Resistance
Athero-sclerosis CHD
ReducedFibrinolysis
VisceralObesity
Hypertension
Type 2 Diabetes
20
Rosiglitazone reduces diastolic blood pressure
versus sulphonylurea
Glibenclamide RSG
5
4
3.8
3
2
Mean change in 24 hours ambulatoryblood pressure
(mm Hg)
1
0.7

0
-1
-0.1
-2
-3
-2.3
Systolic blood pressure
Diastolic blood pressure
n 203, patients were treated with RSG 8
mg/day P 0.0046 compared with
glibenclamide Error bars SE
St John Sutton MS, et al. Diabetes 1999 48
(Supplement 1)A102.
21
Rosiglitazone improves insulin sensitivity and
lowers blood pressure in hypertensive patients

• Treatment with the insulin sensitizer
  rosiglitazone improves blood pressure, insulin
  sensitivity and markers for risk of
  cardiovascular disease in non-diabetic
  hypertensive patients.
• Insulin sensitizers may play a role in the
  treatment of hypertension and its associated
  cardiovascular risks.

American Journal of Hypertension Volume 15,
Issue 4, Supplement 1, April 2002, Page A1
22
BP Insulin Sensitivity
0 Week 16 Week
P value Mean SEM
24hr Mean Systolic mmHg 138 2
134 2 lt
0.01 24hr Mean Diastolic mmHg
85 2 80 2
lt 0.0001 Night time ( 23hrs - 6.00am )
131 3 126 3
lt 0.01 Systolic mmHg Night time (
23hrs - 6.00am ) 79 2
72 2 lt
0.0001 Diastolic mmHg Fasting Insulin (µU/ml)
16 2 12
1 lt 0.01 Peripheral
Insulin Sensitivity 5.0 0.4
5.9 0.5 lt 0.001 -
mg/kg/min
23
Rosiglitazone improves insulin sensitivity and
lowers blood pressure in hypertensive patients

• At the end of rosiglitazone treatment (including
  final 2 weeks off antihypertensive meds) there
  were significant decreases in mean 24-hr,
  nighttime, and daytime systolic and diastolic BP,
  and a significant improvement in IS.
• There was a highly significant correlation
  between the improvement in IS and the decline in
  systolic BP after rosiglitazone treatment
  (r0.68, plt0.002).

24
The metabolic syndrome of insulin resistance
cardiovascular disease
EndothelialDysfunction
Chronic systemicInflammation
Complexdyslipidemia TG, sdLDL HDL
Insulin Resistance
Athero-sclerosis CHD
ReducedFibrinolysis
Hypertension
VisceralObesity
Type 2 Diabetes
25
Role of coagulation and fibrinolysis in thrombosis
26
Rosiglitazone reduces levels of PAI-1
40
SU SU RSG 8 mg/day
30
20
10
0
Mean Change in PAI-1 activity ()
-10
-20
-33.8 P 0.006
-30
-40
n 114, patients were treated for 26 weeks
Freed M, et al. Diabetologia 2000 43 (Supplement
1)A267.
27
The metabolic syndrome of insulin resistance
cardiovascular disease
EndothelialDysfunction
Chronic systemicInflammation
Complexdyslipidemia TG, sdLDL HDL
Insulin Resistance
Athero-sclerosis CHD
ReducedFibrinolysis
Hypertension
VisceralObesity
Type 2 Diabetes
28
Rosiglitazone reduces LDL particle density
Brunzell J, et al. Diabetes 200150 (2) A141
29
Effect of Rosiglitazone on HDL phenotype after 8
weeks treatment
Geometric means (SE) Brunzell J, et al. Diabetes
200150 (2) A141
30
Change in LDL after 16 weeks treatment with
Atorvastatin
RSG PBO
plt0.0001
Data are geometric means (95 CI)
Brunzell J. Diabetes 200150 (2) A141 Abs 567
and Poster
31
The metabolic syndrome of insulin resistance
cardiovascular disease
Chronic systemicInflammation
Complexdyslipidemia TG, sdLDL HDL
EndothelialDysfunction
Insulin Resistance
Athero-sclerosis CHD
ReducedFibrinolysis
Hypertension
VisceralObesity
Type 2 Diabetes
32
Vascular endothelial dysfunction

• Reduced vascular elasticity - loss of insulin
  induced vasodilation (elevated FFA also impair
  vasodilation)
• increased cell adhesion and hence pro-thrombotic
• reduced fibrinolysis via increased PAI-1
• increased vascular permeability, microalbuminuria

33
Activating oxidised LDL atherogenic diet TNF
receptor trimers and adaptor proteins
Inhibitory PPAR agonists
Cytoplasm
IkB
Inactive
NFkB
Active
Membrane
5-GGGRNNYYCC-3
Gene expression in SMC, EC, macrophage in
plaques - fibrinogen levels
- adhesion molecule expression
- cytokinase expression
- growth factor expression
- COX - 2 activity - MCP -1
monocyte migration
Potential mechanism linking nuclear factor- B
activation with vascular inflammation. Schematic
diagram illustrating the balance between
different factors (e.g. oxidized LDL, atherogenic
diet, tumour necrosis factor (TNF) and
peroxisomal proliferator-activated receptor
(PPAR) agonists) capable of modulating nuclear
factor- B (NF- B) activity. Increased NF- B
activity is associated with altered gene
expression of several molecules linked with
vascular inflammation produced by vascular smooth
muscle cells (VSMCs), endothelial cells (EC) and
macrophages.
34
The metabolic syndrome of insulin resistance
cardiovascular disease
EndothelialDysfunction
Chronic systemicInflammation
Complexdyslipidemia TG, sdLDL HDL
Insulin Resistance
Athero-sclerosis CHD
ReducedFibrinolysis
Hypertension
VisceralObesity
Type 2 Diabetes
35
C-Reactive Protein

• In coronary arteries obtained at autopsy, CRP
  only present in segments with atherosclerotic
  lesions
• Present in all early lesions
• Chemotactic for human monocytes promotes
  migration activates complement
• Specific receptor for CRP on monocytes
• CRP is not a marker of inflammation but plays an
  active role in the formation of the atheromatous
  plaque

Torzewski. Arterioscler Thromb Vasc Biol.
2000202094.
36
The importance of C-reactive protein

• Risk factor for coronary heart disease
• (Kuller et al, Am J Epidemiol 144 537-547,
  1996)
• Predicts future myocardial infarction
• (Ridker et al, N Engl J Med 336 973-979,
  1997)
• Predicts a poor outcome in patients with unstable
  angina
• (Liuzzo et al, N Eng J Med 331 417-424,
  1994)
• Risk factor for development of type 2 diabetes
• 
  (Pradhan et al, JAMA 286 327-334, 2001)

37
Relative Risks of Future CHD Among Apparently
Healthy Middle Aged Men
Ridker PM. Ann Intern Med. 1999130933-937.
38
Rosiglitazone reduces serum CRP
Change from baseline
Haffner et al 2002, Circulation 106679
39
Vulnerable plaques are responsible for clinical
events
Fissure
Lumen
Lumen
Lumen with thrombus
core
Normal artery
Atheroma
Ruptured plaque
40
The inflammatory atherosclerotic process
Inflamm markers, CRP
PLAQUE RUPTURE
Lumen of blood vessel
monocyte
sdLDL
MMP-9
endothelium
sdLDL
Inflamm cytokines, IL-6, TNFa
Complex (vulnerable) plaque
MCP-1
fatty streak
chemotaxis
Artery wall
f
m
-
differentiation
O2
ROS
ox-LDL
Smooth muscle cells
foam cell
41
Rosiglitazone reduces serum MMP-9
-19.1 (95 CI -26.6,-10.9)
10
0
(error bars 95C.I.)
change from baseline
-10
-20
26 weeks treatment
-30
Haffner et al 2002, Circulation 106679
42
Rosiglitazone reduces markers of the inflammatory
atherosclerotic process
Inflamm markers, CRP, sVCAM
Lumen of blood vessel
monocyte
Plaque rupture
sdLDL
MMP-9
endothelium
sdLDL
Inflamm cytokines, IL-6, TNFa
Complex (vulnerable) plaque
MCP-1
fatty streak
Artery wall
chemotaxis
f
m
-
differentiation
O2
ROS
ox-LDL
Smooth muscle cell migration
foam cell
43
Rosiglitazone Effect on Human Coronary Artery
Smooth Muscle Cell Proliferation
100

80
3H-Thymidine Incorporation ( bFGF-stimulated)
60



40
20
0
RSG (mmol/L)
P lt .05. P lt .001.
Adapted from Law et al. Circulation.
2000101(11)1311-1318.
44
Rosiglitazone Decreases PDGF-Directed Human
Coronary Artery Smooth Muscle Cell Migration
6
5
4

Migration (x-fold Induction over Control)
3

2

1
0
1
0.1
5
10
PDGF
RSG (?mol/L)
Plt.001
Adapted from Law et al. Circulation 20001011311.
45
The metabolic syndrome of insulin resistance
cardiovascular disease
EndothelialDysfunction
Chronic systemicInflammation
Complexdyslipidemia TG, sdLDL HDL
Insulin Resistance
Athero-sclerosis CHD
ReducedFibrinolysis
Hypertension
VisceralObesity
Type 2 Diabetes
46
The Adipocyte in Obesity-Associated Hypertension
And CV Risk Factor Clustering
Adipose Mass
Energy
Calories
AT1
Ang II
Liver
ACE and Cathepsins
Leptin
PAI-1
TNFa
NEFAs
Angioten-sinogen
SNS
Thrombosis
Insulin Resistance
Aldosterone
Structural and Functional Cardiovascular and
Renal Effects
Potential pathobiologic mechanisms are shown by
which an expanded adipocyte mass may contribute
to cardiovascular risk factor clustering and
target organ changes.
47
Rosiglitazone therapy is not associated with an
increase in visceral fat
48
Rosiglitazone modest weight gain over 2 years
(ITT Patients no LOCF)

Scheen 2002, Ann Endocrinol 63, 2, 1S412-1S44
49
TZDs and Adipocyte

• Shift from peritoneal to subcutaneous space
• Accelerates apoptosis of older lipid laden
  adipocytes
• Formation of new adipocytes
• Decrease in adipocytokines
• TNF?
• Resistin
• PAI1
• Angiotensinogen
• Decrease in FFA leads to a decrease in insulin
  resistance

50
Effect of TZD on Lipids (Free fatty acids)
Glyburide
Free fatty acids (mmol/L)
RSG 4 mg/day
RSG 8 mg/day
Treatment week
ITT with LOCF. Mean ? SE. Given as 2 mgbid
and 4 mg bid RSG. Rosiglitazone.
51
Rosiglitazone and liver function

• TROGLITAZONE Post-Marketing Experience
• Withdrawn worldwide (March 2000)
• 89 Reports of liver failure and 61 deaths
• ROSIGLITAZONE Post-Marketing Experience
• 3 years in clinical use
• gt3 million patients gt20 million scripts
• no evidence of troglitazone-like hepatotoxicity

52
Glitazones safety issues

• Unique to specific glitazones and not related to
  PPAR? activation
• hepatotoxicity troglitazone
• myalgia and CPK elevation pioglitazone
• interaction with drugs metabolised byCYP 3A4
  troglitazone and pioglitazone

53
Metabolism of glitazones
Primary metabolic pathway
Troglitazone Pioglitazone Rosiglitazone
CYP 3A4 CYP 2C8 and CYP 3A4 CYP 2C8
54
Drugs metabolised by CYP 3A4
Cyclosporin FK506 Saquinavir Indinavir Lovastati
n Simvastatin Hydrocortisone Oestradiol Progeste
rone Testosterone Dexamethasone Sildenafil
(Viagra) Cisapride Salmeterol Chlorpheniramine
Macrolide antibiotics Analgesics Non-sedating a
ntihistamines Calcium-channel blockers Benz
odiazepines
Erythromycin Clarithromycin Fentanyl Alfentanil
Terfenadine Astemizole Nifedipine Nitrendipine N
isoldipine Felodipine Diltiazem Verapamil Midazol
am Triazolam Alprazolam
Immuno- suppressives HIV protease inhibitors HMG
CoA reductase inhibitors / fibrates Endogenous a
nd synthetic steroids Miscellaneous
55
Glitazones safety issues

• Related to PPAR? activation
• edema
• weight gain
• congestive heart failure
• decrease in haemoglobin and haematocrit
• increase in plasma volume
• increase in total and LDL-cholesterol

56
Rosiglitazone - update on fluid retention and
oedema

• fluid retention (hemodilution) is a TZD class
  effect (fall in Hb 1g/dl)
• dose related reversible after drug withdrawal
• edema
• 3 in SU/RSG combination
• 4.4 in Met/RSG combination
• higher incidence in triple combination and with
  insulin
• risk of exacerbating or precipitating CHF
• variable response to diuretics
• mechanism of fluid retention/edema?
• potentiation of insulin-mediated vasodilation
• increased endothelial VEGF release
• increased renal sodium uptake

57
Insulin resistance, hyperinsulinemia, and
hypertension. NO--nitric oxide.
58
Abnormalities associated with the metabolic
syndrome
Insulin resistance    Fasting hyperinsulinemia
   Glucose intolerance    Type II diabetes   
Increase in free fatty acids levels (inadequate
suppression of lipolysis) Atherogenic
dyslipidemia    Hypertriglyceridemia   
Increased level of small, dense low-density
lipoprotein cholesterol    Decreased level of
high-density lipoprotein cholesterol Essential
hypertension Nondipping pattern of nocturnal
blood pressure Salt sensitivity High
sodium/lithium counter transport Central obesity
Endothelial dysfunction Increased level of
plasminogen activator inhibitor, dysfibrinolysis,
increased platelet aggregation Microalbuminuria
High hematocrit and hemoglobin Hyperuricemia
Growth hormone deficit
59
Effect of Thiazolidinediones on Inflammation
Suppression of ROS generation Reduction of 9 -
and 13 - HODE Reduction in intranuclear NF -
?B Enhanced expression of inhibitor
?Ba Reduction in p47 phox Reduction in plasma
concentrations of CRP, ICAM-1, MCP-1, TNF-a, PAI
-1 Small, but significant , increase in IL-10 and
TH2
                                               
                           
CRP C-reactive protein HODE
hydroxyoctadecadienoic acid ICAM-1
intracellular Adhesion molecule 1 IL-10
interleukin 10 MCP-1 monocyte chemotactic
protein 1 NF- ? B nuclear factor ? B PAI-1
plasminogen activator inhibitor 1 ROS
reactive oxygen species TNF-?  tumor necrosis
factor ?.
60
Thiazolidinediones Cardiovascular Risk in
Insulin Resistance
Favorable effects on lipoprotein profile,
bp, endothelial dysfunction, arterial
inflammation, fibrinolysis
Fluid retention edema