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1
The Metabolic Syndrome State of the Art Symposium
PATHOPHYSIOLOGY Insulin Resistance
Venice, October 23, 2004
Gaetano Crepaldi University of Padova - Italy
2
P. Avogaro, G. Crepaldi, G. Enzi, A.
Tiengo.Association of hyperlipidemia, diabetes
mellitus and moderate obesity.Acta Diabetol Lat
4167-171, 1967

• in our patients we found a significant
  correlation between fasting blood glucose and
  serum triglycerides both before diet treatment
  and after low carbohydrate diet. These findings,
  together with the notion that high plasma insulin
  concentrations occur after oral glucose load in
  patients with carbohydrate-induced
  hyperlipidemia, indicate that the abnormal
  glucose utilization can be explained by a
  condition of

insulin-resistance.
3
Bruneck Study 1990-1995.

• Bruneck (NE Italy) registered population older
  than 40 in 1990 4793
• Random sample 1000 (125 M and 125 F in each age
  decade)
• Participation 1990/complete data 936/888
• 1990-1995 62 Deaths
• Participation 1995/complete data 826/826

4
Insulin Resistance according to the Number of
Abnormalities composing the Metabolic Syndrome
found in the single individual(Bruneck Study
Bonora et al Int J Obes 271283, 2003)
Abnormalities impaired glucose regulation
(IFG,IGT,DM), hypertension, dyslipidemia, obesity
or central fat distribution, microalbuminuria Sex-
and age-adjusted
5
Prevalence of Insulin Resistance in Selected
Metabolic Disorders(Bonora et al, Diabetes 47
1643, 1998)
100
All cases
Isolated cases
80
60

40
20
0
High TG
IGT/DM
High BP
High Urate
Low HDL-C
N888 age 40-79 yr Insulin resistance estimated
by HOMA-IR in the upper quintile of lean controls
6
Increased insulin resistance is associated with
increased CV risk San Antonio Heart Study
Association between HOMA-IR and 8-year risk of
cardiovascular outcomes
HOMA IR Quintiles
Quintile 5
Quintile 4
Quintile 3
Quintile 2
0
1
2
3
4
5
Odds ratio for risk of CVD (95 CI)
Quintile of HOMA-IR adjusted for age, sex,
ethnicity, LDL, triglyceride, HDL, systolic blood
pressure, smoking, alcohol consumption, leisure
time exercise and waist circumference (median
split)
P (trend) 0.0185
Hanley et al. Diabetes Care 2002 2511771184.
7

• Putative
• Promoting Effects
• of Insulin Resistance
• on Atherogenesis
• Atherogenic Lipoproteins
• Thrombophilic State
• NO Deficiency
• Apoptosis
• Vascular remodeling

Initiating Processes

• Putative
• Promoting Effects
• of Hyperinsulinemia
• on Atherogenesis
• Oxidant Stress
• Growth Factor Synergy
• Endothelial Disfunction

Initial Lesion
Fatty streak
Fibrous plaque
Complicated plaque
8
Endothelial dysfunction correlateswith insulin
resistance
Control (n9)
12
Diabetes (n9)
10
Hypertension (n9)
r0.46, plt0.05
8
Whole body insulin sensitivity (MCR ml/kg/min)
6
4
2
0
20
60
0
20
40
Vasoreactivity ( change in forearm blood flow
ratio)
Cleland SJ et al. Hypertension 2000 35 507-511
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Effects of Insulin on Bradykinin Stimulation of
Forearm Bulk Blood Flow
Forearm Blood Flow (ml/min/kg)
Bradykinin Dose (ng/min/kg forearm)
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Effects of Systemic Insulinization on
Endothelium-Dependent Vasodilation in the Leg
Vascular Bed
Changes in Leg Blood Flow (Insulin / Saline)
Metacholine Infusion Rate (mg/min)
Steinberg HO, et al. JCI 1996
11
Insulin ResistanceIn Vivo effects on Adhesion
Molecules?
Rolling
Monocyte
Vessel Lumen
Sticking
Transmigration
Endothelium
VCAM-1 ICAM-1
E-Selectin
MCP-1
Intima
Charo IF. Curr Opin Lipidol 19923335-343.
12
Circulating Endothelial Adhesion Molecules and
Insulin Resistance (Bruneck Study Bonora et al
Int J Obes 271283, 2003)
VCAM-1 (ng/ml)
ICAM-1 (ng/ml)
E-selectin (ng/ml)
P-selectin (ng/ml)
220
200
180
160
Q1
Q4
Q1
Q4
Q1
Q4
Q1
Q4
N888, age 40-79 yr data adjusted for sex, age,
BMI, smoking
13
Insulin Resistance and Dyslipidemia
14
NF?B increases gene transcription of inflammatory
proteins
? FFA
DAG
PKC
Barnes K et al. 1997NEJM 3361066
Itani SI et al. Diabetes 2002 512005
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Insulin-mediated FFA metabolism in Type 2 diabetes
FFA turnover (?mol//m2/min)
Plasma FFA (mmol/l)
Groop L et al. J Clin Invest 1989
16
Effect of free-fatty acids on the endothelial
function
BASELINE
LCT
500
500
increase in blood forearm ratio (infused/control
arm)
increase in blood forearm ratio (infused/control
arm)
250
250
0
0
7.5
15
30
7.5
15
30
Acetylcholine dose (µg/min)
Acetylcholine dose (µg/min)
Vigili de Kreutzenberg et al. JCEM 2000
17
Insulin Resistance and Dyslipidemia
18
Lipoprotein Classes and Inflammation
HDL
LDL
VLDL and their catabolic remnants
gt 30 nm
2022 nm
915 nm
Potentially anti- inflammatory
Potentially proinflammatory
Doi H et al. Circulation 2000102670-676 Colome
C et al. Atherosclerosis 2000149295-302
Cockerill GW et al. Arterioscler Thromb Vasc Biol
1995151987-1994.
19
Metabolic SyndromeSmall, Dense LDL and Unstable
Atherosclerotic Plaque
Vessel Lumen
Small, Dense LDL
Endothelium
Intima
Ross R. N Engl J Med 1999340115-126.
20
Oxidized LDL and Insulin Resistance (Bruneck
Study Bonora et al Int J Obes 271283, 2003)
p0.001
Q1
Q4
N888, age 40-79 yr data adjusted for sex, age,
BMI, smoking
21
LDL Oxidation and Endothelial Function
Low Ox-LDL
High Ox-LDL
22
Small, dense LDL
Large, buoyant LDL
SM-E7
SM-E7
ap
m
m
ap
23
hs-CRP Levels and LDL Density
- 35, plt0.01
hs-CRP (mg/L)
8
7
6
5
4
3
2
1
0
Dense LDL
Buoyant LDL
(Zambon et al., Atherosclerosis, submitted)
24
ESR and Insulin Resistance (Bruneck Study Bonora
et al Int J Obes 271283, 2003)
p0.018
Q1
Q4
N888, age 40-79 yr data adjusted for sex, age,
BMI, smoking
25
Fibrinogen and Insulin Resistance (Bruneck Study
Bonora et al Int J Obes 271283, 2003)
p0.006
Fibrinogen (mg/dl)
Q1
Q4
N888, age 40-79 yr data adjusted for sex, age,
BMI, smoking
26
Inflammatory response and the Metabolic Syndrome
r0.59 plt0.00005
Insulin resistance Z-score
Acute phase marker Z-score
Yudkin JS K et al. 1999 Arterioscler Thromb Vasc
Biol. 105311
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Clinical Phenotype (Metabolic Syndrome)
Clinical Event