Defining Insulin Resistance

and Metabolic Syndrome

Didier DEWAILLY, M.D.

Department of Endocrine Gynaecology and

Reproductive Medicine, Hôpital Jeanne de Flandre,
C.H.R.U., 59037 Lille, France

1
Insulin Resistance is a physiological, adaptative
and selective phenomenon

Alan R. Saltiel and C. Ronald Kahn Insulin signalling and the regulation of
glucose and lipid metabolism. Nature 414, 799-
799-806(13 December 2001)
2
 ADIPOTOXICITY
is the main cause of pathological IR

Genes
Environment

INCREASED
CARDIOVASCULAR
& METABOLIC
RISK

3
Muniyappa R et al., Am J Physiol Endocrinol Metab. 2008;294:E15-
2008;294:E15-426.
 Surrogate indexes of insulin sensitivity
using fasting basal determinations of G and I

HOMA-IR:
HOMA-
I (mIU/L) X G (mmol/L)/22.5

QUICKI:
1/ log I (mIU/L) + log G (mg/dl)
Bastard JP et al., Diabetes Metab 2003, 29:285-
29:285-8

G/I:
G (mg/dl) / I (mIU/L)
5
QUICKI is better than G/I

Bastard JP et al., Diabetes Metab 2003, 29:285-

29:285-8

6
 QUICKI and Log(HOMA) are similar

Mather, K. J. et al. J Clin Endocrinol Metab 2001;86:5457-

2001;86:5457-5464

7
Copyright ©2001 The Endocrine Society
 Surrogate indexes of insulin sensitivity

Caveats

Depend on I assay that is
not standardized

Skewed distribution of I
values (improved by log
transformation)

Not optimal in diabetic
subjects (G/I)
Usefulness

Epidemiological
studies

Research clinical
studies (correlations)

Follow up after

Not optimal in healthy therapeutic

insulin--sensitive subjects
insulin interventions

8
Detecting IR in clinical practice

Eyzaguirre F, Mericq V. Insulin resistance markers in children. Horm Res. 2009;71:65-

2009;71:65-749
The Metabolic Syndrome
(MetS)

Requiescat in pace?
G. Reaven
2005

10
The « old » definitions of MetS

11
For women in western
countries: 80 cm !

12
The metabolic syndrome and incidence of cardiovascular
disease in non-
non-diabetic subjects
a population-
population-based study comparing three different definitions
Nilsson PM et al., Diabetic Medicine, 2007, 24, 464– 472

5,047 non-
non-diabetic subjects (66% women), 11 years of follow-
follow-up.

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MetS as a predictor of T2DM

14
 MetS: caveats

Extremely abnormal values for
any particular criterion receive
the same weight as values that
are barely abnormal

Some patients may be
misclassified as "normal" when
indeed they have values that
are close to the upper limit of
normal.

The selection of cutoff points
has been arbitrary, in the most
part, and not guided by
biological and epidemiological
principles of normality

Not appropriate for early
detection of IR in the young
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 Detecting IR and MetS in PCOS

Hyperandrogenism, Dysovulation

Metabolic Syndrome

15 yrs 25-30 yrs 45 yrs 55 yrs

- Clinical
hyperandrogenism - Infertility - Hyperandrogenism - Cardiovascular events
-Menstrual - Hyperandrogenism - Glucose intolerance - Type 2 diabetes
irregularities

ENDOCRINOLOGIST CARDIOLOGIST
GYNAECOLOGIST DIABETOLOGIST
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 PCOS:
the « chance » of women at risk

Genes
Environment

Early
detection increased
CARDIOVASCULAR
& METABOLIC
risk

17
 % of Metabolic Syndrome in PCOS
according to age

25
22
20
18
17
16
15

% 11
10 9

5 4
1
0 0
16-20 yrs 20-30 yrs 30-40 yrs TOTAL
PCOS Lille controls Lille 2005 ATP III IRSA (20-74 yrs)

North--American Population (n=160)

North
Lille Population (n=864)
ATP III Classification
IDF classification Apridonidze T et al, J Clin Endocrinol Metab.
Dewailly D et al. BJOG. 2009 Oct 13 1935.
2005; 90: 1929 - 1935.
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% of each item included in MetS classification
according to age in PCOS (IDF thresholds)
Dewailly D, Contestin M, Gallo C, Catteau-Jonard S.
BJOG. 2009 Oct 13

70
60
16-20 (n=55)
50 20-30 (n=541)
%
30-40 (n=268)
40
30
20
10
0 Wrong thresholds?
TT>80 cm HTA TG>1,5 HyperG HDL<0,5
g/L g/L
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 Definition of MetS
in children and adolescents

Eyzaguirre F, Mericq V. Insulin resistance markers in children.

Horm Res. 2009;71(2):65-
2009;71(2):65-74

20
 % of each item included in MetS classification
according to age in PCOS (IDF thresholds)

Dewailly D, Contestin M, Gallo C, Catteau-Jonard S.

BJOG. 2009 Oct 13

70
16-20 (n=55)
60
20-30 (n=548)
HDL-C<0.4 g/L
50 30-40 (n=238)

40
% 30
20

10
0
TT>80 cm HTA TG>1,5 g/L HyperG HDL<0,5 g/L

?
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 Upper normal limit for WC in
adolescent girls: similar to adults

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 Waist circumference:
the most cost-
cost-effective predictor for insulin
resistance and CV risk

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 CONCLUSIONS

Detecting IR in clinical
practice should rely on
clinical data (WC+++);

Defining IR in clinical
research can rely on
simple surrogate indexes;

Stratifying patients
according to the MetS
yields an incomplete
estimation of the CV&M
risk.

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25
 CHD events and new-
new-onset diabetes stratified by both CRP (</>=3 mg/L) and
presence of absence of metabolic syndrome (MS)

Sattar, N. et al. Circulation 2003;108:414-

2003;108:414-419

26
Copyright ©2003 American Heart Association
 Hazard ratios for coronary heart disease by waist and hip circumference
quintiles in men and women 45 to 79 years of age
with adjustment for body mass index, age, systolic blood pressure, total cholesterol, cigarette smoking, physical
activity, and alcohol intake.

Canoy, D. et al. Circulation 2007;116:2933-

2007;116:2933-2943

27
Copyright ©2007 American Heart Association
 Definition of MetS
in children and in adolescents

Eyzaguirre F, Mericq V. Insulin resistance markers in children.

Horm Res. 2009;71(2):65-
2009;71(2):65-74

28
 ADIPOTOXICITY

Genes
Environment

INCREASED
CARDIOVASCULAR
& METABOLIC
RISK

29
The hypertriglyceridemic waist
phenotype

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 The "building blocks" of global cardiometabolic risk

Despres, J.-P. et al. Arterioscler Thromb Vasc Biol 2008;28:1039-1049

31
Copyright ©2008 American Heart Association

MIRACLE score included: family history (early cardiovascular disease, type 2
diabetes, and hypertension), individual history (small for gestational age and ethnic
origin), clinical features (BMI, waist circumference > 90th percentile and blood
pressure > 95th percentile) and metabolic abnormalities (glucose intolerance or type
2 diabetes). It was assigned a value of 1 to "presence" and 0 to" absence" in every
patient. The children were considered as having metabolic risk when at least 5 items
were present. Triglycerides, HDL-
HDL-cholesterol, apolipoprotein B, apolipoprotein A1,
glucose and HOMA index, were measured too. The most frequent clinical features of
MIRACLE score were: excess waist circumference (95.4%) and hypertension
(41.8%). Family history criteria were frequent (55.3% for type 2 diabetes, 39.1% for
hypertension and 31.3% for early cardiovascular disease). Individual risk factors were
not frequent. Glucose intolerance was detected in 22.2% of the obese patients. A
MIRACLE score > or = 5 was found in 37.4% of the children studied, being
associated with a significant risk of dyslipidemia (triglycerides, p = 0.040; HDL-
HDL-
cholesterol, p = 0.006; LDL-
LDL-cholesterol p = 0.038; apolipoprotein B, p = 0.008) only in
females.

J Physiol Biochem. 2007 Dec;63(4):347-
Dec;63(4):347-55.

Metabolic risk-
risk-factor clustering estimation in obese children.

Bueno G,G,

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 En pratique, chez
l’adolescente…

Mesurez le tour de taille

Dosez le HDL-
HDL-C…
Si vous avez une norme
adaptée à l’âge!
l’âge!
• Oubliez le score
métabolique!

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Ford ES Diabetes Care. 2005;28:1769-
2005;28:1769-78. 34
35
36
37
38
 Le Syndrome Métabolique (IDF):
effet de l’âge
Population Lilloise (2009): 854 SOPMK

25
22
P<0.04
20
% 16
15
11
10

0
16-20 ans 20-30 ans 30-40 ans

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MetS: is it a good predictor of the
major risks?

Cardiovascular risk T2DM risk

Ford ES Diabetes Care. 2005;28:1769-

2005;28:1769-78. 40
MetS: is it a good predictor of the
major risks?

41
 No Caption Found

Dunaif, A. Endocr Rev 1997;18:774-800

42
Copyright ©1997 The Endocrine Society
Figure 3

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THE CONSTRAINT and LIMITATIONS OF
DEFINITIONS…

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The pitfall of arbitrary thresholds:
normal HDL-
HDL-C in young women with PCOS: >0.4 or 0.5 g/L?
Dewailly D, Contestin M, Gallo C, Catteau-Jonard S.
BJOG. 2009 Oct 13

45