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Giorgio Sesti
Il paradosso dell’obesità metabolicamente sana
Università “Magna Graecia” di Catanzaro ITALY
Il Prof Giorgio Sesti dichiara di
essere tifoso del PALERMO
Potenziali conflitti di interesse
Agenda
1. Definition of Metabolically Healthy Obese (MHO) and Insulin Resistance
Obese (IRO or Metabolically Abnormal Obese [MAO]);
2. Phenotypic differences between Metabolically Healthy Obese (MHO) and
Insulin Resistance Obese (IRO or Metabolically Abnormal Obese [MAO]);
3. Are MHO protected from the development of T2D, CVD and mortality?
4. Treatment options for MHO and IRO.
Definition of “Metabolically Healthy Obesity”
“Metabolically healthy obese” phenotypes in NHANES III if < 1 metabolic
syndrome components:
1) triglycerides >150 mg/dL or medications;
2) systolic blood pressure >130 mmHg, diastolic blood pressure >85
mmHg, or medications;
3) Glucose >100 mg/dl or medications;
4) HDL cholesterol <40 mg/dL for men and <50 mg/dL for women;
Plus additional criteria
5) HOMA-IR
6) hsCRP level
Iacobellis S et al. Obes Res 13:1116-1122, 2005 Wildman RP et al. Arch Intern Med 168:1617–1624, 2008
Karelis AD et al. Diabetes Metab 34:183-184, 2008 Kuk Jl et al. Diabetes Care 32:2297–2299, 2009
Definition of “Metabolically Healthy Obesity”
In the obese group (BMI ≥ 30 kg/m2), subjects were divided into quartiles
according to their insulin sensitivity estimated from hyperinsulinemic-
euglycemic clamp studies, OGTT-derived index or HOMA-IR.
Subjects with insulin sensitivity values in the upper quartile were classified
as having MHO, while subjects in the lowest quartiles were classified as
Metabolically Abnormal Obese (MAO).
Karelis AD et al. J Clin Endocrinol Metab 90: 4145–4150, 2005 Marini et al. Diabetes Care 30: 2145-2147, 2007
Stephan N et al. Arch Intern Med 168:1609-1616, 2008 Succurro E. et al. Obesity 16: 1881–1886, 2008
Subjects were defined as Metabolically Healthy Obese if their glucose disposal rate was in the upper quartile
Marini et al. Diabetes Care 30: 2145-2147, 2007
6,4
15,1 14,3
0
4
8
12
16
Insu
lin
-sti
mu
late
d g
luco
se
dis
po
sa
l (
mg
/m
in x
Kg
FFM
)
P<0.0001
Metabolically Abnormal Obese (MAO)
Metabolically healthy
obese (MHO)
Nonobese Subjects
(BMI <27 kg/m2)
Agenda
1. Definition of Metabolically Healthy Obese (MHO) and Insulin Resistance
Obese (IRO or Metabolically Abnormal Obese [MAO]);
2. Phenotypic differences between Metabolically Healthy Obese (MHO) and
Insulin Resistance Obese (IRO or Metabolically Abnormal Obese [MAO]):
a) Cardio-metabolic risk factors
b) Organ damage
3. Are MHO protected from the development of T2D, CVD and mortality?
4. Treatment options for MHO and IRO.
BMI in MHO, insulin resistant obese subjects, and nonobese subiects
23,8
37,7 39
0
5
10
15
20
25
30
35
40
BM
I (K
g/m
2) P<0.0001
Metabolically healthy obese
(MHO)
Nonobese subjects
P=0.56
Marini et al. Diabetes Care 30: 2145-2147, 2007
Insulin resistant obese subjects
(IRO)
Waist circumference is lower in MHO as compared with IRO, but it is higher as compared with nonobese subjects
76
98
106
40
60
80
100
120
Wa
ist
cir
cu
mfe
ren
ce
(c
m)
P<0.0001
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
Nonobese subjects
P=0.04
Succurro E. et al. Obesity 16: 1881–1886, 2008
Klöting eN t al. Am J Physiol Endocrinol Metab 299:E506-E515, 2010
Macrophage infiltration was significantly higher in omental fat of IRO subjects
Insulin resistant obese
subjects (IRO)
Metabolically healthy,
but obese (MHO)
Marini et al. Diabetes Care 30: 2145-2147, 2007
113
122
132
70
80
90
100
110
120
130
140
Systo
lic b
loo
d p
ressu
re
(mm
Hg
) P=0.002
Nonobese subjects
P=0.05
Systolic blood pressure is higher in MHO as compared with nonobese subjects, but lower as compared with IRO
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
Marini et al. Diabetes Care 30: 2145-2147, 2007
73
77
84
40
45
50
55
60
65
70
75
80
85
Dia
sto
lic b
loo
d p
ressu
re
(mm
Hg
) P=0.02
Nonobese subjects
P=0.02
Diastolic blood pressure is higher in MHO as compared with nonobese subjects, but lower as compared with IRO
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
Marini et al. Diabetes Care 30: 2145-2147, 2007
77
98
152
0
20
40
60
80
100
120
140
160
Tri
gly
red
ide
s
(mg
/d
l) P=0.06
Nonobese subjects
P=0.008
Triglyceride levels are higher in MHO as compared with nonobese subjects, but lower as compared with IRO
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
0,51
0,59
0,94
0
0,2
0,4
0,6
0,8
1
FFA
(m
Eq
/l)
Nonobese subjects
Free fatty acid levels are higher in IRO as compared with nonobese subjects, and MHO
P=0.24 P=0.04
P=0.001
Succurro E. et al. Obesity 16: 1881–1886, 2008
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
Marini et al. Diabetes Care 30: 2145-2147, 2007
64
49 52
0
10
20
30
40
50
60
70
HD
L
(mg
/d
l) P<0.0001
Nonobese subjects
P=0.28
HDL levels are lower in MHO as compared with nonobese subjects
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
Marini et al. Acta Diabetol l51:257–261, 2014
87 89 92
0
20
40
60
80
100
Fa
sti
ng
pla
sm
a g
luco
se
(m
g/d
l) P=0.57
Nonobese subjects
P=0.58
Fasting plasma glucose levels do not differ between MHO and IRO subjects
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
103
114
127
0
20
40
60
80
100
120
140
2-h
glu
co
se
(m
g/d
l) P=0.08
Nonobese subjects
P=0.02
2-h glucose levels are lower in MHO as compared with IRO subjects
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
Marini et al. Acta Diabetol l51:257–261, 2014
597
560
461
0
100
200
300
400
500
600
P=0.39
P=0.04
Nonobese subjects
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
Marini et al. Acta Diabetol l51:257–261, 2014
Insulin clearance during euglycemic hyper-insulinemic clamp is lower in IRO as compared with MHO subjects
Insu
lin
cle
rea
nce
(
ml/
min
x m
2)
7
10
18
0
2
4
6
8
10
12
14
16
18
20
In
su
lin
(µ
U/m
l)
Nonobese Subjects
without MetS
Obese with Mets (MAO)
Obese without MetS (MHO)
42
56
120
0
20
40
60
80
100
120
140
Fasting insulin 2-h Insulin
Nonobese subjects
Insulin resistant obese (IRO)
Metabolically healthy obese
(MHO)
Fasting and 2-h insulin levels are lower in MHO as compared with IRO subjects
Marini et al. Acta Diabetol l51:257–261, 2014
P<0.0001 P<0.0001
P<0.0001
P=0.01 P<0.0001
P<0.0001
Agenda
1. Definition of Metabolically Healthy Obese (MHO) and Insulin Resistance
Obese (IRO or Metabolically Abnormal Obese [MAO]);
2. Phenotypic differences between Metabolically Healthy Obese (MHO) and
Insulin Resistance Obese (IRO or Metabolically Abnormal Obese [MAO]):
a) Cardio-metabolic risk factors
b) Organ damage
3. Are MHO protected from the development of T2D, CVD and mortality?
4. Treatment options for MHO and IRO.
Marini et al. Diabetes Care 30: 2145-2147, 2007
0,68
0,79
0,89
0
0,2
0,4
0,6
0,8
1
IMT
(m
m)
P<0.0001
Nonobese subjects
P=0.03
IMT is higher in MHO as compared with nonobese subjects, but lower as compared with IRO
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
Sesti G. et al. Nutr Metab Cardiovasc Dis 21: 933-940, 2011
eGFR is significantly lower in IRO subjects as compared to MHO subjects after adjusting for age, gender, and BMI
102 101
94
50
60
70
80
90
100
110
P=0.18
Nonobese subjects
P<0.0001 e
GFR
(m
l/m
in/1
.73
m2)
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
19
23
32
0
10
20
30
40
ALT
le
ve
ls
(U/l)
P<0.0001
Nonobese subjects
P=0.007
ALT levels are lower in MHO as compared IRO with subjects
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
P adjusted for age and gender
Marini et al. Acta Diabetol l51:257–261, 2014
19 20
24
0
10
20
30
AS
T l
eve
ls
(U/l)
P=0.02
Nonobese subjects
P<0.0001
AST levels are lower in MHO as compared IRO with subjects
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
P adjusted for age and gender
Marini et al. Acta Diabetol l51:257–261, 2014
Stephan N et al. Arch Intern Med 168:1609-1616, 2008
Liver fat in MHO is lower as compared with IRO, but higher as compared with nonobese
Insulin-resistant obese subjects
Insulin-sensitive obese subjects
overweight subjects
Normal weight subjects
Agenda
1. Definition of Metabolically Healthy Obese (MHO) and Insulin Resistance
Obese (IRO or Metabolically Abnormal Obese [MAO]);
2. Phenotypic differences between Metabolically Healthy Obese (MHO) and
Insulin Resistance Obese (IRO or Metabolically Abnormal Obese [MAO]):
a) Cardio-metabolic risk factors
b) Organ damage
3. Are MHO protected from the development of T2D, CVD and mortality?
4. Treatment options for MHO and IRO.
MHO have a lower RR for incident type 2 diabetes as compared with IRO subjects - Framingham Offspring Study 6.8 yr follow-up (IS definition)
Meigs JB et al. J Clin Endocrinol Metab 91: 2906–2912, 2006
1
3,79
15,1
0
4
8
12
16 A
dju
ste
d R
Rs f
or
incid
en
t ty
pe
2 d
iab
ete
s
CI 7.8-29.3
CI 1.6-8.6
Nonobese subjects
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
MHO have similar OR for incident type 2 diabetes compared with MAO subjects - Uppsala Longitudinal Study 20 yr follow-up (MetS definition)
Arnlov J al. Diabetes Care 34:61–65, 2011
1
12,2
11,0
0
2
4
6
8
10
12
14 A
dju
ste
d R
Rs f
or
incid
en
t ty
pe
2 d
iab
ete
s
CI 5.71-21.18
CI 5.10-28.96)
Nonobese Subjects without
MetS
Obese with Mets (MAO)
Obese without MetS (MHO)
MHO have a lower RR for incident CVD as compared with IRO subjects - Framingham Offspring Study 11.4 yr follow-up (IS definition)
Meigs JB et al. J Clin Endocrinol Metab 91: 2906–2912, 2006
1
1,49
2,14
0
0,5
1
1,5
2
2,5
Ad
juste
d R
Rs f
or
incid
en
t C
VD
(n
ew
on
se
t a
ng
ina
, fa
tal
an
d n
on
fata
l M
I o
r str
ok
e,
tra
nsie
nt
isch
em
ic a
tta
ck
, h
ea
rt f
ail
ure
, o
r in
term
itte
nt
cla
ud
ica
tio
n)
CI 1.4-3.2
CI 0.9-2.4
Nonobese subjects
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
MHO have similar OR for incident CVD as compared with MAO subjects - San Antonio Heart Study, 7.4 yr follow-up (MetS definition)
Aung K et al. J Clin Endocrinol Metab 98, 2013
1
3,9
5,2
0
1
2
3
4
5
6
OR
fo
r in
cid
en
t C
VD
(m
yo
ca
rdia
l in
farc
tio
n,
str
ok
e,
or
co
ron
ary
re
va
scu
lari
za
tio
n p
roce
du
re
at
foll
ow
-up
or
an
y m
en
tio
n o
f ca
rdio
va
scu
lar
de
ath
on
th
e d
ea
th
ce
rtif
ica
te)
CI 2.8-9.7
CI 2.0-7.7
Nonobese Subjects without
MetS
Obese with Mets (MAO)
Obese without MetS (MHO)
Metabolically Healthy Obesity and Risk of Mortality Does the definition of metabolic health matter? Whitehall II study, 17.7 yr follow-up
Hinnouho G-M et al. Diabetes Care 36:2294–2300, 2013
1
2,49
2,94
0
1
2
3
HR
fo
r C
V m
ort
ali
ty
CI 1.56-5.56
CI 1.05-5.91
Nonobese Subjects
without MetS
Obese with Mets (MAO)
Obese without MetS (MHO)
1 1,04
2,63
0
1
2
3
ATP-III HOMA
CI 1.51-4.60
CI 0.41-2.66
Nonobese subjects
Insulin resistant obese (IRO)
Metabolically healthy obese
(MHO)
Agenda
1. Definition of Metabolically Healthy Obese (MHO) and Insulin Resistance
Obese (IRO or Metabolically Abnormal Obese [MAO]);
2. Phenotypic differences between Metabolically Healthy Obese (MHO) and
Insulin Resistance Obese (IRO or Metabolically Abnormal Obese [MAO]):
a) Cardio-metabolic risk factors
b) Organ damage
3. Are MHO protected from the development of T2D, CVD and mortality?
4. Treatment options for MHO and IRO.
Incidence of the metabolic syndrome among IGT participants without the syndrome at baseline in the Diabetes Prevention Program
(MHO equivalent?)
Orchard TJ et al. Ann Intern Med 142:611-61, 2005
53
47
38
0
10
20
30
40
50
60
Incid
en
ce
of
me
tab
oli
c s
yn
dro
me
(P <0.001)
Placebo group (n=490)
Metformin group (n=503)
Lifestyle group (n=530)
3 years follow-up
Effect of lifestyle-induced weight loss on insulin sensitivity in Metabolically Healthy Obese subjects
Follow-up (months)
MHO % change in
weight
MAO % change in
weight
MHO % change in
insulin sensitivity
MAO % change in
insulin sensitivity
Shin M-J et al. (2006) 3 3% 3% +7% (HOMA)
+8% (HOMA)
Karelis AD et al. (2008) 6 -6% -7% -13% (Clamp)
+26% (Clamp)
Janiszewski PM et al. (2010) Men Women
3-6 -4%
-3.5%
-6% -5%
+22% +19% (Clamp)
+52% +31% (Clamp)
Kantartzis K et al. (2011) 9 -2.4% -3% -6% (OGTT)
+30% (OGTT)
Shin MJ et al. Int J Obes (Lond) 30: 1529–1534, 2006 Karelis AD et al. Diabetologia 51:1752–1754, 2008
Janiszewski PM et al. Diab Care 33, 1957–1959, 2010 Kantartzis K et al. Diabetologia 54, 864–868, 2011
Effects of weight loss on body weight in MHO and MAO subjects after laparoscopic adjustable gastric banding and hypocaloric diet
Sesti G et al PLoS ONE 6(3): e17737, 2011
108
118
92
102
0
20
40
60
80
100
120
MHO (n=48)
Bo
dy w
eig
ht
(K
g)
Baseline 6-months follow-up
Baseline 6-months follow-up
P<0.0001
14% change
13% change
MAO (n=142)
P<0.0001
Effects of weight loss on insulin sensitivity in Metabolically Healthy Obese subjects after laparoscopic adjustable gastric banding and hypocaloric diet
108
47
141
84
0
20
40
60
80
100
120
140
160
MHO (n=48)
P=0.02
Ma
tsu
da
in
de
x
Sesti G et al PLoS ONE 6(3): e17737, 2011
Baseline 6-months follow-up
Baseline 6-months follow-up
P<0.0001
31% change
96% change
MAO (n=142)
Conclusions
1. Metabolically Healthy Obese (MHO) subjects have an intermediate cardiovascular
risk profile between healthy nonobese subjects and Obese Insulin-Resistant (IRO)
subjects
2. Obese Insulin-Resistant (IRO) subjects exhibit defects in compensatory β-cell
function as compared with Metabolically Healthy Obese (MHO) subjects;
3. Lifestyle intervention is the more appropriate treatment for MHO;
4. If diet and exercise do not work, pharmacological treatment (metformin) or
bariatric surgery may be considered.
THANK YOU !
Sesti lecture
Metabolically healthy, but obese
(MHO)
Insulin resistant obese subjects
(IRO)
Visceral fat
Fat liver =
Fasting glucose =
2-h Post-load glucose =
Blood pressure
Triglycerides
HDL
IGF-1 =
IMT
eGFR =
1st Phase insulin secretion
Disposition index
Risk of development of DM2
Risk for CVD =/
Phenotypic differences between Metabolically Healthy Obese
(MHO) and Metabolically Abnormal Obese (MAO or Insulin
Resistance Obese [IRO]) in insulin secretion.
1st phase insulin secretion during OGTT is lower in Metabolically Healthy Obese (MHO) as compared with IRO subjects
Sesti G ADA 2013
1179
1597
0
400
800
1200
1600 S
tum
vo
ll 1
st
ph
ase
in
de
x P=0.001
Metabolically healthy
obese (MHO)
Insulin resistant obese subjects
(IRO)
Disposition index is higher in Metabolically Healthy Obese (MHO) as compared with IRO subjects
55
Dis
po
sit
ion
in
de
x
(Stu
mvo
ll 1
st p
ha
se
in
de
x x
MFFM
)
55
18046
11159
0
5000
10000
15000
20000
P<0.0001
Metabolically healthy
obese (MHO)
Sesti G ADA 2013
Insulin resistant obese subjects
(IRO)
13,8
13,0
7,9
0
2
4
6
8
10
12
14
16
P=0.50
P<0.0001
Nonobese subjects
Insulin resistant obese subjects
(IRO)
Metabolically healthy obese
(MHO)
Marini et al. Acta Diabetol 2013
Insulin hepatic extraction is lower in IRO as compared with MHO subjects
Pla
sm
a C
-pe
pti
de
/
Pla
sm
a in
su
lin
ra
tio