T h e n e w e n g l a n d j o u r n

a l o f m e d i c i n e
original article
Retinol-Binding Protein 4
and Insulin Resistance in Lean, Obese,
and Diabetic Subjects
Timoth !" #raham, $"D", %in &ang, $"D", Ph"D", $atthias Bl'her, $"D",
(nn )ammarstedt, Ph"D", Theodore P" *iaraldi, Ph"D", Robert R" )enr,
$"D", *hristo+her ," -ason, B"S", (ndreas Oberbach, Ph"D", Per-(nders
,ansson, $"D", Ph"D", .l/ Smith, $"D", Ph"D", and Barbara B" 0ahn, $"D"
( b s t r a c t
1rom the Di2ision o/ !ndocrinolog, Dia-betes,
and $etabolism, De+artment o/ $edicine, Beth
Israel Deaconess $edi-cal *enter and )ar2ard
$edical School, Boston 3T"!"#", %"&", *","-",
B"B"0"45 the De+artment o/ $edicine,
.ni2ersit o/ Lei+6ig $edical *enter, Lei+6ig,
#erman 3$"B", ("O"45 the Lundberg
Laborator /or
Diabetes
Research,
De+artment o/
Inter-nal
$edicine,
Sahlgrens7a
.ni2ersit )os-
+ital, #8teborg,
Sweden 3(")",
P"-(" ,", ."S"45
and the 9eterans (//airs San Diego )ealth-
care Sstem, San Diego, *ali/", and the De-
+artment o/ $edicine, .ni2ersit o/ *ali-/ornia,
San Diego, La ,olla 3T"P"*", R"R")"4" (ddress
re+rint re:uests to Dr" 0ahn at the Di2ision o/
!ndocrinolog, Diabetes, and $etabolism,
Beth Israel Deaconess $edical *enter, ;;
Broo7line (2e", Boston, $( <==>?, or at
b7ahn@bidmc"har2ard" edu"
Drs" #raham and &ang contributed
e:uall to this article"
A !ngl , $ed =<<B5C?4D=??=-BC"
Copyright 2006 Massachusetts Medical Society.
Backgroun
d
Insulin
resistance
has a
causal role
in t+e =
diabetes"
Serum
le2els o/
retinol-
binding
+rotein 4
3RBP44, a
+rotein
secreted b
adi+octes,
are
increased
in insulin-
resistant
states"
!E+eriment
s in mice
suggest
that
ele2ated
RBP4
le2els
cause
insulin
resis-tance"
-e sought
to
determine
whether
serum
RBP4
le2els
correlate
with insulin
re-sistance
and change
a/ter an
inter2ention
that im+ro2es insulin sensiti2it"
-e also determined whether
ele2ated serum RBP4 le2els
are associated with reduced
eE+res-sion o/ glucose
trans+orter 4 3#L.T44 in
adi+octes, an earl
+athological /eature o/ insulin
resistance"
Methods
-e measured serum RBP4,
insulin resistance, and
com+onents o/ the metabolic sn-
drome in three grou+s o/
subjects" $easurements were
re+eated a/ter eEercise train-ing
in one grou+" #L.T4 +rotein was
measured in isolated adi+octes"
Results
Serum RBP4 le2els correlated
with the magnitude o/ insulin
resistance in subjects with
obesit, im+aired glucose
tolerance, or t+e = diabetes
and in nonobese, non-diabetic
subjects with a strong /amil
histor o/ t+e = diabetes"
!le2ated serum RBP4 was
associated with com+onents o/
the metabolic sndrome,
including increased bod-mass
indeE, waist-to-hi+ ratio, serum
triglceride le2els, and sstolic
blood +res-sure and decreased
high-densit li+o+rotein
cholesterol le2els" !Eercise
training was associated with a
reduction in serum RBP4 le2els
onl in subjects in whom insulin
resistance im+ro2ed" (di+octe
#L.T4 +rotein and serum
RBP4 le2els were in2ersel
correlated"
Conclusions
RBP4 is an
adi+octe-
secreted
molecule that
is ele2ated in
the serum
be/ore the de2el-o+ment o/
/ran7 diabetes and a++ears
to identi/ insulin resistance
and associated
cardio2ascular ris7 /actors in
subjects with 2aried clinical
+resentations" These
/indings +ro2ide a rationale
/or antidiabetic
thera+ies
aimed at
lowering
serum RBP4
le2els"
=??= n engl j med C?45=4
www"nejm"org june
>?, =<<B
The
New
England
Journal
of
Medi
cine
Downloaded from nejm.org on April
1, 2014. For personal use only.
No other uses without
permission. Copyright 2006
Massachusetts Medical
Society. All rights
reserved.
r etinol-binding +rotein 4 and insulin r esistance
+e = diabetes is caused b resistance
ters4"
>4
De/initions o/ normal glucose
tolerance,
to insulin action in multi+le tissues, accom- im+aired glucose tolerance, and t+e = diabetes
T +anied b /ailure o/ the +ancreatic beta were based on the >;;F (merican Diabetes (s-
cells to com+ensate su//icientl b increased
in-
sociation criteria /or glucose 2alues obtained
a/ter
sulin secretion"
>
$easurement o/ insulin
resistance
an o2ernight /ast and a two-hour oral glucose-
tol-
+ro2ides an earl and strong +redictor o/
t+e = erance test 3O#TT4, conducted with a standard
diabetes"
=
!2en in the absence o/
h+erglcemia
loading dose o/ F? g"
>?
1or clam+ studies, the
rate
or diabetes, insulin resistance constitutes an
im-
o/ glucose dis+osal was de/ined as the glucose
in-
+ortant ris7 /actor /or cardio2ascular disease
and /usion rate during the /inal C< minutes"
>B
Standard
earl death"
C
Obesit, which has reached
e+idem-
techni:ues were used to measure +lasma
glucose,
ic +ro+ortions worldwide, is a major cause o/
in- serum or +lasma insulin, and serum li+ids"
>F,>G
sulin resistance"
4
)owe2er, insulin resistance
does
-ritten in/ormed consent was obtained /rom
each
not de2elo+ in all obese +ersons, and genetic
bac7-
subject" Sam+les were collected and clam+
studies
ground contributes strongl to insulin
resistance, were conducted between >;;B and =<<4"
e2en in nonobese +ersons"
?
In insulin-resistant states, the eE+ression o/
the Measurement of Serum RBP4
glucose-trans+orter 4 3#L.T44, the +rinci+al
in-
Serum RBP4 was measured b an en6me-
lin7ed
sulin-stimulated glucose trans+orter, is down-
reg-
immunosorbent assa 3!LIS(4 3(LP*O
Diag-
ulated selecti2el in adi+octes and not in
s7eletal nostics4 in grou+s > and C and b :uantitati2e
muscle
B
5 this results in im+aired insulin-
stimu- -estern blotting
;
with +uri/ied human RBP4
lated glucose trans+ort in adi+octes"
B
These
de-
standards in grou+ =" Immunodetection was
+er-
/ects +recede glucose intolerance"
B,F
)owe2er,
the
/ormed with a +olclonal antibod to human
RBP4
conse:uences o/ decreased #L.T4 eE+ression
in 3Da7o*tomation4" !LIS( sam+les were run in
adi+octes ha2e been unclear, since adi+ose
tissue
du+licate, and -estern blotting sam+les were
run
contributes little to whole-bod glucose
dis+osal"
B
once" The coe//icient o/ 2ariation /or interassa
#enetic 7noc7out o/ #L.T4 selecti2el in
adi+o- re+licate sam+les was less than F +ercent /or
ctes o/ mice
G
results in increased serum le2els
o/ !LIS( and less than >< +ercent /or :uantitati2e
retinol-binding +rotein 4 3RBP44"
;
Injection o/
+uri- -estern blotting"
/ied RBP4 into mice or transgenic
o2ereE+ression
o/ RBP4 in mice im+airs insulin signaling
in Group 1
muscle and induces the eE+ression o/ the
gluco- The eE+erimental +rotocol /or grou+ > was a+-
neogenic en6me +hos+hoenol+ru2ate
carboE- +ro2ed b the *ommittee on )uman In2estiga-
7inase in the li2er"
;
RBP4 is the onl
s+eci/ic tion o/ the .ni2ersit o/ *ali/ornia, San Diego"
trans+ort +rotein /or retinol 32itamin (4 in
the
Subjects were recruited as +re2iousl
described,
>F
circulation"
><,>>
!le2ated RBP4 le2els ha2e been
re-
and serum RBP4 le2els were measured" (ll
lean
+orted in +eo+le with t+e = diabetes"
>=,>C
In
an
subjects, none o/ whom were diabetic, and all
non-
earlier stud, we /ound that serum RBP4 le2els
are
diabetic o2erweight or obese subjects had
normal
increased in man insulin-resistant states
induced
glucose tolerance" .ntil se2eral wee7s be/ore
the
b genetic and dietar /actors"
;
There/ore, we
as- stud, diabetic subjects recei2ed treatment with
sessed whether serum RBP4 le2els are
correlated met/ormin, sul/onlurea, or insulin, alone or in
with the magnitude o/ insulin resistance and
car- combination, but not treatment with thia6olidin-
dio2ascular ris7 /actors and whether a
thera+eutic ediones" (ll diabetes-s+eci/ic medications were
inter2ention that im+ro2es insulin sensiti2it is
as-
withdrawn at least two wee7s be/ore studies
were
sociated with a reduction in serum RBP4
le2els"
+er/ormed" Subjects with t+e = diabetes were
oth-
erwise well and were not ta7ing other medica-
$ e t hod s tions 7nown to in/luence glucose metabolism"
The euglcemicHh+erinsulinemic clam+
+rotocol
Study Groups has been described +re2iousl"
>F
O2erweight and obesit were de/ined
according
to the -orld )ealth Organi6ation criteria on
the Group 2
basis o/ the bod-mass indeE 3the weight in
7ilo-
1or grou+ =, the stud was a++ro2ed b the
ethics
grams di2ided b the s:uare o/ the height in
me-
committee o/ the .ni2ersit o/ Lei+6ig" SiEt
white
n engl j med C?45=4www"nejm"orgjune >?, =<<B =??C
The New England Journal of Medicine
Downloaded from nejm.org on April 1, 2014. For personal use only. No other uses without permission.
Copyright 2006 Massachusetts Medical Society. All rights reserved.
=??4

C
o
r
M
a
.
2
Ne
wT
he
m
e
d
j
e
n
g
l
n
Tale 1! Relationship of Serum RBP4 "e#els to $nsulin Resistance and %ssociated Metaolic &alues!'
Group 1
Clinical
No. and
Sex RBP4 Age yr BMI GDR Insulin Glucose Glycated
Triglycerides

eatures o! Su"#ects $g%&l 'range( 'range( 'range( &g%)g%&in $*%&l &g%dl +e&oglo"in &g%dl
'range(, 'range(- 'range(. / 'range( 'range(0
1ean
'controls( 2 M 34.567.8 45677 34.568.2 74.963.3 4.967.9 :864 2.868.3 ::644
'34.8;34.4( '38;45( '34.8;34.4( '73;79( '3.2;<.9( '54;:4( '4.5;2.4( '97;727(
="ese> no 9 M 4:.462.8?? 456: 43.464.3?? 5.263.4?? 7<.262.5?? :<69 2.268.< 3736747??
dia"etes '42.7;45.:( '49;<4( '48.8;49.4( '2;74( ':.3;32.:( '55;785( '4.4;<.7( '24;47<(
="ese> ty@e 3 : M 48.5678.5?? 2565?? 47.<64.2?? <.267.4?? 7<.<64.3?? 743644??,, <.567.7??,, 7<56:4
dia"etesAA '34.:;28.4( '4<;<5( '39.9;48.:( '2;:( '4.3;28.3( ':2;38:( '2.4;5.2( '22;424(
S@ear&an correlation
coe!!iB 8.35 8.<4 C8.22 8.93 8.48 8.24 8.48
cient 'R( DitE seru& 'C8.79 to 8.<4( '8.48 to 8.54( 'C8.9: to C8.7<( '8.47 to 8.55( 'C8.84 to 8.98( '8.74 to 8.95( 'C8.83 to 8.97(
RBP4 ':2/ CI(
T

h
.
res
erv
edr
igh
tsA
ll.S
oci
ety
Me
dic
alw
ith
out
use
sot
her
No.
onl
yus
epe
rso
nal
For
Me
dic
ine
ofJ
our
nal
En
gla
nd
=
<
<
B
>
?
,j
u
n
e
o
r
g
"
n
e
j
m
"
w
w
w
C
?
4
5
=
4
.
p
er
m
is
si
o
n
P Falue 8.33 8.887
Clinical
No. and
Sex RBP4 Age yr BMI
eatures o! Su"#ects $g%&l 'range( 'range( 'range(
Nor&al
glucose 38 3<.469.7 44677 34.467.2
tolerance ': M%77 ( '74.8;44.:( '37;25( '37.9;39.2(
'controls(
I&@aired
glucose 38 2:.:643.5?? 2<673?? 3:.564.:??
tolerance ': M%77 ( '35.:;74:.8( '32;94( '32.8;43.7(
Ty@e 3
dia"etes 38 <4.3634.:?? 2469?? 48.964.3??
'77 M%: ( '3:.<;73:.7( '45;<2( '39.4;45.4(
S@ear&an correlation
coe!!iB 8.32 8.<3
cient 'R( DitE seru& RBP4 'C8.87 to 8.49( '8.44 to 8.92(
':2/ CI(
P Falue 8.8< G8.887
Clinical
No. and
Sex RBP4 Age yr BMI
eatures o! Su"#ects $g%&l 'range( 'range( 'range(
8.88: G8.887 8.8< 8.87 8.8<
Group 2
HaistBtoB
+i@ GDR Insulin Glucose Glycated +D1
Systolic
Blood
Ratio &g%)g%&in $*%&l &g%dl +e&oglo"in CEolesterol Pressure
'range( 'range( 'range( 'range( / 'range( &g%dl && +g
'range(-- 'range(
8.:68.83 74.264.8 4.563.2 :46: 2.368.7 24673 734678
'8.9;7.7( ':;75( '3.4;73.:( '94;785( '2.8;2.2( '48;99( '782;748(
7.368.84?? 4.467.<?? 28.3642.9?? 784678?? 2.968.3?? 4869?? 7496<??
'8.5;7.4( '7;<( '3.4;747.5( '99;732( '2.4;<.3( '44;24( '73<;74<(
7.468.84?? 4.567.9??
34.7672.4??,, 774677??,, <.468.4??,,
4965?? 74:62??
'7.7;7.4( '3;5( '5.4;9<.7( ':8;744( '2.:;9.7( '34;49( '73:;728(
8.<5
C8.95
8.29 8.4< 8.<2
C8.22
8.<3
'8.4: to 8.53( 'C8.5< to C8.<2( '8.49 to 8.93( '8.34 to 8.<4( '8.49 to 8.99( 'C8.98 to C8.44( '8.44 to 8.9<(
G8.887 G8.887 G8.887 8.883 G8.887 G8.887 G8.887
Group (
GDR Insulin Glucose
Triglycerides

Systolic
Blood
&g%)g%&in $*%&l &g%dl &g%dl Pressure
'range( 'range( 'range( 'range( && +g 'range(
l

r etinol-binding +rotein
Aon
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s
=B
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=
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L
<
"
<
<
>
<
"
<
<
;
M Blood
/or all
studies
was
drawn
with the
subject
in the
/asting
state"
Data are
gi2en as
means
ISD"
0rus7alH
-allis
analsis
o/
2ariance
with
+airwise
com+ari
sons
was
used to
deter-
minedi//
erences
amongth
ethreecli
nicalcate
goriesin
grou+s>
and="RB
P4denot
esretinol
-
binding+
rotein4,
B$Ibod
-
massind
eE,#DR
glucose
dis+osal
rate,and
)DLhigh
-den-
sitli+o+r
otein"NT
ocon2ert
2alues/o
rglucose
dis+osalt
omicrom
oles+er7
ilogram+
erminute
,multi+l
b?"?4;"
OTocon2
ert2alue
s/orinsuli
nto+ico
moles+e
rliter,mul
ti+lbF"
>F?"PTo
con2ert2
alues/or
glucoset
omillimol
es+erlite
r,multi+l
b<"<??
4;"QToc
on2ert2a
lues/ortri
glcerid
estomilli
moles+e
rliter,mul
ti+lb<"
<>>=;"RR
PL<"<?/
ortheco
m+ariso
nwithlea
ncontrol
subjectsi
ngrou+>
orcontrol
subjects
withnor
malgluc
osetoler
anceingr
ou+="MMT
wosubje
ctsinthe
obese,t
+e=diab
etesgrou
+hadbod
-mass-
indeE2al
ueso/les
sthanC<
atthetim
ethebloo
dwasdra
wn/orthi
sstud"N
NPL<"<?
/ortheco
m+ariso
nbetwee
nobeses
ubjectsw
ithoutdia
betesan
dobeses
ubjectsw
ithdiabet
esingrou
+>orbet
weensu
bjectswit
hnormal
glucoset
olerance
andsubj
ectswitht
+e=dia
betesing
rou+="OO
Tocon2e
rt2alues/
or)DLch
olesterol
tomillim
oles+erli
ter,multi
+lb<"<
=?;"
4 and insulin r esistance
men and women with normal glucose tolerance, im+aired glucose tolerance, or t+e = diabetes 3=< +er grou+4 were randoml
selected /rom 4B; +eo-+le screened b O#TT as +artici+ants in a health sur2e"
>G
Be/ore screening, the subjects had no
histor o/ t+e = diabetes, gestational diabetes, in-sulin resistance, or the metabolic sndrome and had not +re2iousl been
treated with medications /or diabetes" Thus, those with abnormal glucose metabolism had newl recei2ed the diagnosis on
the basis o/ /asting glucose le2els and the results o/ O#TT" In addition, subjects with normal glu-cose tolerance had no /amil
histor o/ diabetes" Other eEclusion criteria are described elsewhere"
>G
The subjects underwent su+er2ised +hsical training 3B< minutes o/ biccling and running +er da /or at least three das
+er wee74" (t base-line and a/ter /our wee7s o/ training, but at least three das a/ter the last eEercise session, /asting blood
sam+les were obtained /or metabolic assas" Be/ore and a/ter training, the bod-mass indeE and waist-to-hi+ ratio were
determined5 the +er-centage o/ bod /at was measured b dual-energ E-ra absor+tiometr5 a euglcemicHh+erinsulin-emic
clam+ stud was +er/ormed5 and a graded biccle ergometr stud to 2olitional eEhaustion was +er/ormed" The highest
oEgen u+ta7e +er
minute 3O= 4 was measured" The clam+ +rotocol
$(S
and assas /or adi+onectin, le+tin, interleu7in-B, and *-reacti2e +rotein ha2e been described +re-
2iousl"
>G,>;
The subjects were di2ided into three grou+s on the basis o/ the magnitude o/ the change in insulin sensiti2it during
the clam+ stud 3glucose dis+osal rate4 with eEercise training" Subjects in the lowest third had small or no
im+ro2ements in the rate o/ glucose dis+osal 3mean TISDU in-crease, <"BI<"C mg +er 7ilogram +er minute, or less than
>? +ercent o2er baseline4 and were cat-egori6ed as ha2ing a marginal insulin-sensiti2it res+onse to eEercise training"
Similar results were obtained with a :uartile-based ran7ing sstem 3data not shown4"
Group (
1or grou+ C, the stud was a++ro2ed b the ethics committee o/ #8teborg .ni2ersit and was con-ducted in a manner
consistent with the +rinci+les o/ the Declaration o/ )elsin7i" )ealth men with at least one /irst-degree relati2e with t+e = dia-
betes were recruited b ad2ertisements in local news+a+ers" The inclusion criteria were an age o/
n engl j med C?45=4www"nejm"orgjune >?, =<<B =???
The New
England
Journal of
Medicine
Downloaded from nejm.org on April 1, 2014. For personal use
only. No other uses without permission. Copyright
2006 Massachusetts Medical
Society. All rights reserved.
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
=? to ?? ears, a
bod-mass
indeE o/ == to
C<, nor-mal
glucose
tolerance,
/asting
triglceride le2el
less than >?<
mg +er deciliter
3>"F mmol +er li-
ter4, and the
absence o/
7nown
endocrine or
met-abolic
disease" The
subjects were
as7ed to abstain
/rom alcohol and
eEcessi2e
+hsical
eEercise /or two
das be/ore
each
eEamination or
s+ecimen-
collection da"
The clam+
+rotocol has
been de-scribed
+re2iousl"
=<
Se2eral das
be/ore the clam+
stud,
subcutaneous
adi+ose-tissue
bio+sies were
+er/ormed and
adi+octes were
immediatel iso-
lated b
collagenase
digestion"
#L.T4 was
mea-sured in
lsates b
-estern
blotting"
=<,=>
Statistical
%nalysis
The results are
eE+ressed as
means ISD"
Linear
correlations and
non+arametric
statistical tests
were +er/ormed
with (nalse-it
32ersion >"F>,
(nalse-it
So/tware4, and
inde+endentl
con/irmed with
Stat9iew
32ersion ?"<,
S(S Institute4"
(ll re-+orted P
2alues are two-
tailed and are
not ad-justed /or
multi+le testing"
$ulti2ariate
regres-sion
analsis was
+er/ormed with
Data Des7VSL
32ersion >">,
DataDescri+tion
4"
R e
s u
l t s
Serum RBP4
in )ese
Su*ects
+ith and
those +ithout
Type 2
,iaetes
Obese,
nondiabetic
subjects and
obese subjects
with t+e =
diabetes had
similar bod-
mass indeE
2alues5 all but
two subjects
had a bod-
mass in-deE o/
C< or greater
3Table >4" The
a2erage rate o/
glucose
dis+osal during
the clam+ stud
was 4= +ercent
lower in obese,
nondiabetic
subjects and ?B
+ercent lower in
subjects with
t+e = diabetes
than in lean
control subjects"
The mean
serum RBP4
le2el in grou+ >
control subjects
was con-sistent
with re+orted
normal 2alues
in health
inhabitants o/
2itamin (H
su//icient
regions 3Ta-ble
>4"
><
The mean
serum RBP4
le2els were
ele2at-ed in
both
nondiabetic and
diabetic obese
sub-jects and
serum RBP4
le2els
correlated
+ositi2el with
bod-mass
indeE 31ig" >(4
3P W <"<<>4 and
/asting insulin
le2els 31ig" >B4
3PL<"<<>4 and
cor-related
in2ersel with
the rate o/
glucose
dis+osal 3Table
>4 3P W <"<<;4"
$ulti2ariate
regression
anal-sis
showed that the
RBP4 le2el
correlated with
the rate o/
glucose
dis+osal
inde+endentl
o/ age 3P W
<"<<44 but not
inde+endentl
o/ bod-mass
in-deE 3P W
<"<B45 RBP4
also correlated
with /asting
insulin
inde+endentl
o/ the rate o/
glucose dis-
+osal 3P W
<"<<C4" The
serum RBP4
le2el correlat-ed
with the glcated
hemoglobin
2alue but not
with the /asting
glucose le2el
3Table >4" Thus,
e2en in the
absence o/
h+erglcemia
or diabetes,
serum le2els o/
RBP4 were
ele2ated and
were correlated
with bod-mass
indeE and insulin
re-sistance in
o2erweight and
obese subjects"
-ffects of
-.ercise
Training in
Su*ects
+ith $mpaired
Glucose
Tolerance
Subjects with
im+aired
glucose
tolerance or
t+e = diabetes
underwent
eEercise
training to
deter-mine the
e//ects o/ an
insulin-
sensiti6ing
thera+ on
serum RBP4" In
grou+ =,
subjects with
diabe-tes had
higher /asting
blood glucose
le2els but lower
insulin le2els
than subjects
with im+aired
glucose
tolerance, a
/inding
consistent with
di-minished
beta-cell
com+ensation
/or insulin re-
sistance 3Table
>4" The
baseline
glucose
dis+osal rate
was reduced in
all subjects
with im+aired
glu-cose
tolerance or
diabetes as
com+ared with
the rate in
controls, a
/inding
indicating
insulin re-
sistance" The
subjects in
grou+ = 3Table
>4 with
im+aired
glucose
tolerance or
diabetes had
high-er
baseline le2els
o/ +lasma
le+tin, +lasma
*-reac-ti2e
+rotein,
+lasma
interleu7in-B,
and serum /ree
/att acids than
control
subjects 3data
not shown4,
whereas the
had lower
+lasma le2els
o/ high-densit
li+o+rotein
3)DL4
cholesterol
3Table >4 and
adi+onectin
3data not
shown4, a
/inding consis-
tent with those
o/ other
re+orts"
==,=C
(lthough the
had the same
degree o/
insulin
resistance,
subjects with
diabetes had
higher baseline
le2els o/ *-
reac-ti2e
+rotein,
interleu7in-B,
and /ree /att
acids than
those with
im+aired
glucose
tolerance 3data
not shown4"
Serum
RBP4 le2els
were higher in
subjects with
im+aired
glucose
tolerance or
diabetes than in
controls 31ig"
=(4" There was
no a++arent
e//ect o/ seE on
serum RBP4
le2els 31ig" =(4"
RBP4 le2els
correlated
in2ersel with
the rate o/
glucose dis-
+osal 31ig" =B4,
e2en a/ter the
combined
contri-butions o/
age and bod-
mass indeE had
been controlled
/or b
multi2ariate
regression
analsis
3PL<"<<>4" In
grou+ =, the
serum RBP4
le2el corre-lated
+ositi2el with
the /asting
glucose le2el,
insu-lin le2el,
glcated
hemoglobin
2alue, and
sstolic blood
+ressure and
correlated
in2ersel with
the )DL
cholesterol le2el
3Table >4" (lso
in grou+ =, the
serum RBP4
le2el was more
highl
correlated with
the waist-to-hi+
ratio than with
the bod-mass
indeE 3Table >4
or the
+ercentage o/
bod
=??B
n engl j
med
C?45=4
www"nejm"
org june >?,
=<<B
The
New
Engla
nd
Journal
of
Medici
ne
Downloaded from
nejm.or
g on
April 1,
2014.
For
personal
use only. No
other uses
without
permission.
Copyright
2006
Massachusett
s Medical
Society. All
rights
reserved.
r etinol-binding +rotein 4 and insulin r esistance
Lean subjects
Obese
nondiabetic
Obese
diabetic
subjects subjects
%
R
B
P
4
(

g
/
m
l)
B
B
?
RW<"
B4
B
<
PW<"
<<>
?
?
?
<
4
?
4
<
C
?
C
<
=
?
=
<
<

<
==
=F
C=
CF 4=
B
o
d
y-
M
as
s
In
d
ex
R
B
P
4

(

g
/
m
l
)
B
?
RW<"F=
B
<
PL<"<<>
?
?
?
<
4
?
4
<
C
?
C
<
=
?
=
<
<
< =< 4< B<
I
n
s
u
l
i
n

(

U
/
m
l
)
/igure 1!
R
e
lationshi
p of
S
e
In Panel
(, the ;?
+ercent con/idence inter2al
/or the S+earman
correlation
coe//icient o/
<"B4 was <"C<
to <"G4" In Panel
B, the ;?
+ercent
con/idence
inter2al /or the
S+earman
correlation
coe//icient o/
<"F= was <"4>
to <"GG" (ll
blood was
drawn a/ter an
o2ernight /ast"
To con2ert
2alues /or
insulin to
+icomoles +er
liter, multi+l b
F">F?"
/at 3data
not
shown45
this
obser2ati
on
suggests
a s+eci/ic
associatio
n
between
the serum
RBP4
le2el and
abdomina
l obesit,
a 7nown
ris7 /actor
/or insulin
resistance
and
cardio2as
cular
disease"
=
4-=B
The
res+onse
o/ whole-
bod
insulin
sensiti2-
it to one
month o/
eEercise
training
was
2ariable5
some
subjects
had little
or no
im+ro2em
ent in in-
sulin
sensiti2it"
*hanges
in serum
RBP4
le2els
correlated
in2ersel
with
changes
in the rate
o/ glucose
dis+osal
31ig" C(4"
In
contrast,
changes
in the rate
o
/
+
r
RB
P4
le2els
decre
ased
/rom
baseli
ne
le2els
a/ter
eEerci
se
trainin
g in all
subjec
ts in
the
highe
st
third
eEce+
t /or
one
subjec
t who
had a
norma
l
baseli
ne
RBP4
le2el
31ig"
CB4"
In
contra
st,
serum
RBP4
le2els
did
not
chang
e or
increa
sed in
all but
one
subjec
t in
the
lowest
third"
In the
middl
e
third,
RBP4
le2els
decre
ased
basel
ine
le2el
s
a/ter
eEerc
ise
traini
ng in
all
subje
cts in
the
highe
st
third
eEce
+t /or
one
subje
ct
who
had
a
norm
al
basel
ine
RBP
4
le2el
31ig"
CB4"
In
contr
ast,
seru
m
RBP
4
le2el
s did
not
chan
ge or
incre
ased
in all
but
one
subje
ct in
the
lowe
st
third"
In
the
middl
e
third,
RBP
4 le2els
decreased in >>
subjects, albeit
onl slightl in
some, and
increased in =
subjects" The
u++er two thirds
were grou+ed
/or metabolic
analses 3Table
=4" (erobic
conditioning,
assessed b
O=maE during
eEercise,
increased to a
similar eEtent in
both those with
marginal insulin
sen-siti2it
3lowest third4
and those with
im+ro2ed insulin
sensiti2it 3u++er
two thirds5 data
not shown4" In
subjects with
either marginal
or im-+ro2ed
insulin
sensiti2it,
eEercise training
was associated
with reductions
in bod-mass
indeE, bod-/at
+ercentage,
waist-to-hi+
ratio, and /ast-
ing insulin le2els
and an increase
in )DL choles-
terol le2els
3Table =4"
)owe2er, onl
subjects with
im+ro2ed insulin
sensiti2it had a
signi/icant im-
+ro2ement in
/asting glucose
le2els and
glucose le2els
during an O#TT
3Table =4"
!Eercise
training
increased
+lasma
adi+onec-tin
le2els
and
lowere
d *-
reacti2
e
+rotein
le2els
to the
same
eEtent
regardl
ess o/
whethe
r insulin
sensiti2
it
im+ro2
ed
3Table
=4"
!Eercis
e
training
was not
associa
ted with
change
s in
le+tin
or inter-
n engl j med C?45=4www"nejm"orgjune >?, =<<B =??F
The New
England
Journal of
Medicine
Downloaded from April 1, 2014.
use
onl
y.
No other
uses without
permission.
Copy
right

2006
Mass
achus
etts Medical
Society. All
rights
reserved.
%
B
0
m
g1
k
g1
m
in
2
Gl
u
c
o
se
,i
s
p
o
sa
l
R
at
e
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
>B<
(g/ml)
RPB4
Serum
=
<
>
B
>
=
G
4
<
>"
<
/
i
P
a
E

J
<
;
4
5
a
n
d

/
o
r
w
o
m
e
n
,
R
W
J
<
"
F
;

3
;
?

+
er
c
e
nt
c
o
n/
id
e
n
c
e
in
te
r2
al
,
J
<"
G
;
to
J
<"
B
<4
"
T
o
c
o
n2ert 2alues /or glu-cose dis+osal to
micromoles +er 7ilogram +er minute, multi+l
b ?"?4;"
l
e
u
7
i
n
-
B

l
e
2els" There/ore, a
change in the RBP4
le2el in res+onse to
eEercise training in a
gi2en subject +redicted
the degree o/
im+ro2ement in insulin
sensiti2it with greater
s+eci/icit than did the
res+onses o/ other
adi+o7ines or mar7ers o/
in/lammation that are
altered in obesit, t+e =
diabetes, or both"
Serum RBP4
and Genetic
Risk of Type
2
,iaetes
To determine
whether RBP4
is ele2ated
when in-sulin
resistance is
+resent in
+ersons
without obesit
or clinicall
a++arent
disease, we
studied
nonobese,
normoglcemi
c men with at
least one /irst-
degree relati2e
with t+e =
diabetes"
=<
The rate
= ??G n engl j med C?45=4 www"nejm"org
june >?, =<<B
The New
Engl
and
Jour
nal
of
Medicin
e
Downloaded from nejm.org on April 1,
2014. For
personal
use only.
No other
uses
without
permission.
Copyright 2006
Massachusetts
Medical Society.
All rights
reserved.
r etinol-binding +rotein 4 and insulin r esistance
/igure (!
Changes in
Serum RBP4
"e#els and
$nsulin Sensiti#ity
after -.ercise
Training in
Su*ects +ith
3e+ly ,iagnosed
$mpaired
Glucose
Tolerance or
Type 2
,iaetes in
Group 2!
Panel ( shows
coordinate and
in2erse
res+onses o/
the serum
RBP4 le2el
and insulin
sensiti2it o/
indi2idual
subjects to
eEercise
training" The
correlation
between
changes in
serum RBP4
l
e
2
e
l
s

3
l
o
g
Tbase->< scaleU
E aEis4 and changes
in the glucose
dis+osal rate 3linear
aEis4 caused b
one month o/
eEercise training
are shown5
S+earman
correlation
coe//icient R W
J<"GC 3;? +ercent
con/idence inter2al,
J<";> to J<"F<4"
Panel B shows
insulin sensiti2it
3glucose dis+osal
rate, le/t4 and serum
RBP4 le2els 3right4
in indi2idual
subjects se+arated
into thirds on the
basis o/ the
res+onse o/ glucose
dis+osal rate to
eEercise training"
Baseline and a/ter
eEercise re/er to
clam+ studies or
sam+ling o/ blood
be/ore eEercise
training and a/ter
one month o/
eEercise training"
Studies were
+er/ormed at least
three das a/ter the
last eEercise
session" The
asteris7 indi-cates P
W <"<<?, the dagger
PW<"<<=, and the
double dagger
PL<"<<> /or the
change in glucose
dis+osal rate or
RBP4 a/ter eEercise
training as
com+ared with
base-line 3-ilcoEon
signed-ran7 test4"
To con2ert 2alues
/or glucose dis+osal
to micromoles +er
7ilogram +er min-
ute, multi+l b
?"?4;"
o/ glucose dis+osal
during a
euglcemicHh+er-
insulinemic clam+
stud is a strong
+redictor o/ diabetes
in such +ersons,
who are at high ris7
/or t+e =
diabetes"
=>,=F-=;
These subjects had
a wide range o/
insulin sensiti2ities,
h+erinsulinemi
a, dsli+idemia,
and
h+ertension
3Table >4, a /ind-
ing consistent
with the 2ariable
contributions o/
their li/estles
and genetics to
their ris7 o/ t+e
= diabetes and
the metabolic
sndrome"
Serum RBP4
le2els correlated
in2ersel with
the rate o/
glucose dis+osal
31ig" 4(4 and
correlated +osi-
ti2el with
/asting insulin
le2els, the
insulin le2el in
res+onse to the
O#TT, /asting
triglceride
le2el, and
sstolic blood
+ressure 31ig"
4B4" Simi-lar
correlations
were obser2ed
between RBP4
le2el and these
metabolic
2alues in /emale
o//-s+ring o/
+ersons with
t+e = diabetes
3data not
shown4"
$ulti2ariate
regression
analsis showed
that the serum
RBP4 le2el
correlated with
the rate o/
glucose dis+osal
inde+endentl o/
both age and
bod-mass
indeE 3P W
<"<<;4 and with
the triglceride
le2el
inde+endentl o/
the rate o/ glu-
cose dis+osal
3PL<"<<>4"
Subjects in
grou+ C had a
restricted range
o/ bod-mass-
indeE 2alues
and had normal
/asting glucose
le2els 3Table >4
and glucose
le2els a/ter an
O#TT 3data not
shown4" The
RBP4 le2el did
not correlate
with these 2al-
ues or with age
3Table >4 or
waist-to-hi+
ratio 3data not
shown4"
%
>
=
RW
J<"G
C
Change in
GlucoseDisposalRate(mg/g/min)
>
<
PL<"
<<>
G
B
4
=
<
J
=
J<"B
J
<
"
4
J
<"
= <
<"
=
<
"
4
Change in RBP4 (log g/ml)
B
"o+est Third
0marginal response2
G
l
u
c
o
s
e
D
i
s
p
o
s
a
l
R
a
t
e
>
=
>
?
<
(
m
g
/

g
/
m
i
n
)
>
<
M
!
e
"
u
m

R
B
#
$

(

g
/
m
l
)
>=
<
G
;<
B
B<
4
=
C<
< <
%fter
-.ercise Baseline Baseline
Middle Third 0impro#ed insulin sensiti#ity2
G
l
u
c
o
s
e
D
i
s
p
o
s
a
l
R
a
t
e
>
=
>?
<
(
m
g
/

g
/
m
i
n
)
>
< O
!
e
"
u
m

R
B
#
$

(

g
/
m
l
)
>=
<
G
;<
B
B<
4
=
C<
< <
%fter
-.ercise Baseline Baseline
4ighest Third 0impro#ed insulin sensiti#ity2
G
l
u
c
o
s
e
D
i
s
p
o
>
B O
>?
<
>
=
!
e
"
u
m

R
B
#
$

(

g
/
m
l
)
(
m
g
/

g
/
m
i
n
>
<
>=
<
G ;<
B
B<
4
=
C<
< <
Baseline
#L.T4
messenger RA(
and +rotein are re-
duced in
adi+octes in man
insulin-resistant
states,
B
o/ten long
be/ore t+e =
diabetes de2el-
o+s"
=<
-e
+re2iousl re+orted
that genetic 7noc7-
out o/ #L.T4
selecti2el in the
adi+octes o/ mice
is su//icient to
induce the
eE+ression o/
RBP4 in
adi+ose tissue,
increase serum
le2els o/ RBP4,
and induce
sstemic
insulin
resistance"
G,;
)owe2er, we
cannot
eliminate the
+ossibilit that
the se-cretion
o/ RBP4 /rom
li2er or other
tissues ma
also be
increased" To
determine
whether
reduced
N
%fter -.ercise
%ft
er
-.
erc
ise
O
%ft
er
-.
erc
ise
n engl j med C?45=4www"nejm"orgjune >?, =<<B =??;
Th
e
Ne
w
Engla
nd
Journ
al of
Medic
ine
Downloaded from
nejm.or
g on
April 1,
2
0
1
4
.
For personal use
only. No other uses
without
permission.
Copyright 2006
Massachusetts
Medical
Society. All
rights
reserved.
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
Tale 2! -ffects of -.ercise Training on Metaolic &alues and Serum %dipokine "e#els in Su*ects +ith 3e+ly
,iagnosed $mpaired Glucose Tolerance or Type 2 ,iaetes!'
Measurement
Marginal Response 03 5
1426
$mpro#ed $nsulin Sensiti#ity 03 5
2728
Post;Ixercise Hilcoxon Post;Ixercise Hilcoxon
Baseline Training P Jalue Baseline Training P Jalue
GDR '&g%)g%&in(. 4.763.8 4.963.7 8.882 4.467.8 9.767.90 G8.887
BMI 47.364.9 48.264.4 8.84 48.463.4 3:.468.9 G8.887
HaistBtoBEi@ ratio 7.3:68.74 7.3268.78 8.882 7.3368.78 7.7568.77 G8.887
asting glucose '&g%dl(?? 785674 78<678 8.75 78<69 ::6< 8.889
3BEr =GTT glucose '&g%dl(?? 3756: 382679 8.85 7:4639 79<.4647 8.83
asting insulin '$*%&l(AA <4.7648.< 4:.<675.4 8.883 94.464<.3 44.463:.3 G8.887
RBP4 '$g%&l( 22.267:.9 <2.:633.5 8.883 <:.563<.2
48.7678.2
0 G8.887
1e@tin '@&ol%liter ( 7:.:673.4 79.5679.4 8.48 75.5677.: 79.:678.2 8.47
Adi@onectin '$g%&l( 4.<67.9 2.563.8 G8.887 4.467.8 <.767.9 G8.887
Interleu)inB< '@g%&l( <.264.4 2.:64.7 8.89 4.563.4 2.763.4 8.85
CBreactiFe @rotein '$g%dl( 8.968.4 8.468.4 8.882 8.268.3 8.368.70 G8.887
ree !atty acids '&&ol%liter( 8.4:68.34 8.4468.79 8.79 8.2568.79 8.2368.32 8.89
+D1 cEolesterol '&g%dl(,, 4462 4:6< 8.884 4<64 4364 G8.887
1* Blood !or all studies Das draDn DitE tEe su"#ect in tEe !asting state. Data are giFen as &eans 6SD. Su"#ects Dere ran)ed into tEirds on
tEe "asis o! i&@roFe&ent in tEeir insulin sensitiFity 'glucose dis@osal rate( associated DitE exercise training. KMarginal res@onseL re!ers to
su"#ects in tEe loDest tEird o! tEis ran)ing> DEo exEi"ited tEe least i&@roFe&ent in insulin sensitiFity. KI&@roFed insulin sensitiFityL re!ers to
tEe re&aining su"#ects in tEe u@@er tDo tEirds. Di!!erences a!ter one &ontE o! exercise training Dere analyMed "y tEe Hilcoxon signedBran)
test. GDR denotes glucose dis@osal rate> BMI "odyB&ass index> and +D1 EigEBdensity li@o@rotein.
1 A&ong tEe 74 su"#ects DitE a &arginal res@onse> 5 Dere &en and < Dere Do&enN 2 Ead i&@aired glucose tolerance and : Ead ty@e 3
diaB"etesN and tEe aFerage age Das 2269 years.
1 A&ong tEe 3< su"#ects DitE i&@roFed insulin sensitiFity> 77 Dere &en and 72 Dere Do&enN 72 Ead i&@aired glucose tolerance and 77
Ead ty@e 3 dia"etesN and tEe aFerage age Das 2469 years.
. To conFert Falues to &icro&oles @er )ilogra& @er &inute> &ulti@ly "y 2.24:.
1 PG8.82 !or tEe co&@arison o! eitEer "aseline Falues or tEose a!ter exercise training "etDeen tEe tDo grou@s '&arginal res@onse or i&B
@roFed insulin sensitiFity( "y tEe Hilcoxon signedBran) test.
?? To conFert Falues to &illli&oles @er liter> &ulti@ly "y 8.8224:. AA To
conFert Falues to @ico&oles @er liter> &ulti@ly "y 9.792. ,, To conFert
Falues to &illli&oles @er liter> &ulti@ly "y 8.832:.
adi+octe le2els o/ #L.T4 might contribute to ele2ated serum
RBP4 and insulin resistance in humans, we measured #L.T4
+rotein in isolated subcutaneous adi+octes o/ subjects in grou+
C" The le2el o/ adi+octe #L.T4 +rotein correlated +ositi2el
with the rate o/ glucose dis+osal and correlated in2ersel with
the serum RBP4 le2el 31ig" 4* and 4D4" These data +ro2ide
su++ort /or the eEistence o/ a mechanistic lin7 between re-
duced #L.T4 +rotein in adi+octes, ele2ated se-rum RBP4,
and insulin resistance"
Di s c u s sion
RBP4, a molecule secreted b adi+octes and li2-er, ma contribute
to sstemic insulin resistance"
;
-e /ound that the
magnitude o/ increase in
serum RBP4 correlates
with insulin resistance
among humans with
obesit, im+aired glucose
tolerance, or t+e =
diabetes and among
nonobese, nondia-betic
subjects with strong /amil
histories o/ t+e = diabetes"
The serum RBP4 le2el is
correlated with a cluster o/
cardio2ascular ris7 /actors
ac-com+aning insulin
resistance as +art o/ the
meta-bolic sndrome"
=C
!2en though the serum
RBP4 le2el correlated with
bod-mass indeE, the rela-
tionshi+ between the serum
RBP4 le2el and insu-lin
resistance was
inde+endent o/ obesit, and
nonobese, insulin-resistant
subjects also eEhib-ited
increased serum RBP4
le2els" In these non-obese
subjects, decreased
eE+ression o/ #L.T4 in
adi+octes +redicts
increased serum RBP4
le2els
=?B< n engl j
med C?45=4
www"nejm"org june >?,
=<<B
The New England Journal of
M
ed
ici
ne
Downloaded from nejm.org on
April 1, 2014. For
personal use only.
No other uses without permission.
Copyright 2006 Massachusetts
Medical Society. All rights
reserved.
r etinol-binding +rotein
/igure 4! Serum "e#els of RBP49 Risk /actors for Type 2
,iaetes and Cardio#ascular ,isease9 and %dipocyte
G":T4 Protein in 3onoese9 3ormoglycemic Su*ects
+ith a /amily 4istory of Type 2 ,iaetes in Group (!
Panel ( shows the in2erse correlation o/ serum RBP4 le2els
3log Tbase->< scaleU E aEis4 with insulin sensiti2it during
euglcemicHh+erinsulinemic clam+ studies 3glucose
dis+osal rate, linear aEis4" S+earman correla-tion
coe//icient RWJ<"?; 3;? +ercent con/idence inter-2al, J<"G<
to J<"=C4, P W <"<<=" Panel B shows the asso-ciation o/
RBP4 le2els with cardio2ascular ris7 /actors, including
/asting +lasma insulin le2el, two-hour O#TT-stimulated
insulin le2el, /asting triglceride le2el, and sstolic blood
+ressure 3all linear4" The S+earman cor-relation coe//icients
are as /ollowsD /or /asting insulin, R W <"F> 3;? +ercent
con/idence inter2al, <"4F to <"G?4, PL<"<<>5 /or the insulin
le2el a/ter the O#TT, R W <"?> 3;? +ercent con/idence
inter2al, <"=G to <"F44, PL<"<<>5 /or /asting triglceride le2el,
R W <"F> 3;? +ercent con/i-dence inter2al, <"4< to <"GB4,
PL<"<<>5 /or sstolic blood +ressure, R W <"?< 3;? +ercent
con/idence inter-2al, <">C to <"F44, P W <"<<;" Panel *
shows the +ositi2e correlation between adi+octe #L.T4
+rotein le2els and insulin sensiti2it 3glucose dis+osal rate,
le/t4 and the in2erse correlation between adi+octe #L.T4
+ro-tein le2els and serum RBP4 le2els 3right4" The S+ear-
man correlation coe//icients are as /ollowsD R W <"BG 3;?
+ercent con/idence inter2al, <"=G to <"GG4, P W <"<<C /or
glucose dis+osal rate and #L.T45 RWJ<"?= 3;? +ercent
con/idence inter2al, J<"G= to J<"<F4, P W <"<4 /or serum
RBP4 and #L.T4" Panel D shows immunodetection o/
#L.T4 in isolated subcutaneous adi+octes /rom indi-2idual
subjects 3to+4 and serum RBP4 3bottom4 in the same
subject" !ach lane in the blot re+resents a di//er-ent subject
in grou+ C" To con2ert 2alues /or glucose dis+osal to
micromoles +er 7ilogram +er minute, mul-ti+l b ?"?4;" To
con2ert 2alues /or insulin to +icomoles +er liter, multi+l b
F">F?" To con2ert 2alues /or triglc-erides to milligrams +er
deciliter, multi+l b <"<>>="
and insulin resistance" The mechanism b which a
decrease in adi+octe #L.T4 results in an in crease
in RBP4 eE+ression is un7nown, but it might in2ol2e
sensing o/ glucose b adi+octes"
C<
The correlation o/ serum RBP4 le2els with
+lasma insulin le2els suggests that the eE+res-
sion o/ RBP4 in adi+ose tissue might be a direct
conse:uence o/ h+erinsulinemia" )owe2er, sub-
jects with t+e = diabetes had lower /asting +las-
ma insulin le2els than subjects with im+aired
glucose tolerance with similar degrees o/ insulin
resistance, but the RBP4 le2els were similar in
the two grou+s" $oreo2er, RBP4 and +lasma
insu-lin le2els were dissociated in subjects who
did not ha2e an im+ro2ement in insulin sensiti2it
a/-ter eEercise" There/ore, a +rimar reduction in
the +lasma insulin le2el alone does not determine
4 and insulin r esistance
%
Rate
>
G
RW
J<"?;
>
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(
m
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Glucose
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<
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=
<
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C?
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? >"??
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B
?
RB#$ (log
g/ml)
B
%
a
s
t
i
n
g

I
n
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u
l
i
n
>
G RW<"F>
&
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? >"F >"C >"?
RB#$ (log g/ml)
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4
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J<"?=
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4
<
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>"
=
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*dipocyte G+U($ (densitomet"y units)
, *dipocyte G+U($ #"otein ,s- !e"um RB#$ in Indi,idual
!u./ects
0 *dipocyte
G+U($
0 !e"um RB#$
serum RBP4 le2els" Ae2ertheless,
there ma be a threshold at which
+lasma insulin is +ermissi2e /or
increased RBP4 eE+ression in
adi+octes, since
n engl j med C?45=4www"nejm"orgjune >?, =<<B
T
h
e
Ne
w
En
gla
nd
Journal of
Medicine
Downloaded from nejm.org on April 1,
2014. For personal use
only. No other uses
without permission.
Copyright 2006
Massachusetts
Medical Society. All
rights reserved.
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
the serum
RBP4 le2el is
reduced in
subjects with
new-onset
t+e >
diabetes and
returns to
normal a/ter
insulin
treatment"
C>
The abilit to
assess a
+ersonXs ris7 o/
im-+aired
glucose
tolerance and
t+e = diabetes
be-/ore the
onset o/ the
disease would
+ro2ide a ra-
tional means /or
im+lementing
+re2enti2e
li/estle
inter2entions or
+harmacologic
treatment" Be-
cause the serum
RBP4 le2el
correlates with
insu-lin
resistance and
the clinical signs
and bio-
chemical
com+onents o/
the metabolic
sndrome,
measurement o/
serum RBP4
could become a
nonin2asi2e and
accessible
method /or
assessing the
ris7s o/ im+aired
glucose
tolerance, t+e =
dia-betes, and
cardio2ascular
disease" (ltered
le2els o/ se2eral
adi+octe-
secreted
+roteins 3e"g",
le+tin and
adi+onectin4,
in/lammator
cto7ines 3e"g",
interleu7in-B,
monocte
chemoattractant
+rotein >, and
tumor necrosis
/actor 4, or
in/lammator
mar7ers 3e"g",
*-reacti2e
+rotein4 ha2e
been ob-ser2ed
in +atients with
obesit or
insulin resis-
tance"
==
Our
studies suggest
that the serum
RBP4 le2el is
correlated more
s+eci/icall with
insulin
resistance and
changes in
insulin
sensiti2it than
are the le2els o/
se2eral o/ these
+roteins 3i"e",
le+tin,
adi+onectin,
interleu7in-B,
and *-reacti2e
+rotein4" -e
obser2ed that
the RBP4 le2el
corre-lated with
insulin
resistance,
e2en in lean
subjects, whose
genetic ris7 /or
diabetes ma
be o2erloo7ed
in some clinical
settings" -e
studied adults,
and nearl all
were white5
/urther studies
are needed in
more di2erse
grou+s"
Since
ele2ated serum
RBP4 le2els
lead to in-sulin
resistance in
mice,
;
our
obser2ations
raise the
+ossibilit that
the serum
RBP4 le2el
might contribute
to sstemic
insulin
resistance in
hu-mans" In
mice, increased
serum RBP4
le2els im-+air
+ostrece+tor
insulin signaling
at the le2el o/
+hos+hoinositid
e-C 7inase in
muscle and
enhance the
eE+ression o/
+hos+hoenol+r
u2ate
carboE7i-nase
in li2er"
;
There/ore,
increased
serum RBP4
le2els in
humans might
contribute to
im+aired in-
sulin-stimulated
glucose u+ta7e
in muscle and
ele2ated
he+atic glucose
+roduction, both
o/ which are
characteristic o/
t+e =
diabetes"
>
Regions near
the RBP4 locus
on human
chromosome
><: ha2e been
lin7ed to
h+erinsulinemi
a or earl onset
o/ t+e =
diabetes in two
+o+ulations, a
/inding con-
sistent with a
+athogenic
role /or RBP4
in insulin
resistance
and t+e =
diabetes"
C=,CC
Since RBP4
is the +rinci+al
trans+ort +rotein
/or retinol
32itamin (4 in the
circulation,
><,>>
our /indings
/urther raise the
+ossibilit that
altera-tions o/
retinol
metabolism
might in/luence
the action o/
insulin and the
ris7 o/ t+e =
diabetes" (t
+resent, there
are no
com+elling data
to suggest that
dietar 2itamin (
contributes to
the ele2ation in
serum RBP4
le2els obser2ed
in insulin-
resistant states
or to insulin
resistance"
)owe2er, admin-
istration o/ the
snthetic retinoid
/enretinide, an
antineo+lastic
agent that
reduces serum
RBP4 and total-
bod retinol
le2els in
humans,
C4
im+ro2es insulin
sensiti2it and
glucose
tolerance in
obese mice"
;
There/ore, it will
be im+ortant to
determine
whether the
dietar inta7e o/
retinol
in/luences
insulin
sensiti2it and
whether
lowering bod
retinol or RBP4
through the
administration
o/ /enretinide or
related
com+ounds
im+ro2es in-
sulin sensiti2it
in humans"
Su++orted b
grants /rom the
Aational Institutes o/
)ealth 3R<> D0-
4C<?> Tto Dr" 0ahnU,
R<> D0-?G=;> Tto
Dr" )enrU, 0<G D0-
B;B=4 Tto Dr"
#rahamU, and $<>
RR-<<G=F Tto Dr"
)enrU45 the Swedish
Research *ouncil
30=<<4-F=S-<C?<B-
CC(45 the !u-ro+ean
*ommunitXs 1PB
!.#!A!= 3LS)$-
*T-=<<4-?>=<>C Tto
Dr" SmithU45 the
Deutsche
1orschungsgemeins
cha/t 3BL ?G<VC-> to
Dr" Bluher45 the
$edical Research
Ser2ice, De+artment
o/ 9eterans (//airs
39(4 and 9( San
Diego )ealthcare
Sstem 3to Dr"
)enr45 the (merican
Diabetes (ssociation
3to Drs" )enr,
*iaraldi, and 0ahn45
the Swedish
Diabetes (ssociation
3to Drs"
)ammarstedt,
,ansson, and Smith45
the Inga Britt and
(rne Lundberg
1oundation and the
Torsten and Ragnar
S8derberg
1oundation 3to Drs"
)ammarstedt and
Smith45 the Ao2o
Aordis7 1oundation
3to Drs"
)ammarstedt,
,ansson, and Smith45
and the Ta7eda
Pharmaceutical
*om+an 3to Dr"
0ahn4"
Dr" *iaraldi
re+orts ha2ing
recei2ed lecture
/ees /rom Sano/i-
(2entis" Dr" )enr
re+orts ha2ing
recei2ed consulting
/ees /rom (mlin
Pharmaceuticals,
(straYeneca,
Bristol-$ers
S:uibb, Roche, Isis
Pharmaceuticals,
Ta7eda, and Ydus
*adila5 ad2iso-r-
board /ees /rom
(mlin
Pharmaceuticals,
(straYeneca, Bris-
tol-$ers S:uibb,
DiObeE, !li Lill,
#laEoSmith0line,
Roche, Isis
Pharmaceuticals,
San7o, Sano/i-
(2entis, and
Ta7eda5 lec-ture
/ees /rom !li Lill,
#laEoSmith0line,
P/i6er, Sano/i-
(2entis, and
Ta7eda5 grant
su++ort /rom
#laEoSmith0line,
Sano/i-(2en-tis,
and Ta7eda5
holding e:uit in
DiObeE5 and
ser2ing as an
eE+ert witness /or
Ta7eda" Dr" Smith
re+orts ha2ing
recei2ed ad2isor-
board /ees /rom
$erc7 and Ta7eda
and lecture /ees
/rom !li Lill" Dr"
0ahn re+orts
ha2ing recei2ed
ad2isor-board /ees
/rom Boehringer
Ingelheim,
*!PT&R, and
-eth5 consult-ing
/ees /rom #en6me
and 1ibrogen5 and
grant su++ort /rom
Ta7eda and
#laEoSmith0line"
Drs" 0ahn,
#raham, and &ang
are listed as
in2entors on +atent
a++lications related
to RBP4" Ao other
+otential con/lict o/
interest rele2ant to
this article was
re+orted"
=?B=
n engl j
med
C?45=4
www"nejm"org
june >?,
=<<B
The
New
Engla
nd
Journal
of
Medici
ne
Downloaded from
nejm.or
g on
April 1,
2014.
For
personal
use only. No
other uses
without
permission.
Copyright
2006
Massachusett
s Medical
Society. All
rights
reserved.
r etinol-binding +rotein 4 and insulin r esistance
References
1. 0ahn BB" T+e = diabetesD when insu-lin
secretion /ails to com+ensate /or insu-lin
resistance" *ell >;;G5;=D?;C-B"
2. !ri7sson ,, 1ranssila-0allun7i (,
!7strand (, et al" !arl metabolic de/ects in
+ersons at increased ris7 /or non-insu-lin-
de+endent diabetes mellitus" A !ngl , $ed
>;G;5C=>DCCF-4C"
3. De1ron6o R(, 1errannini !" Insulin
resistanceD a multi/aceted sndrome res+on-
sible /or AIDD$, obesit, h+ertension,
dsli+idemia, and atherosclerotic cardio-
2ascular disease" Diabetes *are >;;>5>4D
>FC-;4"
4. 0ahn BB, 1lier ,S" Obesit and insulin
resistance" , *lin In2est =<<<5><BD4FC-
81.
5. Perseghin #, #hosh S, #erow 0, Shul-man
#I" $etabolic de/ects in lean nondia-betic
o//s+ring o/ AIDD$ +arentsD a cross-sectional
stud" Diabetes >;;F54BD><<>-;"
6. She+herd PR, 0ahn BB" #lucose trans-
+orters and insulin action Z im+lications /or
insulin resistance and diabetes melli-tus" A !ngl
, $ed >;;;5C4>D=4G-?F"
7. Smith ." Im+aired 3[diabeticX4 insulin
signaling and action occur in /at cells long
be/ore glucose intolerance Z is in-sulin
resistance initiated in the adi+ose tissue\
Int , Obes Relat $etab Disord
=<<=5=BDG;F-;<4"
8. (bel !D, Peroni O, 0im ,0, et al" (di-
+ose-selecti2e targeting o/ the #L.T4 gene
im+airs insulin action in muscle and li2er"
Aature =<<>54<;DF=;-CC"
9. &ang %, #raham T!, $od A, et al"
Serum retinol binding +rotein contributes to
insulin resistance in obesit and t+e =
diabetes" Aature =<<?54CBDC?B-B="
10. Blaner -S" Retinol-binding
+roteinD the serum trans+ort +rotein /or
2itamin (" !ndocr Re2 >;G;5><DC<G->B"
11. Aewcomer $!, Ong D!" Plasma
retinol binding +roteinD structure and /unction
o/ the +rotot+ic li+ocalin" Biochim Bio+hs
(cta =<<<5>4G=D?F-B4"
12. Basualdo *#, -ein !!, Basu T0"
9ita-min ( 3retinol4 status o/ /irst nation adults
with non-insulin-de+endent diabetes mel-litus" ,
(m *oll Autr >;;F5>BDC;-4?"
13. (bahusain $(, -right ,,
Dic7erson ,-, de 9ol !B" Retinol, al+ha-
toco+herol and carotenoids in diabetes" !ur
, *lin Autr >;;;5?CDBC<-?"
14. Obes
itD +re2enting
and managing
the global
e+idemic"
#ene2aD -orld
)ealth
Organi6ation,
>;;G"
15. Re+o
rt o/ the !E+ert
*ommittee on
the Diagnosis
and
*lassi/ication o/
Dia-betes
$ellitus"
Diabetes *are
=<<<5=CDSu++l
>DS4->;"
16. De1ro
n6o R(, Tobin ,D,
(ndres R"
#lucose clam+
techni:ueD a
method /or
:uanti/ing insulin
secretion and
resis-tance" (m ,
Phsiol
>;F;5=CFD!=>4-
!==C"
17. Thorb
urn (-, #umbiner
B, Bulacan 1,
-allace P, )enr
RR" Intracellular
glu-cose oEidation
and glcogen
snthase ac-ti2it
are reduced in
non-insulin-
de+endent 3t+e
II4 diabetes
inde+endent o/
im+aired glucose
u+ta7e" , *lin
In2est
>;;<5G?D?==-
9.
18. Bluhe
r $, 1asshauer
$, Tonjes (,
0rat6sch ,,
Schon $R,
Pasch7e R"
(ssocia-tion o/
interleu7in-B, *-
reacti2e +rotein,
interleu7in-><
and adi+onectin
+lasma
concentrations
with measures o/
obesit, insulin
sensiti2it and
glucose
metabolism" !E+
*lin !ndocrinol
Diabetes
=<<?5>>CD ?C4-F"
19. Bluhe
r $, .nger R,
Rassoul 1,
Richter 9,
Pasch7e R"
Relation
between
glcaemic
control,
h+erinsulinaem
ia and +lasma
concentrations
o/ soluble
adhesion mole-
cules in +atients
with im+aired
glucose
tolerance or
T+e II diabetes"
Diabetolo-gia
=<<=54?D=><-B"
20. *ar2
alho !, ,ansson
P(, Aagae2 I,
-enth6el ($,
Smith ." Insulin
resistance with
low cellular IRS-
> eE+ression is
also associated
with low #L.T4
eE+ression and
im+aired insulin-
stimulated
glucose
trans+ort"
1(S!B ,
=<<>5>?D>><>-C"
21. ,ans
son P(, Pellme
1, )ammarstedt
(, et al" ( no2el
cellular mar7er
o/ insulin
resistance and
earl
atherosclerosis
in hu-mans is
related to
im+aired /at cell
di/-/erentiation
and low
adi+onectin"
1(S!B ,
=<<C5>FD>4C4-
4<"
22. 0ers
haw !!, 1lier
,S" (di+ose
tissue as an
endocrine
organ" , *lin
!ndocrinol
$etab
=<<45G;D=?4G-
?B"
23. Rea
2en #$" The
insulin
resistance
sndromeD
de/inition and
dietar
a++roach-es to
treatment"
(nnu Re2 Autr
=<<?5=?D C;>-
4<B"
24. ReEr
ode 0$, *are
9,, )enne7ens
*), et al"
(bdominal
adi+osit and
coro-
nar heart disease in women" ,($(
>;;G5 =G<D>G4C-G"
25. ReErode 0$, Buring ,!, $anson
,!" (bdominal and total adi+osit and ris7 o/
coronar heart disease in men" Int , Obes Relat
$etab Disord =<<>5=?D><4F-?B"
26. $ia6a7i &, #lass L, Tri+litt *,
-ajc-berg !, $andarino L,, De1ron6o R("
(b-dominal /at distribution and +eri+heral
and he+atic insulin resistance in t+e =
diabetes mellitus" (m , Phsiol !ndocri-nol
$etab =<<=5=GCD!>>C?-!>>4C"
27. Rea2en #$" Resistance to insulin-
stimulated glucose u+ta7e and h+erinsu-
linemiaD role in non-insulin-de+endent dia-betes,
high blood +ressure, dsli+idemia and coronar
heart disease" Diabete $etab >;;>5>FDFG-GB"
28. 0ahn *R, 9icent D, Doria ("
#enetics o/ non-insulin-de+endent 3t+e-II4
diabetes mellitus" (nnu Re2 $ed >;;B54FD?<;-
C>"
29. ,ohanson !), ,ansson P(, Lonn
L, et al" 1at distribution, li+id accumulation in
the li2er, and
eEercise ca+acit
do not eE-+lain
the insulin
resistance in
health males
with a /amil
histor /or t+e =
dia-betes" , *lin
!ndocrinol
$etab =<<C5GGD
4=C=-G"
30. Tamo
ri &, Sa7aue ),
0asuga $"
RBP4, an
uneE+ected
adi+o7ine" Aat
$ed =<<B5>=D
C<->"
31. Basu
T0, Basualdo
*" 9itamin ( ho-
meostasis and
diabetes
mellitus"
Autrition
>;;F5>CDG<4-B"
32. Dugg
irala R, Blangero
,, (lmas L, et al"
Lin7age o/ t+e =
diabetes mellitus
and o/ age at
onset to a genetic
location on
chromosome ><:
in $eEican
(mericans" (m ,
)um #enet
>;;;5B4D>>=F-4<"
33. $eig
s ,B,
Panhusen *I,
$ers R),
-ilson P-,
*u++les L(" (
genome-wide
scan /or loci
lin7ed to +lasma
le2els o/ glu-
cose and
)b(3>c4 in a
communit-
based sam+le o/
*aucasian
+edigreesD The
1ram-ingham
O//s+ring Stud"
Diabetes
=<<=5?>D GCC-4<"
34. Dimitr
o2 A9, $eer
*,, Perlo// $, et
al" (lteration o/
retinol-binding-
+rotein con-
centrations b
the snthetic
retinoid /en-
retinide in
health human
subjects" (m ,
*lin Autr
>;;<5?>D><G=-F"
Copyright 2006
Massachusetts
Medical Society.
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