Vol. 81, No. 12
Prmted in U.S.A.
0021-972x/96/$03
00/o
Journal
of Chmcal Endocrmology
and Metabolism
CopyrIght
0 1996 by The Endocrme
Smety
Short-Term
Dexamethasone
Treatment
Increases
Plasma
Leptin Independently
of Changes in Insulin
Sensitivity
in Healthy
Women*
HILLEVI
LARSSON
Department
of Medicine,
AND
Lund
BO AHRliN
University,
MalmS,
Sweden
ABSTRACT
to 45 2 5% (P = 0.001). The increase
in leptin
correlated
with the
reduction
of insulin
sensitivity
(r = 0.68; P = 0.044), but this correlation was no longer significant
after correction
for body mass index.
The correlation
between
the change in plasma leptin and body mass
index (r = 0.79; P = 0.012), however,
was independent
of the change
in both fasting insulin
and insulin
sensitivity.
We conclude that short
term corticosteroid
treatment
induces
a doubling
of fasting leptin in
healthy
humans.
The dexamethasone-induced
increase
in leptin
is
dependent
of body mass index,
but not of insulin
levels or insulin
sensitivity,
which suggests
that the influence
of dexamethasone
on
plasma
leptin is not mediated
by its influences
on fasting
insulin
or
insulin
sensitivity.
(J Clin Endocrinol Metab 81: 4428-4432,
1996)
Leptin has been demonstrated
to correlate
with body fat content in
humans,
but the regulation
of leptin
levels is poorly
understood.
Therefore,
we studied
the relation
between
fasting
insulin,
plasma
leptin, and insulin
sensitivity,
as assessed
by the hyperinsulinemic
euglycemic
clamp, before and after short term corticosteroid
treatment, which is known
to induce insulin
resistance
(3.0 mg dexamethasone, twice daily, for 48 h; total dose, 15 mg) in nine healthy
women
(mean + SE age, 58.6 5 0.1 yr; body mass index, 25.9 ? 1.7 kg/m?.
Dexamethasone
increased
fasting leptin levels by 114 * 14% (18.4 ?
3.3 us. 39.4 5 7.3 rig/ml; P = 0.001) and increased
fasting
insulin
by
51 rt_ 128 (P = 0.004). Concomitantly,
insulin
sensitivity
was reduced
R
ECENTLY,
16-kDa
the oh gene product
protein,
leptin,
was
was cloned
demonstrated
(l), and the
to reduce
food intake and increase energy expenditure
in mice (2, 3).
Plasma leptin levels in mice and humans exhibit
a close
correlation
with body fat content (4-6). Therefore, leptin has
been suggested as a sense parameter
for the adipose tissue
(7-9). The regulation
of leptin gene expression
and plasma
leptin levels remains to be elucidated.
Recent studies in mice
have shown that food intake and short term insulin administration
increase oh gene expression
(lo), suggesting
that
insulin might be a part of ob gene regulation.
Supporting
this
idea is the finding that in mice, long term hyperinsulinemia
with maintained
euglycemia
up-regulates
ob gene expression, whereas long term fasting, producing
hypoinsulinemia,
down-regulates
ob messenger
ribonucleic
acid (11). Moreover, decreases in body weight, associated with reductions
in fasting insulin levels, were also demonstrated
to reduce ob
messenger ribonucleic
acid expression
in mice and to reduce
both ob gene expression and plasma leptin levels in humans
(12,13). In contrast to the findings in mice, acute changes in
insulinemia
have not been demonstrated
to affect leptin levels in humans (13-16). However,
long term insulin infusion
(72 h) was recently shown to slightly increase plasma leptin,
and insulin
was found to increase oh gene expression
in
Received
May 31,1996. Revision
received August
12,1996. Accepted
August
19, 1996.
Address
all correspondence
and requests for reprints
to: Hillevi
Larsson, M.D., Department
of Medicine,
Lund University,
MalmG University
Hospital,
S-205
02 Malmo,
Sweden.
E-mail:
Hillevi.Larsson@
medforsk.mas.lu.se.
* This work was supported
by the Swedish Medical
Research Council
(Grant
14X-6834);
the Ernhold
Lundstrom,
Albert Pahlsson,
Crafoord,
and Novo
Nordic
Foundations;
the Swedish
Diabetes
Association;
MalmG University
Hospital;
and the Faculty
of Medicine,
Lund.
4428
human adipocytes
(16). Thus, it is not established
whether
changes in plasma leptin are due to changes in insulin
levels. Furthermore,
obesity
is accompanied
by insulin
resistance
(17, 18), and reduction
of body weight
is associated with an increase in insulin sensitivity
(19). It is thus
also possible
that plasma leptin levels are regulated
by
insulin
sensitivity.
This needs to be explored
by altering
insulin
sensitivity
with maintained
body weight.
Short term corticosteroid
treatment
is known
to induce
insulin resistance in humans, with a simultaneous
increase
in fasting
insulin
levels, without
affecting
body weight
(20). In this study, we, therefore,
explored
whether
short
term corticosteroid
treatment
affects leptin levels in parallel
with
the reduction
in insulin
sensitivity.
We
measured
plasma leptin levels and insulin
sensitivity,
using the hyperinsulinemic
euglycemic
clamp, before and
after dexamethasone
treatment
in healthy
middle-aged
women.
Subjects
and Methods
Subjects
Nine nondiabetic
women,
aged 58 or 59 yr (mean 2 SD age, 58 yr 7
months
-t 5 months)
were invited
to take part in the study. They were
all healthy,
and none was taking any medication
known
to affect glucose
metabolism.
The study group was selected to be homogenous;
therefore,
all subjects were of the same age and sex. The body weight of the subjects
was 67.7 -t- 13.9 kg (mean 2 SD), the body mass index (BMI) was 25.9 -C
5.0 kg/m’,
the fasting plasma glucose was 5.5 + 0.4 mmol/L,
the fasting
serum insulin
was 75 ? 40 pmol/ L, the 2-h plasma glucose value after
a 75-g oral glucose load, according
to the WHO glucose tolerance
test
(21), was 8.5 i- 1.9 mmol/L,
and the hemoglobin
A,, was 5.0 ? 0.5%. The
study was approved
by the ethics committee
of Lund University,
and
all subjects signed a written
informed
consent before the start of the
study.
PLASMA
Research
LEPTIN
AND INSULIN
design
Glucose tolerance was determined
to ascertain
that the study subjects
were nondiabetic.
Thereafter,
fasting plasma leptin and insulin
levels
and insulin sensitivity
were measured
in the baseline condition
and after
dexamethasone
treatment.
The treatment
regimen
consisted
of 3.0 mg
dexamethasone,
twice daily, during
the 2 days before the study and the
final dose on the morning
of the study (total dose, 15 mg). The study
subjects
did not report
any adverse
effects of the dexamethasone
treatment.
Insulin
sensitivity
Insulin
sensitivity
was determined
with the standardized
hyperinsulinemic
euglycemic
clamp technique,
performed
according
to the
method of DeFronzo
et RI. (22). Subjects arrived
at the research clinic in
the morning
after an overnight
fast. Intraveneous
catheters
were inserted into antecubital
veins in both arms. One arm was used for the
infusion
of glucose
and insulin.
The contralateral
arm was used for
intermittent
sampling,
and the catheter
was kept patent with slow infusion of 0.9% saline. Baseline
samples
of glucose
and insulin
were
taken. A primed constant infusion
of insulin (100 U/ml; Actrapid,
Novo
Nordisk,
Bagsvaerd,
Denmark)
with a constant
infusion
rate of 0.28
nmol/m*
body surface area.min
was started. After 4 min, a variable
rate
20% glucose infusion
was added, and its infusion
rate was adjusted
manually
throughout
the clamp procedure
to maintain
the blood glucose level at 5.0 mmol/L.
Blood glucose was determined
at the bedside
every 5 min. Samples for analysis of the achieved
insulin concentration
were taken at 60 and 120 min.
Analyses
Capillary
blood glucose samples from the oral glucose tolerance
test
were chilled at 4 C and analyzed
with an automatic
glucose oxidase
method
at the hospital
central laboratory.
The blood glucose concentration was determined
at the bedside by the glucose dehydrogenase
technique
with a Hemocue
(Hemocue
AB, Angelholm,
Sweden)
during
the hyperinsulinemic
euglycemic
clamp. Samples for analysis of leptin
were taken in prechilled
tubes containing
0.084 ml ethylenediamine
tetraacetate
(0.34 mol/L).
The analysis was performed
in duplicate
with
a double antibody
RIA using rabbit antihuman
leptin, i’sI-labeled
human leptin as tracer, and human leptin as standard
(Linco Research, St
Louis, MO). Blood samples for analysis of insulin and glucose from the
clamp study were immediately
centrifuged
at 5 C, and serum or plasma
was frozen at -20 C until analysis in duplicate.
Serum insulin concentrations were analyzed
with a double antibody
RIA technique.
Guinea
pig antihuman
insulin antibodies,
[ “sI]Tyr-human
insulin as tracer, and
human
insulin
standard
(Linco Research)
were used. Plasma glucose
concentrations
were analyzed
using the glucose oxidase method.
The
concentrations
of insulin, glucose, and leptin reported
are the means of
duplicate
samples.
Calculations
and statistics
Data are presented
as the mean + SEM unless otherwise
noted. For
calculation
of insulin sensitivity,
a steady state condition
was assumed
during
the second hour of the clamp. Calculations
were performed
according
to the method
of DeFronzo
ef al. (22). Thus, insulin sensitivity
(nanomoles
of glucose/kg
BW.min/picomoles
of insulin
per L) was
TABLE
1. Fasting
insulin,
(dex) treatment
in the nine
glucose,
and leptin
women
studied
and parameters
Parameter
Fasting
plasma
glucose (mmol/L)
Fasting
serum insulin
(pmol/L)
Fasting
plasma
leptin
(rig/ml)
Clamp plasma
glucose, 60-120
min (mmol/L)
Clamp serum insulin,
60-120
min (pmol/L)
Glucose infusion
rate, 60-120
min (Fmol/kg/min)
Insulin
sensitivity,
60-120
min
(nmol glucose/kgmin/pmol
insulin/L)
Data
are the mean
+
SEM.
SENSITIVITY
4429
calculated
as the glucose infusion
rate during
the second hour divided
by the mean insulin
concentration
during
the second hour.
Statistical
analysis was performed
with the SPSS for Windows
system
(23). Pearson’s
product-moment
correlation
was used to estimate linear
relationships
betwen variables.
Differences
between experiments
before
and after dexamethasone
treatment
were tested with Student’s
t test for
paired samples.
Results
Fasting plasma glucose, serum insulin, and plasma leptin
levels before and after dexamethasone
treatment are shown
in Table 1. After dexamethasone
treatment,
plasma leptin
increased considerably,
from 18.4 + 3.3 to 39.4 2 7.3 ng/mL,
or by 114 2 14% of the baseline values (P = 0.001; Fig. 1A).
Concomitantly,
there was a significant
increase in serum
insulin by 51 k 12% (P = 0.004). There was, however,
no
change in fasting plasma glucose (P = NS).
Figure 1B shows the insulin
sensitivity,
determined
by
the hyperinsulinemic
euglycemic
clamp before and after
dexamethasone
treatment.
It is evident
that the short period of dexamethasone
treatment
induced
a significant
and rapid reduction
of insulin sensitivity,
to 45 + 5% of the
baseline
value (P = 0.001; Table 1). The mean plasma
glucose
and serum insulin
levels achieved
during
the
clamp did not differ before and after dexamethasone
treatment (Table 1).
Analyses
of linear
correlation
among
the levels of
plasma leptin, serum insulin,
insulin
sensitivity,
and BMI
was performed
(Table 2). We found that in the baseline
condition,
plasma leptin correlated
positively
with BMI
(r = 0.77; P = 0.015), and negatively
with insulin
sensitivity (r = -0.71, P = 0.032). The correlation
with fasting
insulin
(r = 0.63) was not significant
(P = 0.068). Partial
correlations
controlling
for BMI were performed,
showing
that the correlation
between
insulin sensitivity
and leptin
was no longer significant.
After dexamethasone
treatment,
fasting leptin still correlated
with BMI (r = 0.82; P = 0.007),
but not with insulin
sensitivity
or fasting
insulin.
The
increase in plasma leptin after dexamethasone
treatment
(A leptin) correlated
significantly
to BMI (Table 3 and Fig.
2). Moreover,
A leptin was significantly
correlated
to the
decrease in insulin
sensitivity
(A insulin
sensitivity),
but
not to the increase (A) in fasting insulin
(Table 3). When
controlling
for BMI, the correlation
between
A leptin and
A insulin
sensitivity
was no longer statistically
significant
(r = 0.59; P = 0.127). Controlling
for insulin sensitivity
had
no effect on the correlation
between
A leptin and BMI (r =
0.73; P = 0.040). Thus, the relation
between
dexametha-
of the euglycemic
dex
Before
5.5
75
18.4
5.0
764
51.0
73.1
hyperinsulinemic
2
k
t
2
5
+
%
0.4
13
3.3
0.1
50
8.0
12.2
clamp
After
6.0
104
39.4
5.1
723
22.5
33.5
before
dex
k
k
2
i2
k
k
0.3
14
7.3
0.1
52
4.6
7.6
and after
dexamethasone
P value
NS
0.004
0.001
NS
NS
<O.OOl
0.001
LARSSON
4430
A
100
50
,
=
2E
80-
E
E
2
6040-
2
ii
n.
20
JCE & M . 1996
Vol 81 . No 12
AND AHRtiN
-
0 ’
Before
,“D
4
Dex
After
g
40
3l
=
.g
30
5
20
2
0”
1
l=o.79
p=o.o12
a
l
0
I
a
0
0
10
! lljljl
ok
0
Dex
7
00
I
,
I
I
I
20
25
30
35
40
Body
Mass
Index
(kg/m’)
FIG. 2. The increase in leptin after dexamethasone
tin) plotted
against
BMI in nine healthy
women.
lation
coefficient
(r) was 0.79 (P = 0.012).
Before
Dex
After
Dex
FIG. 1. Fasting
leptin levels (A) and insulin
sensitivity
with the hyperinsulinemic
euglycemic
clamp before
methasone
(dex) treatment
in nine healthy
women.
TABLE
2. Pearson’s
product-moment
analysis
of linear association
between
insulin,
and insulin
sensitivity
before
(dex) treatment
Before
P values
correlation
coefficients
leptin
and BMI, fasting
and after dexamethasone
from
Leptin
Parameter
BMI
Fasting
Insulin
(B) measured
and after dexa-
dex
After
0.77 (0.015)
0.63 (0.068)
-0.71 (0.032)
insulin
sensitivity
are given
dex
0.82 CO.0071
0.47 (0.197)
-0.42 (0.260)
in parentheses.
TABLE
3. Pearson’s
product-moment
correlation
coefficients
from
analysis
of linear association
between
the change in leptin
induced
by dexamethasone
treatment
and the BMI, the change in fasting
insulin,
and the change in insulin
sensitivity
Parameter
BMI
A fasting
A insulin
P values
A leptin
0.79 (0.012)
-0.20
(0.610)
0.68 (0.044)
insulin
sensitivity
are given
in parentheses.
sone-induced
changes
dependent
on BMI.
in insulin
sensitivity
and leptin
was
Discussion
We studied
the effect of corticosteroid
treatment
on
plasma leptin and insulin sensitivity
in healthy women. The
main finding was that the short period of dexamethasone
treatment increased plasma leptin levels to twice the baseline
levels, whereas fasting insulin was increased
by 51% and
treatment
The Pearson
(A lepcorre-
insulin sensitivity
reduced to 45% of baseline values. Thus,
along with the marked increase in the leptin levels, corticosteroid treatment
induced severe insulin resistance, and this
was evident without
any effect on body weight.
It is known
that plasma leptin levels are highly correlated with body fat content in mice and humans
(4-6). It
has, therefore,
been suggested
that leptin
is a sensing
parameter
for the adipose tissue and acts as a satiety factor
(7-9). The regulation
of leptin
levels, however,
is still
largely
unknown.
Previous
studies in mice have shown
that plasma
leptin levels are regulated
in parallel
with
insulin levels (10, 11). In contrast, in humans, the effect of
insulin on plasma leptin is more controversial.
Short term
insulinemia,
such as after food intake, has not been demonstrated
to affect leptin levels (13-16), although
long term
insulin
infusion
slightly
increases plasma leptin (16). Furthermore,
reduced body weight,
which lowers plasma insulin, results in decreased
plasma leptin levels (12). It is of
importance
to elucidate
whether
it is the reduction
in
insulinemia
that reduces
plasma
leptin or whether
the
decreases in leptin and insulin
are parallel
phenomena.
It
could be speculated
that the increased
insulin
sensitivity
associated
with weight
loss (19) affects both plasma insulin and leptin levels.
We found
significant
correlations
between
baseline
plasma leptin, on the one hand, and fasting insulin, BMI, and
insulin sensitivity,
as measured with the euglycemic
hyperinsulinemic
clamp, on the other hand. It has previously
been
demonstrated
that plasma leptin correlates
with BMI (12),
with a correlation
coefficient of similar magnitude
as in the
present study. Partial correlation
analysis controlling
for the
effect of BMI revealed that the correlations
between fasting
leptin and fasting insulin as well as insulin sensitivity
were
dependent
on BMI. This suggests that the fasting insulin
levels do not directly
regulate
leptin levels, although
this
needs to be explored
in more detail in a larger study group.
To separate the effects of changes in body weight
and
insulin sensitivity
on plasma leptin, we induced
insulin resistance by short term corticosteroid
treatment.
We found
that plasma leptin increased to twice the normal levels in
48 h. This is in agreement
with a previous report in rats, in
which corticosteroid
treatment rapidly induced increased oh
PLASMA
LEPTIN
AND
gene expression
(24). The corticosteroid
dose was very high
in the study by De Vos et al. (24), resulting
in reduced food
intake and decreased
body weight,
which could have influenced
the results. In our study, body weight
was not
affected by the short steroid treatment.
Thus, the increase
in plasma leptin could not be attributed
to a different
body
weight
or body fat content. We found that the increase in
plasma leptin seen after dexamethasone
treatment
correlated with both BMI and the decrease in insulin sensitivity.
However,
when correcting
for the BMI in a partial correlation analysis,
the correlation
between
the increase
in
plasma leptin and the decrease in insulin
sensitivity
was
no longer significant.
On the contrary,
the correlation
betweeen BMI and the increase in leptin was independent
of
insulin
sensitivity.
This suggests that it is the size of the
adipose tissue that determines
the effect of corticosteroid
treatment
to increase
plasma leptin,
and that the dexamethasone-induced
change in plasma
leptin is not secondary to the decrease
in insulin
sensitivity.
Rather, it
seems that the changes in plasma leptin and insulin
sensitivity induced
by dexamethasone
are parallel
phenomena, both caused by the dexamethasone
treatment
yer se.
Dexamethasone
increased
fasting insulin.
This effect is
mainly due to a compensatory
increase in insulin secretion
as a response
to insulin
resistance
(20). Dexamethasone
might also inhibit insulin secretion through a direct action on
the islets (25, 26), although
the direct influence
of this glucocorticoid
on islet function remains to be established.
In any
case, as the dexamethasone-induced
increase in fasting insulin in the present study did not correlate to the increase in
leptin, insulin does not seem to mediate the dexamethasoneinduced hyperleptinemia.
The effect of dexamethasone
could be a direct effect of
the steroid
on ob gene expression
in adipose
tissue, as
inferred
from the previous
study in rats (24) and also
previously
reported
after direct administration
of dexamethasone
to isolated
rat adipocytes
(27, 28). Alternatively, the influence
of dexamethasone
could be indirectly
mediated
through
increased
neuropeptide
Y (NPY) in the
hypothalamus.
It is known
from studies in rats that corticosteroids
influence
central NPY (29), and that NPY may
regulate
ob gene expression
(30). Furthermore,
in animal
studies, central NPY has been demonstrated
to affect insulin sensitivity
(31). Thus, it can be speculated
that the
dexamethasone
treatment
increases
hypothalamic
NPY,
which results in both increased
leptin levels and decreased
peripheral
insulin
sensitivity.
The exact mechanisms
underlying
the hyperleptinemia,
insulin
resistance,
and hyperinsulinemia
induced
by dexamethasone,
however,
remain to be established.
Also, it would
be of interest to
examine the influence
of dexamethasone
on plasma leptin
in obese subjects who already exhibit high plasma leptin
levels. The subjects in this study had a BMI in the upper
limit of normality,
but were not obese, and their mean
plasma leptin level (18.4 ng/mL)
was lower than that in a
larger group of postmenopausal
women,
including
obese
women
(22.3 ng/mL)
(32).
In conclusion,
we have demonstrated
that short term
corticosteroid
treatment,
which induces insulin resistance,
increases
plasma
leptin
to twice the normal
values in
INSULIN
SENSITIVITY
4431
healthy
subjects. The dexamethasone-induced
increase in
leptin was independent
of the degree of change in insulin
sensitivity
and fasting insulin
when BMI was controlled
for. Instead, it seems that it is the BMI of the subjects that
determines
the degree of leptin up-regulation
after short
term dexamethasone
treatment,
and, therefore,
that it is
not plasma
insulin
or insulin
sensitivity
that mediates
dexamethasone-induced
changes in plasma leptin levels in
humans.
Acknowledgments
The authors
are grateful
to Lilian Bengtsson,
Eva Holmstr6m,
Margaretha
Persson for expert technical
assistance.
and
References
1. Zhang
Y, Proenca
R, Maffei
M, Barone
M, Leopold
L, Friedman
JM. 1994
Positional
cloning
of the mouse obese gene and its human homologue.
Nature.
3721425-432.
2. Pelleymounter
MA, Cullen
MJ, Baker MB, et al. 1995 Effects of the obese
gene
product
on body
weight
regulation
in oh/oh
mice.
Science.
269:540-543.
3. H&as
JL, Gajiwala
KS, Maffei
M, et al. 1995 Weight-reducing
effects of the
plasma
protein
encoded
by the obese gene. Science.
269:543-546.
4. Frederich
RC, Hamann
A, Anderson
S, LBllman
B, Lowell
BB, Flier JS. 1995
Leptin
levels reflect
body lipid
content
in mice: evidence
for diet-induced
resistance
to leptin actlon.
Nat Med. 1:1311-1314.
5. LGnnqvist
F, Arner P, Nordfors
L, Schalling
M. 1995 Overexpression
of the
obese
(oh) gene in adipose
tissue
of human
obese
subjects.
Nat Med.
1:950-953.
6. Hamilton
BS, Paglia
D, Kwan AYM, Deitel
M. 1995 Increased
obese mRNA
exoression
in “mental
fat cells from masswelv
obese humans.
Nat Med.
1:453-956.
7. Campfield
LA, Smith
FJ, Guisez
Y, Devos
R, Burn I’. 1995 Recombinant
mouse
ob protein:
evidence
for a peripheral
signal
linking
adiposity
and
central
“e&al
networks.
Science.
26%546-549.
8. Frederich
RC, Liillman
B, Hamann
A, et al. 1995 Expression
of oh mRNA
and
its encoded
orotein
in rodents.
Imoact of nutrition
and obesity. I 1 Clin Invest.
96:1658-166%
9. Lindpaintner
K. 1995 Chnical
implications
of basic research:
finding
a” obesity
gene-a
tale of mice and ma”. N Engl J Med. 322:679-680.
10. Saladin
R, De Vos P, Guerro-Milo
b, et al. 1995 Transient
increase
in obese
gene expression
after
food
intake
or insulin
administratlon.
Nature.
377527-529.
11. Cusin I, Sainsbury
A, Doyle P, Rohner-Jeanrenaud
F, Jeanrenaud
B. 1995 The
oh gene and insulin.
A relationship
leading
to clues to the understandmg
of
obesity.
Diabetes.
44:1467-1470.
12. Maffei
M, H&as
J, Ravussin
E, et al. 1995 Leptin levels in human and rodent:
measurement
of plasma
leptin
and ob RNA in obese and weight-reduced
subjects.
Nat Med. 1:1155-1161.
13. Considine
RV, Sinha MK, Heiman
ML, et al. 1996 Serum immunoreactiveleptin
concentrations
in normal-weight
and obese humans.
N Engl J Med.
334:292-295.
14. Sinha MK, Ohannesian
JP, Heiman
ML, et al. 1996 Nocturnal
rise of leptm
in lean. obese. and non-insulin-deuendent
diabetes
mellitus
subiects.
I Clin
Invest.‘97:1344-1347.
15. Dagogo-Jack
S, Fanelli
C, Paramore
D, Brothers
J, Landt M. 1996 Plasma
leptin
and insulin
relationships
in obese and nonobese
humans.
Diabetes.
4<:695-698.
16. Kolaczynski
JW, Nyce MR, Considine
RV, et al. 1996 Acute and chronic
effect
of insulin
on leptin production
in humans.
Studies itI oiru and IF? rutro. Diabetes.
45:699-701.
17. Bonadonna
RC, De Fronzo RA. 1991 Glucose
metabolism
in obesity
and type
2 diabetes.
Diabete
Metab.
17:112-135.
18. Bogardus
C, Lillioja
S, Mott DM, Hollenbeck
C, Reaven
G. 1985 Relationship
between
degree of obesity
and i,l vioo insulin
action in man. Am J I’hysiol.
248:E286-E291.
19. Franssila-Kallunki
L, Rissanen
A, Ekstrand
A, 011~s A, Groop L. 1992 Effects
of weight
loss on substrate
oxidation,
energy
expenditure,
and Insulin
sensitwity in obese individuals.
Am J Clin Nutr. 55:356-361.
20. Beard JC, Halter JB, Best JD, Pfeiffer
MA, Porte Jr D. 1984 Dexamethasoneinduced
insulin
resistance
enhances
B cell responsiveness
to glucose
level in
normal
me”. Am J Physiol.
247:E592-E596.
21. WHO.
1985 Diabetes
mellitus:
report
of a study group.
Geneva:
WHO; Tech
Rep Ser 727.
22. DeFronzo
RA, Tobin
JD, Andres
R. 1979 Glucose
clamp
technique:
a
LARSSON
23.
24.
25.
26.
27.
28.
method
for quantifying
Insulin
secretion
and resistance.
Am J Physiol.
237:E214-E223.
Norusis
MJ. 1992 SPSS for Windows.
Base system user’s guide,
release 5.0.
Chicago:
srss.
De Vos I’, S&din
R, Auwerx
J, Staels B. 1995 Induction
of of] gene expression
by corticosteroids
1s accompanied
by weight
loss and reduced
food intake.
J Biol Chem. 270~15958-15961.
Gronda
CM, Diaz GB, Rossi JP, Gagliardino
JJ. lYY2 Correlation
between
Ca’+-ATl’ase
activity
of rat islet cells and insulin
secretion.
J Endocrinol.
134:221-225
Chan C, Lejeune
J. 1992 Reduced
sensitivity
to dcxamethasone
of pancreatic
islets from obese (fnlfn) rats. Can J Physml
Pharmacol.
70:1518-1522.
Murakami
T, Iida M, Shima K. 1995 Dexamethasone
regulates
obese expression in isolated
rat adipocytes.
Biochem
Biophys
Res Commun.
214:1260-1267.
Slicker
LJ, Sloop KW, Surface
PL, et al. 1996 Regulation
of expression
of O/I
mRNA
and protein
by glucocorticosteroids
and CAMP. J Biol Chem.
AMERICAN
1997 Certification
Registration
Examination
Period:
Date:
Important note: beginning
annually in November.
BOARD
Examination
-,
3.
31
32
271:5301-5304.
Wilding
JPH, GiIbey
SG, Lambert
I’D, Ghatei
MA, Bloom SR. 1993 Increases
in neuropeptide
Y content
and gene expression
in the hypothalamus
of rats
treated
with dexamethasone
are prevented
by insulin.
Neuroendocrinology.
57:581&587.
Sainsbury
A, Cusin
I, Doyle
I’, Rohner-Jeanrenaud
F, Jeanrenaud
B. 1996
Intracerebroventricular
administration
of neuropeptide
Y to normal
rats increases
obese
gene expression
in white
adipose
tissue.
Diabetologia.
39:353-356.
Vettor
R, Zarjevski
N, Cusin
1, Rohner-Jeanrenaud
F, Jeanrenaud
8.1994
Induction
and reversibility
of an obesity
syndrome
by intracerebroventricular
neuropeptide
Y administration
to normal
rats.
Diabetologia.
37:1202-1208.
Larsson
H, Elmstdhl
S, Ahren B. Plasma leptin levels correlate
to islet function
independently
of body fat in postmenopausal
women.
Diabetes.
in press.
OF INTERNAL
in Endocrinology,
January 1, 1997-April
November 19, 1997
in 1997, the Board will
JCE & M . 1996
Vol 81. No 12
AND AHRtiN
MEDICINE
Diabetes,
and Metabolism
1, 1997
offer all of its Subspecialty
Certification
Examinations
For more information
and application
forms, please contact: Registration Section, American Board of Internal
Medicine, 3624 Market Street, Philadelphia,
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19104-2675. Telephone:
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