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(TNF-)-Induced Insulin Resistance: Evidence for Differential Regulation of Insulin Signaling by TNF-
Departments of Physiology (A.T.C.) and Medicine (J.F. and D.H.C.), Tulane University and Department of Medicine, Louisiana State University (J.K.K.), New Orleans, Louisiana; and Department of Medicine, University of Tennessee and Research Service, Veterans Administration Medical Center (D.R., M.B.A.), Memphis, Tennessee 38104
Address all correspondence and requests for reprints to: Michael Bryer-Ash, Department of Medicine-Room 340M, University of Tennessee College of Medicine, 951 Court Avenue, Memphis, Tennessee 38163. E-mail: mbryerash{at}utmem1.utmem.edu
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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(TNF-) has been shown to induce
insulin resistance in cultured cells as well as in animal models. The
aim of this study was to map the in vivo mechanism
whereby TNF- contributes to the pathogenesis of impaired insulin
signaling, using obese and lean Zucker rats in which TNF- activity
was inhibited through adenovirus-mediated gene transfer. We employed a
replication-incompetent adenovirus-5 (Ad5) vector to endogenously
express a TNF inhibitor (TNFi) gene, which encodes a chimeric protein
consisting of the extracellular domain of the human 55-kDa TNF receptor
joined to a mouse IgG heavy chain. Control animals consisted of rats
infected with the same titer of adenovirus carrying the lac-z
complementary DNA, encoding for ß-galactosidase. There was a
significant reduction in plasma insulin and free fatty acid levels in
TNFi obese rats 2 days following Ad5 administration. The peripheral
insulin sensitivity index was 50% greater, whereas hepatic glucose
output was completely suppressed during hyperinsulinemic glucose clamps
in TNFi obese animals, with no differences observed between the two
lean groups. The improvement in peripheral and hepatic sensitivity to
insulin seen in the obese animals was independent of insulin receptor
(IR) number and insulin binding affinity for IR. However, TNF-
neutralization led to a 2.5-fold increase in tyrosine phosphorylation
of IR in skeletal muscle, whereas this was unchanged in liver. There
was also a 4-fold increase in particulate protein tyrosine phosphatase
activity of skeletal muscle in TNFi obese animals vs.
ß-galactosidase controls, whereas protein tyrosine phosphatase
activity in liver was unchanged. These results suggest that TNF- is
a mediator of insulin resistance in obesity and may modulate IR
signaling in skeletal muscle and liver through different pathways.
TNF- may affect insulin action in the liver either at sites distal
to the IR or indirectly, possibly because of increased provision of
gluconeogenic substrates or altered counterregulation. In addition, the
Ad5-mediated gene delivery system employed here provides an in
vivo model that is efficient and economical for exploring
mechanisms involved in TNF--induced insulin resistance in various
genetic models of obesity-linked diabetes.
is unclear, but the hyperglycemia that is its final clinical expression
results from a combination of insulin resistance in important metabolic
target tissues such as liver, muscle, and adipose tissue, as well as a
relative or absolute insulin secretory defect at the level of the
pancreatic ß-cell (1). The precise cause of insulin resistance is yet
to be determined, but its association with obesity has long been
established (2). Numerous recent data have implicated tumor necrosis
factor- (TNF-) as a link between insulin resistance and obesity
(3–5). However, the mechanism(s) whereby TNF- attenuates insulin
action in obese individuals is not well understood. Attempts have been
made to delineate the cellular mechanism involved using in
vitro systems, but these have yet to be studied in detail in
intact animals. Given the complexity of glucose homeostasis and the
fact that the pathogenesis of insulin resistance involves multiple
organs, an obese insulin-resistant animal model of DM devoid of TNF-
activity would be most valuable in elucidating how TNF- induces
insulin resistance.
The objective of this project was to further investigate the in
vivo cellular mechanism(s) whereby TNF- contributes to the
pathogenesis of impaired insulin signal transduction in obesity and DM2
using obese Zucker rats (fa/fa) in which effective blockade
of TNF- activity has been achieved through adenovirus 5
(Ad5)-mediated gene transfer. We show that TNF- inhibition improves
both hepatic and peripheral insulin sensitivity in vivo, and
that both tyrosine phosphorylation of insulin receptor (IR) and protein
tyrosine phosphatase (PTP) activity in skeletal muscle were increased
during glucose clamps, whereas in the liver they were unchanged. This
implies that TNF- may exert its effects on skeletal muscle and liver
through different mechanisms.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Administration of replication-incompetent recombinant adenovirus to
Zucker rats
The study was approved by the Animal Research and Use Committee
of Tulane University and the Subcommittee on Animal Studies of the
Memphis Veterans Administration Medical Center. Seven-week-old obese
fa/fa or lean Zucker rats (Pennington Biomedical Research
Center, Baton Rouge, LA, or Harlan Sprague Dawley, Inc.,
Indianapolis, IN) were infected with 109 plaque-forming
units of recombinant Ad5 carrying TNFi complementary DNA
(Ad5-TNFi) or the lac-z gene, which encodes for ß-galactosidase
(Ad5-ß-gal). Under brief isofluorane inhalational anesthesia,
109 plaque-forming units of virus in 30 µl PBS was
delivered via the tail vein. Infected rats were housed individually and
weighed daily. Rats from the control groups were infected with same
titer of Ad5-ß-gal.
Measurement of TNF- inhibitory activity
Plasma TNFi activity was assayed 4 days after Ad5 injection
according to a previously described technique (7). Briefly, serum
samples were serially diluted and 1 µl of each dilution was incubated
in separate wells of a 96-well plate with 1.0 ng/ml murine TNF- for
1 h at 37 C, in the presence of 100 µg/ml cyclohexamide; 7
x 104 SKMEL-109 cells were then added to each well
and incubated overnight. The next morning, cells were washed and
stained with crystal violet. The cell-bound dye was then solubilized in
acetic acid and quantified at OD490 nm. The number of
neutralizing units was calculated as the reciprocal dilution that
completely prevented the TNF--mediated cytotoxicity.
Analytical methods of plasma samples
Tail-nick blood samples were taken in the mid-afternoon into
microfuge tubes containing a solution of 1.0 mM EDTA in
final dilution and spun, and the separated plasma was frozen at -70 C
until use. Both free fatty acids and lactate were measured by enzymatic
colorimetric assay kits (Boehringer Mannheim Corp.,
Indianapolis, IN and Sigma Chemical Co., St. Louis, MO,
respectively). Insulin was measured by a double antibody-coated tube
RIA kit for rat insulin with 100% cross-reactivity with human insulin
(Linco Research, Inc., St. Charles, MO). Plasma glucose
was measured by glucose oxidase methodology for microsamples using a
One-Touch Profile glucose meter (Lifescan, Inc., Milpitas, CA). For
determination of d-3[H]3-glucose concentrations, serum
was diluted 1:4 with water and then added to an equal volume of
perchloric acid, with a final concentration of 2.5%. Proteins were
precipitated by centrifugation at 2000 x g for 10 min.
Aliquots of supernatant were then dehydrated for 6 h at 55 C and
counted in a ß-scintillation counter.
Hyperinsulinemic glucose clamps
Four days after Ad5 injection, animals were clamped according to
a previously described method (8). Briefly, overnight fasted rats were
anesthetized with ketamine/xylazine
(60/6·mg-1·kg-1 ip) and then
underwent tracheostomy and cannulation of the internal jugular vein and
common carotid artery. After approximately 90 min, a booster of
10–15% of the original dose was given if necessary to maintain
anesthesia. During the first 20 min after surgery, baseline serum
glucose measurements were obtained. A loading dose of regular insulin
of 3, 2, and 1.5 times the steady state infusion rate was then
administered iv via the jugular vein over the first, second, and third
minutes, respectively, followed by a constant infusion of insulin at 70
pmol·kg-1·min-1.
3[H]-3-glucose was infused simultaneously at 0.09
µCi/min, after an initial 100x square-wave bolus over 1 min for
isotopic determination of glucose utilization as described by Steele
(9); 20% dextrose was infused as needed to maintain serum glucose at
basal concentrations. Somatostatin 1–14 (Sigma Chemical Co.) was infused at 920
pmol·kg-1·min-1 after basal measurements
throughout the clamp to suppress endogenous insulin output, as
previously described (8). When steady state glucose requirements had
been achieved, as determined by a <10% fluctuation in glucose
requirements for the maintenance of basal glucose over at least 15 min
(attained after 
90 min), 200 µl of blood was withdrawn at three
10-min intervals for determination of steady state serum glucose,
insulin levels, and tracer dilution for quantification of glucose
disposal rate (Rd) and hepatic glucose output (HGO). Liver
and rectus muscle were exposed and snap-frozen in liquid nitrogen.
Animals were then killed in a CO2 chamber. In a subsequent
set of clamp studies on lean animals, ip sodium pentobarbital
anesthesia (45 mg/kg) was employed.
Isolation of IR and measurement of insulin binding
Muscle and liver tissues were homogenized with a Polytron
(Brinkmann Instruments, Inc.) and solubilized in the
presence of 1.5% Triton X-100, 5 mM EDTA, 100
mM NaF, 10 mM Na3VO4,
10 mM Na4P2O7, and
various protease inhibitors (8). The tissue homogenate was centrifuged
at 100,000 x g. IR were purified from the supernatant
by wheat germ affinity column chromatography. Receptors were eluted
with 0.3 M N-acetyl glucosamine, and protein quantified
according to the Bradford dye method (Bio-Rad Laboratories, Inc.). Samples were stored at -80 C until further use.
Duplicate receptor preparations were then diluted to 0.3 mg/ml eluate
protein and added to 0.5 ng/ml of
A14-[125I]monoiodoinsulin and increasing concentrations
of unlabeled insulin. Following 12–15 h of incubation at 4 C,
ligand-receptor complexes were precipitated by polyethylene glycol and
-globulin. Counts in pellets with 5000 ng/ml of unlabeled insulin
were subtracted as nonspecific binding.
Analysis of IR tyrosine phosphorylation
Two milligrams of protein extract from various tissues was
incubated with 1.5 µg anti-IR antibody (29B4, Oncogene Science, Inc., Cambridge, MA) and agarose-conjugated protein G
(Pierce, Rockford, IL) at 4 C overnight. The
immunoprecipitates were then washed extensively in a buffer containing
50 mM HEPES, 100 mM
Na4P2O7, 100 mM NaF, 10
mM EDTA, 2 mM Na3VO4, 2
mM phenylmethylsulfonyl fluoride (PMSF), and 0.1 mg/ml
aprotinin, boiled in 2x Laemmli buffer, and separated by 7.5%
SDS-PAGE. The proteins were then electroblotted to nitrocellulose
membranes (Schleicher & Schuell, Inc., Keene, NH) and the
membrane was blocked in 5% nonfat dry milk in TBS containing 0.1%
Tween-20 and immunoblotted with horseradish peroxidase-conjugated
antiphosphotyrosine antibody (PY20, Transduction Laboratories, Inc., Lexington, KY). Results were visualized with
SuperSignal chemiluminescence kit (Pierce). The membrane
was then stripped and reblotted with a rabbit polyclonal antibody
specific for the IR ß-subunit and a horseradish peroxidase-conjugated
antirabbit secondary antibody (C19, Santa Cruz Biotechnology, Santa Cruz, CA) to determine the amount of IR
protein. Quantitation of immunoblots was made with a PDI densitometer
and the accompanying Quantity One image analysis software (PDI
Imageware Systems, Huntington Way, NY).
Measurement of PTP activity in tissue homogenates
One gram of frozen tissue was homogenized into 10 ml 0.25
M sucrose buffer containing 10 mM Tris-HCl, 0.2
mM MgCl2, 5 mM KCl, 4
mM dithiothreitol, 5 µg/ml leupeptin, 5 µg/ml
pepstatin, 1 mM PMSF, 25 mM benzamidine, and 5
µg/ml aprotinin. Cytosolic and particulate fractions were separated
by 100,000 x g centrifugation, and the membrane
fraction was solubilized in the same buffer containing 1.5% Triton
X-100. PTP activity in the particulate fraction was measured with a
malachite green microtiter plate assay according to a previously
described method (10). The substrate used in this assay is a synthetic
diphosphotyrosyl dodecapeptide,
TRDIYLTDYC(PO3)Y(PO3)RL, corresponding to
residues 1142–1153 of the major phosphorylation site of the human IR
(11). The phosphopeptide substrate was synthesized using solid-phase
methodology with t-Boc-dibenzyl-tyrosine phosphate, according to
Clark-Lewis et al. (12). The mass of the phosphopeptide and
the presence of the two phosphotyrosyl residues in the synthetic
peptide were determined using electrospray ionization mass spectrometry
on a Perkin-Elmer Sciex AP III triple quadrupole instrument
(Perkin-Elmer Corp. Sciex, Norwalk, CT). Lyophilized
phosphopeptide was redissolved in dH2O, and the
dephosphorylation of phosphopeptide substrate was carried out in
half-volume 96-well microtiter plates (Costar, Cambridge,
MA) in a final volume of 50 µl. The dephosphorylation reaction
consisted of 10 mM phosphopeptide and 10 µg soluble
particulate protein. The final volume of 50 µl was made up with
dephosphorylation buffer (25 mM imidazole, pH 7, 1
mM EDTA, 0.1% 2-mercaptoethanol, 2 mM
MgCl2, 2 mM PMSF, 1 mg/ml leupeptin, 0.1
mM benzamidine, and 0.25 M sucrose). The
reaction was allowed to proceed for 6 min at 30 C. One hundred
microliters of malachite green solution was added to terminate the
reaction, which was then further incubated for 20 min at room
temperature to allow for color development. The plate was then read at
OD650 nm by the ThermoMax microplate reader
(Molecular Devices, Menlo Park, CA). The amount of
inorganic phosphate released was quantified by extrapolation from the
malachite green standard curve, generated using
KH2PO4.
Statistical analysis
All statistical comparisons were conducted using Student’s
t test for paired or unpaired samples as appropriate. Data
are reported as mean ± SEM.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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inhibitory activity in experimental animals
Characteristics of rats and plasma levels of metabolic
variables
Basal weights and weight gain were matched within the two lean and
two obese groups, but were significantly different from each other at
all time points (Table 1
). Blood was
taken by tail-nick 1 day before and on days 2 and 4 post-Ad5
administration. Plasma glucose fell in all four groups in the
postinjection period in comparison with basal levels, possibly
as a result of acclimatization to the brief restraint and the tail-nick
procedure. Plasma insulin and plasma free fatty acids showed a tendency
to rise in the obese ß-gal group, and this rise was blunted in the
TNFi-treated group. When the data were expressed as change in insulin
and free fatty acids compared with pretreatment values as shown in Fig. 1, both were significantly lower in TNFi
than in ß-gal obese animals by day 2 (P < 0.05 in
both cases). Although this trend persisted at Day 4, statistical
significance was not reached. The same trend was evident for plasma
lactate levels, which were unchanged from pretreatment levels in the
ß-gal obese rats (Fig. 1C), but appeared to reach lower levels in
TNFi animals, narrowly failing to achieve significance
(P = 0.056) at day 4. None of these variables was
significantly altered at any time point in the lean animals.
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Serum insulin concentration at steady state during clamps was TNFi
= 565 ± 14 pM and ß-gal = 633 ± 5
pM in the obese rats. Corresponding values for glucose
disposal (Rd) were 3.2 ± 0.3 and 2.4 ± 0.1
mmol·kg-1·h-1 (9.6 ± 0.8 and
7.2 ± 0.4 mg·kg-1·min-1),
respectively (P < 0.05). To account for the modestly,
but statistically significantly, higher steady state mean serum insulin
level in the ß-gal rats, the Rd data are presented using
the insulin sensitivity index (ISI) as shown in Fig. 2, which also illustrates HGO. The
peripheral insulin sensitivity of the obese TNF-neutralized rats was
thus significantly greater than ß-gal controls, with a 50% higher
ISI (P < 0.02). In addition, neutralization of TNF in
fa/fa rats also resulted in marked improvement of hepatic
insulin sensitivity as shown by the complete suppression of HGO at
steady state (Fig. 2). Among the lean animals, there was no difference
in ISI (6.0 ± 1.0 vs. 6.8 ± 0.5
mmol-kg-1·h-1 nM, P
= NS) or HGO (-2.5 ± 0.4 vs. -3.0 ± 0.4
mmol·kg-1·h-1, P = NS)
between the TNFi and ß-gal-treated groups, respectively. TNF
neutralization in the obese rats resulted in an ISI during glucose
clamps that was similar to that in lean control rats (obese TNFi =
5.7 ± 0.5 vs. lean ß-gal = 6.8 ± 0.5
mmol·kg-1·h-1 nM, P =
NS).
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inhibition on IR tyrosine phosphorylation). This is consistent with the
increase in insulin- mediated Rd in these animals.
However, improvement in tyrosine phosphorylation was not observed in
liver IR despite the significant improvement in hepatic insulin
sensitivity, shown previously in Fig. 2
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. In the TNFi-treated
obese animals, there was an approximately 4-fold higher PTP activity in
the particulate fraction of tissue homogenates from skeletal muscle
isolated at steady state during glucose clamps compared with ß-gal
rats. Conversely, no difference could be shown in PTP activity in
homogenates of liver tissue.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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inhibition has not been found
previously (3, 13). Although chronic administration of TNF- led to
impairment of insulin action on Rd and HGO in normal rats
(16), TNF- inhibition by daily iv injection of the soluble TNFi
protein in Zucker rats had no effect on HGO (3, 13). A possible
explanation for the discrepancy could be the level and consistency of
TNFi levels during treatment periods. It has been shown that
Ad5-mediated TNFi gene expression provided a sustained high level of
soluble circulating TNFi protein in mice (14). Furthermore, TNF
inhibitory activity in our TNF-neutralized animals at the time of clamp
studies was much higher than the control group, in which no such
activity was detectable. To our knowledge, previous similar studies
have not measured TNF-inhibitory activity, although Hotamisligil
et al. (3) confirmed high levels of circulating TNF
receptor-IgG following administration of an IgG-bound
TNF-inhibitory protein. However, uniform access to tissue and
extracellular fluid compartments of a sizable protein cannot be assumed
following exogenous infusion, even when optimal plasma levels are
achieved. Thus, discrepancies between our findings and those of others
may be caused by fluctuations in tissue concentrations or rapid tissue
clearance of TNFi proteins by the host immune response in other animal
models, where TNFi proteins were administered exogenously.
We have also shown that TNF--induced insulin resistance in obese
Zucker rats is not mediated through reduction of IR number nor insulin
binding affinity. Overall, our results indicate that TNF- may induce
insulin resistance in skeletal muscle and liver through different
mechanisms. Apparently, TNF- attenuates insulin action in skeletal
muscle by down-regulation of both insulin-stimulated IR
autophosphorylation and of PTP activity. We and others have reported
impaired tissue PTP activity in both obese Zucker rats (17) and obese
human subjects with DM2 (18, 19, 20), circumstances in which TNF-
expression is known to be increased in insulin-responsive tissues
(21, 22, 23). Thus it appears that inhibition of TNF- is associated with
improved insulin signaling, possibly resulting from restoration of
impaired PTP activity. Recent data have suggested that PTPs may play a
positive regulatory role in insulin signaling. Yamauchi et
al. (24) showed that activation of SH-PTP2 occurs in
response to insulin binding, and that SH-PTP2 promotes insulin
signaling. Furthermore, Ren et al. (25) recently reported
that mice rendered deficient in leukocyte-antigen-related-PTP, a
transmembrane PTP, by homozygous transgenic knock-out, exhibited
insulin resistance during euglycemic hyperinsulinemic clamps.
It is unclear whether the effects we report here occur as a result of a
direct intracellular interaction between the TNF- and insulin
signaling cascades or secondary to the observed alterations in
circulating metabolic influences, e.g. free fatty acids and lactate.
Although reduced insulin binding and internalization of IR have been
reported after exposure to free fatty acids (26, 27), IR kinase has
been shown to be unaffected (26). By contrast, in the liver, TNF-
appears to either exert its effects at site(s) downstream from the IR
or indirectly via alterations in metabolic parameters that do not
influence insulin action via the IR kinase, e.g. free fatty
acids, gluconeogenic substrates, or glucagon (28, 29). With our
animal model, these questions can be investigated in future
studies.
Reduction in both circulating free fatty acid and insulin levels in
obese Zucker rats has been reported following TNF inhibition by
infusion of neutralizing TNF antibodies (4). Following transgenic
knock-out of the TNF- gene (5), reductions in plasma levels of both
insulin and free fatty acids in ligand-deficient mice were only seen
when the animals were challenged with a high fat diet. To our
knowledge, lactate levels in response to either TNF- administration
or inhibition have not been studied. In our model, a reduction in
circulating insulin and free fatty acids levels was seen in the
nonfasting state on a standard rat-chow diet within 2 days of Ad5
injection. It is unclear why this was not sustained at day 4, because
profound alterations in both peripheral and hepatic insulin sensitivity
were demonstrable on glucose clamps at this point.
Presently, the mode of action of TNF- on insulin-sensitive tissues
remains speculative. However, available data favors the likelihood of a
paracrine and/or autocrine pathway (30). If TNF- acts locally around
its site of production in the muscle and adipose tissue, the
accessibility of those compartments to TNFi protein delivered iv could
be an obstacle. The use of Ad5-mediated expression of TNFi in
vivo reported here may circumvent this problem. It has been
reported that efficient and long-term in vivo gene transfer
throughout skeletal muscle and the liver of mice can be easily
accomplished by iv administration of an adenoviral vector (31). With
the adenovirus-mediated gene transfer technique, it is possible to
specifically target TNF inhibition to insulin responsive tissues by
injecting the virus vector directly into those tissues (32), simulating
a condition of tissue-specific TNF inhibition. The Ad5-TNFi vector can
also be administered to animals at different stages in the evolution of
obesity or insulin resistance. Moreover, it also allows for comparison
of the effects of long-term vs. short-term TNF inhibition on
whole-animal glucose metabolism and molecular pathways of insulin
signaling to further understanding of the spatial and temporal
requirements for TNF--induced insulin resistance in obesity.
Furthermore, transgenic animal models in which either TNF- itself
(5, 33) or the TNF receptor (5) is not expressed, while providing
important information, are subject to the limitation that abnormal
TNF- signaling pertains throughout the entire life span of the
animal. Increased TNF- expression in obesity, which may initially
manifest itself or progress in severity in adult life, presumably only
occurs after the development of the obese state, because weight
reduction has been shown to diminish TNF- expression in both humans
(23) and rodents (21). In addition, permanent complete absence of a
receptor or its ligand may result in compensatory developmental
alterations in other signaling components (34).
DM2 is a complex pathophysiological condition involving multiple
organs. Thus, the model proposed here provides an efficient and
cost-effective alternative to transgenics. Moreover, the technique
permits rapid evaluation of effects of TNF- in different genetic
models of obesity-linked insulin resistance (e.g. ob/ob,
db/db, tub, and agouti), while
minimizing the time and cost constraint of cross-breeding and
maintaining a sufficient number of animals to study a given genetic
background.
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Acknowledgments |
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Footnotes |
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2 Supported by NIH Medical Student Research Fellowship DK-07405.
3 Supported by NIH Grant R-29-AA-10384 and a grant from the Cystic
Fibrosis Foundation.
4 Recipient of research grants from the American Diabetes Association
and the University of Tennessee Medical Group.
Received June 15, 1998.
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, and its receptors during drug and
dietary modulation of insulin resistance. Endocrinology 134:264–270 by human muscle: relationship to insulin
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J. J. Senn, P. J. Klover, I. A. Nowak, and R. A. Mooney Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes Diabetes, December 1, 2002; 51(12): 3391 - 3399. [Abstract] [Full Text] [PDF]
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M. G. Wallis, C. M. Wheatley, S. Rattigan, E. J. Barrett, A. D.H. Clark, and M. G. Clark Insulin-Mediated Hemodynamic Changes Are Impaired in Muscle of Zucker Obese Rats Diabetes, December 1, 2002; 51(12): 3492 - 3498. [Abstract] [Full Text] [PDF]
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H. Xu, K. T. Uysal, J. D. Becherer, P. Arner, and G. S. Hotamisligil Altered Tumor Necrosis Factor-{alpha} (TNF-{alpha}) Processing in Adipocytes and Increased Expression of Transmembrane TNF-{alpha} in Obesity Diabetes, June 1, 2002; 51(6): 1876 - 1883. [Abstract] [Full Text] [PDF]
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H. Xu, J. Hirosumi, K. T. Uysal, A. D. Guler, and G. S. Hotamisligil Exclusive Action of Transmembrane TNF{alpha} in Adipose Tissue Leads to Reduced Adipose Mass and Local But Not Systemic Insulin Resistance Endocrinology, April 1, 2002; 143(4): 1502 - 1511. [Abstract] [Full Text] [PDF]
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M. Li, J. F. Youngren, V. P. Manchem, M. Kozlowski, B. B. Zhang, B. A. Maddux, and I. D. Goldfine Small Molecule Insulin Receptor Activators Potentiate Insulin Action in Insulin-Resistant Cells Diabetes, October 1, 2001; 50(10): 2323 - 2328. [Abstract] [Full Text]
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J. I. Barzilay, L. Abraham, S. R. Heckbert, M. Cushman, L. H. Kuller, H. E. Resnick, and R. P. Tracy The Relation of Markers of Inflammation to the Development of Glucose Disorders in the Elderly: The Cardiovascular Health Study Diabetes, October 1, 2001; 50(10): 2384 - 2389. [Abstract] [Full Text]
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 R. P. Tracy Is Visceral Adiposity the "Enemy Within"? Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 881 - 883. [Full Text] [PDF]
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P. A. Kern, S. Ranganathan, C. Li, L. Wood, and G. Ranganathan Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance Am J Physiol Endocrinol Metab, May 1, 2001; 280(5): E745 - E751. [Abstract] [Full Text] [PDF]
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 M. P. Wajnrajch, J. M. Gertner, Z. Huma, J. Popovic, K. Lin, P. C. Verlander, S. D. Batish, P. F. Giampietro, J. G. Davis, M. I. New, et al. Evaluation of Growth and Hormonal Status in Patients Referred to the International Fanconi Anemia Registry Pediatrics, April 1, 2001; 107(4): 744 - 754. [Abstract] [Full Text] [PDF]
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 D. Le Roith and Y. Zick Recent Advances in Our Understanding of Insulin Action and Insulin Resistance Diabetes Care, March 1, 2001; 24(3): 588 - 597. [Abstract] [Full Text]
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M. Blüher, J. Kratzsch, and R. Paschke Plasma Levels of Tumor Necrosis Factor-{alpha}, Angiotensin II, Growth Hormone, and IGF-I Are Not Elevated in Insulin-Resistant Obese Individuals With Impaired Glucose Tolerance Diabetes Care, February 1, 2001; 24(2): 328 - 334. [Abstract] [Full Text]
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T. H. Elsasser, J. L. Sartin, A. Martínez, S. Kahl, L. Montuenga, R. Pío, R. Fayer, M. J. Miller, and F. Cuttitta Underlying Disease Stress Augments Plasma and Tissue Adrenomedullin (AM) Responses to Endotoxin: Colocalized Increases in AM and Inducible Nitric Oxide Synthase within Pancreatic Islets Endocrinology, November 1, 1999; 140(11): 5402 - 5411. [Abstract] [Full Text]
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H. Xu, J. K. Sethi, and G. S. Hotamisligil Transmembrane Tumor Necrosis Factor (TNF)-alpha Inhibits Adipocyte Differentiation by Selectively Activating TNF Receptor 1 J. Biol. Chem., September 10, 1999; 274(37): 26287 - 26295. [Abstract] [Full Text] [PDF]
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 L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]
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, TNFi and 
, ß-gal
groups. Insulin = -7.7 ± 4.0% and -3.0 ± 3.0% for
TNFi (N = 5); +1.9 ± 1.5% and +4.5 ± 4.4% for
ß-gal (N = 5) on days 2 and 4, respectively, vs.
preinjection levels. FFA = 90.3 ± 24.7 µM and
87.0 ± 36.5 µM for TNFi (N = 4); 179.1 ±
23.1 µM, and 157.1 ± 64.1 µM for
ß-gal (N = 4) on days 2 and 4, respectively, vs.
preinjection levels. Lactate = -6.7 ± 4.1 mg/dl and
-9.2 ± 3.1 mg/dl for TNFi (N = 5); -2.6 ± 2.1 mg/dl
and -1.8 ± 1.1 mg/dl for ß-gal (N = 5) on days 2 and 4,
respectively, vs. preinjection levels. *,
P < 0.05 vs. ß-gal.
