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(Received for publication, November 6, 1995; and in revised form, January 9, 1996) From the
Glucose catabolism induces the expression of the L-type pyruvate
kinase (L-PK) gene through the glucose response element (GIRE). The
metabolic pathway used by glucose after its phosphorylation to glucose
6-phosphate by glucokinase to induce L-PK gene expression in
hepatocytes remains unknown. The sugar alcohol xylitol is metabolized
to xylulose 5-phosphate, an intermediate of the nonoxidative branch of
the pentose phosphate pathway. In this study, we demonstrated that
xylitol at low concentration (O.5 mM) induced the expression
of the L-PK/CAT construct in glucose-responsive mhAT3F hepatoma cells
at the same level as 20 mM glucose, while it did not affect
intracellular concentration of glucose 6-phosphate significantly. The
effect of xylitol on the induction of the L-PK gene expression was
noncumulative with that of glucose since 20 mM glucose plus 5
mM xylitol induced the expression of the L-PK/CAT construct
similarly to 20 mM glucose alone. In hepatocytes in primary
culture, 5 mM xylitol induced accumulation of the L-PK mRNA
even in the absence of insulin. Furthermore, the response to xylitol as
well as glucose required the presence of a functional GIRE. It can be
assumed from these results that glucose induces the expression of the
L-PK gene through the nonoxidative branch of the pentose phosphate
pathway. The effect of xylitol at low concentration suggests that the
glucose signal to the transcriptional machinery is mediated by xylulose
5-phosphate. Glucose, a major fuel of mammalian tissues, induces the
transcription of several glycolytic and lipogenic genes in hepatocytes
and adipocytes(1, 2, 3, 4) . In
particular, it induces the expression of the L-type pyruvate kinase
(L-PK) ( In this study, we show that
xylitol is active at a lower concentration than glucose for stimulating
the L-PK promoter in both mhAT3F hepatoma cells and hepatocytes. In
mhAT3F cells, the activating xylitol concentration is too low to modify
intracellular glucose 6-phosphate concentration. The xylitol acts as
glucose through the GIRE. Since xylitol is transformed into xylulose
5-phosphate in the cells, we suggest that glucose acts on
glucose-responsive genes in the liver, and probably adipocytes, through
the nonoxidative branch of the pentose phosphate pathway. Consequently,
xylulose 5-phosphate is the major metabolite candidate of the
nonoxidative branch of the pentose phosphate pathway responsible for
mediating transcriptional machinery induction by glucose catabolism.
The different L-PK/CAT constructs
(termed -183 PK/CAT, -150 PK/CAT, -96 PK/CAT, L4mi-L3
-119 PK/CAT) have been previously
described(5, 20) . The KSV2 CAT plasmid, used as a
transfection control, contains the CAT gene directed by the early
promoter and enhancer of simian virus 40 (SV40)(14) .
The mhAT3F hepatocyte-like cell lines were derived from tumoral
liver of transgenic mice expressing the SV40 large T and small T
antigens under the direction of the liver-specific antithrombin III
promoter (14, 23, 24) . Cells were cultured
in Ham's F-12-Dulbecco's modified Eagle's medium
(v/v) (Life Technologies, Inc.) medium supplemented with penicillin,
streptomycin, 20 nM insulin, 1 µM triiodothyronine, 1 µM dexamethasone, and 5% (v/v)
fetal calf serum. Twenty-four h before the experiment, cells were
cultured in a serum-free, glucose-free medium containing 10 mM lactate and supplemented with the same mixture of hormones as
described above. Induction of the different L-PK/CAT constructs was
measured in the presence of the various concentrations of glucose and
xylitol.
Figure 1:
Effect of xylitol on the activation of
the L-PK gene promoter in mhAT3F cells. The mhAT3F cells were incubated
for 24 h in the medium containing 20 nM insulin, 1 µM triiodothyronine, 1 µM dexamethasone, and 10 mM lactate and, after the induction of the L-PK/CAT construct, were
measured in the presence of the various concentrations of glucose and
xylitol with the same mixture of hormones as described above. The CAT
activities of the -183 PK/CAT construct transfected in mhAT3F
cells was determined by the percentage of chloramphenicol conversion to
its acetylated forms. The CAT activities were normalized with respect
to the activity of KSV2 CAT and expressed in percentage with respect to
the results obtained with 20 mM glucose equal to 100%.
Transfection assays were performed by lipofection with 5 µg of
plasmid DNA. All values represent the means ± S.D. of at least
seven independent experiments. *, significantly higher than lactate (p < 0.05).**, significantly higher than lactate (p < 0.001).
Figure 2:
Effect of xylitol on the activation of the
CAT activities generated by various 5`-deleted L-PK/CAT gene constructs
in mhAT3F cells. A, the 5` deletions of the L-PK gene
constructs were introduced by lipofection in mhAT3F cells. Broken
lines between the box represent the 8 bp introduced during the
preparation of the constructs. B, the cell culture condition
was the same as described in Fig. 1. The CAT activities were
normalized with respect to the activity of KSV2 CAT used as a
transfection standard and expressed in percentage by reference to the
results obtained with 20 mM glucose equal to 100%. Each value
represents the mean ± S.D. of four experiments.**, significantly
higher than lactate (p <
0.001).
Figure 3:
Effects of xylitol on the level of L-type
pyruvate kinase mRNA in cultured hepatocytes. Hepatocytes were isolated
from 3-day-starved male rats and plated on 10-cm dishes in a medium
supplemented with penicillin, streptomycin, and 10% (v/v) dialyzed
fetal calf serum. After culture in the presence of 1 µM triiodothyronine, 1 µM dexamethasone, xylitol (5 and
10 mM) or glucose (25 mM), with or without insulin
(20 nM), hepatocytes were harvested and total RNA was
purified. Total RNA was purified from the hepatic cells. The L-type
pyruvate kinase mRNA was quantified by scanning the autoradiograms of
Northern blot analysis. The values are the means of three distinct
experiments and are expressed relative to the value obtained under the
lactate culture condition.
In addition, the role of a
pentose phosphate as an inducer of the signaling pathway leading to
activation of glucose-responsive genes is concordant with the effect of
2-deoxyglucose in adipocytes (11) and insulinoma INS-1
cells(16) . Indeed, it has been reported that in some cells (e.g. granulocytes, monocytes, and macrophages) the
2-deoxyglucose 6-phosphate can enter the pentose phosphate pathway and
be metabolized into a decarboxylated intermediate, most likely a
pentose phosphate, although 40-fold less efficiently than glucose
6-phosphate(17) . However, the considerable accumulation of
2-deoxyglucose 6-phosphate as compared to glucose 6-phosphate (15, 17, 18) can partly compensate for its
decreased metabolism through the pentose phosphate pathway, especially
in cells in which this pathway is very active, as in
adipocytes(36) . In contrast, the pentose phosphate pathway is
much less active in hepatocytes(37) . This, associated with a
glucose-6-phosphatase activity decreasing the accumulation of
2-deoxyglucose 6-phosphate(18) , could explain why
2-deoxyglucose is unable to stimulate glucose-responsive genes in
hepatic cells(14) . Accordingly, we found that 2-deoxyglucose
6-phosphate concentration enzymatically determined after incubation for
20 min with 10 mM 2-deoxyglucose, was 4-fold lower in mhAT3F
cells than in rat and hamster insulinoma cell lines (R1N and H1T cells,
respectively). ( In conclusion, we have demonstrated that
a pentose entering the nonoxidative branch of the pentose phosphate
pathway is active at very low concentrations for stimulating the L-PK
gene through its glucose response elements. We suggest that xylulose
5-phosphate, capable of activating a protein phosphatase
activity(31, 32) , could trigger a
phosphorylation/dephosphorylation cascade modulating the activity of
the glucose response complex assembled on the glucose-responsive
elements in hepatocytes and adipocytes.
Volume 271,
Number 10,
Issue of March 8, 1996 pp. 5321-5324
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
)gene in the liver through the glucose response
element (GIRE) located at position -168 to -144 bp with
respect to the cap site(5, 6, 7) . This GIRE
consists of two palindromic binding sites for upstream stimulating
factor (USF) proteins separated by 5 base
pairs(5, 8, 9) . Similar elements, also
termed carbohydrate response element, have been identified in the
regulatory regions of several glucose-responsive genes, i.e. the spot 14 gene (10) and the fatty acid synthase
gene(11, 12) . We have shown that activation of the
L-PK promoter through its GIRE requires phosphorylation of glucose to
glucose 6-phosphate, mediated by insulin-dependent glucokinase
induction in hepatocytes(13) . However, insulin can be replaced
in hepatocytes by transfection of a glucokinase expression vector and
by low concentrations of fructose acting through fructose
1-phosphate-dependent activation of residual glucokinase (13) .
Furthermore, insulin is not necessary in the glucose-responsive
hepatoma cell lines in which glucokinase is replaced by other isoforms
of insulin-independent hexokinases(14) . However, the pathway
by which glucose 6-phosphate activates transcription of the L-PK gene
and other glucose-responsive genes remains unknown. Glucose 6-phosphate
is an important compound at the junction of several metabolic pathways
(glycolysis, gluconeogenesis, pentose phosphate pathway, glycogenesis,
and glycogenolysis). In adipocytes, the glucose analogue 2-deoxyglucose
(transported in the cell, phosphorylated into 2-deoxyglucose
6-phosphate but was not further metabolized in the Embden Meyerhoff
pathway) has been shown to stimulate expression of the fatty acid
synthase and acetyl-CoA carboxylase genes(15) . Similarly,
2-deoxyglucose can activate the L-PK promoter in the insulinoma cell
line INS-1(16) , but not in hepatocyte or hepatoma
cells(14) . However, the efficiency of 2-deoxyglucose in
mimicking the glucose effect in some cells does not signify that the
observed induction was mediated by 2-deoxyglucose 6-phosphate itself.
Indeed, although its isomerization into fructose 6-phosphate is
impossible, 2-deoxyglucose 6-phosphate is partly further metabolized
into various compounds(17, 18) . Therefore, if the
2-deoxyglucose-dependent induction of glucose-responsive genes in
adipocytes and INS-1 cells rules out the involvement of the Embden
Meyerhoff pathway, it does not rule out the involvement of
intermediates rising from 2-deoxyglucose 6-phosphate, especially
through the pentose phosphate pathway.
Plasmids
All plasmids were constructed by using
standard DNA cloning procedures(19) . The constructs were
verified by nucleotide sequencing.Cell Culture Conditions
Hepatocytes were isolated
by collagenase perfusion method from male Sprague-Dawley rats
(180-200 g) fasted since 3
days(5, 21, 22) . Hepatocyte suspensions were
plated on 10-cm dishes in a final volume of 10 ml of a medium 199 (Life
Technologies, Inc.) supplemented with penicillin, streptomycin, and 10%
(v/v) dialyzed fetal calf serum. After 12 h of attachment, the medium
was removed and replaced by a hormone-supplemented fresh medium 199
with different glucose and/or xylitol concentrations in the presence or
absence of insulin (20 nM). The medium was replaced every 24
h.Transfections and CAT Assays
Transfection of the
mhAT3F was performed by lipofection using N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium
methylsulfate (DOTAP, Boehringer Mannheim, Mannheim, Germany) according
to the manufacturer's instructions, in cells cultured under
lactate conditions. Five micrograms of plasmids was transfected when
cells were 60-80% confluent in 60-mm plastic dishes (Falcon,
Oxnard, CA) The medium containing the liposome-DNA complex was removed
12 h later and replaced with medium as described above for glucose and
xylitol regulation studies. Cells were harvested 36 h later. CAT
activity assay was performed as described(5, 14) . The
CAT activity was normalized with respect to the KSV2 CAT activity as a
transfection standard.Northern Blot Analysis
Total RNAs were isolated
from adult rat hepatocytes in primary culture by lysis in guanidinium,
followed by phenol extraction(25) . The RNA concentration was
determined spectrophotometrically. RNA was denaturated with
methylmercury hydroxide, electrophoretically separated on formaldehyde
agarose gels, and finally transferred and UV-cross-linked to nylon
filters (Hybond-N, Amersham). Prehybridization (2 h with 100 µg/ml
salmon sperm DNA) and hybridization were carried out as described
previously(6) .Determination of Glucose 6-Phosphate
Concentration
Glucose 6-phosphate concentration in cultured
mhAT3F cells was assayed enzymatically according to Slein (26) as described previously(13) .Statistics
Results are given as means ±
S.D. Statistical significance of differences between treatment groups
in these studies was determined by Student's t-test. The
minimal level of significance chosen was p < 0.05.
Xylitol Stimulates the L-PK Promoter at Low
Concentration in mhAT3F Cells
Glucose 6-phosphate synthesis is
the first step of glucose-dependent activation of glucose-responsive
genes in the liver and hepatocytes(13) . It is consumed through
the Embden Meyerhoff pathway and pentose phosphate pathway. It can also
be used for the synthesis of glycogen, that occurs mainly in muscle and
liver. In the liver, glucose 6-phosphate can be produced by
gluconeogenesis and glycogenolysis. The Embden Meyerhoff pathway or
pentose phosphate pathway, more or less active in all cells, are
therefore the most likely source of active intermediates mediating
transcriptional stimulation of glucose responsive genes through their
GIRE. However, the efficiency of 2-deoxyglucose for stimulating the
L-PK promoter through its GIRE in insulinoma INS-1 cells seems to rule
out the involvement of the Embden Meyerhoff pathway(16) . To
test the role of intermediates of the nonoxidative branch of the
pentose phosphate pathway in activation of the L-PK GIRE, we compared
the efficiency of various concentrations of either xylitol or glucose
in stimulating CAT activity of L-PK/CAT constructs transiently
transfected in mhAT3F cells. Fig. 1shows that 0.5 mM xylitol was as efficient as 20 mM glucose, and a
detectable stimulation was observed for xylitol concentrations as low
as 0.1 mM. In contrast, we have previously demonstrated that
stimulation of the -183 PK/CAT construct was undetectable in
mhAT3F cells for a glucose concentration lower than 5
mM(14) . Xylitol and glucose-dependent activation
appeared to be noncumulative since similar CAT activity was observed in
the presence of 20 mM glucose regardless of the presence of 5
mM xylitol.
Both Xylitol and Glucose Effects on the Activity of the
L-PK Promoter Are Mediated by the L-PK GIRE
The positive
response of the L-PK gene to glucose is mediated by the GIRE,
corresponding to box L4 spanning from -168 to -144 bp with
respect to the cap site. Any mutation impairing binding of USF proteins
to the GIRE suppresses the glucose responsiveness of the L-PK promoter
in hepatocytes in primary cultures (5, 8) as well as
in mhAT3F cells(14) . Fig. 2shows that all PK/CAT
constructs lacking the box L4 (-96 PK/CAT and L3 -119
PK/CAT constructs) or with a mutant box L4 unable to bind USF (L4miL3
-119 PK/CAT construct) were unresponsive to both glucose and
xylitol in mhAT3F cells. In the L4miL3 -119 PK/CAT construct, the
downstream USF binding site of the GIRE was inactivated by transforming
the CCCGTG E box into CCCTTG(5) . These results suggest that
xylitol uses the same way as glucose to induce expression of the L-PK
gene through the GIRE. Consequently, we suggest that glucose induces
L-PK gene expression through the nonoxidative branch of the pentose
phosphate pathway. Indeed, xylitol is first oxidized to D-xylulose, which is then phosphorylated to D-xylulose 5-phosphate and further metabolized by the
nonoxidative branch of the pentose phosphate pathway(27) . The
activation of the L-PK promoter by xylitol concentrations as low as 0.1
and 0.5 mM practically rules out the hypothesis that this
pentose could act through conversion of xylulose 5-phosphate to hexose
phosphate by the nonoxidative branch and then re-enter the Embden
Meyerhoff pathway. Indeed, 0.5 mM xylitol was unable to
increase glucose 6-phosphate in mhAT3F cell. A xylitol-dependent
glucose 6-phosphate accumulation through the pentose phosphate pathway
and gluconeogenesis was detectable only for much higher xylitol
concentrations (Table 1). In addition, we have previously shown
that in hepatocytes in primary culture, fructose alone at 0.2 mM was inactive on the L-PK promoter, while it was able to stimulate
the glucose effect regardless of the presence of insulin(13) .
This signifies that fructose 1-phosphate, a product of the fructokinase
reaction, was able to stimulate glucokinase-dependent phosphorylation
of glucose, but was inactive by itself or by its metabolism through the
Embden Meyerhoff pathway.
Xylitol Activates the Endogenous L-PK Gene without
Insulin in Hepatocytes in Primary Culture
Insulin dependence of
the glucose effect in hepatocytes is due to the transcriptional
induction of the glucokinase gene by insulin allowing for glucose
phosphorylation to glucose 6-phosphate(13) . Xylitol is
oxidized to D-xylulose by L-iditol dehydrogenase and
then phosphorylated to xylulose 5-phosphate by a specific
xylulokinase(27) . Therefore, the xylitol effect in hepatocytes
is not expected to depend on the insulin-dependent glucokinase gene
activation. Indeed, detection by a Northern blot of the endogenous L-PK
mRNA shows that 5 mM xylitol alone, without insulin, leads to
L-PK mRNA accumulation while 25 mM glucose was practically
inefficient in an insulin-free medium (Fig. 3). As expected, 20
nM insulin strongly stimulated the glucose responsiveness, but
did not significantly change the xylitol responsiveness of the L-PK
gene. The extent of xylitol-dependent induction of the L-PK gene in
hepatocytes, with or without insulin, was 3-fold lower than with
glucose plus insulin. As a matter of fact, the use of xylitol as the
only fuel can provoke cellular ATP depletion due to inorganic phosphate
trapping in the phosphate esters of the pentose phosphate
pathway(28, 29) , which could explain this apparent
lower efficiency of xylitol as compared to glucose plus insulin.
Moreover, xylitol was active in hepatocytes at a lower concentration
than glucose (5 mMversus more than 10 mM),
as already commented upon with mhAT3F hepatoma cells. The need for a
higher carbohydrate concentration to induce the L-PK gene in
hepatocytes compared with mhAT3F cells seems to be a general phenomenon
which could be explained by several features, such as differences in
transporters, membrane permeability, enzyme activities, very low
metabolism, and transcriptional activities of hepatocytes in primary
culture, etc.
Role of the Pentose Phosphate Pathway in Glucose
Signaling toward the Transcriptional Machinery
The pentose
phosphate pathway was described in its classical form as a cycle by
Horecker and Mehler(30) . This cycle occurs in two separate
stages: the oxidative step, which involves oxidations by
NADP, occurs in the reaction from glucose or glucose
6-phosphate to ribulose 5-phosphate, and the nonoxidative step, which
involves sugar interconversion reactions, occurs in the pathway from
ribulose 5-phosphate back to glucose 6-phosphate. The main biological
function of the oxidative step exists in the generation of NADPH as a
source of reducing equivalents for biosynthetic reactions. Therefore,
this oxidative phase is especially important in adipocytes, since NADPH
is essential for the biosynthesis of fatty acids. The main function of
the nonoxidative step is the maintenance of the monosaccharide pool in
the cell cytosol, especially the ribose 5-phosphate for nucleotide and
nucleic acid synthesis. Our results with xylitol suggests that the
nonoxidative branch of the pentose phosphate pathway is also a crucial
step for triggering the induction signal of the L-PK gene expression.
Recently, Nishimura et al.(31, 32) demonstrated the stimulation by xylulose
5-phosphate of a protein phosphatase 2A active on
phosphophosphofructokinase-2. The activation of this protein
phosphatase 2A requires at least 10 µM xylulose
5-phosphate, and its activation curve was highly sigmoidal. Xylulose
5-phosphate appeared to be a specific activator of the protein
phosphatase because none of the other sugar phosphates tested,
including glucose 6-phosphate or fructose 6-phosphate, was effective.
Consistently with the involvement of protein phosphatase(s) in the
response of the L-PK gene to glucose, we found that okadaic acid, that
specifically inhibits protein phosphatases 2A and 1(33) ,
blocks the induction of both transiently transfected L-PK/CAT
constructs and endogenous mhAT3F cells. (
)Therefore, we
suggest that glucose induces expression of the L-PK gene through the
nonoxidative branch of the pentose phosphate pathway by increasing the
concentration of xylulose 5-phosphate. The xylulose 5-phosphate could
then activate a protein phosphatase at the origin of a cascade leading
to activation of the glucose response complex assembled on the GIRE of
the L-type PK gene and most likely of other glucose response genes. The
role of xylulose 5-phosphate in glucose signaling is made more probable
by its accumulation due to high xylulokinase and transketolase
activities compared to the transaldolase
activity(34, 35) .
)
)))
We thank Dr. Jean Claude Depezay for his helpful
discussion about the chemical propriety of the 2-deoxyglucose. We thank
Drs. Mohamed Chikri, Alexandra Henrion, Soledad Lopez, Michel
Raymondjean, Virginie Vallet, and Sophie Vaulont for the revision of
the text. We are grateful for the gift of the mhAT3F cell by Dr.
Bénédicte Antoine.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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J.-i. Hasegawa, K. Osatomi, R.-F. Wu, and K. Uyeda A Novel Factor Binding to the Glucose Response Elements of Liver Pyruvate Kinase and Fatty Acid Synthase Genes J. Biol. Chem., January 8, 1999; 274(2): 1100 - 1107. [Abstract] [Full Text] [PDF]
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E. Plee-Gautier, M. Aggerbeck, F. Beurton, B. Antoine, H. Grimal, R. Barouki, and C. Forest Identification of an Adipocyte-Specific Negative Glucose Response Region in the Cytosolic Aspartate Aminotransferase Gene Endocrinology, December 1, 1998; 139(12): 4936 - 4944. [Abstract] [Full Text] [PDF]
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D. K. Scott, R. M. O'Doherty, J. M. Stafford, C. B. Newgard, and D. K. Granner The Repression of Hormone-activated PEPCK Gene Expression by Glucose Is Insulin-independent but Requires Glucose Metabolism J. Biol. Chem., September 11, 1998; 273(37): 24145 - 24151. [Abstract] [Full Text] [PDF]
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M. Foretz, D. Carling, C. Guichard, P. Ferre, and F. Foufelle AMP-activated Protein Kinase Inhibits the Glucose-activated Expression of Fatty Acid Synthase Gene in Rat Hepatocytes J. Biol. Chem., June 12, 1998; 273(24): 14767 - 14771. [Abstract] [Full Text] [PDF]
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F. B. Hillgartner and T. Charron Glucose stimulates transcription of fatty acid synthase and malic enzyme in avian hepatocytes Am J Physiol Endocrinol Metab, March 1, 1998; 274(3): E493 - E501. [Abstract] [Full Text] [PDF]
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D. Massillon, W. Chen, N. Barzilai, D. Prus-Wertheimer, M. Hawkins, R. Liu, R. Taub, and L. Rossetti Carbon Flux via the Pentose Phosphate Pathway Regulates the Hepatic Expression of the Glucose-6-phosphatase and Phosphoenolpyruvate Carboxykinase Genes in Conscious Rats J. Biol. Chem., January 2, 1998; 273(1): 228 - 234. [Abstract] [Full Text] [PDF]
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H. J. Kennedy, B. Viollet, I. Rafiq, A. Kahn, and G. A. Rutter Upstream Stimulatory Factor-2 (USF2) Activity Is Required for Glucose Stimulation of L-Pyruvate Kinase Promoter Activity in Single Living Islet beta -Cells J. Biol. Chem., August 15, 1997; 272(33): 20636 - 20640. [Abstract] [Full Text] [PDF]
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 D. Mitanchez, B. Doiron, R. Chen, and A. Kahn Glucose-Stimulated Genes and Prospects of Gene Therapy for Type I Diabetes Endocr. Rev., August 1, 1997; 18(4): 520 - 540. [Abstract] [Full Text] [PDF]
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B. Antoine, A.-M. Lefrancois-Martinez, G. Le Guillou, A. Leturque, A. Vandewalle, and A. Kahn Role of the GLUT 2 Glucose Transporter in the Response of the L-type Pyruvate Kinase Gene to Glucose in Liver-derived Cells J. Biol. Chem., July 18, 1997; 272(29): 17937 - 17943. [Abstract] [Full Text] [PDF]
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D. Argaud, T. L. Kirby, C. B. Newgard, and A. J. Lange Stimulation of Glucose-6-phosphatase Gene Expression by Glucose and Fructose-2,6-bisphosphate J. Biol. Chem., May 9, 1997; 272(19): 12854 - 12861. [Abstract] [Full Text] [PDF]
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H. Wang and P. B. Iynedjian Modulation of glucose responsiveness of insulinoma beta -cells by graded overexpression of glucokinase PNAS, April 29, 1997; 94(9): 4372 - 4377. [Abstract] [Full Text] [PDF]
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E. N. Kaytor, H.-m. Shih, and H. C. Towle Carbohydrate Regulation of Hepatic Gene Expression. EVIDENCE AGAINST A ROLE FOR THE UPSTREAM STIMULATORY FACTOR J. Biol. Chem., March 14, 1997; 272(11): 7525 - 7531. [Abstract] [Full Text] [PDF]
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E. Roche, F. Assimacopoulos-Jeannet, L. A. Witters, B. Perruchoud, G. Yaney, B. Corkey, M. Asfari, and M. Prentki Induction by Glucose of Genes Coding for Glycolytic Enzymes in a Pancreatic beta -Cell Line (INS-1) J. Biol. Chem., January 31, 1997; 272(5): 3091 - 3098. [Abstract] [Full Text] [PDF]
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R. Roduit, J. Morin, F. Masse, L. Segall, E. Roche, C. B. Newgard, F. Assimacopoulos-Jeannet, and M. Prentki Glucose Down-regulates the Expression of the Peroxisome Proliferator-activated Receptor-alpha Gene in the Pancreatic beta -Cell J. Biol. Chem., November 10, 2000; 275(46): 35799 - 35806. [Abstract] [Full Text] [PDF]
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G. da Silva Xavier, A. Varadi, E. K. Ainscow, and G. A. Rutter Regulation of Gene Expression by Glucose in Pancreatic beta -Cells (MIN6) via Insulin Secretion and Activation of Phosphatidylinositol 3'-Kinase J. Biol. Chem., November 10, 2000; 275(46): 36269 - 36277. [Abstract] [Full Text] [PDF]
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D. Massillon Regulation of the Glucose-6-phosphatase Gene by Glucose Occurs by Transcriptional and Post-transcriptional Mechanisms. DIFFERENTIAL EFFECT OF GLUCOSE AND XYLITOL J. Biol. Chem., February 2, 2001; 276(6): 4055 - 4062. [Abstract] [Full Text] [PDF]
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S. Vaulont, M. Vasseur-Cognet, and A. Kahn Glucose Regulation of Gene Transcription J. Biol. Chem., October 6, 2000; 275(41): 31555 - 31558. [Full Text] [PDF]
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