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Departments of Medicine of the University of Mississippi Medical Center (D.A.M., R.C.C., L.F.H., P.W.), Jackson, Mississippi 39216 and the Medical University of South Carolina (J.-H.Z., W.T.G.) Charleston, South Carolina 29425; and the Veterans Affairs Medical Centers at Jackson, Mississippi 39216 (D.A.M., R.C.C.) and Charleston, South Carolina 29425 (W.T.G.)
Address all correspondence and requests for reprints to: Donald A. McClain, Division of Endocrinology, University of Mississippi Medical Center, 2500 North State Street, Jackson, Mississippi 39216-4505. E-mail: dam{at}fiona.umsmed.edu
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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0.01). No differences were observed in
hepatic glucose output, serum insulin levels, or muscle ATP levels.
Uptake of 2-deoxyglucose, measured under conditions of
hyperinsulinemia, was significantly lower in transgenic hindlimb
muscle, compared with controls (85.9 ± 17.8 vs.
166.8 ± 15.1 pmol deoxyglucose/g·min). The decrease in glucose
uptake by transgenic muscle was associated with a disruption in the
translocation of the insulin-stimulated glucose transporter GLUT4.
Fractionation of muscle membranes on a discontinuous sucrose gradient
revealed that insulin stimulation of control muscle led to a 28.8%
increase in GLUT4 content in the 25% fraction and a 61.2% decrease in
the 35% fraction. In transgenic muscle, the insulin-stimulated shifts
in GLUT4 distribution were inhibited by over 70%. Treatment of the
transgenic animals with the thiazolidinedione troglitazone
completely reversed the defect in glucose disposal without changing GFA
activity or the levels of uridine
5'-diphosphate-N-acetylglucosamine. Overexpression of
GFA in skeletal muscle thus leads to defects in glucose transport
similar to those seen in type 2 diabetes. These data support the
hypothesis that excess glucose metabolism through the hexosamine
pathway may be responsible for the diminished insulin sensitivity and
defective glucose uptake that are seen with hyperglycemia. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously demonstrated that overexpression of
glutamine:fructose-6-phosphate amidotransferase (GFA), the first and
rate-limiting enzyme of the hexosamine biosynthetic pathway, in muscle
and adipose tissue of transgenic mice leads to increased hexosamine
levels and causes insulin resistance in vivo (9). The
current study was undertaken to explore further the relationship of the
defects in glucose uptake seen in this transgenic model to those of
type 2 diabetes, in terms of the mechanism for the decreased glucose
uptake and its reversal by the peroxisome proliferator-activated
receptor (PPAR)
agonist troglitazone. The results are
consistent with the hypothesis that excess glucose metabolism through
the hexosamine pathway may be responsible for the diminished insulin
sensitivity and defective glucose uptake that are seen in
hyperglycemia. Furthermore, the defects in glucose transport seen in
the transgenic mice are very similar to those seen in human type 2
diabetes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine the effects of troglitazone, age- and weight-matched heterozygote transgenic and control mice were treated daily for 30 days with either 10 mg troglitazone mixed in 100 mg of peanut butter or with 100 mg of peanut butter alone. Five mice in each group were then studied by the hyperinsulinemic euglycemic clamp technique, after which the animals were killed and their hindlimb muscles harvested for analysis of GFA activity and uridine 5'-diphosphate (UDP)-N-acetylglucosamine levels.
Determination of glucose infusion rate and hepatic glucose output
(HGO)
All experiments were performed in awake, weight-matched,
nonsedated transgenic and littermate control mice using a euglycemic
clamp technique previously described (9). Catheters were implanted into
the right internal jugular vein. The animals were allowed to recover
from surgery for 1 day and were then fasted 18 h before the
experiment. [3-3H]glucose (New England Nuclear, Boston,
MA) was infused throughout the clamp experiment to determine the
glucose turnover rate. A priming dose of 0.33 µCi (19 Ci/mmol) in
11.2 µl saline (0.9%) was infused, followed by continuous infusion
at a rate of 0.08 µCi/min (2.5 µl/min) for the duration of the
experiment. Animals were infused with recombinant human insulin
(HumulinR, Eli Lilly & Co., Indianapolis, IN) at a rate of
2, 15, or 20 mU/kg·min, while 50% dextrose was infused by a variable
infusion pump (Harvard Apparatus Inc., South Natick, MA). Whole-blood
samples (3 µl) were collected every 5–10 min from tail bleeds and
measured by the glucose oxidase method (Glucometer Elite, Bayer Corp., Tarrytown, NY). Blood glucose concentrations and glucose
infusion rates were clamped at steady state for a minimum of 20 min.
Serum samples were then taken for calculating insulin levels and HGO.
Insulin concentrations were measured by RIA using porcine standards
(Binax, Portland, ME); this assay detects both human and rodent
insulin. The rate of glucose appearance (or glucose turnover rate) was
calculated by dividing the [3-3H]glucose infusion rate
(dpm/kg·min) by the mean serum glucose specific activity (dpm/mg
glucose). The rate of HGO was calculated by subtracting the glucose
infusion rate from the glucose turnover rate. Isotopically determined
glucose disposal rates (GDRs) were calculated by subtracting the HGO
from the glucose infusion rate.
Determination of skeletal muscle glucose uptake, GFA activity,
UDP-N-acetylglucosamine levels, and ATP levels
Mice were catheterized, allowed to recover from surgery the
following day, and fasted 18 h before the experiment. With no
priming dose or continuous infusion of 3H-glucose, the
animals were infused with recombinant human insulin at a rate of 20
mU/kg·min, while 50% dextrose was infused by a variable infusion
pump. After the animals’ serum glucose levels were stabilized (minimum
of 10 min), a bolus injection of
2-deoxy-D-[1-3H]glucose
([3H]2-DOG) and [U-14C]sucrose (200 pmol of
each, 11 Ci/mmol and 667 mCi/mmol, respectively; Amersham, Arlington
Heights, IL) was administered. The clamp was continued for an
additional 10 min, after which time the animal was killed, blood was
collected, and the triceps surae group from each hind limb was
extracted, weighed, and frozen in liquid nitrogen. The triceps surae
group was selected because its muscle fiber composition is
representative of total hindlimb fiber composition (10). Muscle samples
were processed as described by Brozinick et al. (11). Muscle
samples were homogenized in 2 ml of 10% trichloroacetic acid (TCA) at
4 C. Muscle homogenates and serum samples (20 µl serum with 40 µl
10% TCA) were centrifuged in a microcentrifuge at 14,000 x
g for 10 min. Radioactivity in duplicate samples of the
muscle and serum supernatants (300 µl of muscle supernatant and 15
µl of the serum supernatant) was measured by scintillation counting.
The accumulation of intracellular [3H]2-DOG was
calculated by subtracting the amount in the extracellular space from
the total in the muscle samples, using the facts that glucose and
sucrose will both diffuse in the extracellular space but sucrose
will not be transported into cells. Thus, intracellular glucose =
total muscle glucose - extracellular glucose, where extracellular
glucose = (serum glucose) · (muscle sucrose) · (serum
sucrose)-1.
GFA activity and UDP-N-acetylglucosamine levels were assayed as described (9). ATP measurements were performed on triceps surae group muscle that had been homogenized and sonicated in 12% TCA, using a kit from Sigma Chemical Co. (St. Louis, MO), based on the principle that ATP levels can be determined by measuring the change in absorbance at 340 nm that takes place when NADH is oxidized to NAD.
Membrane subfractionation of skeletal muscle
Hindlimb muscle from transgenic and control mice that had been
either fasted (basal) or subjected to a hyperinsulinemic-euglycemic
clamp (insulin-stimulated) was rapidly isolated, frozen in liquid
nitrogen, and stored at -80 C. The muscle tissue was placed in Tris
buffer (20 mM Tris-base, 0.25 M sucrose, 0.2
mM EDTA, 40 mM phenylmethylsulfonylfluoride, 5
µg/ml leupeptin, 5 µg/ml aprotinin, and 1 µg/ml pepstatin), pH
7.4, at 4 C. Subfractionation of muscle membranes was as described by
Baron and colleagues (7), whose procedure was modified from that of
Klip and colleagues (12, 13). The muscle was homogenized with a
Polytron tissue disrupter (Brinkmann Instruments, Inc.,
Westbury, NY) using five 5-sec bursts at a setting of 5 and then with
10 up-and-down strokes of a motor-driven Teflon pestle in a glass
homogenization tube (Thomas Scientific, Philadelphia, PA). The
homogenate was centrifuged at 1,000 x g for 10 min,
and the supernatant was saved. The resulting pellet was resuspended in
the buffer and rehomogenized with the glass homogenization tube and
Teflon pestle (as described above), and the supernatant was combined
with the first supernatant and centrifuged at 9,000 x
g for 10 min. The resulting supernatant was then centrifuged
at 190,000 x g for 60 min; the resuspended pellet
constituted the total postnuclear membrane fraction. These membranes
were then applied to a discontinuous sucrose gradient containing 25%,
30%, and 35% sucrose (wt/vol) solutions and was centrifuged at
40,000 x g for 16 h in a swinging-bucket rotor.
Membranes were collected atop each of the sucrose gradients,
resuspended in Tris buffer, pelleted by centrifugation at 190,000
x g for 60 min, and resuspended in Tris buffer. All
suspensions of membrane subfractions were kept at -80 C for subsequent
immunoblot analyzes. To monitor membrane subfractionation, we measured
5'nucleotidase activity using the method of Avruch and Wallach (14),
oubain-inhibitable Na+/K+ ATPase activity, as
described previously (15), and immunoreactive phospholemman (16, 17) as
markers for sarcolemma in total membranes and membrane
subfractions.
Immunoblot analysis
Thirty micrograms of membrane protein were solubilized in
Laemmli sample buffer (18), electrophoresed by SDS-PAGE on 1.5-mm slab
gels, and transferred to nitrocellulose filters (19). Immunological
detection of GLUT4 was accomplished as previously described (20).
Nitrocellulose filters were incubated with affinity-purified rabbit
antiserum (1:1000 dilution) specific for the COOH-terminal segment (12
amino acids) of rat GLUT4 (21) (East Acres Biologicals,
Southbridge, MA), followed by 125I-protein A. Detection of
phospholemman was accomplished by incubating filters with
affinity-purified rabbit antiserum raised against canine phospholemman
(16, 17) (a gift of Dr. Larry Jones, Indiana University), followed by
125I-protein A. Quantitation of GLUT4 levels was
accomplished by excising the GLUT4 band and measuring radioactive
counts. Phospholemman was measured with scanning densitometry (Bio-Rad,
Richmond, CA) of autoradiographs. For measurement of both GLUT4 and
phospholemman, background measurements were subtracted from signal, to
obtain relative levels of the immunoreactive protein; and measurements
were consistently in the range where the relationship between
increasing amounts of membrane protein and signal was linear.
Statistical analysis
All values are presented as mean ± SEM.
Student’s t test was performed for comparisons of means
between two groups.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The transgenic mice required a 90,
45, 39, and 40% reduction of the glucose infusion rate to maintain
euglycemia during the clamp at insulin infusion rates of 0.5, 2, 15,
and 20 mU/kg·min, respectively. HGO did not differ between transgenic
and control mice under basal conditions and during the euglycemic clamp
with insulin infusion rates of 2, 15, and 20 mU/kg·min (Fig. 1B).
Serum insulin levels also did not differ between transgenic and control
mice during the euglycemic clamp (Fig. 1C).
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shows the GDRs for the transgenic and
control mice during the clamp studies. Transgenic mice had a GDR that
was 35% lower than that of the control mice. Fig. 2B shows that
[3H]2-DOG uptake by skeletal muscle was decreased by 49%
in transgenic mice, compared with control littermates.
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In vitro studies of skeletal muscle GLUT4 distribution
Hindlimb skeletal muscle from weight-matched, fasted transgenic
and control mice (26.4 ± 0.8 and 25.2 ± 1.8 µg,
respectively) was harvested either in the basal state or after a clamp
at 9.3 ± 0.3 mM glucose with an insulin dose of 20
mU/kg·min. The muscle was subjected to a membrane subfractionation
protocol employing centrifugation on discontinuous sucrose density
gradients. GLUT4 levels in the various subcellular fractions were
quantitated by PAGE of membrane proteins, followed by immunoblot
analysis. The results of these analyzes are shown in Table 1. Total GLUT4 content did not differ
between transgenic and control muscle. GLUT4 distribution also did not
differ in the basal state between transgenic and control muscle, but
differences did emerge with insulin stimulation. After insulin
stimulation of control muscle, GLUT4 distribution increased in the 25%
fraction by 28.8 ± 1.9% (P < 0.05) and
decreased in the 35% fraction by 61.2 ± 1.1% (P
< 0.001). Insulin led to smaller and statistically insignificant
changes in GLUT4 distribution in transgenic muscle, increasing in the
25% fraction by 8.5 ± 5.0% and decreasing in the 35% fraction
by 7.5 ± 5.3%. The differences in insulin-induced GLUT4
redistribution between the transgenic and control muscles were
significant in the 25% fractions (P < 0.05) and in
the 35% fractions (P < 0.001). No differences,
comparing either transgenic to control or insulin-stimulated to basal,
were noted in the GLUT4 content in the 30% fraction. Two sarcolemmal
markers, 5'-nucleotidase activity and immunoreactive phospholemman,
were measured and found to be greatest in the 25% fraction (data not
shown). These data are consistent with previous studies and have been
interpreted to reflect insulin-mediated translocation of GLUT4 from
intracellular membranes in the 35% sucrose fraction to sarcolemma
retrieved in the 25% fraction (7, 12, 13).
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, the decrease in glucose disposal in
the transgenic animals was completely reversed by
troglitazone treatment (P < 0.001, n
= 5/group). The drug was without a significant effect in the control
animals.
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). As had been previously demonstrated,
GFA activity was higher in the transgenic animals, compared with
controls (P < 0.05 for the nondrug-treated animals,
P < 0.03 for the drug-treated animals). However,
troglitazone had no effect on GFA activity, either in
control or transgenic animals. Similarly, the principal end product of
hexosamine biosynthesis UDP-N-acetylglucosamine was higher
in the transgenic animals (P < 0.02) but was also
unaffected by troglitazone treatment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,
such as troglitazone. Early strategies to investigate the effects of increased hexosamine synthesis and its effects on insulin-stimulated glucose disposal in vivo have involved infusions with glucose or glucosamine. Glucosamine affects other tissues involved in glucose homeostasis, specifically impairing the suppression of HGO by hyperglycemia (24) and impairing insulin secretion (25). Furthermore, at high concentrations, glucosamine has effects not directly related to increases in hexosamine flux. For example, glucosamine treatment can deplete cellular ATP (26) and directly affect enzymes such as glucokinase (24). Thus, to avoid the multiple effects of infusing animals with glucosamine and to implicate the hexosamine pathway more directly in the regulation of insulin-stimulated glucose uptake in skeletal muscle, our laboratory has taken a tissue-specific transgenic approach to investigate the effects of increased hexosamine biosynthesis. By overexpressing the rate-limiting enzyme for hexosamine synthesis GFA in the target tissues of insulin-stimulated glucose disposal, we sought to investigate the effects of increased hexosamine biosynthesis in muscle and adipose tissue, without the additional effects known to be caused by treatment with nonphysiologic concentrations of glucosamine (24, 25, 26). With approximately a 2-fold increase in skeletal muscle GFA activity in the transgenic animals (9), total cellular glucose flux into the hexosamine pathway would be estimated to increase from approximately 2% to only 4–6%, and thus should neither significantly alter glucose availability for oxidative or nonoxidative metabolism nor cause significant changes in cellular ATP pools.
Overexpression of GFA in skeletal muscle and adipose tissue of transgenic mice did result in the inhibition of insulin-stimulated glucose disposal in intact animals (9). These results are confirmed and expanded in the current study, with the demonstration that the transgenic mice are insulin resistant, compared with their nontransgenic littermates, over a wide range of insulin doses, with no difference in HGO. More importantly, we demonstrate directly that this peripheral insulin resistance can be accounted for by a decrease in glucose uptake, as determined by [3H]2-DOG uptake during a hyperinsulinemic clamp.
The decrease in 2-DOG uptake in muscle overexpressing GFA is paralleled by a significant defect in GLUT4 translocation after insulin stimulation. Skeletal muscle from animals infused with glucosamine has also been shown to be insulin resistant, primarily because of an inhibition of GLUT4 translocation (7). Although we previously reported a decrease in GLUT4 protein (but not messenger RNA) levels in these transgenic mice (9), the current study demonstrates that skeletal muscle GLUT4 protein levels, assessed by immunoblotting, did not differ between the transgenic and control mice. The reasons for this discrepancy are not clear. The previous immunoblots for GLUT4 were performed using a different antibody and on mice whose genetic background was in flux, because they were being back-bred onto a C57Bl6 background to facilitate the detection of diabetes- and obesity-related phenotypes. The current study was performed using mice that had been bred on the C57Bl6 background for more than 6 generations. Regardless of the reasons for the discrepancy, the current evidence shows clearly that the translocation defect can account for the defect in glucose uptake. Thus, there seems to be a common mechanism by which diabetes, glucosamine infusion, or overexpression of GFA cause insulin resistance to glucose uptake in skeletal muscle.
Further evidence for the similarity of hexosamine-induced insulin
resistance to human type 2 diabetes is provided by reversal of the
insulin resistance in the transgenic animals by
troglitazone. The mechanism of action of PPAR agonists
is still unknown. Although the most parsimonious explanation of the
current results would involve a direct effect of the drug on skeletal
muscle, there is controversy about the possible contribution of muscle
to troglitazone action. Several recent studies have been
able to demonstrate PPAR messenger RNA and troglitazone
action in skeletal muscle and in muscle-derived cells (27, 28, 29, 30, 31).
Furthermore, PPAR levels in muscle have been reported to be altered
in insulin-resistant states (32), and there is rationale for PPAR
action in muscle, given the regulation by PPAR of genes involved in
fatty acid oxidation by muscle (33). At this time, however, we cannot
rule out an indirect effect of troglitazone, such as an
alteration in delivery of fuel or regulatory factors, from fat to
muscle, that reverses the hexosamine-induced defect.
The results on the effects of troglitazone are at variance with those of a previous study wherein glucose-, but not glucosamine-induced insulin resistance could be reversed by troglitazone (34). However, the latter study employed an acute infusion with a high concentration of glucosamine, and whether this acute model is analogous to chronic diabetes or chronically increased hexosamine flux is not known. In the absence of information on the dose responsiveness of the insulin resistance for glucosamine or troglitazone, the significance of the previously published negative data is unclear. Furthermore, the appropriateness of using acute glucosamine exposure to study hexosamine-induced insulin resistance has been raised in a recent publication, indicating that some of the observed effects on glucose uptake in glucosamine infused animals might be accounted for by decreased ATP levels (26). This was not the case in the current study, because the transgenic animals did not exhibit decreased muscle ATP levels. This result was not surprising, given the relatively small increase in glucose flux into the hexosamine pathway achieved by overexpressing GFA. The results do illustrate, however, the advantages of studying the effects of hexosamine flux in the transgenic model system, as opposed to acute exposure of cells and animals to high concentrations of glucosamine.
The lack of an effect of troglitazone on GFA and UDP-N-acetylglucosamine levels argues that the effect of that drug in reversing insulin resistance is distal to the generation of hexosamines. How increased hexosamine flux or troglitazone exerts these effects on glucose uptake is unknown. The final product of hexosamine synthesis, UDP-N-acetylglucosamine, is a substrate for protein glycosylation, both N- and O-linked. Recently, O-linked glycosylation has been hypothesized to be a regulatory modification, analogous to phosphorylation, that may play a role in mediating the assembly of regulatory protein complexes (35). Unlike N-linked glycosylation, O-linked glycosylation is dynamic and has a rapid turnover rate. Identification of the O-glycosylation sites on c-myc (36) and RNA polymerase suggests a possible reciprocal functional relationship of O-glycosylation with phosphorylation. Synthetic peptides corresponding to sequences of glycogen synthase have been shown to be effective substrates for O-glycosylation (35). Thus, both transcriptional and posttranslational changes, mediated by O-glycosylation, are candidate mechanisms by which cells use hexosamine synthesis as a glucose-sensing mechanism (35, 36, 37).
In conclusion, we have demonstrated that overexpression of GFA, the rate-limiting enzyme in hexosamine synthesis, in muscle and adipose tissue of transgenic mice, causes insulin resistance over a wide range of insulin doses. Furthermore, this insulin resistance is directly demonstrated to be caused by a decrease in glucose uptake in skeletal muscle, secondary to an inhibition of GLUT4 translocation from intracellular vesicles to the plasma membrane. The thiazolidinedione troglitazone reverses this insulin resistance by acting at a point distal to the generation of hexosamines. Thus, the similarities revealed between type 2 diabetes and hexosamine-induced insulin resistance are striking. We have hypothesized that the hexosamine pathway serves the as a satiety sensor for insulin-dependent tissues (22); and these studies lend further support to the hypothesis that increased glucose flux through the hexosamine pathway mediates adverse effects of hyperglycemia, as well. Further characterization of these mice should be instrumental in clarifying the role that hexosamines and hexosamine synthesis play in cellular sensing of glucose and the responses to hyperglycemia.
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Acknowledgments |
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Footnotes |
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2 Both authors should be considered as first authors of this
manuscript.
Received September 18, 1998.
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References |
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and PPAR.
J Biol Chem 272:28210–282172
versus PPAR1 and activation with retinoid x receptor agonists and
antagonists. J Biol Chem 272:8071–8076 gene expression is elevated in
skeletal muscle of obese and type II diabetic subjects. Diabetes 46:1230–1234[Abstract]
expression is mediated by products of the hexosamine
biosynthesis pathway. Mol Endocrinol 7:1041–1048This article has been cited by other articles:
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 L. R. James, I. G. Fantus, H. Goldberg, H. Ly, and J. W. Scholey Overexpression of GFAT activates PAI-1 promoter in mesangial cells Am J Physiol Renal Physiol, October 1, 2000; 279(4): F718 - F727. [Abstract] [Full Text] [PDF]
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E. D. Crook, G. Crenshaw, G. Veerababu, and L. P. Singh Overexpression of Glutamine:Fructose-6-Phosphate Amidotransferase in Rat-1 Fibroblasts Enhances Glucose-Mediated Glycogen Accumulation via Suppression of Glycogen Phosphorylase Activity Endocrinology, June 1, 2000; 141(6): 1962 - 1970. [Abstract] [Full Text] [PDF]
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B. Draznin, P. Miles, Y. Kruszynska, J. Olefsky, J. Friedman, I. Golovchenko, R. Stjernholm, K. Wall, M. Reitman, D. Accili, et al. Effects of Insulin on Prenylation as a Mechanism of Potentially Detrimental Influence of Hyperinsulinemia Endocrinology, April 1, 2000; 141(4): 1310 - 1316. [Abstract] [Full Text] [PDF]
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Q. Chang, K. Su, J. R. Baker, X. Yang, A. J. Paterson, and J. E. Kudlow Phosphorylation of Human Glutamine:Fructose-6-phosphate Amidotransferase by cAMP-dependent Protein Kinase at Serine 205 Blocks the Enzyme Activity J. Biol. Chem., July 14, 2000; 275(29): 21981 - 21987. [Abstract] [Full Text] [PDF]
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Y. Gao, L. Wells, F. I. Comer, G. J. Parker, and G. W. Hart Dynamic O-Glycosylation of Nuclear and Cytosolic Proteins. CLONING AND CHARACTERIZATION OF A NEUTRAL, CYTOSOLIC beta -N-ACETYLGLUCOSAMINIDASE FROM HUMAN BRAIN J. Biol. Chem., March 23, 2001; 276(13): 9838 - 9845. [Abstract] [Full Text] [PDF]
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