1 Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona 85721; and 2 Chiron Corporation, Emeryville, California 94608
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A role for elevated glycogen synthase kinase-3 (GSK-3) activity in the multifactorial etiology of insulin resistance is now emerging. However, the utility of specific GSK-3 inhibition in modulating insulin resistance of skeletal muscle glucose transport is not yet fully understood. Therefore, we assessed the effects of novel, selective organic inhibitors of GSK-3 (CT-98014 and CT-98023) on glucose transport in insulin-resistant muscles of Zucker diabetic fatty (ZDF) rats. Incubation of type IIb epitrochlearis and type I soleus muscles from ZDF rats with CT-98014 increased glycogen synthase activity (49 and 50%, respectively, P < 0.05) but did not alter basal glucose transport (2-deoxyglucose uptake). In contrast, CT-98014 significantly increased the stimulatory effects of both submaximal and maximal insulin concentrations in epitrochlearis (37 and 24%) and soleus (43 and 26%), and these effects were associated with increased cell-surface GLUT4 protein. Lithium enhanced glycogen synthase activity and both basal and insulin-stimulated glucose transport in muscles from ZDF rats. Acute oral administration (2 × 30 mg/kg) of CT-98023 to ZDF rats caused elevations in GSK-3 inhibitor concentrations in plasma and muscle. The glucose and insulin responses during a subsequent oral glucose tolerance test were reduced by 26 and 34%, respectively, in the GSK-3 inhibitor-treated animals. Thirty minutes after the final GSK-3 inhibitor treatment, insulin-stimulated glucose transport was significantly enhanced in epitrochlearis (57%) and soleus (43%). Two hours after the final treatment, insulin-mediated glucose transport was still significantly elevated (26%) only in the soleus. These results indicate that specific inhibition of GSK-3 enhances insulin action on glucose transport in skeletal muscle of the insulin-resistant ZDF rat. This unique approach may hold promise as a pharmacological treatment against insulin resistance of skeletal muscle glucose disposal.
glycogen synthase kinase-3; type 2 diabetes; glucose transport; epitrochlearis; soleus; cell surface glucose transporter-4; lithium
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
INSULIN RESISTANCE OF SKELETAL MUSCLE glucose transport and metabolism is considered to be one of the primary defects underlying the development of glucose intolerance and type 2 diabetes (reviewed in Ref. 38). The insulin resistance and the accompanying hyperinsulinemia are closely associated with a number of additional atherogenic risk factors, including hypertension, dyslipidemia, and central obesity, collectively referred to as "syndrome X" (25) or the "insulin resistance syndrome" (9). Therefore, developing strategies to overcome the insulin resistance of skeletal muscle glucose transport is an important step in treating type 2 diabetes.
Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase that
consists of highly homologous - and
-isoforms (36), functions to phosphorylate and inactivate glycogen synthase (GS) (24, 28, 37). GSK-3 activity can be acutely inactivated by
insulin signaling through insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI 3-kinase), and ultimately via the
action of protein kinase B (Akt) to phosphorylate specific serine
residues on the enzyme (7). An additional substrate of
GSK-3 is IRS-1, and phosphorylation of IRS-1 on serine/threonine residues leads to impairment of insulin signaling (10).
Therefore, GSK-3 can be a negative modulator of insulin action on GS
and, potentially, on glucose transport activity.
Although the etiology of skeletal muscle insulin resistance is multifactorial (38), recent evidence supports a role of elevated GSK-3 as a contributing factor in this pathophysiological state (2, 11, 19, 21, 22). GSK-3 is elevated in tissues of insulin-resistant obese rodent models (2, 11) and in skeletal muscle of obese humans (2) and type 2 diabetic humans (22). Moreover, the elevation in GSK-3 protein in skeletal muscle of type 2 diabetic subjects is negatively correlated with both insulin-stimulated skeletal muscle GS activity and whole body glucose disposal (22). Finally, lithium ions, a noncompetitive and relatively nonselective inhibitor of GSK-3 with a Ki in the millimolar range (8, 16, 18, 32), can enhance both insulin-independent and insulin-dependent glucose transport in skeletal muscle from insulin-sensitive rats (34). Taken collectively, these findings are consistent with GSK-3 as a potential target of inhibition for the enhancement of insulin-stimulated glucose transport in insulin-resistant skeletal muscle.
Recently, a class of novel and selective organic inhibitors of GSK-3
has been developed (27) and has shown promise as
modulators of GS activity, glucose disposal, and glucose transport
activity in diabetic rodent models (27) and in human
muscle cells (21). These compounds are substituted
aminopyrimidine molecules and act as potent competitive inhibitors
(acting at the ATP-binding site) of human GSK-3
(Ki < 10 nM) with 500-fold selectivity
against 20 other protein kinases (27). The purposes of the
present investigation were 1) to compare the in vitro
effects of a novel, selective organic inhibitor of GSK-3 (CT-98014) and
lithium ions on basal and insulin-stimulated GS activity and glucose
transport activity in type I (soleus) and type IIb (epitrochlearis)
skeletal muscle of insulin-sensitive lean Zucker
(Fa+/
)
and insulin-resistant Zucker diabetic fatty (ZDF) rats, the latter
being a model of type 2 diabetes; 2) to assess whether any
improvement of muscle glucose transport activity due to this GSK-3
inhibitor is associated with enhanced cell-surface GLUT4 protein; and
3) to determine the effect of the acute oral administration of a GSK-3 inhibitor (CT-98023) to ZDF rats on glucose tolerance and
skeletal muscle glucose transport activity.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals. Male ZDF/Gmi-fa rats were obtained from Genetic Models (Indianapolis, IN), and lean Zucker rats were purchased from Harlan (Indianapolis, IN) at the age of 8-9 wk and used in the experiments at 10 wk of age. At the time of their use, the ZDF rats weighed 300-340 g, whereas the age-matched lean Zucker rats weighed 180-210 g. Lean animals were maintained on regular lab chow (Purina, St. Louis, MO), whereas ZDF animals had free access to diabetogenic chow (Purina 5008). All procedures were approved by the University of Arizona Animal Use and Care Committee.
In vitro treatments of skeletal muscle. After an overnight fast, animals were deeply anesthetized with an intraperitoneal injection of pentobarbital sodium (50 mg/kg), and intact epitrochlearis muscles and strips of soleus muscles (~25 mg) were prepared for in vitro incubation in the unmounted state. Each muscle was incubated for 1 h at 37°C in 3 ml of oxygenated (95% O2-5% CO2) Krebs-Henseleit buffer (KHB) with the NaHCO3 concentration set at 14 mM. This KHB was supplemented with 8 mM glucose, 32 mM mannitol, 0.1% BSA (radioimmunoassay grade, Sigma Chemical, St. Louis, MO), 0.5% dimethyl sulfoxide, and the indicated additions of GSK-3 inhibitor, insulin, or lithium chloride. Thereafter, the muscles were used for the determination of glucose transport activity [as assessed using 2-deoxyglucose (2-DG) uptake] or GS activity as described in Muscle glucose transport activity.
Oral administration of GSK-3 inhibitor.
Animals were fasted after 6 PM of the evening before the test. At 8 AM
and then again at 11:30 AM, the animals received by gavage either
vehicle (1% carboxymethylcellulose sodium/0.1% Tween) or a
bolus of GSK-3 inhibitor CT-98023 at a dose of 30 mg/kg body wt. Thirty
minutes after the second administration, some animals underwent an oral
glucose tolerance test (OGTT). These animals received a 2 g/kg body wt
glucose load by gavage. Blood was collected from a small cut at the tip
of the tail immediately before and at 30, 60, 90, and 120 min after
glucose administration, thoroughly mixed with EDTA (final concentration
of 18 mg/ml), and centrifuged at 13,000 g to isolate the
plasma. The plasma was stored at 80°C and subsequently assayed for
glucose (Sigma Chemical) and insulin by radioimmunoassay (Linco, St.
Louis, MO).
GS activity. GS was assayed essentially as described by Thomas et al. (35), with slight modifications (15). Muscles were homogenized in a Duall tube containing 2 ml of ice-cold 50 mM Tris buffer (pH 7.8), 100 mM KF, 10 mM EDTA, 2 mM EGTA, and 2 mM KH2PO4 at 4°C. The homogenates were centrifuged at 13,000 g for 15 min. An aliquot (30 µl) of the supernatant was added to 60 µl of 50 mM Tris buffer (pH 7.8), 20 mM EDTA, 25 mM KF, 10 mg/ml rabbit liver glycogen, and 5 mM UDP-[U-14C]glucose (150 µCi/mmol) and incubated for 20 min at 30°C without glucose 6-phosphate (GSI activity). Total GS activity was assessed in the presence of 5 mM glucose 6-phosphate.
Muscle glucose transport activity. After the initial incubation period, the muscles were rinsed for 10 min at 37°C in 3 ml of oxygenated KHB containing 40 mmol/l mannitol, 0.1% BSA, and any addition present previously. Thereafter, the muscles were transferred to 2 ml of KHB containing 1 mM 2-deoxy-[1,2-3H]glucose (300 mCi/mmol; Sigma), 39 mM [U-14C]mannitol (0.8 mCi/mmol; ICN Radiochemicals, Irvine, CA), 0.1% BSA, and any additions present previously. At the end of this final 20-min incubation period at 37°C, the muscles were removed, trimmed of excess fat and connective tissue, quickly frozen between aluminum blocks cooled in liquid nitrogen, and weighed. The frozen muscles were dissolved in 0.5 ml of 0.5 N NaOH. After the muscles were completely solubilized, 5 ml of scintillation cocktail were added, and the specific intracellular accumulation of 2-DG was determined as described previously (14). This method for assessing glucose transport activity in isolated muscle has been validated (12).
Statistical analysis. All data are presented as means ± SE. The significance of differences between multiple groups was assessed by a factorial ANOVA with a post hoc Fisher's paired least significant difference test (StatView version 5.0, SAS Institute, Cary, NC). Differences between two groups were determined by an unpaired Student's t-test. A P value of <0.05 was considered to be statistically significant.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In vitro effects of GSK-3 inhibitor CT-98014 or lithium on GS
activity.
We initially determined the effectiveness of CT-98014 in inhibiting
GSK-3 in isolated skeletal muscle preparations by use of an increase in
GSI activity as the biomarker. As shown in Fig. 1, 500 nM CT-98014 caused increases of 51 and 48% in GSI activity in the epitrochlearis and soleus
muscles, respectively, of the lean Zucker rat. These increases due to
CT-98014 were comparable to those elicited by 2 mU/ml insulin in these
muscles (47 and 78%). The effects of CT-98014 and insulin on
activation of GSI in these muscles of the lean Zucker rats
were completely additive. The total activity of GS was not altered in
these muscles, due to the interventions (data not shown).
|
|
In vitro effects of GSK-3 inhibitor CT-98014 or lithium on glucose
transport activity.
CT-98014 (500 nM) had no effect on basal glucose transport or on
submaximally or maximally insulin-stimulated glucose transport activity
in epitrochlearis and soleus muscle from the lean Zucker rat (Fig.
3). In contrast, 10 mM lithium elicited
significant increases in both basal glucose transport and
insulin-stimulated glucose transport activity in skeletal muscle from
the lean Zucker rats.
|
|
In vitro effects of GSK-3 inhibitor CT-98014 on cell surface
GLUT4.
To gain some insight into the molecular mechanism for the effects
of CT-98014 on glucose transport, we assessed the level of exofacial
GLUT4 protein, using the impermeable photolabel
2-N-[4-(1-azi-2,2,2-trifluoroethyl)benzonyl]-1,3-bis(D-mannos-4-yloxy)-2-propylamine (ATB-[2-3H]BMPA) (ATB-[3H]BMPA; Fig.
5). In the absence of insulin, CT-98014
did not alter cell-surface GLUT4 in either epitrochlearis or soleus
muscles of the ZDF rat. Insulin caused significant increases in
cell-surface GLUT4 in these muscles. Moreover, the insulin-stimulated
increases in cell-surface GLUT4 were significantly enhanced by CT-98014 in both the epitrochlearis (29%) and the soleus (21%) muscles of the
ZDF rat.
|
Effects of oral administration of GSK-3 inhibitor CT-98023 on
glucose tolerance.
The acute oral administration of the GSK-3 inhibitor CT-98023 (30 mg/kg
body wt) led to substantial increases of the compound in plasma and
skeletal muscle of the ZDF rats 30 min after completion of the
treatments (Fig. 6), indicating that the
metabolic actions of the compound in vivo should not be limited by
bioavailability. Thirty minutes after the completion of these
treatments, an OGTT was performed, and the responses of plasma glucose
and insulin were assessed (Fig. 7). In
vehicle-treated ZDF rats, the glucose feeding led to a large increase
in plasma glucose at 30 min, and this glucose response was
substantially reduced in the GSK-3 inhibitor-treated animals. The total
glucose area under the curve (AUC) was 26% less in the GSK-3
inhibitor-treated ZDF rats than in the vehicle-treated control group
(Fig. 8). Moreover, the insulin response
during the OGTT was also dramatically reduced in the GSK-3
inhibitor-treated group, and the total insulin AUC was 34% less in the
GSK-3 inhibitor-treated ZDF rats than in the control group. These
decreases in the glucose and insulin responses of the OGTT following
the GSK-3 inhibitor treatment were even more pronounced when the
incremental AUCs for glucose (13,620 ± 1,216 vs. 6,600 ± 644 mg · dl1 · min)
and insulin (4,290 ± 540 vs. 1,020 ± 205 µU · ml
1 · min)
were calculated. The dose of GSK-3 inhibitor used in this in vivo study
(30 mg/kg) is maximally effective in enhancing oral glucose tolerance,
as a higher dose (48 mg/kg) does not have any further effect
(27).
|
|
|
Effects of oral administration of GSK-3 inhibitor CT-98023 on
muscle glucose transport.
To identify a potential cellular locus for the improved peripheral
insulin sensitivity, insulin-stimulated glucose transport activity was
determined in epitrochlearis and soleus muscles of the ZDF rats at
various time points after the acute administration of CT-98023 (Fig.
9). Thirty minutes after the completion
of the oral GSK-3 inhibitor treatment, the maximal insulin-mediated
increase in glucose transport activity was enhanced in both the
epitrochlearis (56%) and soleus (43%) compared with the corresponding
control groups. At this same time point, glucose transport activity due to a submaximally effective concentration of insulin (150 µU/ml) was
similarly enhanced in these muscles from the CT-98023-treated ZDF rats
(data not shown). Two hours after the oral administration of CT-98023,
the enhanced action of the maximally effective concentration of insulin
was still detectable in the soleus muscle (26%) but not in the
epitrochlearis muscle, consistent with the diminished glucose-lowering
effect of the treatment at this time point (Fig. 7). The enhanced
insulin action on glucose transport activity due to the GSK-3 inhibitor
treatment was no longer detectable in the soleus after 4 h.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We have demonstrated in the present investigation that the selective inhibition of GSK-3 in insulin-resistant skeletal muscle of the ZDF rat was associated with a potentiation of the ability of insulin to stimulate both GS activity (Fig. 1) and glucose transport activity (Fig. 3). These effects of the GSK-3 inhibitor CT-98014 were elicited at concentrations in the nanomolar range, with maximal effects at 500 nM. Interestingly, although the GSK-3 inhibitor CT-98014 clearly activated GS activity in skeletal muscle from the insulin-sensitive lean Zucker rat (Fig. 1), it had absolutely no effect on either basal or insulin-stimulated glucose transport activity in muscle from these lean animals. These results support the idea that an elevation in GSK-3 activity, which exists in muscle of the ZDF rat but not the lean rat (2), is necessary for a cell to respond to GSK-3 inhibition for enhancement of insulin-stimulated glucose transport activity.
These results demonstrating a potentiation of in vitro insulin action on GS and glucose transport in rat muscle by selective GSK-3 inhibition are in agreement with the recent findings of Nikoulina et al. (21), who showed in cultured human myocytes that these same GSK-3 inhibitors, when administered acutely (30 min), can upregulate insulin-stimulated GS activity and, when administered chronically (4 days), can enhance insulin-mediated glucose transport activity. Interestingly, these investigators also demonstrated that chronic treatment of cultured human muscle cells with GSK-3 inhibitor caused a downregulation of GSK-3 protein expression and activity and a large upregulation of IRS-1 protein level. Whether the chronic administration of GSK-3 inhibitor causes similar effects in insulin-resistant muscle from rodent models or humans remains to be determined.
At least part of the beneficial effect of the GSK-3 inhibitor CT-98014
on insulin-stimulated glucose transport activity in skeletal muscle of
the ZDF rat was due to an enhancement of GLUT4 protein at the cell
surface (Fig. 5). This is in contrast to the finding that the
nonspecific GSK-3 inhibitor lithium did not enhance insulin-stimulated
GLUT4 translocation in 3T3-L1 adipocytes overexpressing GSK-3
(33). The underlying molecular mechanism for the increased GLUT4 translocation in response to the GSK-3 inhibition in
insulin-resistant skeletal muscle was not addressed in the present
study. However, it is known that intact activation of PI 3-kinase by
tyrosine-phosphorylated IRS-1 is necessary for this insulin-stimulated
GLUT4 translocation to take place (reviewed in Ref. 38).
Because GSK-3 is known to inhibit IRS-1 action by serine/threonine
phosphorylation (10), one possibility for the beneficial
effect of the GSK-3 inhibitor is through a disinhibition of IRS-1
functionality, with a subsequent enhancement of PI 3-kinase activity
and increased GLUT4 translocation. It is clear that this would be a
fruitful area for future investigations.
We also compared the metabolic effects of lithium, which has been used previously as an inhibitor of GSK-3, with those of the more selective GSK-3 inhibitor CT-98014 (Figs. 1-4). Both lithium (at 10 mM) and CT-98014 (at 500 nM) elicited enhancement of GS activity in muscle from lean Zucker and ZDF rats and displayed an additive interaction with insulin for stimulation of GS activity in muscle from lean animals. This additivity between lithium and insulin for activation of GS in insulin-sensitive cells is consistent with previous studies (3, 6, 23, 33). Moreover, lithium and CT-98014 both displayed a synergistic interaction with insulin for stimulation of GS activity and glucose transport activity in muscle from ZDF rats. However, there were some striking differences between lithum and CT-98014 concerning stimulation of glucose transport activity. Although CT-98014 had no effects on glucose transport activity in the absence of insulin in both the lean Zucker and the ZDF groups or on insulin-stimulated glucose transport activity in the lean group, lithium caused an increase in basal glucose transport in both groups and in insulin-stimulated glucose transport activity in the lean group. Whereas lithium can certainly inhibit GSK-3, this ion obviously has additional effects that must account for its actions on basal and insulin-stimulated glucose transport in insulin-sensitive skeletal muscle and on basal glucose transport activity in insulin-resistant skeletal muscle. Therefore, one must exercise caution in using lithium as an inhibitor of GSK-3 in skeletal muscle studies, as other effects of this ion apart from those on GSK-3 may confound interpretation of the results.
There were some important differences in the glucose transport
responses of the epitrochlearis, which consists primarily of type IIb
fibers (20, 29), and the soleus, which consists mainly of
type I fibers (1), to the GSK-3 inhibitor CT-98014 (Fig. 4). The absolute increase in insulin-stimulated glucose transport activity due to GSK-3 inhibition was 34-37
pmol · mg1 · 20 min
1 in the epitrochlearis, whereas in the soleus this
increase was substantially greater (122-126
pmol · mg
1 · 20 min
1). This greater response to GSK-3 inhibition in the
soleus may reflect the fact that type I fibers express a much higher
level of insulin-signaling factors (31) and GLUT4 protein
(13, 17) than type IIb fibers and therefore may have a
higher capacity for insulin signaling once inhibition of one of these
factors [e.g., GSK-3 inhibition of IRS-1 (10)] is removed.
The oral administration of GSK-3 inhibitors to the insulin-resistant
ZDF rat also elicited improvements in glucose metabolism. The disposal
of an oral glucose load by the ZDF rats acutely treated with the GSK-3
inhibitor CT-98023 was markedly enhanced compared with the
vehicle-treated animals (Figs. 7 and 8). One potential cellular locus
for this increased glucose disposal was skeletal muscle, as
insulin-stimulated glucose transport activity in both the
epitrochlearis and the soleus was substantially increased at the 30-min
time point, when the glucose response during the OGTT was maximally
reduced (Fig. 7). Indeed, at the 120-min time point following the final
administration of the GSK-3 inhibitor, the enhancement of
insulin-stimulated glucose transport activity was no longer observed in
the epitrochlearis and was substantially diminished in the soleus (Fig.
9), whereas at this same time point the glucose levels during the OGTT
were not different between the GSK-3 inhibitor-treated and the
vehicle-treated control animals (Fig. 7). This apparent reversibility
of the GSK-3 inhibition is consistent with the observation that removal
of the compound from tumor cells causes -catenin levels to decrease
(Harrison SD, unpublished data).
One additional potential site of action of GSK-3 inhibitors that could contribute to an improvement in whole body glucose homeostasis is the liver (4, 19). Cline et al. (4) have recently reported that treatment of ZDF rats with the selective GSK-3 inhibitor CT-98023 significantly enhances GS activity and glycogen synthesis in the liver. Moreover, Lochhead et al. (19) have demonstrated that the selective reduction of GSK-3 activity in rat hepatoma cells by treatment with lithium or cell-permeable, small-molecular-weight compounds (SB-216763 and SB-415286) (5) is associated with a reduction in the expression of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Therefore, an enhancement of hepatic glycogen synthesis and a reduction in hepatic glucose output likely contribute to the glucose-lowering effect of GSK-3 inhibitors in rodent models of type 2 diabetes (27).
In summary, we have demonstrated that direct in vitro exposure of insulin-resistant type I and type IIb skeletal muscle from the ZDF rat to a novel, selective organic inhibitor of GSK-3 can potentiate the action of insulin to stimulate GS activity and glucose transport. Although lithium also potentiated insulin-stimulated GS activity and glucose transport in insulin-resistant muscle, it additionally elicited effects on basal glucose transport and on insulin-stimulated glucose transport in muscle from lean Zucker rats that were not affected by the selective GSK-3 inhibitor. The effect of the GSK-3 inhibitor on insulin-stimulated glucose transport in skeletal muscle from the ZDF rat was due, at least in part, to an enhanced cell surface GLUT4 protein level. Moreover, the acute oral administration of a selective GSK-3 inhibitor caused a significant improvement in whole body glucose disposal and insulin sensitivity that was associated with enhanced skeletal muscle glucose transport activity. This novel approach using selective organic GSK-3 inhibitors appears useful as a pharmacological treatment against insulin resistance of skeletal muscle glucose disposal.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Melanie B. Schmit, Stephen A. Miller, Thomas Maier, and Julie A. Sloniger for excellent technical assistance.
![]() |
FOOTNOTES |
---|
The research was supported by a grant from Chiron Corporation (to E. J. Henriksen) and the American Diabetes Association (to E. J. Henriksen).
Address for reprint requests and other correspondence: E. J. Henriksen, Dept. of Physiology, Ina E. Gittings Bldg. #93, Univ. of Arizona, Tucson, AZ 85721-0093 (E-mail: ejhenrik{at}u.arizona.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published January 7, 2003;10.1152/ajpendo.00346.2002
Received 5 August 2002; accepted in final form 30 December 2002.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Ariano, MA,
Armstrong RB,
and
Edgerton VR.
Hindlimb muscle fiber populations of five animals.
J Histochem Cytochem
21:
51-55,
1973[ISI][Medline].
2.
Brozinick, JT,
Misener EA,
Ni B,
Ryder JW,
and
Dohm GL.
Impaired insulin signaling through GSK3 in insulin resistant skeletal muscle (Abstract).
Diabetes
49, Suppl 1:
A326,
2000.
3.
Choi, WS,
and
Sung CK.
Effects of lithium and insulin on glycogen synthesis in L6 myocytes: additive effects on inactivation of glycogen synthase kinase-3.
Biochim Biophys Acta
1475:
225-230,
2000[ISI][Medline].
4.
Cline, GW,
Johnson K,
Regittnig W,
Perret P,
Tozzo E,
Xiao L,
Damico C,
and
Shulman GI.
Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (fa/fa) rats.
Diabetes
51:
2903-2910,
2002
5.
Coghlan, MP,
Culbert AA,
Cross DAE,
Corcoran SL,
Yates JW,
Pearce NJ,
Rausch OL,
Murphy GL,
Carter PS,
Cox LR,
Mills D.,
Brown MJ,
Haigh D,
Ward RW,
Smith DG,
Murray KJ,
Reith AD,
and
Holder JC.
Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription.
Chem Biol
24:
1-11,
2000.
6.
Cortez, MY,
Torgan CE,
Brozinick JT,
and
Ivy JL.
Insulin resistance of obese Zucker rats exercise trained at two different intensities.
Am J Physiol Endocrinol Metab
261:
E613-E619,
1991
7.
Cross, DA,
Alessi DR,
Cohen P,
Andjelkovich M,
and
Hemmings BA.
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.
Nature
378:
785-789,
1995[ISI][Medline].
8.
Davies, SP,
Reddy H,
Caviano M,
and
Cohen P.
Specificity and mechanism of action of some commonly used protein kinase inhibitors.
Biochem J
351:
95-105,
2000[ISI][Medline].
9.
DeFronzo, RA,
and
Ferrannini E.
Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease.
Diabetes Care
14:
173-194,
1991[Abstract].
10.
Eldar-Finkelman, H,
and
Krebs EG.
Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action.
Proc Natl Acad Sci USA
94:
960-9664,
1997.
11.
Eldar-Finkelman, H,
Schreyer SA,
Shinohara MM,
LeBoeuf RC,
and
Krebs EG.
Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice.
Diabetes
48:
1662-1666,
1999[Abstract].
12.
Hansen, PA,
Gulve EA,
and
Holloszy JO.
Suitability of 2-deoxyglucose for in vitro measurement of glucose transport activity in skeletal muscle.
J Appl Physiol
76:
979-985,
1994
13.
Henriksen, EJ,
Bourey RE,
Rodnick KJ,
Koranyi L,
Permutt MA,
and
Holloszy JO.
Glucose transporter protein content and glucose transport capacity in rat skeletal muscles.
Am J Physiol Endocrinol Metab
259:
E593-E598,
1990
14.
Henriksen, EJ,
and
Halseth AE.
Early alterations in soleus GLUT-4, glucose transport, and glycogen in voluntary running rats.
J Appl Physiol
76:
1862-1867,
1994
15.
Henriksen, EJ,
Tischler ME,
and
Johnson DG.
Increased response to insulin of glucose metabolism in the six-day unloaded rat soleus muscle.
J Biol Chem
261:
10707-10712,
1986
16.
Hong, M,
Chen DC,
Klein PS,
and
Lee VM.
Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3.
J Biol Chem
272:
25326-25332,
1997
17.
Kern, M,
Wells JA,
Stephens JM,
Elton CW,
Friedman JE,
Tapscott EB,
Pekala PH,
and
Dohm GL.
Insulin responsiveness in skeletal muscle is determined by glucose transporter (Glut4) protein level.
Biochem J
270:
397-400,
1990[ISI][Medline].
18.
Klein, PS,
and
Melton DA.
A molecular mechanism for the effect of lithium on development.
Proc Natl Acad Sci USA
93:
8455-8459,
1996
19.
Lochhead, PA,
Coghlan M,
Rice SQJ,
and
Sutherland C.
Inhibition of GSK-3 selectively reduces glucose-6-phosphate and phosphoenolpyruvate carboxykinase gene expression.
Diabetes
50:
937-946,
2001
20.
Nesher, R,
Karl IE,
Kaiser KK,
and
Kipnis DM.
Epitrochlearis muscle. I. Mechanical performance, energetics, and fiber composition.
Am J Physiol Endocrinol Metab
239:
E454-E460,
1980
21.
Nikoulina, SE,
Cirialdi TP,
Mudaliar S,
Carter L,
Johnson K,
and
Henry RR.
Inhibition of glycogen synthase kinase-3 improves insulin action and glucose metabolism in human skeletal muscle.
Diabetes
51:
2190-2198,
2002
22.
Nikoulina, SE,
Cirialdi TP,
Mudaliar S,
Mohideen P,
Carter L,
and
Henry RR.
Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes.
Diabetes
49:
263-271,
2000[Abstract].
23.
Orena, SJ,
Torchia AJ,
and
Garofalo RS.
Inhibition of glycogen synthase kinase-3 stimulates glycogen synthase and glucose transport by distinct mechanisms in 3T3-L1 adipocytes.
J Biol Chem
275:
15765-15772,
2000
24.
Parker, PJ,
Caudwell FB,
and
Cohen P.
Glycogen synthase from rabbit skeletal muscle: effect of insulin on the state of phosphorylation of the seven phosphoserine residues in vivo.
Eur J Biochem
130:
227-234,
1983[ISI][Medline].
25.
Reaven, GM.
Role of insulin resistance in human disease (syndrome X): an expanded definition.
Annu Rev Med
44:
121-131,
1993[ISI][Medline].
27.
Ring D, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST,
Reeder JW, Samuels I, Slabiak T, Wagman A, Wernette-Hammond ME, and
Harrison SD. Selective GSK3 inhibitors potentiate insulin action
on glucose transport and utilization in vitro and in vivo.
Diabetes. In press.
28.
Roach, PJ.
Control of glycogen synthase by hierarchal protein phosphorylation.
FASEB J
4:
2961-2968,
1990[Abstract].
29.
Rodnick, KJ,
Henriksen EJ,
James DE,
and
Holloszy JO.
Exercise training, glucose transporters, and glucose transport in rat skeletal muscles.
Am J Physiol Cell Physiol
262:
C9-C14,
1992
30.
Sherman, WM,
Katz AL,
Cutler CL,
Withers RT,
and
Ivy JL.
Glucose transport: locus of muscle insulin resistance in obese Zucker rats.
Am J Physiol Endocrinol Metab
255:
E374-E382,
1988
31.
Song, XM,
Ryder JW,
Kawano Y,
Chibalin AV,
Krook A,
and
Zierath JR.
Muscle fiber type specificity in insulin signal transduction.
Am J Physiol Regul Integr Comp Physiol
277:
R1690-R1696,
1999
32.
Stambolic, V,
Ruel L,
and
Woodgett JR.
Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells.
Curr Biol
6:
1664-1668,
1996[ISI][Medline].
33.
Summers, SA,
Kao AW,
Kohn AD,
Backus GS,
Roth RR,
Pessin JE,
and
Birnbaum MJ.
The role of glycogen synthase kinase 3 in insulin-stimulated glucose metabolism.
J Biol Chem
274:
17934-17940,
1999
34.
Tabata, I,
Schluter J,
Gulve EA,
and
Holloszy JO.
Lithium increases susceptibility of muscle glucose transport to stimulation by various agents.
Diabetes
43:
903-907,
1994[Abstract].
35.
Thomas, JA,
Schlender KK,
and
Larner J.
A rapid filter paper assay for UDP-glucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose.
Anal Biochem
25:
486-499,
1968[ISI][Medline].
36.
Woodgett, JR.
Molecular cloning and expression of glycogen synthase kinase-3/factor A.
EMBO J
9:
2431-2438,
1990[Abstract].
37.
Zhang, W,
DePaoli-Roach AA,
and
Roach PJ.
Mechanisms of multisite phosphorylation and inactivation of rabbit muscle glycogen synthase.
Arch Biochem Biophys
304:
219-225,
1993[ISI][Medline].
38.
Zierath, JR,
Krook A,
and
Wallberg-Henriksson H.
Insulin action and insulin resistance in human skeletal muscle.
Diabetologia
43:
821-835,
2000[ISI][Medline].