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J. A. Haley Veterans Hospital Research Service, and the Departments of Internal Medicine and Biochemistry and Molecular Biology, University of South Florida College of Medicine (M.L.S., G.B., L.G., J.S., R.V.F.), Tampa, Florida 33612; the Faculty of Science, Kobe University (Y.O., U.K.), Kobe, Japan 657; and Max Planck Institute for Immunobiology (M.L.), D79108 Freiburg, Germany
Address all correspondence and requests for reprints to: Robert V. Farese, M.D., Research Service (VAR 151), J. A. Haley Veterans Hospital, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612. E-mail: rfarese{at}com1.med.usf.ed
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and/or PKC
, but not PKCß,
PKC
, PKC
, or PKC
, may be required for insulin-stimulated
glucose transport. Unfortunately, these studies did not convincingly
answer the question of whether there is a requirement for PKCß2
during insulin stimulation of glucose transport. For example, allegedly
specific inhibitors and expression of large amounts of the
above-mentioned truncated PKCß2 or, for that matter, any PKC could
have produced nonspecific inhibitory effects; also, in studies in which
PKC inhibitors and phorbol ester-induced PKC down-regulation were used,
it is not certain that there was full inhibition or sufficient
depletion of all DAG-sensitive PKC isoforms that may be required for
insulin effects on glucose transport. Accordingly, other experimental
approaches are needed to answer the question of whether a specific PKC
isoform is required for insulin stimulation of glucose transport. The importance of the question of the role of PKCß2 during insulin stimulation of glucose transport is underscored by the fact that PKCß2 has been suggested to play a role in causing, and inhibitors of PKCß2 appear to be useful for preventing or diminishing, eye and renal complications of diabetes mellitus in laboratory animals (2): indeed, such inhibitors of PKCß2 are currently being used in clinical trials in humans. In addition, the overexpression of PKCß2 and PKCß1 leads to inhibition of insulin signaling mechanisms (1), and some investigators have suggested that excessive activity of these and other DAG-sensitive PKCs (presumably resulting from excessive levels of glucose, fatty acids or insulin itself, e.g. in certain diabetic states) may impair insulin signaling at the level of the insulin receptor (7, 8, 9) or insulin receptor substrate-1 (IRS-1)-dependent activation of phosphatidylinositol (PI) 3-kinase (10), and thereby cause insulin resistance (11). As the latter postulation further implies that inhibition of PKCß2 or other DAG-sensitive PKCs may, in fact, improve not only diabetic complications, but also clinical insulin resistance, it becomes all the more important to have a better understanding of the importance of various PKC isoforms in insulin action, particularly in a physiological setting and as related to glucose transport. Presently, we addressed this question by examining overall glucose homeostasis in vivo and glucose transport responses in insulin-sensitive tissues of mice in which the PKCß gene, including both of its splice products, PKCß1 and PKCß2, was knocked out by homologous recombination.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), to minimize
genetic differences other than the absence of the PKCß gene, we used
offspring of heterozygous C57BL/6 mice (PKCß+/-) that
were derived by repeated backcrossing with normal C57BL/6 mice: this
approach was not extensively used, as it was difficult to obtain
sufficient numbers of both PKCß-/- and
PKCß+/+ male mice for direct comparisons. All mice were
housed in an environmentally controlled environment with 12-h light,
12-h dark cycles and were fed the same standard chow for at least 2
weeks before experimentation. The mice used in all studies were
sexually mature males or, in a few instances (where indicated),
nonpregnant females that were 8–12 weeks of age. Body weights of
control and PKCß knockout mice were not significantly different, and
except for coat color, there were no obvious somatic differences
between PKCß knockout and various control mice.
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Adipocyte transfections and assay of epitope-tagged GLUT4
translocation
Adipocytes were transiently transfected using electroporation as
described previously (6) with pCIS2 (provided by Drs. Michael Quon and
Simeon Taylor, NIH, Bethesda, MD), which contained a cytomegalovirus
promoter and enhancer with a generic intron located upstream of the
multiple cloning site, and a complementary DNA (cDNA) encoding
hemagglutinin antigen (HA)-tagged (in an exofacial loop) GLUT4 (3 µg
DNA/0.8 ml adipocyte suspension), with or without (as indicated) pTB701
(7 µg DNA/0.8 ml adipocyte suspension) containing no insert
(i.e. vector only) or cDNA insert encoding PKCß1 or
PKCß2. After overnight incubation to allow time for expression
(verified by the appearance of immunoreactive PKCß1, PKCß2, and
HA-GLUT4), cells were suspended in glucose-free KRP buffer and treated
for 30 min with or without 10 nM insulin. Cell surface HA
epitope (i.e. translocation) was then measured by stopping
the reaction with 2 mM KCN, followed by incubation first
with mouse monoclonal anti-HA antibody (Babco, Berkeley, CA) and second
with 125I-labeled antimouse IGG antiserum (Amersham Pharmacia Biotech, Arlington Heights, IL), as previously
described (6). The expression of immunoreactive HA-GLUT4 was comparable
in wild-type control cells and PKCß knockout cells transfected with
vector alone or vector containing cDNA encoding PKCß1 and PKCß2.
Expression of PKCß1 and PKCß2 in transfected cells was documented
both with isoform-specific antisera that target unique C-terminal
epitopes and by an antiserum that targets an internal epitope common to
both PKCß1 and PKCß2.
In vivo studies
Glucose tolerance tests were conducted in overnight fasted,
unanesthetized mice by injecting 2 mg glucose/g BW, ip; tail blood was
sampled at 0, 10, 30, and 60 min. THe effects of insulin on
[3H]2-DOG uptake in the gastrocnemius muscle in
vivo were studied essentially as described previously (14);
overnight fasted mice were injected im with 1 µCi
[3H]2-DOG glucose and 0.1 µCi
L-[14C]glucose with or without 0.2 U insulin.
After 15 min, the mice were killed, and samples of serum and muscle
were obtained to determine the specific activity of serum 2-DOG
(i.e. counts per min of 3H in 2-DOG relative to
the total glucose level) and uptake of 3H and
14C in the gastrocnemius muscles. Nonspecific trapping of
[3H]2-DOG in muscles was determined by examining the
level of L-[14C]glucose in the sample.
Overall uptake of 2-DOG in muscle was then calculated using the
specific activity of [3H]2-DOG in the plasma.
PI 3-kinase assay
Activation of PI 3-kinase was determined in extracts of control
and insulin-stimulated tissues using methods described previously (15),
namely, measurement of PI 3-kinase activity in IRS-1
immuno-precipitates.
Western analyses
Tissues were examined for levels of immunoreactive GLUT4, GLUT1,
PKC, PKCß1, PKCß2, total PKCß1+ß2, PKC, PKC, and
PKC as previosuly described (4, 5, 6). Except for the anti-PKCß1+2
antiserum [a polyclonal antiserum raised against an epitope in the C3
region in the catalytic domain; described previously (5)] and the
PKCß1 antiserum (raised against a C-terminal V5 epitope; provided by
Dr. Mildred Acevedo-Duncan), anti-PKC polyclonal antisera were
purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz,
CA). Anti-GLUT4 polyclonal antiserum was purchased from
Biogenesis (Sandown, NH). Anti-GLUT1 polyclonal antiserum
was provided by Dr. Ian Simpson, NIH. Anti IRS-1 polyclonal antiserum
was provided by Dr. Alan Saltiel, Parke-Davis (Ann Arbor,
MI). Anti-HA mouse monoclonal antibody was purchased from Covance
(Berkeley, CA). Levels of immunoreactivity were quantitated by
measurement of chemiluminescence in a Bio-Rad
Chemiluminescence/32P Molecular Analyst Imaging System
(Bio-Rad Laboratories, Inc., Hercules, CA) or by laser
densitometric scanning (LKB, Rockville, MD) of
autoradiographs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, fasting serum glucose levels were
approximately 10% lower, but not statistically different, in PKCß
knockout mice (PKCß-/-) compared with those in their
PKCß+/+ littermates despite similar or slightly lower
insulin levels. Similarly, after ip glucose (1 mg/g BW) administration,
serum glucose levels in PKCß-/- male mice were 10%
less than those in PKCß+/+ male mice (P
< 0.05) despite slightly lower, albeit not significantly, insulin
levels. These findings indicated that overall glucose homeostasis was
mildly, but significantly, enhanced in mice in which the PKCß gene
was knocked out by homologous recombination. These findings also
suggested that glucose metabolism or insulin action, rather than
insulin secretion, may be enhanced in PKCß knockout mice. Unfortunately, this backcrossing approach, although in theory preferable, did not provide sufficient members of PKCß-/- and PKCß+/+ mice for direct comparisons, and subsequent studies were conducted in which PKCß-/- mice were compared with commercially obtained control PKCß+/+ mice (see Materials and Methods).
Comparison of serum glucose and insulin levels in various PKCß
knockout mice and various commercially available control mice
Fasting and fed (ad libitum) serum glucose levels were
not significantly different when PKCß knockout mice were compared
with commercially available control mice with a similar genetic
background, i.e. as C57BL/6–129/SV hybrids (Table 2). Similarly, fasting serum glucose
levels were not significantly different when the PKCß knockout mice
were compared with controls that were pure strains of C57BL/6 mice
(Table 2). Control 129/SV mice, on the other hand, had lower fasting
serum glucose levels. Of particular importance, fasting serum insulin
levels were lowest in PKCß knockout mice (Table 2).
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), i.e. serum glucose levels were similar
in PKCß knockout, C57BL/6, and C57BL/6–129/SV hybrid mice; serum
glucose values were lowest in 129/SV mice; and serum insulin levels
were lowest in PKCß knockout mice. Increases in serum glucose levels
were surprisingly high, and increases in serum insulin levels were
relatively small in all mouse strains after ip injection of glucose;
this apparently limited insulin response may reflect the effects of
stress and/or a need for gut incretins to stimulate insulin secretion
more effectively. In support of the latter explanation, higher serum
insulin levels were observed along with lower serum glucose levels in
fed mice (Table 2). Regardless of the cause of the lesser insulin
response to ip glucose administration, it is clear that serum insulin
levels, relative to serum glucose levels, were not increased in PKCß
knockout mice regardless of whether the mice were fasting, fed, or
challenged with ip glucose.
2-DOG uptake in adipocytes and soleus muscles in vitro
As shown in Fig. 1, insulin-stimulated, but not basal, [3H]2-DOG uptake was
increased in adipocytes prepared from PKCß knockout mice compared
with 2-DOG uptake in adipocytes of C57BL/6–129/SV hybrid, C57BL/6, or
129/SV mice; the major change appeared to be an increase in the maximal
rate of 2-DOG uptake, with no change in insulin sensitivity. As shown
in Fig. 2, results were somewhat
different in soleus muscles. 2-DOG uptake was mildly, but
significantly, increased in the basal state, and this appeared to
largely account for increases observed during insulin treatment in
muscles of PKCß knockout mice compared with those of C57BL/6–129/SV
hybrid mice.
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). Blood glucose levels decreased from 140 to
45 mg/dl in both groups of mice over the course of the 15-min insulin
treatment period in vivo, and kinetic information at earlier
time points was not apparent in this study. Nevertheless, these
findings provided clear evidence that insulin-stimulated hexose
transport and subsequent phosphorylation (and thus trapping of
2-DOG-6-PO4) were not compromised in gastrocnemius muscles
of PKCß knockout mice.
Activation of PI 3-kinase in skeletal muscle in vivo
Insulin provoked increases in IRS-1-dependent PI 3-kinase activity
in adipocytes (Fig. 3) and gastrocnemius
muscles (Fig. 2) of PKCß knockout mice that were not significantly
different from the increases observed in control mice. These results
suggested that initial steps of signaling in this pathway in response
to maximally effective doses of insulin were not significantly altered
in adipocytes and skeletal muscles of PKCß knockout mice.
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). In contrast, levels of other
PKCs (, , , and ) were comparable in insulin-sensitive
tissues, including liver, adipocytes, and skeletal muscles of PKCß
knockout mice and control mice (Fig. 5).
Similarly, levels of GLUT4 and GLUT1 glucose transporters were not
significantly different in adipocytes and skeletal muscles of PKCß
knockout and control mice (see Fig. 4 and Table 3).
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).
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). The significance of increases in
basal GLUT4 translocation, however, is uncertain, as such basal GLUT4
translocation and glucose transport activity may have been increased as
a result of electroporation and overnight culturing, and this
artifactual increase may have been exaggerated in the more active
PKCß knockout adipocyte.
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, the expression of PKCß1,
but not PKCß2, resulted in 33% inhibition of insulin-stimulated, but
not basal, HA-GLUT4 translocation, despite the fact that expression of
PKCß2 was greater than that of PKCß1. These findings suggested that
PKCß1 might exert an inhibitory effect on the glucose transport
process. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Serum insulin levels were not elevated and, moreover, in some cases they appeared to be slightly lower in PKCß knockout mice; clearly, PKCß knockout mice were not insulin resistant. Moreover, the finding that blood glucose levels were slightly lower in PKCß-/- knockout mice than in their littermate PKCß+/+ controls (in the face of similar or lower insulin levels) suggested that the absence of the PKCß gene and its splice products, PKB-ß1 and PKCß2, caused either an increase in sensitivity to insulin or an alteration in insulin-independent glucose metabolism, e.g. decreased hepatic glucose output or enhanced glucose disposal. In keeping with the possibility of enhanced glucose disposal, glucose transport was enhanced in adipocytes and skeletal muscle preparations in PKCß knockout mice, and translocation of HA-tagged GLUT4 was increased in adipocytes of PKCß knockout mice.
The reason for presently observed increases in glucose transport in adipocytes and soleus muscles, and GLUT4 translocation in adipocytes, of PKCß knockout mice was uncertain. We did not detect significant differences in the overall activation of PI 3-kinase in adipocytes and skeletal muscle, and levels of GLUT4 and GLUT1 glucose transporters were not significantly different in skeletal muscles and adipocytes of control and PKCß knockout mice. Although we did not presently study insulin receptor activation, diminished activation of insulin receptor tyrosine kinase has been reported during both phorbol ester-induced activation of PKCß and other DAG-sensitive kinases in rat adipocytes and other cells (7, 8, 9) and after transfection of PKCß1 and PKCß2 into HEK 293 cells (1). We cannot exclude the possibility that increases in glucose transport in PKCß knockout mice may have reflected enhanced signaling at the level of the insulin receptor despite the fact that we did not observe significant increases in IRS-1-dependent PI 3-kinase activation. However, it seems more plausible to suggest that signaling processes different from or subsequent to PI 3-kinase activation may have been enhanced in PKCß knockout mice. It also seems likely that these enhanced signaling processes resulted in increases in the translocation of GLUT4 glucose transporters, at least in adipocytes, in PKCß knockout mice. Further studies will be required to determine the exact reason(s) for increases in glucose transport in adipocytes and soleus muscles of PKCß knockout mice.
Whereas our studies did not identify the signaling factor that was responsible for increases in glucose transport in PKCß knockout mice, our "knockin" studies in adipocytes of PKCß knockout mice suggested that PKCß1 is more likely than PKCß2 to serve as a negative modulator of insulin-stimulated GLUT4 translocation. Interestingly, we found (16) that transient overexpression of PKCß1, but not PKCß2, also inhibits HA-GLUT4 translocation in adipocytes of normal rats. The apparent selectivity of PKCß1 as a negative modulator of insulin-stimulated glucose transport merits further study.
Although our findings demonstrated that insulin readily stimulates
glucose transport in the complete absence of both PKCß and PKCß2,
it may be argued that findings in PKCß knockout mice may not be
relevant to the situation in mice that have normal amounts of PKCß
and other signaling factors. For example, it is possible that the
absence of the functional PKCß gene may have caused other signaling
factors to hypertrophy. However, we did not observe increases in levels
of other PKCs or in GLUT4 or GLUT1 glucose transporters in PKCß
knockout mice. Furthermore, the present finding of uncompromised
insulin action in PKCß knockout mice is in accord with findings in
studies in which PKCß was acutely inhibited or markedly depleted in
various types of otherwise normal cells (4, 5, 6, 17, 18). As another
possibility, it could be argued that normal or wild-type cells have
redundant signaling pathways and kinases that participate in activating
glucose transport, including PKCß2, atypical PKCs, PKC and PKC,
PKB, and/or PKN; thus, the loss of a single kinase would not compromise
the effects of insulin on glucose transport. This possibility, however,
seems unlikely, as transient expression of kinase-inactive PKC or
PKC, but not kinase-inactive PKCß2, markedly inhibits
epitope-tagged GLUT4 translocation in rat adipocytes (6, 16). Taken
together, the present and several other independent lines of evidence
lead us to conclude that PKCß is not required for insulin stimulation
of glucose transport.
In summary, our findings in PKCß knockout mice provide clear evidence that PKCß2 or PKCß1 cannot be considered to be essential for insulin stimulation of glucose transport in mouse tissues. Moreover, overall glucose homeostasis in vivo and glucose transport in two tissues that are largely dependent upon GLUT4 translocation during insulin stimulation, viz. adipocytes and soleus muscles, were significantly enhanced in PKCß knockout mice. Our findings therefore suggest that selective PKCß inhibitors are unlikely to adversely affect insulin action and overall glucose homeostasis; indeed, in view of the present findings, the opposite result may be observed with PKCß inhibitors, i.e. there may be increases in insulin action and glucose tolerance. Determining whether such inhibitors will adversely affect other functions remains for future studies.
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Acknowledgments |
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Footnotes |
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Received March 8, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and noninvolvement of diacylglycerol-sensitive PKCs in
insulin-stimulated glucose transport in L6 myotubes. Endocrinology 138:4721–4731, ß, and ) by insulin in 3T3/L1 cells.
Transfection studies suggest a role for PKC- in glucose transport.
J Biol Chem 272:2551–2558 as a downstream
effector of phosphatidylinositol 3-kinase during insulin stimulation in
rat adipocytes. Potential role in glucose transport. J Biol Chem 272:30075–30082, ß1, , and
in cells overexpressing the insulin receptor. Effects on receptor
phosphorylation and signaling. J Biol Chem 268:6338–6347,
), conventional (, ß) and novel (, ) protein kinase C
isoforms on insulin-stimulated translocation of epitope-tagged GLUT4
glucose transporters in rat adipcocytes: specific interchangeable
effects of protein kinase C- and C-. Biochem J 337:461–470
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