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ARTICLE |
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by Insulin and Phosphatidylinositol-3,4,5-(PO4)3 in Skeletal Muscle of Rats Following High-Fat Feeding and Streptozotocin-Induced Diabetes
Research Service, James A. Haley Veterans Administration Medical Center and Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612
Address all correspondence and requests for reprints to: Robert V. Farese, M.D., ACOS-151, James A. Haley Veterans Administration Hospital, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612. E-mail: rfarese{at}hsc.med.usf.edu.
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Abstract |
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activation loop, as this phosphorylation was increased even in the absence of insulin treatment in high-fat-fed rats. Conclusions: 1) muscle aPKCs are activated at relatively low, presumably physiological, as well as higher supraphysiological, insulin concentrations; 2) aPKC activation is defective in muscles of high-fat-fed and STZ-diabetic rats; and 3) defective aPKC activation in these states is at least partly due to impaired responsiveness to PI-3,4,5-(PO4)3, apparently at activation steps distal to PDK-1-dependent loop phosphorylation. |
Introduction |
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and 
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(3, 4, 5, 6, 7, 8, 9, 10, 11). Defects in insulin-stimulated glucose disposal in vivo, presumably reflecting defects in insulin-stimulated glucose transport and subsequent storage in glycogen in skeletal muscle, have been observed in hyperinsulinemic/euglycemic clamp studies of type 2 diabetic animals and humans. More specifically, defects in insulin-stimulated glucose transport have been observed in adipocytes isolated from type 2 diabetic rats (12, 13) and humans (14, 15), and in muscles of type 2 diabetic rats (16, 17). Further, defects in insulin-induced activation of IRS-1-dependent PI 3-kinase (13, 16, 17) and aPKCs (13, 17) have been observed in skeletal muscles and adipocytes isolated from type 2 diabetic rats. Similarly, defective activation of IRS-1-dependent PI 3kinase (18, 19) has been observed in muscles and adipocytes of type 2 diabetic humans, and, more recently, defective activation of aPKCs by insulin has been observed in skeletal muscles of obese type 2 diabetic humans (20) and obese monkeys (21). In addition to type 2 diabetes, defects in insulin action are present in poorly controlled, type 1 diabetes, most likely largely through insulin deficiency and resulting hyperglycemia, i.e. via glucose toxicity (22, 23) and/or concomitant increases in plasma free fatty acid levels, i.e. lipotoxicity. With respect to signaling in insulinopenic forms of diabetes, it was recently reported that, unexpectedly, there were increases in insulin-stimulated IRS-1- and IRS-2dependent PI 3-kinase activities, whereas protein kinase B (PKB) activation was diminished in rats rendered diabetic by neonatal streptozotocin (STZ) treatment; however, aPKC activation was not measured in this study (24), or, to our knowledge, other studies, of STZ diabetes.
Similarly, systemic insulin resistance and defects in insulin-stimulated glucose transport have been observed in skeletal muscles of rats that were fed diets in which fats provided 55–60% of total calories (25, 26). Notably, in these dietary studies, defective activation of IRS-1-dependent PI 3-kinase was observed (25, 26), and elevated basal aPKC activity with no response to insulin was reported in one of these studies (26). Effects of feeding diets containing more modest increases in fat content on these insulin-sensitive signaling factors have not been reported.
Although the above-described findings (20, 21, 26) are in keeping with the concept that aPKCs may play important roles in controlling glucose uptake in skeletal muscle, thereby contributing to the regulation of total body glucose disposal in vivo, there is relatively little available information on time-dependent and dose-dependent activation of aPKCs by insulin in muscles of intact normal animals. Similarly, there is as yet limited available information on the activation of aPKCs in various insulin-resistant states. Presently, we examined the activation of aPKCs in skeletal muscle during administration of insulin or glucose in normal chow-fed rats, and during insulin administration in hypoinsulinemic/hyperglycemic STZ-diabetic rats, and in hyperinsulinemic/normoglycemic rats fed a moderately high-fat diet, providing 42% of its calories as fat. Interestingly, in both STZ diabetes and feeding of a moderately high-fat diet, we observed similar defects in the activation of aPKCs by insulin, despite seemingly normal activation of IRS-1- and IRS-2-dependent PI 3-kinase. Moreover, the activation of aPKCs by PIP3 in vitro was diminished in muscles of high-fat-fed and STZ-diabetic rats. These findings suggested that a defect in responsiveness of aPKCs to PIP3 may play an important role in the pathogenesis of defective aPKC activation and skeletal muscle insulin resistance in these insulin-resistant states.
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Materials and Methods |
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Where indicated, rats were injected ip with STZ (Sigma, St. Louis, MO) (60 mg/kg body weight; freshly dissolved in 0.05 M citrate buffer, pH, 4.5), and, 7–8 d later, these STZ-diabetic rats had nonfasting serum glucose levels of 438 ± 30 mg/dl (mean ± SE; n = 28; range 210–724).
Except in studies of glucose tolerance in which rats were fasted overnight, rats were used in the nonfasting state at approximately 1000–1200 h. As seen in Figs. 1–3
, serum glucose levels were approximately 90–120 mg/dl after overnight fasting, and 150–170 mg/dl without fasting. It may be noted that without fasting, stomachs and intestines regularly contained large amounts of undigested chow, despite the fact that most feeding had been finished before the actual time of experimentation and killing.
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All experimental procedures were fully approved by the Institutional Animal Care and Use Committee of the University of South Florida College of Medicine and the James A. Haley Veterans Administration Medical Center Research and Development Committee.
Enzyme assays
Muscle samples were homogenized with a polytron in appropriate buffers, as described (17). For studies of aPKC activation, homogenizing buffer contained 250 mM sucrose, 20 mM Tris/HCl (pH, 7.5), 1.2 mM EGTA, 20 mM ß-mercaptoethanol, 1 mM phenylmethylsulfonyl fluoride (PMSF) (Sigma), 10 µg/ml aprotinin (Sigma), 20 µg/ml leupeptin (Sigma), 1 mM Na3VO4, 1 mM NaF, 1 mM Na4P2O7, and 1 µM L-arginine-microcystin (Sigma). For studies of PI 3-kinase activation, homogenizing buffer contained 255 mM sucrose, 20 mM Tris/HCl (pH 7.4), 5 mM EDTA, 5 mM EGTA, 1 mM NA3V04, 1 mM NaF, 1 mM NA4P207, 1 mM PMSF, 10 µg/ml aprotinin, 20 µg/ml leupeptin, and 1 µM L-arginine-microcystin. Homogenates were centrifuged for 10 min at 1000 x g to remove nuclei and cellular debris. Supernatants were then supplemented with 0.15 M NaCl, 1% Triton X-100, and 0.5% Nonidet P-40 and used for immunoprecipitation of aPKCs or IRS-1-or IRS-2-dependent PI 3-kinase as described at the end of this section.
Muscle aPKC activity was measured as described previously (17). In brief, aPKCs, and /, were immunoprecipitated from cell lysates with a rabbit polyclonal antiserum (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) that recognizes the nearly identical C termini of PKC-, and PKC-/. Precipitates were collected on Sepharose-A/G beads (Santa Cruz Biotechnology, Inc.), and incubated for 8 min at 30 C in 100 µl buffer containing 50 mM Tris/HCl (pH 7.5), 100 µM Na3VO4, 100 µM Na4 P2O7, 1 mM NaF, 100 µM PMSF, 4 µg phosphatidylserine (Sigma), 50 µM [
-32P]ATP (NEN Life Science Products, Boston, MA), 1 mM EGTA, 5 mM MgCl2 and, as substrate, 40 µM serine analog of the PKC-
pseudosubstrate (Biosource Technologies, Inc., Hopkington, MA), a preferred substrate for aPKCs. After incubation, 32P-labeled substrate was trapped on P-81 filter paper and counted.
Immunoprecipitable IRS-1-dependent [rabbit polyclonal antiserum purchased from Upstate Biotechnology, Inc. (Lake Placid, NY) and IRS-2-dependent PI 3-kinase (rabbit polyclonal antiserum kindly supplied by Dr. Morris White, Harvard University, Boston, MA) activities were determined as described previously (17).
Western analyses
Lysate proteins were resolved by SDS-PAGE, transferred to nitrocellulose membranes, and immunoblotted as described (17). Antibodies used for blotting included: rabbit polyclonal anti-C-terminal PKC-// antiserum (Santa Cruz Biotechnology, Inc.) (PKCs , and have nearly identical C termini that are recognized by this antiserum); mouse monoclonal isoform-specific anti-PKC-/ antibodies that recognize both PKC- and PKC-, which are 98% homologous (Transduction Laboratories, Inc., Lexington, KY); rabbit polyclonal isoform-specific anti-N-terminal PKC- antiserum (kindly supplied by Dr. Todd Sacktor, SUNY Downstate Medical Center, Brooklyn, NY); rabbit polyclonal anti-Glut1 antiserum (kindly provided by Dr. Ian Simpson, Penn State University, Hershey, PA); mouse monoclonal anti-Glut4 antibodies (Biogenesis, Hopkington, MA); rabbit polyclonal anti-PDK-1 antiserum (Upstate Biotechnology, Inc.); rabbit polyclonal anti-p85 PI 3-kinase subunit antiserum (Upstate Biotechnology, Inc.); rabbit polyclonal anti-IRS-1 antiserum (Upstate Biotechnology, Inc.); rabbit polyclonal anti-PKB antiserum (Upstate Biotechnology, Inc.); rabbit polyclonal anti-phospho-serine-473-PKB antiserum (Cell Signaling Technology, Beverly, MA); and rabbit polyclonal anti-phospho-threonine-PKC- antiserum (Cell Signaling Technology). Immunoblot signal intensity was quantified by measurement of chemiluminescence in a Bio-Rad Laboratories, Inc. (Hercules, CA) Molecular Analyst chemiluminescence/Phosphorescence Imaging System or by scanning densitometry.
Serum analyses
Glucose, free fatty acid, and insulin levels were measured as described (17, 27).
Hexose uptake into muscle
As described (27), hexose uptake into the vastus lateralis muscle over 15 min was determined by injection (see Animals section) of a tracer amounts of transportable/nonmetabolizable [3H]2-deoxyglucose and nontransportable/nonmetabolizable [14C]L-glucose (the latter to correct for nonspecific uptake) and measuring muscle uptake of [3H]2-deoxyglucose radioactivity (cpm) and specific activity of serum hexose, i.e. serum [3H]2-deoxyglucose cpm per nmol serum glucose. Uptake was calculated by dividing cpm in muscle by the specific activity of serum hexose.
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Results |
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). Serum glucose diminished over 15 min to a lower level that was then maintained over the next 15 min. IRS-1-dependent PI 3-kinase and PKC-/ activity increased progressively over 15 min to reach maximal or near maximal levels at 15–30 min.
As seen in Fig. 2, both IRS-1-dependent PI 3-kinase and PKC-/ activity, measured 15 min after im injection of 0, 0.1, 0.3, and 1 U insulin/kg body weight, increased progressively in response to each dose of insulin.
In subsequent studies of insulin action in insulin-resistant states, we examined signaling factors 15 min after administering 1 U insulin/kg body weight, as this time and dose appeared to be optimal for observing maximal alterations in IRS-1-dependent PI 3-kinase and aPKC activities.
Activation by glucose administration.
In addition to treating rats with insulin, we injected glucose ip to modestly raise plasma glucose levels to examine alterations in muscle PKC-/ activity in response to relatively low, presumably more physiologic increases in endogenously secreted insulin. As seen in Fig. 3, after an overnight fast, and following ip injection of 2 mg glucose/kg body weight, serum glucose increased modestly from approximately 110 to 200 mg/dl within 15 min and remained near this level during the next 45 min. Serum insulin levels increased approximately 4-fold within 15 min and then diminished to 3-fold and then to 2-fold increases during the next 45 min. PKC-/ activity increased approximately 2-fold within 15 min and remained at or about this level during the next 45 min. As may be surmised from the finding that basal noninsulin-stimulated aPKC activity was not increased in muscles of hyperglycemic STZ-diabetic rats (see Section III), it seems unlikely that increases in muscle aPKC activity presently seen after ip glucose administration were due to increases in plasma glucose, rather than insulin, levels.
In response to a stronger glycemic stimulus, ip injection of 4 mg glucose/kg body weight, serum glucose increased to approximately 350–500 mg/dl, and serum insulin levels increased more than 10-fold within 30 min and then diminished modestly thereafter (Fig. 3). In these conditions, PKC-/ activity increased apparently maximally or near maximally at 15 min and tended to diminish, but nevertheless remain substantially elevated, thereafter.
As there are no reports on the activation of PKC-/ in specific types of muscle fibers, it was interesting to find that, in addition to the activation in mixed-fiber vastus lateralis muscles, PKC-/ activity was increased in both predominantly red fiber slow-twitch soleus muscles and predominantly white fiber fast-twitch extensor digitorum longis muscles 15 min after im insulin administration in vivo (Fig. 4).
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). This defect in hexose uptake was accompanied by a defect in insulin-induced activation of PKC-/, but, in contrast, the activation of IRS-1- and IRS-2-dependent PI 3-kinase by insulin was not significantly altered by high-fat feeding (Fig. 5). Basal activities of IRS-1-dependent and IRS-1-dependent PI 3-kinase trended upward in high-fat-fed rats, but these changes were not significant (Fig. 6). High-fat feeding did not alter the levels of aPKCs, IRS-1, IRS-2, PKB
, phospho-PKB/ß, PDK-1, the p85 subunit of PI 3-kinase, or Glut4 or Glut1 glucose transporters in rat vastus lateralis muscle (Fig. 6).
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and threonine-411 in PKC-) by PDK-1; 2) PDK-1-independent auto(trans)phosphorylation; and 3) allosteric relief of pseudosubstrate-dependent auto-inhibition (11). Accordingly, we examined effects of addition of PIP3 to aPKCs immunoprecipitated from muscle lysates prepared from rats fed high-fat and low-fat diets. Interestingly, whereas a maximally effective concentration (10 µM; see Refs. 5 and 11) of PIP3 increased aPKC activity of unstimulated muscle to a level comparable with that seen in insulin-stimulated muscle obtained from rats fed a low-fat diet, the response of aPKCs to PIP3 was markedly reduced in unstimulated muscles obtained from high-fat fed rats (Fig. 7). Similar to findings in previous studies of adipocytes (5, 11), there was little or no effect of PIP3 on aPKC activity in immunoprecipitates prepared from insulin-stimulated muscles; this failure to see a stimulatory effect of PIP3 on aPKC activity probably reflects maximal or near maximal stimulation by prior insulin treatment (see Refs. 5 and 11). Note that the immunoprecipitates prepared from muscles of low-fat-fed and high-fat-fed rats contained equal amounts of immunoreactive aPKCs and PDK-1, which is known to coimmunoprecipitate with aPKCs (data not shown).
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, at phosphorylation of the autophosphorylation site (threonine-560), or at the level of allosteric relief of pseudosubstrate-dependent auto-inhibition. It was therefore of interest to find that phosphorylation of threonine-410 was increased not only, as expected, by acute insulin treatment in standard chow-fed rats, but also basally (however, see Table 1 regarding serum insulin levels) in high-fat-fed rats (Fig. 8). Moreover, administration of insulin failed to provoke further increases in threonine-410 phosphorylation in high-fat-fed rats (Fig. 8), possibly reflecting apparently maximal activation by endogenous insulin (see below) and perhaps the modest, albeit statistically insignificant, increases in basal PI 3-kinase activity (see above).
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), presumably reflective of insulin resistance in these rats.
III. Activation of signaling factors in muscles of STZ-diabetic rats
We have previously reported that insulin-induced activation of PKC-/ is defective in vastus lateralis muscles of nonobese diabetic Goto-Kakazaki rats, most likely largely as a result of increases in plasma glucose levels (17). Similarly, insulin-stimulated increases in PKC-/ activity were markedly diminished in muscles of STZ-diabetic rats (Fig. 9). In contrast, surprisingly, IRS-1- and IRS-2-dependent PI 3kinase activities were not diminished in STZ-diabetic rats (Fig. 9). In this regard, note that a similar preservation of PI 3-kinase activation was observed in the previous study of diabetes induced by neonatal STZ treatment (24).
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/ activation in vastus lateralis muscles of STZ-diabetic rats could not be explained by an alteration in levels of PKC- or PKC- (Fig. 6). Similarly, levels of other related signaling factors (IRS-1, IRS-2, PDK-1, the p85 subunit of PI 3-kinase, PKB, phospho-PKB/ß) in the vastus lateralis muscles were not altered by STZ treatment (Fig. 6). On the other hand, Glut4 glucose transporter levels were diminished in vastus lateralis muscles of STZ rats (Fig. 6), and this, as well as defective activation of aPKCs, may contribute to decreases in insulin-stimulated glucose uptake in STZ-diabetic muscle (see 24).
In view of the fact that PKC-/ activation was compromised in the face of apparently normal or heightened activation of IRS-1- and IRS-2-dependent PI 3-kinase, and unchanged levels of aPKCs in muscles of STZ-diabetic rats, we examined the possibility that there may be a defect in the response of PKC-/ to PIP3. Indeed, as seen in Fig. 10, 10 µM PIP3 provoked significant increases in PKC-/ enzyme activity when added to PKC-/ immunoprecipitates prepared from muscles of unstimulated (i.e. not treated with insulin) nondiabetic rats, but had little or no effect when added to PKC-/ immunoprecipitates prepared from muscles of unstimulated STZ-diabetic rats.
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). As expected, serum insulin levels were diminished in STZ-diabetic rats (Table 1). |
Discussion |
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Interestingly, insulin-induced activation of aPKCs was diminished in muscles of both high-fat-fed and STZ-diabetic rats, despite seemingly normal activation of IRS-1- and IRS-2-dependent PI 3-kinase. Also interesting was our finding that these defects in aPKC activation appeared to be at least partly due to defects in the ability of PIP3, the lipid product of PI 3-kinase, to directly activate aPKCs. Although defects in aPKC responsiveness to PIP3 in vitro could theoretically account for defects in aPKC activation by insulin in intact muscles of high fat-fed or STZ-diabetic rats, we cannot discount the possibility that: 1) seemingly normal IRS-1/2dependent PI 3-kinase may be uncoupled to aPKC activation, or 2) signaling factors other than IRS-1/2 that function upstream of, or in parallel to, PI 3-kinase and aPKCs may have been down-regulated.
Our failure to observe a decrease in IRS-1-dependent PI 3-kinase during moderate high-fat feeding (42% calories from fat) differs from findings (25, 26) seen in muscles of rats fed a higher fat diet (55–60% calories from fat). Although a higher fat diet was not presently studied, it seems reasonable to suggest that higher fat feeding has more profound effects on signaling through IRS-1 and IRS-2.
The present finding of an essentially unaltered basal level of aPKC activation and diminished activation by insulin in high-fat-fed rats differs from findings of a large increase in basal aPKC activity and no further increase after insulin treatment in muscles of high-fat-fed rats (25). The reason(s) for these differences is uncertain but may reflect different experimental conditions. First, the level of dietary fat in high-fat-fed rats used presently, 42% of total calories, was considerably less than that used in the previous study, 65% of total calories. Second, our method for measurement of aPKC enzyme activity differs from that used previously in that our assays contained phosphatidylserine to amplify aPKC activity and a preferred aPKC substrate, the serine analog of the PKC- pseudosubstrate. Third, we measured insulin-stimulated aPKC activity 15 min after im injection of insulin, as opposed to 4 min after iv administration. Although it is difficult to identify the reason(s) for differences in findings, there is at least agreement in both studies that there is a defect in insulin-induced activation of aPKCs in muscles of high-fat-fed rats.
It is interesting to speculate on potential reasons for finding remarkably similar alterations in insulin-sensitive signaling factors in both high-fat-fed and STZ-diabetic rats, namely, defects in aPKC activation by insulin in vivo and PIP3 in vitro, in the absence of alterations in IRS-1- or IRS-2-dependent PI 3-kinase activation. Thus, elevations in serum glucose in STZ-diabetic rats may have increased de novo synthesis of im lipids, including diacylglycerol (DAG), thereby activating DAG-dependent PKCs, which have been found to down-regulate insulin-stimulated aPKC activation (9, 28). Germane to the possibility that hyperglycemia may have been important in down-regulating aPKCs in STZ-diabetic rats is the finding of improved aPKC activation, notably in the absence of increases in IRS-1-dependent PI 3-kinase activation, following improvement of serum glucose levels by several means in Goto-Kakazaki-diabetic rats (17). On the other hand, STZ-diabetic rats also had increases in serum free fatty acids, and, as in high-fat-fed rats, increases in serum fatty acids and/or other lipids may have increased im lipid/DAG content, thereby activating DAG-dependent PKCs. Alternatively, increases in serum glucose and fatty acids may have inhibited aPKC activation by mechanisms involving increases in im glucosamine levels and subsequent glycosylation of key proteins, or increases in the activity of ERK or other potential insulin-inhibitory factors.
It is also interesting to speculate on potential reasons for impaired responsiveness of aPKCs to PIP3 in muscles of high-fat-fed and STZ-diabetic rats. A defect in activity or action of PDK-1 seems unlikely, as threonine-410, the target of PDK-1 in PKC-, was well phosphorylated in the basal state in high-fat-fed rats, presumably in response to increases in endogenous insulin levels. On the other hand, subsequent insulin treatment did not provoke further increases in threonine-410 phosphorylation in high-fat-fed rats, most likely reflecting maximal activation even before insulin administration. In any event, aPKC enzyme activity was not increased in muscles of high-fat-fed rats, either basally or in response to insulin administration, despite increases in phosphorylation of threonine-410. This dissociation suggested that steps distal to threonine-410 phosphorylation that are needed for aPKC activation (see Ref. 11) were compromised in high-fat-fed rats. In this regard, note that PIP3 increases phosphorylation of threonine-560, the autophosphorylation site, and provokes an allosteric alteration that results in relief of pseudosubstrate-dependent auto-inhibition, both of which, along with PDK-1-dependent phosphorylation of threonine-410, are required for full activation of PKC-/ (11). Accordingly, one or both of these steps may be compromised in high-fat-fed and STZ-diabetic rats, or, alternatively, the enzyme activity of aPKCs may be diminished. In either scenario, altered phosphorylation or glycosylation of critical regulatory sites in aPKCs may be responsible for defects in activation or activity of aPKCs.
To summarize, moderately high-fat feeding and STZ diabetes induced similar defects in aPKC activation in rat skeletal muscle. These defects in aPKC activation were not accompanied by measurable alterations in IRS-1- or IRS-2-dependent PI 3-kinase activation, or PDK-1-dependent phosphorylation of threonine-410 in the activation loops of aPKCs. On the other hand, the ability of PIP3, the lipid product of PI 3-kinase, to activate aPKC was impaired, presumably reflecting a molecular alteration(s) that either 1) inhibited the ability of PIP3 to stimulate autophosphorylation or disinhibit pseudosubstrate-dependent auto-inhibition, or 2) diminished the catalytic activity of aPKCs. Further studies are needed to gain further insight into the molecular alterations that diminish aPKC activity/responsiveness in these and other insulin-resistant states.
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Footnotes |
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Abbreviations: aPKC, Atypical PKC; DAG, diacylglycerol; IRS, insulin receptor substrate; PI, phosphatidylinositol; PIP3, PI-3,4,5-(PO4)3; PKB, protein kinase B; PKC, protein kinase C; PKD-1, 3-phosphoinositide-dependent protein kinase-1; PMSF, phenylmethylsulfonyl fluoride; STZ, streptozotocin.
Received October 1, 2002.
Accepted for publication November 14, 2002.
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References |
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, ) protein kinase C isoforms on insulin-stimulated translocation of epitope-tagged GLUT4 glucose transporters in rat adipocytes: specific interchangeable effects of protein kinases C- and C-. Biochem J 337:461–470
on insulin-stimulated glucose transport in L6 myotubes. Endocrinology 141:4120–4127 activation inhibits PKC- and mediates the action of PED/PEA-15 on glucose transport in the L6 skeletal muscle cells. Diabetes 50:1244–1252. Mol Endocrinol 13:1766–1771 by mechanisms that are both dependent and independent of activation loop (T410) and autophosphorylation (T560) sites. Biochemistry 40:249–255[CrossRef][Medline]
/ activation and glucose transport in adipocytes of nondiabetic and Goto-Kakizaki type II diabetic rats. J Biol Chem 275:16690–16696/ by insulin in vastus lateralis muscles and adipocytes of diabetic rats. Endocrinology 142:1595–1605/ activity is impaired in muscle of insulin resistant subjects. Diabetes (Suppl 2)250:A62 (Abstract 250-R)
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P. Weyrich, K. Kapp, G. Niederfellner, M. Melzer, R. Lehmann, H.-U. Haring, and R. Lammers Partitioning-Defective Protein 6 Regulates Insulin-Dependent Glycogen Synthesis via Atypical Protein Kinase C Mol. Endocrinol., May 1, 2004; 18(5): 1287 - 1300. [Abstract] [Full Text] [PDF]
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J. D. Fluckey, R. N. Cortright, E. Tapscott, T. Koves, L. Smith, S. Pohnert, and G. L. Dohm Active involvement of PKC for insulin-mediated rates of muscle protein synthesis in Zucker rats Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E753 - E758. [Abstract] [Full Text] [PDF]
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M. Beeson, M. P. Sajan, M. Dizon, D. Grebenev, J. Gomez-Daspet, A. Miura, Y. Kanoh, J. Powe, G. Bandyopadhyay, M. L. Standaert, et al. Activation of Protein Kinase C-{zeta} by Insulin and Phosphatidylinositol-3,4,5-(PO4)3 Is Defective in Muscle in Type 2 Diabetes and Impaired Glucose Tolerance: Amelioration by Rosiglitazone and Exercise Diabetes, August 1, 2003; 52(8): 1926 - 1934. [Abstract] [Full Text] [PDF]
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