title: Effects of knockout of the protein kinase C beta gene on glucose transport and glucose homeostasis.
abstract: The beta-isoform of protein kinase C (PKC) has paradoxically been suggested to be important for both insulin action and insulin resistance as well as for contributing to the pathogenesis of diabetic complications. Presently, we evaluated the effects of knockout of the PKCbeta gene on overall glucose homeostasis and insulin regulation of glucose transport. To evaluate subtle differences in glucose homeostasis in vivo, knockout mice were extensively backcrossed in C57BL/6 mice to diminish genetic differences other than the absence of the PKCbeta gene. PKCbeta-/- knockout offspring obtained through this backcrossing had 10% lower blood glucose levels than those observed in PKCbeta+/+ wild-type offspring in both the fasting state and 30 min after i.p. injection of glucose despite having similar or slightly lower serum insulin levels. Also, compared with commercially obtained C57BL/6-129/SV hybrid control mice, serum glucose levels were similar, and serum insulin levels were similar or slightly lower, in C57BL/6-129/SV hybrid PKCbeta knockout mice in fasting and fed states and after i.p. glucose administration. In keeping with a tendency for slightly lower serum glucose and/or insulin levels in PKCbeta knockout mice, insulin-stimulated 2-deoxyglucose (2-DOG) uptake was enhanced by 50-100% in isolated adipocytes; basal and insulin-stimulated epitope-tagged GLUT4 translocations in adipocytes were increased by 41% and 27%, respectively; and basal 2-DOG uptake was mildly increased by 20-25% in soleus muscles incubated in vitro. The reason for increased 2-DOG uptake and/or GLUT4 translocation in these tissues was uncertain, as there were no significant alterations in phosphatidylinositol 3-kinase activity or activation or in levels of GLUT1 or GLUT4 glucose transporters or other PKC isoforms. On the other hand, increases in 2-DOG uptake may have been partly caused by the loss of PKCbeta1, rather than PKCbeta2, as transient expression of PKCbeta1 selectively inhibited insulin-stimulated translocation of epitope-tagged GLUT4 in adipocytes prepared from PKCbeta knockout mice. Our findings suggest that 1) PKCbeta is not required for insulin-stimulated glucose transport; 2) overall glucose homeostasis in vivo is mildly enhanced by knockout of the PKCbeta gene; 3) glucose transport is increased in some tissues in PKCbeta knockout mice; and 4) increased glucose transport may be partly due to loss of PKCbeta1, which negatively modulates insulin-stimulated GLUT4 translocation.
authors.affiliation: J.A. Haley Veterans Hospital Research Service, and Department of Internal Medicine, University of South Florida College of Medicine, Tampa 33612, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Standaert
authors.forename: G
authors.initials: G
authors.lastname: Bandyopadhyay
authors.forename: L
authors.initials: L
authors.lastname: Galloway
authors.forename: J
authors.initials: J
authors.lastname: Soto
authors.forename: Y
authors.initials: Y
authors.lastname: Ono
authors.forename: U
authors.initials: U
authors.lastname: Kikkawa
authors.forename: R V
authors.initials: RV
authors.lastname: Farese
authors.forename: M
authors.initials: M
authors.lastname: Leitges
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000032:analysis; D003847:Deoxyglucose / Q000493:pharmacokinetics; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006579:Heterozygote; D006706:Homeostasis; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics* / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics*; D064546:Protein Kinase C beta
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D007527:Isoenzymes; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495693:Slc2a4 protein, mouse; D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D005947:Glucose