title: Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance.
abstract: Clinical and experimental evidence indicates that atypical antipsychotics impair glucose metabolism. We investigated whether clozapine may directly affect insulin action by analyzing insulin signaling in vitro and in vivo. Clozapine reduced insulin-stimulated glucose uptake in PC12 and in L6 cells, representative models of neuron and skeletal muscle, respectively. Consistently, clozapine reduced insulin effect on insulin receptor (IR) by 40% and on IR substrate-1 (IRS1) tyrosine phosphorylation by 60%. Insulin-stimulated Akt phosphorylation was also reduced by about 40%. Moreover, insulin-dependent phosphorylation of protein kinase C-ζ (PKC-ζ) was completely blunted in clozapine-treated cells. Interestingly, clozapine treatment was accompanied by an insulin-independent increase of Akt phosphorylation, with no change of IR, IRS1, and PKC-ζ basal phosphorylation. The cellular abundance of Ped/Pea-15, an Akt substrate and inducer of insulin resistance, was also increased following clozapine exposure, both in the absence and in the presence of cyclohexymide, a protein synthesis inhibitor. Similar as in cellular models, in the caudate-putamen and in the tibialis muscle of clozapine-treated C57/BL/KsJ mice, Akt phosphorylation and Ped/Pea-15 protein levels were increased and PKC-ζ phosphorylation was decreased. Thus, in these experimental models, clozapine deranged Akt function and up-regulated Ped/Pea-15, thereby inhibiting insulin stimulation of PKC-ζ and of glucose uptake.
authors: Dipartimento di Neuroscienze, Sezione di Psichiatria, Laboratorio di Psichiatria Molecolare, University of Napoli Federico II, Napoli, Italy.
authors: Fabio
authors: F
authors: Panariello
authors: Giuseppe
authors: G
authors: Perruolo
authors: Angela
authors: A
authors: Cassese
authors: Ferdinando
authors: F
authors: Giacco
authors: Ginevra
authors: G
authors: Botta
authors: Alessia P M
authors: AP
authors: Barbagallo
authors: Giovanni
authors: G
authors: Muscettola
authors: Francesco
authors: F
authors: Beguinot
authors: Pietro
authors: P
authors: Formisano
authors: Andrea
authors: A
authors: de Bartolomeis
references: Nat Genet. 2004 Feb;36(2):131-7
references: 14745448
references: J Neurochem. 2007 Jul;102(1):153-69
references: 17472703
references: Psychiatr Serv. 1996 Dec;47(12):1356-63
references: 9117475
references: Biol Psychiatry. 1998 Oct 15;44(8):778-83
references: 9798083
references: Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E592-601
references: 19531639
references: Diabetologia. 2006 Dec;49(12):3058-66
references: 17021921
references: Lancet. 1989 Mar 4;1(8636):495
references: 2563862
references: EMBO J. 1998 Jul 15;17(14):3858-66
references: 9670003
references: Neuroscience. 2004;126(2):263-75
references: 15207344
references: CNS Neurol Disord Drug Targets. 2007 Aug;6(4):265-72
references: 17691983
references: J Endocrinol. 2009 Oct;203(1):1-18
references: 19389739
references: Mol Pharmacol. 2008 Dec;74(6):1678-86
references: 18801918
references: Can J Psychiatry. 1991 May;36(4):239-45
references: 1868416
references: Am J Med. 2001 Dec 15;111(9):716-23
references: 11747852
references: Lancet. 2004 Jun 19;363(9426):2063-72
references: 15207959
references: Clin Ther. 2004 Dec;26(12):1936-46
references: 15823759
references: J Biol Chem. 1993 Mar 15;268(8):5911-20
references: 8449955
references: South Med J. 2005 Jul;98(7):714-20
references: 16108240
references: Compr Psychiatry. 1996 Jan-Feb;37(1):68-73
references: 8770530
references: J Clin Psychiatry. 2007 Nov;68(11):1733-40
references: 18052567
references: Vital Health Stat 10. 1995 Dec;(193 Pt 1):1-260
references: 15789506
references: Curr Biol. 1994 Aug 1;4(8):702-8
references: 7953556
references: FEBS Lett. 2004 Feb 27;560(1-3):115-9
references: 14988008
references: Am J Psychiatry. 2004 Feb;161(2):361-3
references: 14754788
references: Schizophr Res. 2004 Dec 1;71(2-3):195-212
references: 15474892
references: Ann Pharmacother. 2007 Oct;41(10):1593-603
references: 17785613
references: Br J Psychiatry. 1997 Dec;171:502-8
references: 9519087
references: J Psychopharmacol. 2004 Sep;18(3):340-5
references: 15358977
references: Trends Biochem Sci. 2004 May;29(5):233-42
references: 15130559
references: Curr Protein Pept Sci. 2006 Apr;7(2):113-21
references: 16611137
references: Diabetes Care. 2003 May;26(5):1597-605
references: 12716824
references: Arch Neurol. 2004 May;61(5):641-4
references: 15148138
references: Biochim Biophys Acta. 2008 Jun;1783(6):994-1002
references: 18348871
references: J Biol Chem. 2003 May 2;278(18):15641-51
references: 12594228
references: Diabetes. 2001 Jun;50(6):1244-52
references: 11375323
references: Cell. 2005 Jul 29;122(2):261-73
references: 16051150
references: J Biol Chem. 2007 Mar 23;282(12):8648-57
references: 17227770
references: Metabolism. 2005 Dec;54(12):1687-93
references: 16311104
references: Diabetes. 2003 Apr;52(4):935-41
references: 12663464
references: Va Med Mon (1918). 1969 Jun;96(6):3340
references: 5802023
references: Mol Cell Biol. 2004 Jun;24(11):5005-15
references: 15143191
references: Trends Neurosci. 2007 Apr;30(4):142-9
references: 17324475
references: Br J Psychiatry. 2005 Jun;186:455-6
references: 15928352
references: J Clin Psychiatry. 2004 May;65(5):702-6
references: 15163259
references: Curr Opin Investig Drugs. 2008 Jan;9(1):37-46
references: 18183530
references: Mol Cell Biol. 2003 Jul;23(13):4511-21
references: 12808093
references: J Biol Chem. 2002 Jul 12;277(28):25020-5
references: 11976344
references: Life Sci. 2005 Mar 25;76(19):2269-73
references: 15733941
references: Neuropsychopharmacology. 2007 Apr;32(4):765-72
references: 16823387
references: Diabetologia. 2005 Feb;48(2):215-21
references: 15688206
references: Curr Opin Cell Biol. 2007 Aug;19(4):466-73
references: 17644329
references: Am J Psychiatry. 2003 Feb;160(2):284-9
references: 12562574
references: Brain Res. 2009 Nov 3;1296:35-45
references: 19679110
references: J Cell Physiol. 2003 Oct;197(1):122-30
references: 12942548
references: Diabetes. 2005 Mar;54(3):862-71
references: 15734866
references: Prog Neuropsychopharmacol Biol Psychiatry. 2002 Feb;26(2):277-85
references: 11817504
references: Prog Neuropsychopharmacol Biol Psychiatry. 1999 Jan;23(1):69-80
references: 10368857
references: J Mol Neurosci. 2005;27(1):43-64
references: 16055946
references: J Clin Psychiatry. 2007 Oct;68(10):e24
references: 17960957
references: Oncogene. 2008 Feb 14;27(8):1155-66
references: 17700518
references: Psychiatr Q. 2003 Fall;74(3):277-90
references: 12918602
references: Diabetes Care. 2004 Aug;27(8):2087-8; author reply 2089-90
references: 15277450
references: J Biol Chem. 2004 Mar 19;279(12):11137-45
references: 14711831
references: Am J Psychiatry. 2002 Apr;159(4):561-6
references: 11925293
references: Pharmacotherapy. 2002 Jul;22(7):841-52
references: 12126218