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PMID: 19007436 Published · epublish English Journal Article Research Support, Non-U.S. Gov't Review

The UPS in diabetes and obesity.

BMC biochemistry ·Vol. 9 Suppl 1 ·2008-10-21 ·Pages S6

Wing SS

Abstract

Type 2 diabetes is caused by defects in both insulin signaling and insulin secretion. Though the role of the ubiquitin proteasome system (UPS) in the pathogenesis of type 2 diabetes remains largely unexplored, the few examples present in the literature are interesting and suggest targets for drug development. Studies indicate that insulin resistance can be induced by stimulating the degradation of important molecules in the insulin signaling pathway, in particular the insulin receptor substrate proteins IRS1, IRS2 and the kinase AKT1 (Akt). In addition, a defect in insulin secretion could occur due to UPS-mediated degradation of IRS2 in the beta-cells of the pancreas. The UPS also appears to be involved in regulating lipid synthesis in adipocytes and lipid production by the liver and could influence the development of obesity. Other possible mechanisms for inducing defects in insulin signaling and secretion remain to be explored, including the role of ubiquitylation in insulin receptor internalization and trafficking. PUBLICATION HISTORY : Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

MeSH Terms
Animals Diabetes Mellitus, Type 2/metabolism Humans Insulin/metabolism Insulin Receptor Substrate Proteins/metabolism Insulin Resistance Models, Biological Obesity/metabolism Proteasome Endopeptidase Complex/metabolism Proto-Oncogene Proteins c-akt/metabolism Ubiquitin/metabolism
Chemicals
Insulin Insulin Receptor Substrate Proteins Ubiquitin Proto-Oncogene Proteins c-akt Proteasome Endopeptidase Complex
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Wing Simon S
Polypeptide Laboratory, Division of Endocrinology and Metabolism, Department of Medicine, McGill University and McGill University Health Centre, Montreal, Quebec, H3A 2B2, Canada. simon.wing@mcgill.ca
References (75)
75 references, click to expand
  1. Glucose-sensing mechanisms in pancreatic beta-cells.
    Philos Trans R Soc Lond B Biol Sci. 2005 Dec 29;360(1464):2211-25 PMID: 16321791
  2. The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation.
    Mol Cell. 2008 May 23;30(4):403-14 PMID: 18498745
  3. Regulation of insulin receptor kinase activity by endosomal processes: possible areas for therapeutic intervention.
    Curr Opin Investig Drugs. 2003 Apr;4(4):430-4 PMID: 12808882
  4. From mice to men: insights into the insulin resistance syndromes.
    Annu Rev Physiol. 2006;68:123-58 PMID: 16460269
  5. The emerging epidemic of obesity in developing countries.
    Int J Epidemiol. 2006 Feb;35(1):93-9 PMID: 16326822
  6. Ubiquitin ligase gene expression in healthy volunteers with 20-day bedrest.
    Muscle Nerve. 2006 Oct;34(4):463-9 PMID: 16868939
  7. Adipose tissue-derived factors: impact on health and disease.
    Endocr Rev. 2006 Dec;27(7):762-78 PMID: 17056740
  8. The degradation of apolipoprotein B100 is mediated by the ubiquitin-proteasome pathway and involves heat shock protein 70.
    J Biol Chem. 1997 Aug 15;272(33):20427-34 PMID: 9252351
  9. Inducible nitric-oxide synthase and NO donor induce insulin receptor substrate-1 degradation in skeletal muscle cells.
    J Biol Chem. 2005 Apr 8;280(14):14203-11 PMID: 15805118
  10. Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling.
    J Biol Chem. 1994 Feb 25;269(8):6051-7 PMID: 8119950
  11. Use of bismannose photolabel to elucidate insulin-regulated GLUT4 subcellular trafficking kinetics in rat adipose cells. Evidence that exocytosis is a critical site of hormone action.
    J Biol Chem. 1993 Aug 25;268(24):17820-9 PMID: 8349666
  12. Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in beta-cells.
    J Biol Chem. 2005 Jan 21;280(3):2282-93 PMID: 15537654
  13. Sepsis is associated with increased mRNAs of the ubiquitin-proteasome proteolytic pathway in human skeletal muscle.
    J Clin Invest. 1997 Jan 15;99(2):163-8 PMID: 9005983
  14. Insulin receptor substrate proteins and diabetes.
    Arch Pharm Res. 2004 Apr;27(4):361-70 PMID: 15180298
  15. Global and societal implications of the diabetes epidemic.
    Nature. 2001 Dec 13;414(6865):782-7 PMID: 11742409
  16. Insulin signalling and the regulation of glucose and lipid metabolism.
    Nature. 2001 Dec 13;414(6865):799-806 PMID: 11742412
  17. Homozygous nonsense mutation in the insulin receptor gene in infant with leprechaunism.
    Lancet. 1993 Jul 31;342(8866):277-8 PMID: 8101305
  18. Molecular cloning and characterization of an insulin-regulatable glucose transporter.
    Nature. 1989 Mar 2;338(6210):83-7 PMID: 2645527
  19. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins.
    Annu Rev Cell Dev Biol. 2003;19:141-72 PMID: 14570567
  20. C57BL/6 mice fed high fat diets as models for diabetes-accelerated atherosclerosis.
    Atherosclerosis. 1998 Jan;136(1):17-24 PMID: 9544727
  21. Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy.
    J Physiol. 2006 Nov 1;576(Pt 3):923-33 PMID: 16916907
  22. SUMO wrestling with type 1 diabetes.
    J Mol Med (Berl). 2005 Jul;83(7):504-13 PMID: 15806321
  23. A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus.
    J Biol Chem. 2004 Jun 25;279(26):27233-8 PMID: 15123604
  24. Tyrosine-specific protein kinase activity is associated with the purified insulin receptor.
    Proc Natl Acad Sci U S A. 1983 Apr;80(8):2137-41 PMID: 6188161
  25. Essential role of ubiquitin-proteasome system in normal regulation of insulin secretion.
    J Biol Chem. 2006 May 12;281(19):13015-13020 PMID: 16543239
  26. Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects.
    J Clin Invest. 1995 May;95(5):2195-204 PMID: 7537758
  27. Development and application of rodent models for type 2 diabetes.
    Diabetes Obes Metab. 2005 Jul;7(4):307-17 PMID: 15955116
  28. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.
    Cell. 1999 Mar 19;96(6):857-68 PMID: 10102273
  29. Tumor necrosis factor-{alpha} decreases Akt protein levels in 3T3-L1 adipocytes via the caspase-dependent ubiquitination of Akt.
    Endocrinology. 2005 Jun;146(6):2726-35 PMID: 15746249
  30. Nuclear factor-kappaB regulates beta-cell death: a critical role for A20 in beta-cell protection.
    Diabetes. 2006 Sep;55(9):2491-501 PMID: 16936197
  31. Tissue-specific roles of IRS proteins in insulin signaling and glucose transport.
    Trends Endocrinol Metab. 2006 Mar;17(2):72-8 PMID: 16458527
  32. Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy.
    Diabetes. 2007 Apr;56(4):930-9 PMID: 17395740
  33. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase.
    Science. 1999 Oct 8;286(5438):309-12 PMID: 10514377
  34. Regulation by insulin of amino acid release and protein turnover in the perfused rat hemicorpus.
    J Biol Chem. 1977 Feb 25;252(4):1476-83 PMID: 838725
  35. Fatty acid metabolism in adipose tissue, muscle and liver in health and disease.
    Essays Biochem. 2006;42:89-103 PMID: 17144882
  36. The regulation of body and skeletal muscle protein metabolism by hormones and amino acids.
    J Nutr. 2006 Jan;136(1 Suppl):212S-7S PMID: 16365085
  37. Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation.
    EMBO J. 1992 Sep;11(9):3469-79 PMID: 1380456
  38. The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families.
    Genes Dev. 1998 Dec 15;12(24):3872-81 PMID: 9869640
  39. Impairment of the ubiquitin-proteasome pathway is a downstream endoplasmic reticulum stress response induced by extracellular human islet amyloid polypeptide and contributes to pancreatic beta-cell apoptosis.
    Diabetes. 2007 Sep;56(9):2284-94 PMID: 17563070
  40. Increased expression of proteasome subunits in skeletal muscle of cancer patients with weight loss.
    Int J Biochem Cell Biol. 2005 Oct;37(10):2196-206 PMID: 16125116
  41. Casitas b-lineage lymphoma-deficient mice are protected against high-fat diet-induced obesity and insulin resistance.
    Diabetes. 2006 Mar;55(3):708-15 PMID: 16505234
  42. TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism.
    Science. 2006 Jun 23;312(5781):1763-6 PMID: 16794074
  43. Role of ubiquitin-proteasome degradation pathway in biogenesis efficiency of {beta}-cell ATP-sensitive potassium channels.
    Am J Physiol Cell Physiol. 2005 Nov;289(5):C1351-9 PMID: 15987767
  44. Insulin receptor substrate-1-mediated enhancement of growth hormone-induced mitogen-activated protein kinase activation.
    Endocrinology. 2000 Sep;141(9):3328-36 PMID: 10965905
  45. The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor.
    Mol Cell Biol. 2003 May;23(9):3363-72 PMID: 12697834
  46. Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2.
    Nature. 2007 Sep 20;449(7160):366-9 PMID: 17805301
  47. Leptin receptor missense mutation in the fatty Zucker rat.
    Nat Genet. 1996 May;13(1):18-9 PMID: 8673096
  48. Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity.
    J Clin Invest. 1986 Jul;78(1):249-58 PMID: 3522628
  49. Critical nodes in signalling pathways: insights into insulin action.
    Nat Rev Mol Cell Biol. 2006 Feb;7(2):85-96 PMID: 16493415
  50. Overproduction of intestinal lipoprotein containing apolipoprotein B-48 in Psammomys obesus: impact of dietary n-3 fatty acids.
    Diabetologia. 2006 Aug;49(8):1937-45 PMID: 16788801
  51. Ligand-induced polyubiquitination of receptor tyrosine kinases.
    Biochem Biophys Res Commun. 1995 Aug 4;213(1):32-9 PMID: 7639752
  52. Insulin stimulates mitogen-activated protein kinase by a Ras-independent pathway in 3T3-L1 adipocytes.
    J Biol Chem. 1996 Nov 29;271(48):30625-30 PMID: 8940037
  53. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2.
    J Biol Chem. 2002 Nov 1;277(44):42394-8 PMID: 12228220
  54. A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling.
    EMBO J. 2002 Feb 1;21(3):303-13 PMID: 11823423
  55. Regulation of fatty acid synthesis.
    Fed Proc. 1979 Nov;38(12):2617-21 PMID: 40828
  56. Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein.
    Mol Cell. 2001 Nov;8(5):995-1004 PMID: 11741535
  57. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle.
    Nat Med. 2001 Oct;7(10):1138-43 PMID: 11590438
  58. Inflammation and insulin resistance.
    J Clin Invest. 2006 Jul;116(7):1793-801 PMID: 16823477
  59. The function of GRB2 in linking the insulin receptor to Ras signaling pathways.
    Science. 1993 Jun 25;260(5116):1953-5 PMID: 8316835
  60. Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion.
    Nat Genet. 1992 Apr;1(1):11-5 PMID: 1301992
  61. Escape from Cbl-mediated downregulation: a recurrent theme for oncogenic deregulation of receptor tyrosine kinases.
    Cancer Cell. 2003 Jun;3(6):519-23 PMID: 12842080
  62. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2.
    Mol Cell. 2003 Jun;11(6):1457-66 PMID: 12820960
  63. Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation.
    Oncogene. 2001 Jan 11;20(2):252-9 PMID: 11313952
  64. Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities.
    Nature. 2007 Apr 19;446(7138):876-81 PMID: 17443180
  65. Identification of ubiquitin ligases required for skeletal muscle atrophy.
    Science. 2001 Nov 23;294(5547):1704-8 PMID: 11679633
  66. The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling.
    EMBO J. 1993 May;12(5):1929-36 PMID: 8491186
  67. Single gene obesities in rodents: possible relevance to human obesity.
    J Nutr. 1997 Sep;127(9):1908S PMID: 9278580
  68. Microarray profiling of human skeletal muscle reveals that insulin regulates approximately 800 genes during a hyperinsulinemic clamp.
    J Biol Chem. 2003 May 16;278(20):18063-8 PMID: 12621037
  69. Insulin inhibition of the proteasome is dependent on degradation of insulin by insulin-degrading enzyme.
    J Endocrinol. 2003 Jun;177(3):399-405 PMID: 12773120
  70. Diagnosis and classification of diabetes mellitus.
    Diabetes Care. 2006 Jan;29 Suppl 1:S43-8 PMID: 16373932
  71. Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway.
    Diabetes. 1999 Jul;48(7):1359-64 PMID: 10389839
  72. Minireview: implication of mitochondria in insulin secretion and action.
    Endocrinology. 2006 Jun;147(6):2643-9 PMID: 16556766
  73. Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2.
    J Biol Chem. 2001 Oct 26;276(43):40362-7 PMID: 11546773
  74. Tumour induction by activated abl involves tyrosine phosphorylation of the product of the cbl oncogene.
    EMBO J. 1994 Oct 3;13(19):4515-23 PMID: 7925293
  75. Evidence for a role of the ubiquitin-proteasome pathway in pancreatic islets.
    Diabetes. 2006 May;55(5):1223-31 PMID: 16644676
Article Info
Journal
BMC biochemistry
Abbr.
BMC Biochem
ISSN
1471-2091
DOI
10.1186/1471-2091-9-S1-S6
Email
simon.wing@mcgill.ca
Published
2008-10-21
Epub
2008-00-21
Pages
S6
Language
English
Region
England
NLM ID
101084098
PMCID
PMC2582800
Subset
IM
External Links
PubMed source DOI: 10.1186/1471-2091-9-S1-S6 PMC Full Text View journal details
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