Home LiteratureArticle Details
PMID: 18633112 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Muscle-specific IRS-1 Ser->Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle.

Diabetes ·Vol. 57 ·No. 10 ·2008-10-00 ·Pages 2644-51

Morino K, Neschen S, Bilz S, Sono S, Tsirigotis D, Reznick RM, Moore I, Nagai Y, Samuel V, Sebastian D, White M, Philbrick W, Shulman GI

Abstract

Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes, yet the cellular mechanisms responsible for insulin resistance are poorly understood. In this study, we examine the role of serine phosphorylation of insulin receptor substrate (IRS)-1 in mediating fat-induced insulin resistance in skeletal muscle in vivo. To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated muscle-specific IRS-1 Ser(302), Ser(307), and Ser(612) mutated to alanine (Tg IRS-1 Ser-->Ala) and IRS-1 wild-type (Tg IRS-1 WT) transgenic mice and examined insulin signaling and insulin action in skeletal muscle in vivo. Tg IRS-1 Ser-->Ala mice were protected from fat-induced insulin resistance, as reflected by lower plasma glucose concentrations during a glucose tolerance test and increased insulin-stimulated muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. In contrast, Tg IRS-1 WT mice exhibited no improvement in glucose tolerance after high-fat feeding. Furthermore, Tg IRS-1 Ser-->Ala mice displayed a significant increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation in skeletal muscle in vivo compared with WT control littermates. These data demonstrate that serine phosphorylation of IRS-1 plays an important role in mediating fat-induced insulin resistance in skeletal muscle in vivo.

MeSH Terms
Alanine/genetics,metabolism Amino Acid Substitution Animals Blotting, Western Dietary Fats/administration & dosage,pharmacology Female Glucose Clamp Technique Glucose Tolerance Test Immunoprecipitation Insulin/metabolism Insulin Receptor Substrate Proteins/genetics,metabolism Insulin Resistance Male Mice Mice, Inbred C57BL Mice, Transgenic Muscle, Skeletal/drug effects,metabolism Phosphorylation/drug effects Serine/genetics,metabolism Triglycerides/metabolism
Chemicals
Dietary Fats Insulin Insulin Receptor Substrate Proteins Irs1 protein, mouse Triglycerides Serine Alanine
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Morino Katsutaro
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
Neschen Susanne
Bilz Stefan
Sono Saki
Tsirigotis Dimitrios
Reznick Richard M
Moore Irene
Nagai Yoshio
Samuel Varman
Sebastian David
White Morris
Philbrick William
Shulman Gerald I
References (39)
39 references, click to expand
  1. Protein kinase C-zeta phosphorylates insulin receptor substrate-1 and impairs its ability to activate phosphatidylinositol 3-kinase in response to insulin.
    J Biol Chem. 2001 Feb 2;276(5):3543-9 PMID: 11063744
  2. Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice.
    J Clin Invest. 1995 Jan;95(1):429-32 PMID: 7814644
  3. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy.
    N Engl J Med. 1990 Jan 25;322(4):223-8 PMID: 2403659
  4. Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse.
    J Clin Invest. 1997 Dec 15;100(12):3164-72 PMID: 9399964
  5. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents.
    J Clin Invest. 2005 Dec;115(12):3587-93 PMID: 16284649
  6. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action.
    J Biol Chem. 2002 Jan 11;277(2):1531-7 PMID: 11606564
  7. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.
    Science. 2001 Aug 31;293(5535):1673-7 PMID: 11533494
  8. Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice.
    Cell Metab. 2005 Jul;2(1):55-65 PMID: 16054099
  9. 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
  10. Temporally regulated overexpression of parathyroid hormone-related protein in the mammary gland reveals distinct fetal and pubertal phenotypes.
    J Endocrinol. 2001 Dec;171(3):403-16 PMID: 11739006
  11. Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells.
    Mol Cell Biol. 1997 Mar;17(3):1513-21 PMID: 9032279
  12. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance.
    Science. 1996 Feb 2;271(5249):665-8 PMID: 8571133
  13. Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway.
    J Biol Chem. 1999 Apr 2;274(14):9351-6 PMID: 10092613
  14. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes.
    Hepatology. 2003 Dec;38(6):1384-92 PMID: 14647049
  15. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents.
    Diabetes. 1999 Aug;48(8):1600-6 PMID: 10426379
  16. Phosphorylation of the insulin receptor substrate IRS-1 by casein kinase II.
    J Biol Chem. 1993 Aug 25;268(24):18157-66 PMID: 8349691
  17. Persistent activation of phosphatidylinositol 3-kinase causes insulin resistance due to accelerated insulin-induced insulin receptor substrate-1 degradation in 3T3-L1 adipocytes.
    Endocrinology. 2000 Jun;141(6):1930-5 PMID: 10830273
  18. Cellular mechanisms of insulin resistance.
    J Clin Invest. 2000 Jul;106(2):171-6 PMID: 10903330
  19. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.
    Diabetes. 1999 Jun;48(6):1270-4 PMID: 10342815
  20. PKC-theta knockout mice are protected from fat-induced insulin resistance.
    J Clin Invest. 2004 Sep;114(6):823-7 PMID: 15372106
  21. Mitochondrial dysfunction in the elderly: possible role in insulin resistance.
    Science. 2003 May 16;300(5622):1140-2 PMID: 12750520
  22. Protein kinase C-zeta-induced phosphorylation of Ser318 in insulin receptor substrate-1 (IRS-1) attenuates the interaction with the insulin receptor and the tyrosine phosphorylation of IRS-1.
    J Biol Chem. 2004 Jun 11;279(24):25157-63 PMID: 15069075
  23. Adrenalectomy reverses insulin resistance in muscle from obese (ob/ob) mice.
    Am J Physiol. 1984 Feb;246(2 Pt 1):E193-7 PMID: 6421176
  24. A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation.
    J Biol Chem. 1997 Nov 21;272(47):29911-8 PMID: 9368067
  25. Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation.
    Diabetes. 2001 Jan;50(1):24-31 PMID: 11147790
  26. Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways.
    J Clin Invest. 2001 Jan;107(2):181-9 PMID: 11160134
  27. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes.
    N Engl J Med. 2004 Feb 12;350(7):664-71 PMID: 14960743
  28. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.
    J Clin Invest. 1999 Jan;103(2):253-9 PMID: 9916137
  29. Role of Rho-kinase in regulation of insulin action and glucose homeostasis.
    Cell Metab. 2005 Aug;2(2):119-29 PMID: 16098829
  30. A central role for JNK in obesity and insulin resistance.
    Nature. 2002 Nov 21;420(6913):333-6 PMID: 12447443
  31. IRS-1 transgenic mice show increased epididymal fat mass and insulin resistance.
    Biochem Biophys Res Commun. 2007 Dec 14;364(2):301-7 PMID: 17950694
  32. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction.
    Diabetes. 2006 Dec;55 Suppl 2:S9-S15 PMID: 17130651
  33. Skeletal muscle triacylglycerol in the rat: methods for sampling and measurement, and studies of biological variability.
    J Lipid Res. 1980 Jan;21(1):139-44 PMID: 7354251
  34. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle.
    J Biol Chem. 2002 Dec 27;277(52):50230-6 PMID: 12006582
  35. Phosphorylation of insulin receptor substrate-1 on multiple serine residues, 612, 632, 662, and 731, modulates insulin action.
    J Biol Chem. 1996 May 10;271(19):11222-7 PMID: 8626671
  36. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.
    Nature. 2004 Sep 9;431(7005):200-5 PMID: 15306821
  37. Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302.
    J Biol Chem. 2004 Aug 20;279(34):35298-305 PMID: 15199052
  38. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease.
    J Biol Chem. 2004 Jul 30;279(31):32345-53 PMID: 15166226
  39. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study.
    Diabetologia. 1999 Jan;42(1):113-6 PMID: 10027589
Article Info
Journal
Diabetes
Abbr.
Diabetes
ISSN
1939-327X
DOI
10.2337/db06-0454
Published
2008-10-00
Epub
2008-00-15
Pages
2644-51
Language
English
Region
United States
NLM ID
0372763
PMCID
PMC2551673
Subset
IM
Grants
NIDDK NIH HHS · U24 DK076169 · United States
NIDDK NIH HHS · R01 DK-40936 · United States
Howard Hughes Medical Institute · United States
NIDDK NIH HHS · U24 DK059635 · United States
NIDDK NIH HHS · P30 DK-45735 · United States
NIDDK NIH HHS · R01 DK040936 · United States
NIDDK NIH HHS · P30 DK045735 · United States
NIDDK NIH HHS · U24 DK-76169 · United States
External Links
PubMed source DOI: 10.2337/db06-0454 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2