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Diabetologia
Erschienen in: Diabetologia 4/2006

01.04.2006 | Article

Nutritional upregulation of p85α expression is an early molecular manifestation of insulin resistance

verfasst von: M.-A. Cornier, D. H. Bessesen, I. Gurevich, J. W. Leitner, B. Draznin

Erschienen in: Diabetologia | Ausgabe 4/2006

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Abstract

Aims/hypothesis

We sought to define early molecular alterations associated with nutritionally induced insulin resistance in humans.

Methods

Insulin sensitivity was assessed using a hyperinsulinaemic–euglycaemic clamp in eight healthy women while on an isocaloric diet and after 3 days of overfeeding (50% above eucaloric diet). Expression of phosphatidylinositol (PI) 3-kinase subunits p85α and p110 was assessed and measurements were made of IRS-1-associated PI 3-kinase activity, tyrosine and serine phosphorylation of IRS-1, and serine and threonine phosphorylation of p70S6 kinase. Measurements were made in skeletal muscle biopsies obtained before and after overfeeding.

Results

Three days of overfeeding resulted in a reduction of insulin sensitivity accompanied by: (1) increased expression of skeletal muscle p85α; (2) an alteration in the ratio of p85α to p110; (3) a decrease in the amount of IRS-1-associated p110; and (4) a decrease in PI 3-kinase activity. Increases in expression of p85α and in the p85α:p110 ratio demonstrated a highly significant inverse correlation with insulin sensitivity, and changes in PI 3-kinase activity correlated with changes in insulin sensitivity. Tyrosine and serine phosphorylation of IRS-1 and serine and threonine phosphorylation of p70S6 kinase were unaffected by 3 days of overfeeding.

Conclusions/interpretation

We identified a novel mechanism of nutritionally induced insulin resistance in healthy women of normal weight. We conclude that increased expression of p85α may be one of the earliest molecular alterations in the mechanism of the insulin resistance associated with overfeeding.
Literatur
1.
Reaven GM (1998) Role of insulin resistance in human disease. Diabetes 37:1595–1607CrossRef
2.
3.
Shulman GI (1999) Cellular mechanisms of insulin resistance in humans. Am J Cardiol 84:3J–10JCrossRefPubMed
4.
Qiao L, Goldberg JL, Russell JC, Sun XJ (1999) Identification of enhanced serine kinase activity in insulin resistance. J Biol Chem 274:10625–10632CrossRefPubMed
5.
6.
7.
Um SH, Frigerio F, Watanabe M et al (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205CrossRefPubMed
8.
Patti M-E, Kahn BB (2004) Nutrient sensor links obesity with diabetes risk. Nat Med 10:1049–1050CrossRefPubMed
9.
Ueki K, Fruman DA, Brachmann SM, Tseng YH, Cantley LC, Kahn CR (2002) Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol Cell Biol 22:965–977PubMedCrossRef
10.
Shepherd PR, Withers DJ, Siddle K (1998) Phosphoinositide 3-kinase: the key switch mechanism in insulin signaling. Biochem J 333:471–490PubMed
11.
Terauchi Y, Tsuji Y, Satoh S et al (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85α subunit of phosphoinositide 3-kinase. Nat Genet 21:230–235CrossRefPubMed
12.
Ueki K, Algenstaedt P, Mauvais-Jarvis F, Kahn CR (2000) Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85α regulatory subunit. Mol Cell Biol 20:8035–8046CrossRefPubMed
13.
Mauvais-Jarvis F, Ueki K, Fruman DA et al (2002) Reduced expression of the murine p85α subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J Clin Invest 109:141–149CrossRefPubMed
14.
Ueki K, Fruman DA, Uballe CM et al (2003) Positive and negative roles of p85α and p85β regulatory subunits of phosphoinositide 3-kinase in insulin signaling. J Biol Chem 278:48453–48466CrossRefPubMed
15.
Barbour LA, Shao J, Qiao L et al (2004) Human placental growth hormone increases expression of p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle. Endocrinology 145:1144–1150CrossRefPubMed
16.
Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM (2005) Increased p85/55/50 expression and decreased phosphatidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54:2351–2359PubMedCrossRef
17.
Jensen MD, Heiling VJ (1991) Heated hand vein blood is satisfactory for measurements during free fatty acid kinetic studies. Metabolism 40:406–409CrossRefPubMed
18.
Kadish AH, Hall DA (1965) A new method for the continuous monitoring of blood glucose by measurement of dissolved oxygen. Clin Chem 11:869–875PubMed
19.
Tremblay F, Krebs M, Dombrowski L et al (2005) Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 54:2674–2684PubMedCrossRef
20.
Raught B, Gingras AC, Sonenberg N (2001) The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA 98:7037–7044CrossRefPubMed
21.
Rohde J, Heitman J, Cardenas ME (2001) The TOR kinases link nutrient sensing to cell growth. J Biol Chem 276:9583–9586CrossRefPubMed
22.
Khamzina L, Veilleux A, Bergeron S, Marette A (2005) Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 146:1473–1481CrossRefPubMed
23.
Trembley F, Gagnon A, Veilleux A, Sorisky A, Marette A (2005) Activation of the mammalian target of rapamycin pathway acutely inhibits insulin signaling to Akt and glucose transport in 3T3-L1 and human adipocytes. Endocrinology 146:1328–1337CrossRefPubMed
24.
Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM (1998) RAFT1 phosphorylation of the translational regulators p70S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 95:1432–1437PubMedCrossRef
25.
Hara K, Yonezawa K, Kozlowski MT et al (1997) Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem 272:26457–26463CrossRefPubMed
26.
Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K (1999) Immunopurified mammalian target of rapamycin phosphorylates and activates p70S6 kinase α in vitro. J Biol Chem 274:34493–34498CrossRefPubMed
27.
Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR (1999) Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 344:427–431CrossRefPubMed
28.
Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC Jr (1998) Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci USA 95:7772–7777CrossRefPubMed
29.
Hinault C, Mothe-Satney I, Gautier N, Lawrence JC Jr, Van Obberghen E (2004) Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from db/db mice. FASEB J 18:1894–1896PubMed
30.
Pham P-TT, Heydrick SJ, Fox HL, Kimball SR, Jefferson LS Jr, Lynch CJ (2000) Assessment of cell-signaling pathways in the regulation of mammalian target of rapamycin (mTOR) by amino acids in rat adipocytes. J Cell Biochem 79:427–441CrossRefPubMed
31.
Giorgino F, Pedrini MT, Matera L, Smith RJ (1997) Specific increase in p85α expression in response to dexamethasone is associated with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells. J Biol Chem 272:7455–7463CrossRefPubMed
32.
Ueki K, Yballe CM, Brachmann SM et al (2002) Increased insulin sensitivity in mice lacking p85β subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 99:419–424CrossRefPubMed
33.
Lamia KA, Peroni OD, Kim Y-B, Rameh LE, Kahn BB, Cantley LC (2004) Increased insulin sensitivity and reduced adiposity in phosphatidylinositol 5-phosphate 4-kinase β−/− mice. Mol Cell Biol 24:5080–5087CrossRefPubMed
34.
Luo J, Field SJ, Lee JY, Engelman JA, Cantley LC (2005) The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. J Cell Biol 170:455–464CrossRefPubMed
35.
Kirwan J, Varastehpour A, Jing M et al (2004) Reversal of insulin resistance post-partum is linked to enhanced skeletal muscle insulin signaling. J Clin Endocrinol Metab 89:4678–4684CrossRefPubMed
Metadaten
Titel
Nutritional upregulation of p85α expression is an early molecular manifestation of insulin resistance
verfasst von
M.-A. Cornier
D. H. Bessesen
I. Gurevich
J. W. Leitner
B. Draznin
Publikationsdatum
01.04.2006
Verlag
Springer-Verlag
Erschienen in
Diabetologia / Ausgabe 4/2006
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-006-0148-0

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