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Diabetologia

Erschienen in:

01.07.2004 | Article

WY-14643 and 9-cis-retinoic acid induce IRS-2/PI 3-kinase signalling pathway and increase glucose transport in human skeletal muscle cells: differential effect in myotubes from healthy subjects and Type 2 diabetic patients

verfasst von: K. Bouzakri, M. Roques, C. Debard, V. Berbe, J. Rieusset, M. Laville, H. Vidal

Erschienen in: Diabetologia | Ausgabe 7/2004

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Abstract

Aims/hypothesis

To determine the effects of peroxisome proliferator-activated receptor α (PPARα) and retinoid X receptor (RXR) agonists on insulin action, we investigated the effects of Wy-14643 and 9-cis-retinoic acid (9-cis-RA) on insulin signalling and glucose uptake in human myotubes.

Methods

Primary cultures of differentiated human skeletal muscle cells, established from healthy subjects and Type 2 diabetic patients, were used to study the effects of Wy-14643 and 9-cis-RA on the expression and activity of proteins involved in the insulin signalling cascade. Glucose transport was assessed by measuring the rate of [³H]2-deoxyglucose uptake.

Results

Wy-14643 and 9-cis-RA increased IRS-2 and p85α phosphatidylinositol 3-kinase (PI 3-kinase) mRNA and protein expression in myotubes from non-diabetic and Type 2 diabetic subjects. This resulted in increased insulin stimulation of protein kinase B phosphorylation and increased glucose uptake in cells from control subjects. Myotubes from diabetic patients displayed marked alterations in the stimulation by insulin of the IRS-1/PI 3-kinase pathway. These alterations were associated with blunted stimulation of glucose transport. Treatment with Wy-14643 and 9-cis-RA did not restore these defects but increased the basal rate of glucose uptake.

Conclusions/interpretation

These results demonstrate that PPARα and RXR agonists can directly affect insulin signalling in human muscle cells. They also indicate that an increase in the IRS-2/PI 3-kinase pathway does not overcome the impaired stimulation of the IRS-1-dependent pathway and does not restore insulin-stimulated glucose uptake in myotubes from Type 2 diabetic patients.

DeFronzo RA (1992) Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia 35:389–397CrossRefPubMed

Yki-Jarvinen H (1995) Role of insulin resistance in the pathogenesis of NIDDM. Diabetologia 38:1378–1388CrossRefPubMed

Bjornholm M, Kawano Y, Lehtihet M, Zierath JR (1997) Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 46:524–527CrossRefPubMed

Kim YB, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB (1999) Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Invest 104:733–741CrossRefPubMedPubMedCentral

Cusi K, Maezono K, Osman A et al. (2000) Insulin resistance differentially affects the PI3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 105:311–320CrossRefPubMedPubMedCentral

Krook A, Bjornholm M, Galuska D et al. (2000) Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49:284–292CrossRefPubMed

Pratipanawatr W, Pratipanawatr T, Cusi K et al. (2001) Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. Diabetes 50:2572–2578CrossRefPubMed

Kahn CR (1994) Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 43:1066–1084CrossRefPubMed

Shepherd PR, Withers DJ, Siddle K (1998) Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 333:471–490CrossRefPubMedPubMedCentral

10.

Zierath JR, Krook A, Wallberg-Henriksson H (2000) Insulin action and insulin resistance in human skeletal muscle. Diabetologia 43:821–835CrossRefPubMed

11.

Ducluzeau PH, Perretti N, Laville M et al. (2001) Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes. Diabetes 50:1134–1142CrossRefPubMed

12.

Lefai E, Roques M, Vega N, Laville M, Vidal H (2001) Expression of the splice variants of the p85alpha regulatory subunit of phosphoinositide 3-kinase in muscle and adipose tissue of healthy subjects and type 2 diabetic patients. Biochem J 15:117–126CrossRef

13.

Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL (1995) 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 95:2195–2204CrossRefPubMedPubMedCentral

14.

Terauchi Y, Tsuji Y, Satoh S et al. (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet 21:230–235CrossRefPubMed

15.

Miyake K, Ogawa W, Matsumoto M, Nakamura T, Sakaue H, Kasuga M (2002) Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver. J Clin Invest 110:1483–1491CrossRefPubMedPubMedCentral

16.

Olefsky JM (2000) Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists. J Clin Invest 106:467–472CrossRefPubMedPubMedCentral

17.

Rieusset J, Chambrier C, Bouzakri K et al. (2001) The expression of the p85alpha subunit of phosphatidylinositol 3-kinase is induced by activation of the peroxisome proliferator-activated receptor gamma in human adipocytes. Diabetologia 44:544–554CrossRefPubMed

18.

Rieusset J, Roques M, Bouzakri K, Chevillotte E, Vidal H (2001) Regulation of p85alpha phosphatidylinositol-3-kinase expression by peroxisome proliferator-activated receptors (PPARs) in human muscle cells. FEBS Lett 502:98–102CrossRefPubMed

19.

Guerre-Millo M, Gervois P, Raspe E et al. (2000) Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 275:16638–16642CrossRefPubMed

20.

Mukherjee R, Davies PJ, Crombie DL et al. (1997) Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. Nature 386:407–410CrossRefPubMed

21.

Henry RR, Abrams L, Nikoulina S, Ciaraldi TP (1995) Insulin action and glucose metabolism in nondiabetic control and NIDDM subjects. Comparison using human skeletal muscle cell cultures. Diabetes 44:936–946CrossRefPubMed

22.

Roques M, Vidal H (1999) A phosphatidylinositol 3-kinase/p70 ribosomal S6 protein kinase pathway is required for the regulation by insulin of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase gene expression in human muscle cells. J Biol Chem 274:34005–34010CrossRefPubMed

23.

Ciaraldi TP, Abrams L, Nikoulina S, Mudaliar S, Henry RR (1995) Glucose transport in cultured human skeletal muscle cells. Regulation by insulin and glucose in nondiabetic and non-insulin-dependent diabetes mellitus subjects. J Clin Invest 96:2820–2827CrossRefPubMedPubMedCentral

24.

Henry RR, Ciaraldi TP, Abrams-Carter L, Mudaliar S, Park KS, Nikoulina SE (1996) Glycogen synthase activity is reduced in cultured skeletal muscle cells of non-insulin-dependent diabetes mellitus subjects. Biochemical and molecular mechanisms. J Clin Invest 98:1231–1236CrossRefPubMedPubMedCentral

25.

Jackson S, Bagstaff SM, Lynn S, Yeaman SJ, Turnbull DM, Walker M (2000) Decreased insulin responsiveness of glucose uptake in cultured human skeletal muscle cells from insulin-resistant nondiabetic relatives of type 2 diabetic families. Diabetes 49:1169–1177CrossRefPubMed

26.

Nikoulina SE, Ciaraldi TP, Carter L, Mudaliar S, Park KS, Henry RR (2001) Impaired muscle glycogen synthase in type 2 diabetes is associated with diminished phosphatidylinositol 3-kinase activation. J Clin Endocrinol Metab 86:4307–4314CrossRefPubMed

27.

Gaster M, Petersen I, Hojlund K, Poulsen P, Beck-Nielsen H (2002) The diabetic phenotype is conserved in myotubes established from diabetic subjects: evidence for primary defects in glucose transport and glycogen synthase activity. Diabetes 51:921–927CrossRefPubMed

28.

Bouzakri K, Roques M, Gual P et al. (2003) Reduced activation of phosphatidylinositol-3-kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 52:1319–1325CrossRefPubMed

29.

Garvey WT, Maianu L, Hancock JA, Golichowski AM, Baron A (1992) Gene expression of GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM. Diabetes 41:465–475CrossRefPubMed

30.

Al-Khalili L, Chibalin AV, Kannisto K et al. (2003) Insulin action in cultured human skeletal muscle cells during differentiation: assessment of cell surface GLUT4 and GLUT1 content. Cell Mol Life Sci 60:991–998CrossRefPubMed

31.

Khan AH, Pessin JE (2002) Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia 45:1475–1483CrossRefPubMed

32.

Mothe I, Van Obberghen E (1996) Phosphorylation of insulin receptor substrate-1 on multiple serine residues, 612, 632, 662, and 731, modulates insulin action. J Biol Chem 271:11222–11227CrossRefPubMed

33.

McGarry JD (2002) Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51:7–18CrossRefPubMed

34.

Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 102:171–176CrossRef

35.

Kelley DE, Goodpaster BH, Storlien L (2002) Muscle triglyceride and insulin resistance. Annu Rev Nutr 22:325–346CrossRefPubMed

36.

Yu C, Chen Y, Cline GW et al. (2002) 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 277:50230–50236CrossRefPubMed

37.

Ye JM, Doyle PJ, Iglesias MA, Watson DG, Cooney GJ, Kraegen EW (2001) Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes 50:411–417CrossRefPubMed

38.

Muoio DM, Way JM, Tanner CJ et al. (2002) Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells. Diabetes 51:901–909CrossRefPubMed

39.

Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20:649–688PubMed

40.

Mukherjee R, Jow L, Noonan D, McDonnell DP (1994) Human and rat peroxisome proliferator-activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. J Steroid Biochem Mol Biol 51:157–166CrossRefPubMed

41.

Keller H, Devchand PR, Perroud M, Wahli W (1997) PPAR alpha structure-function relationships derived from species-specific differences in responsiveness to hypolipidemic agents. Biol Chem 378:651–655CrossRefPubMed

42.

Smith U, Gogg S, Johansson A, Olausson T, Rotter V, Svalstedt B (2001) Thiazolidinediones (PPARgamma agonists) but not PPARalpha agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes. FASEB J 15:215–220CrossRefPubMed

Titel: WY-14643 and 9-cis-retinoic acid induce IRS-2/PI 3-kinase signalling pathway and increase glucose transport in human skeletal muscle cells: differential effect in myotubes from healthy subjects and Type 2 diabetic patients
verfasst von: K. Bouzakri
M. Roques
C. Debard
V. Berbe
J. Rieusset
M. Laville
H. Vidal
Publikationsdatum: 01.07.2004
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 7/2004
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-004-1428-1

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