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01.09.2010 | Article

The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion

verfasst von: P. Lebrun, E. Cognard, P. Gontard, R. Bellon-Paul, C. Filloux, M. F. Berthault, C. Magnan, J. Ruberte, M. Luppo, A. Pujol, N. Pachera, A. Herchuelz, F. Bosch, E. Van Obberghen

Erschienen in: Diabetologia | Ausgabe 9/2010

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Abstract

Aims/hypothesis

Suppressor of cytokine signalling (SOCS) proteins are powerful inhibitors of pathways involved in survival and function of pancreatic beta cells. Whereas SOCS1 and SOCS3 have been involved in immune and inflammatory processes, respectively, in beta cells, nothing is known about SOCS2 implication in the pancreas.

Methods

Transgenic (tg) mice were generated that constitutively produced SOCS2 in beta cells (βSOCS2) to define whether this protein is implicated in beta cell functioning and/or survival.

Results

Constitutive production of SOCS2 in beta cells leads to hyperglycaemia and glucose intolerance. This phenotype is not a consequence of decreased beta cell mass or inhibition of insulin synthesis. However, insulin secretion to various secretagogues is profoundly altered in intact animals and isolated islets. Interestingly, constitutive SOCS2 production dampens the rise in cytosolic free calcium concentration induced by glucose, while glucose metabolism is unchanged. Moreover, tg islets have a depletion in endoplasmic reticulum Ca²⁺ stores, suggesting that SOCS2 interferes with calcium fluxes. Finally, in βSOCS2 mice proinsulin maturation is impaired, leading to an altered structure of insulin secretory granules and augmented levels of proinsulin. The latter is likely to be due to decreased production of prohormone convertase 1 (PC1/3), which plays a key role in proinsulin cleavage.

Conclusions/Interpretations

SOCS2 was shown to be a potent regulator of proinsulin processing and insulin secretion in beta cells. While its constitutive production is insufficient to induce overt diabetes in this mouse model, it causes glucose intolerance. Thus, increased SOCS2 production could be an important event predisposing to beta cell failure.

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Feng DD, Zhao YF, Luo ZQ, Keating DJ, Chen C (2008) Linoleic acid induces Ca²⁺-induced inactivation of voltage-dependent Ca²⁺ currents in rat pancreatic beta-cells. J Endocrinol 196:377–384CrossRefPubMed

Ling Z, Kiekens R, Mahler T et al (1996) Effects of chronically elevated glucose levels on the functional properties of rat pancreatic beta-cells. Diabetes 45:1774–1782CrossRefPubMed

Maedler K, Sergeev P, Ris F et al (2002) Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 110:851–860PubMed

Zhao YF, Feng DD, Hernandez M, Chen C (2007) 3T3-L1 adipocytes induce dysfunction of MIN6 insulin-secreting cells via multiple pathways mediated by secretory factors in a co-culture system. Endocrine 31:52–60CrossRefPubMed

Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7:454–465CrossRefPubMed

Emanuelli B, Peraldi P, Filloux C et al (2001) SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 276:47944–47949PubMed

Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, van Obberghen E (2000) SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 275:15985–15991CrossRefPubMed

Greenhalgh CJ, Rico-Bautista E, Lorentzon M et al (2005) SOCS2 negatively regulates growth hormone action in vitro and in vivo. J Clin Invest 115:397–406PubMed

Lindberg K, Ronn SG, Tornehave D et al (2005) Regulation of pancreatic beta-cell mass and proliferation by SOCS-3. J Mol Endocrinol 35:231–243CrossRefPubMed

10.

Ueki K, Kondo T, Kahn CR (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24:5434–5446CrossRefPubMed

11.

Chong MM, Thomas HE, Kay TW (2001) gamma-Interferon signaling in pancreatic beta-cells is persistent but can be terminated by overexpression of suppressor of cytokine signaling-1. Diabetes 50:2744–2751CrossRefPubMed

12.

Chong MM, Thomas HE, Kay TW (2002) Suppressor of cytokine signaling-1 regulates the sensitivity of pancreatic beta cells to tumor necrosis factor. J Biol Chem 277:27945–27952CrossRefPubMed

13.

Karlsen AE, Ronn SG, Lindberg K et al (2001) Suppressor of cytokine signaling 3 (SOCS-3) protects beta-cells against interleukin-1beta- and interferon-gamma-mediated toxicity. Proc Natl Acad Sci USA 98:12191–12196CrossRefPubMed

14.

Emanuelli B, Glondu M, Filloux C, Peraldi P, van Obberghen E (2004) The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells. Diabetes 53(Suppl 3):S97–S103CrossRefPubMed

15.

Bruun C, Heding PE, Ronn SG et al (2009) Suppressor of cytokine signalling-3 inhibits tumor necrosis factor-alpha induced apoptosis and signalling in beta cells. Mol Cell Endocrinol 311:32–38CrossRefPubMed

16.

Jacobsen ML, Ronn SG, Bruun C et al (2009) IL-1beta-induced chemokine and Fas expression are inhibited by suppressor of cytokine signalling-3 in insulin-producing cells. Diabetologia 52:281–288CrossRefPubMed

17.

Ronn SG, Hansen JA, Lindberg K, Karlsen AE, Billestrup N (2002) The effect of suppressor of cytokine signaling 3 on GH signaling in beta-cells. Mol Endocrinol 16:2124–2134CrossRefPubMed

18.

Lorentzon M, Greenhalgh CJ, Mohan S, Alexander WS, Ohlsson C (2005) Reduced bone mineral density in SOCS-2-deficient mice. Pediatr Res 57:223–226CrossRefPubMed

19.

Michaylira CZ, Simmons JG, Ramocki NM et al (2006) Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo. Am J Physiol Gastrointest Liver Physiol 291:G472–G481CrossRefPubMed

20.

Goldshmit Y, Greenhalgh CJ, Turnley AM (2004) Suppressor of cytokine signalling-2 and epidermal growth factor regulate neurite outgrowth of cortical neurons. Eur J Neurosci 20:2260–2266CrossRefPubMed

21.

Ransome MI, Goldshmit Y, Bartlett PF, Waters MJ, Turnley AM (2004) Comparative analysis of CNS populations in knockout mice with altered growth hormone responsiveness. Eur J Neurosci 19:2069–2079CrossRefPubMed

22.

Turnley AM, Faux CH, Rietze RL, Coonan JR, Bartlett PF (2002) Suppressor of cytokine signaling 2 regulates neuronal differentiation by inhibiting growth hormone signaling. Nat Neurosci 5:1155–1162CrossRefPubMed

23.

Machado FS, Johndrow JE, Esper L et al (2006) Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nat Med 12:330–334CrossRefPubMed

24.

Schultheis B, Carapeti-Marootian M, Hochhaus A, Weisser A, Goldman JM, Melo JV (2002) Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia: possible inadequacy of a negative feedback mechanism. Blood 99:1766–1775CrossRefPubMed

25.

Sutherland KD, Lindeman GJ, Choong DY et al (2004) Differential hypermethylation of SOCS genes in ovarian and breast carcinomas. Oncogene 23:7726–7733CrossRefPubMed

26.

Wikman H, Kettunen E, Seppanen JK et al (2002) Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array. Oncogene 21:5804–5813CrossRefPubMed

27.

Kato H, Nomura K, Osabe D et al (2006) Association of single-nucleotide polymorphisms in the suppressor of cytokine signaling 2 (SOCS2) gene with type 2 diabetes in the Japanese. Genomics 87:446–458CrossRefPubMed

28.

Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885CrossRefPubMed

29.

Zeggini E, Weedon MN, Lindgren CM et al (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341CrossRefPubMed

30.

Thorens B, Guillam MT, Beermann F, Burcelin R, Jaquet M (2000) Transgenic reexpression of GLUT1 or GLUT2 in pancreatic beta cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion. J Biol Chem 275:23751–23758CrossRefPubMed

31.

Nicholson SE, Willson TA, Farley A et al (1999) Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. Embo J 18:375–385CrossRefPubMed

32.

Brissova M, Shiota M, Nicholson WE et al (2002) Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion. J Biol Chem 277:11225–11232CrossRefPubMed

33.

Kulkarni RN, Wang ZL, Wang RM et al (1997) Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. J Clin Invest 100:2729–2736CrossRefPubMed

34.

Van Eylen F, Lebeau C, Albuquerque-Silva J, Herchuelz A (1998) Contribution of Na/Ca exchange to Ca²⁺ outflow and entry in the rat pancreatic beta-cell: studies with antisense oligonucleotides. Diabetes 47:1873–1880CrossRefPubMed

35.

Hutton JC, Sener A, Malaisse WJ (1979) The stimulus–secretion coupling 4-methyl-2-oxopentanoate-induced insulin release. Biochem J 184:303–311PubMed

36.

Malaisse WJ, Garcia-Morales P, Gomis R et al (1986) The coupling of metabolic to secretory events in pancreatic islets: inhibition by 2-cyclohexene-1-one of the secretory response to cyclic AMP and cytochalasin B. Biochem Pharmacol 35:3709–3717CrossRefPubMed

37.

Malaisse WJ, Rasschaert J, Zahner D, Sener A (1988) Hexose metabolism in pancreatic islets: the Pasteur effect. Diabetes Res 7:53–58PubMed

38.

Paris M, Bernard-Kargar C, Berthault MF, Bouwens L, Ktorza A (2003) Specific and combined effects of insulin and glucose on functional pancreatic beta-cell mass in vivo in adult rats. Endocrinology 144:2717–2727CrossRefPubMed

39.

Nielsen JH, Galsgaard ED, Moldrup A et al (2001) Regulation of beta-cell mass by hormones and growth factors. Diabetes 50(Suppl 1):S25–S29CrossRefPubMed

40.

Metcalf D, Greenhalgh CJ, Viney E et al (2000) Gigantism in mice lacking suppressor of cytokine signalling-2. Nature 405:1069–1073CrossRefPubMed

41.

Greenhalgh CJ, Metcalf D, Thaus AL et al (2002) Biological evidence that SOCS-2 can act either as an enhancer or suppressor of growth hormone signaling. J Biol Chem 277:40181–40184CrossRefPubMed

42.

Okada T, Liew CW, Hu J et al (2007) Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance. Proc Natl Acad Sci USA 104:8977–8982CrossRefPubMed

43.

Henquin JC (2009) Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia 52:739–751CrossRefPubMed

44.

Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29:42–61CrossRefPubMed

45.

Rutter GA, Tsuboi T, Ravier MA (2006) Ca²⁺ microdomains and the control of insulin secretion. Cell Calcium 40:539–551CrossRefPubMed

46.

Guest PC, Bailyes EM, Hutton JC (1997) Endoplasmic reticulum Ca²⁺ is important for the proteolytic processing and intracellular transport of proinsulin in the pancreatic beta-cell. Biochem J 323(Pt 2):445–450PubMed

47.

Hoppa MB, Collins S, Ramracheya R et al (2009) Chronic palmitate exposure inhibits insulin secretion by dissociation of Ca(2+) channels from secretory granules. Cell Metab 10:455–465CrossRefPubMed

48.

Assmann A, Hinault C, Kulkarni RN (2009) Growth factor control of pancreatic islet regeneration and function. Pediatr Diabetes 10:14–32CrossRefPubMed

49.

Zhu X, Orci L, Carroll R, Norrbom C, Ravazzola M, Steiner DF (2002) Severe block in processing of proinsulin to insulin accompanied by elevation of des-64, 65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Proc Natl Acad Sci USA 99:10299–10304CrossRefPubMed

50.

Zhu X, Zhou A, Dey A et al (2002) Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci USA 99:10293–10298CrossRefPubMed

51.

Li QL, Jansen E, Friedman TC (1999) Regulation of prohormone convertase 1 (PC1) by gp130-related cytokines. Mol Cell Endocrinol 158:143–152CrossRefPubMed

52.

Kirchhoff K, Machicao F, Haupt A et al (2008) Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 51:597–601CrossRefPubMed

53.

Stancakova A, Kuulasmaa T, Paananen J et al (2009) Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnish men. Diabetes 58:2129–2136CrossRefPubMed

Titel: The suppressor of cytokine signalling 2 (SOCS2) is a key repressor of insulin secretion
verfasst von: P. Lebrun
E. Cognard
P. Gontard
R. Bellon-Paul
C. Filloux
M. F. Berthault
C. Magnan
J. Ruberte
M. Luppo
A. Pujol
N. Pachera
A. Herchuelz
F. Bosch
E. Van Obberghen
Publikationsdatum: 01.09.2010
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 9/2010
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-010-1786-9

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