Startseite Locally produced xenin and the neurotensinergic system in pancreatic islet function and β-cell survival
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Locally produced xenin and the neurotensinergic system in pancreatic islet function and β-cell survival

  • Dawood Khan , Srividya Vasu , R. Charlotte Moffett , Victor A. Gault , Peter R. Flatt und Nigel Irwin EMAIL logo
Veröffentlicht/Copyright: 19. August 2017
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 399 Heft 1

Abstract

Modulation of neuropeptide receptors is important for pancreatic β-cell function. Here, islet distribution and effects of the neurotensin (NT) receptor modulators, xenin and NT, was examined. Xenin, but not NT, significantly improved glucose disposal and insulin secretion, in mice. However, both peptides stimulated insulin secretion from rodent β-cells at 5.6 mm glucose, with xenin having similar insulinotropic actions at 16.7 mm glucose. In contrast, NT inhibited glucose-induced insulin secretion. Similar observations were made in human 1.1B4 β-cells and isolated mouse islets. Interestingly, similar xenin levels were recorded in pancreatic and small intestinal tissue. Arginine and glucose stimulated xenin release from islets. Streptozotocin treatment decreased and hydrocortisone treatment increased β-cell mass in mice. Xenin co-localisation with glucagon was increased by streptozotocin, but unaltered in hydrocortisone mice. This corresponded to elevated plasma xenin levels in streptozotocin mice. In addition, co-localisation of xenin with insulin was increased by hydrocortisone, and decreased by streptozotocin. Further in vitro investigations revealed that xenin and NT protected β-cells against streptozotocin-induced cytotoxicity. Xenin augmented rodent and human β-cell proliferation, whereas NT displayed proliferative actions only in human β-cells. These data highlight the involvement of NT signalling pathways for the possible modulation of β-cell function.

Keywords: apoptosis; β-cell; COPA; diabetes; islets; neurotensin (NT); neurotensin receptor (NTSR); xenin

Acknowledgements

This study was supported by an EFSD/Boehringer Ingelheim grant, donation from the SAAD Trading and Contracting Company and award of an Ulster University Vice Chancellor’s research scholarship (Grant/Award Number: PhD scholarship to DK).

  1. Conflict of interest statement: The authors have no conflict of interest to declare.

References

Ahrén, B., Wierup, N., and Sundler, F. (2006). Neuropeptides and the regulation of islet function. Diabetes 55, S98–S107.10.2337/db06-S013Suche in Google Scholar

Anlauf, M., Weihe, E., Hartschuh, W., Hamscher, G., and Feurle, G.E. (2000). Localization of xenin-immunoreactive cells in the duodenal mucosa of humans and various mammals. J. Histochem. Cytochemist. 48, 1617–1626.10.1177/002215540004801205Suche in Google Scholar PubMed

Béraud-Dufour, S., Coppola, T., Massa, F., and Mazella, J. (2009). Neurotensin receptor-2 and -3 are crucial for the anti-apoptotic effect of neurotensin on pancreatic β-TC3 cells. Int. J. Biochem. Cell Biol. 41, 2398–2402.10.1016/j.biocel.2009.04.002Suche in Google Scholar PubMed

Béraud-Dufour, S., Abderrahmani, A., Noel, J., Brau, F., Waeber, G., Mazella, J., and Coppola, T. (2010). Neurotensin is a regulator of insulin secretion in pancreatic β-cells. Int. J. Biochem. Cell Biol. 42, 1681–1688.10.1016/j.biocel.2010.06.018Suche in Google Scholar PubMed

Brown, J.A., Woodworth, H.L., and Leinninger, G.M. (2015). To ingest or rest? Specialized roles of lateral hypothalamic area neurons in coordinating energy balance. Front Syst. Neurosci. 9, 9.10.3389/fnsys.2015.00009Suche in Google Scholar PubMed PubMed Central

Chow, V.T. and Quek, H.H. (1997). Alpha coat protein COPA (HEP-COP): presence of an Alu repeat in cDNA and identity of the amino terminus to xenin. Ann. Hum. Genet. 61, 369–73.10.1017/S0003480097006295Suche in Google Scholar

Chowdhury, S., Wang, S., Dunai, J., Kilpatrick, R., Oestricker, L.Z., Wallendorf, M.J., Patterson, B.W., Reeds, D.N., and Wice, B.M. (2016). Hormonal responses to cholinergic input are different in humans with and without type 2 diabetes mellitus. PLoS One 11, e0156852.10.1371/journal.pone.0156852Suche in Google Scholar PubMed PubMed Central

Coppola, T., Béraud-Dufour, S., Antoine, A., Vincent, J., and Mazella, J. (2008). Neurotensin protects pancreatic β-cells from apoptosis. Int. J. Biochem. Cell Biol. 40, 2296–2302.10.1016/j.biocel.2008.03.015Suche in Google Scholar PubMed

Devader, C., Béraud-Dufour, S., Coppola, T., and Mazella, J. (2013). The anti-apoptotic role of neurotensin. Cells 2, 124–135.10.3390/cells2010124Suche in Google Scholar PubMed PubMed Central

Dolais-Kitabgi, J., Kitabgi, P., Brazeau, P., and Freychet, P. (1979). Effect of neurotensin on insulin, glucagon, and somatostatin release from isolated pancreatic islets. Endocrinol. 105, 256–260.10.1210/endo-105-1-256Suche in Google Scholar PubMed

Fernstrom, M.H., Mirski, M.A., Carraway, R.E., and Leeman, S.E. (1981). Immunoreactive neurotensin levels in pancreas: Elevation in diabetic rats and mice. Metab. 30,853–855.10.1016/0026-0495(81)90063-9Suche in Google Scholar

Feurle, G.E., Hamscher, G., Kusiek, R., Meyer, H.E., and Metzger, J.W. (1992). Identification of xenin, a xenopsin-related peptide, in the human gastric mucosa and its effect on exocrine pancreatic secretion. J. Biol. Chem. 267, 22305–22309.10.1016/S0021-9258(18)41670-5Suche in Google Scholar

Feurle, G.E., Metzger, J.W., Grudinski, A., and Hamscher, G. (2002). Interaction of xenin with the neurotensin receptor of guinea pig enteral smooth muscles. Peptides 23, 523–529.10.1016/S0196-9781(01)00637-4Suche in Google Scholar

Flatt, P.R. and Bailey, C.J. (1982). Plasma glucose and insulin response to glucagon and arginine in Aston ob/ob mice: evidence for a selective defect in glucose-mediated insulin release. Horm. Metab. Res. 14, 127–130.10.1055/s-2007-1018945Suche in Google Scholar

Fujita, Y., Wideman, R.D., Asadi, A., Yang, G.K., Baker, R., Webber, T., Zhang T, Wang R, Ao Z, Warnock GL, et al. (2010). Glucose-dependent insulinotropic polypeptide is expressed in pancreatic islet α-cells and promotes insulin secretion. Gastroenterol 138, 1966–1975.10.1053/j.gastro.2010.01.049Suche in Google Scholar

Gault, V., Martin, C., Flatt, P., Parthsarathy, V., and Irwin, N. (2015). Xenin-25 [Lys13PAL]: A novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential. Acta Diabetol. 52, 461–471.10.1007/s00592-014-0681-0Suche in Google Scholar

Hamid, M., McCluskey, J., McClenaghan, N., and Flatt, P.R. (2002). Comparison of the secretory properties of four insulin-secreting cell lines. Endocr. Res. 28, 35–47.10.1081/ERC-120004536Suche in Google Scholar

Hamscher, G., Meyer, H.E., Metzger, J.W., and Feurle, G.E. (1995). Distribution, formation, and molecular forms of the peptide xenin in various mammals.Peptides 16,791–797.10.1016/0196-9781(95)00053-MSuche in Google Scholar

Heuser, M., Kleiman, I., Pöpken, O., Nustede, R., and Post, S. (2002). Evidence for non-neurotensin receptor-mediated effects of xenin (1–25)—focus on intestinal microcirculation. Regul. Pept. 107, 23–27.10.1016/S0167-0115(02)00062-9Suche in Google Scholar

Kalafatakis, K. and Triantafyllou, K. (2011). Contribution of neurotensin in the immune and neuroendocrine modulation of normal and abnormal enteric function. Regul. Pept. 170, 7–17.10.1016/j.regpep.2011.04.005Suche in Google Scholar PubMed

Khan, D., Vasu, S., Moffett, R.C., Irwin, N., and Flatt, P.R. (2016). Islet distribution of Peptide YY and its regulatory role in primary mouse islets and immortalised rodent and human β-cell function and survival. Mol. Cell Endocrinol. 436, 102–113.10.1016/j.mce.2016.07.020Suche in Google Scholar PubMed

Khan, D., Vasu, S., Moffett, R.C., Irwin, N., and Flatt, P.R. (2017). Influence of neuropeptide Y and pancreatic polypeptide on islet function and β-cell survival. Biochim. Biophys. Acta 1861, 749–75810.1016/j.bbagen.2017.01.005Suche in Google Scholar PubMed

Kim, J.T., Li, J., Song, J., Lee, E.Y., Weiss, H.L., Townsend, C.M. Jr., and Evers, B.M. (2015). Differential expression and tumorigenic function of neurotensin receptor 1 in neuroendocrine tumor cells. Oncotarget 6, 26960–26970.10.18632/oncotarget.4745Suche in Google Scholar PubMed PubMed Central

Leinninger, G.M., Opland, D.M., Jo, Y., Faouzi, M., Christensen, L., Cappellucci, L.A., Rhodes, C.J., Gnegy, M.E., Becker, J.B., Pothos, E.N., et al. (2011). Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab. 14, 313–323.10.1016/j.cmet.2011.06.016Suche in Google Scholar PubMed PubMed Central

Li, J., Song, J., Zaytseva, Y.Y., Liu, Y., Rychahou, P., Jiang, K., Starr, M.E., Kim, J.T., Harris, J.W., Yiannikouris, F.B., et al. (2016). An obligatory role for neurotensin in high-fat-diet-induced obesity. Nature 533, 411–415.10.1038/nature17662Suche in Google Scholar PubMed PubMed Central

Li, J., Casteels, T., Frogne, T., Ingvorsen, C., Honoré, C., Courtney, M., Huber, K.V., Schmitner, N., Kimmel, R.A., Romanov, R.A., et al. (2017). Artemisinins target GABAA receptor signaling and impair α cell identity. Cell 168, 86–100.10.1016/j.cell.2016.11.010Suche in Google Scholar PubMed PubMed Central

Martin, C.M., Gault, V.A., McClean, S., Flatt, P.R., and Irwin, N. (2012). Degradation, insulin secretion, glucose-lowering and GIP additive actions of a palmitate-derivatised analogue of xenin-25.Biochem. Pharm. 84, 312–319.10.1016/j.bcp.2012.04.015Suche in Google Scholar PubMed

Mazella, J., Béraud-Dufour, S., Devader, C., Massa, F., Coppola, T. (2012). Neurotensin and its receptors in the control of glucose homeostasis.Front Endocrinol. 3, 143.10.3389/fendo.2012.00143Suche in Google Scholar PubMed PubMed Central

McClenaghan, N.H., Barnett, C.R., Ah-Sing, E., Abdel-Wahab, Y.H., O’Harte, F.P., Yoon, T.W., Swanston-Flatt, S.K., and Flatt, P.R. (1996). Characterization of a novel glucose-responsive insulin-secreting cell line, BRIN-BD11, produced by electrofusion.Diabetes 45,1132–1140.10.2337/diab.45.8.1132Suche in Google Scholar PubMed

McCluskey, J.T., Hamid, M., Guo-Parke, H., McClenaghan, N.H., Gomis, R., and Flatt, P.R. (2011). Development and functional characterization of insulin-releasing human pancreatic β-cell lines produced by electrofusion. J. Biol. Chem. 286, 21982–21992.10.1074/jbc.M111.226795Suche in Google Scholar PubMed PubMed Central

Melander, O., Maisel, A.S., Almgren, P., Manjer, J., Belting, M., Hedblad, B., Engström, G., Kilger, U., Nilsson, P., Bergmann, A., et al. (2012). Plasma proneurotensin and incidence of diabetes, cardiovascular disease, breast cancer, and mortality. J. Am. Med. Assoc. 308, 1469–1475.10.1001/jama.2012.12998Suche in Google Scholar PubMed

Miguel, J.C., Patterson, S., Abdel-Wahab, Y.H., Mathias, P.C., and Flatt, P.R. (2004). Time-correlation between membrane depolarization and intracellular calcium in insulin secreting BRIN-BD11 cells: Studies using FLIPR.Cell Calcium36, 43–50.10.1016/j.ceca.2003.11.007Suche in Google Scholar PubMed

Moffett, R.C., Irwin, N., Francis, J.M.E., and Flatt, P.R. (2013). Alterations of glucose-dependent insulinotropic polypeptide and expression of genes involved in mammary gland and adipose tissue lipid metabolism during pregnancy and lactation. PloS One 8, e78560.10.1371/journal.pone.0078560Suche in Google Scholar PubMed PubMed Central

Moffett, R.C., Vasu, S., Thorens, B., Drucker, D.J., and Flatt, P.R. (2014). Incretin receptor null mice reveal key role of GLP-1 but not GIP in pancreatic β-cell adaptation to pregnancy. PloS One 9, e96863.10.1371/journal.pone.0096863Suche in Google Scholar PubMed PubMed Central

Parthsarathy, V., Irwin, N., Hasib, A., Martin, C.M., McClean, S., Bhat, V.K., Ng, M.T., Flatt, P.R., and Gault, V.A. (2016). A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties. Biochim. Biophys. Acta 1860, 757–764.10.1016/j.bbagen.2016.01.015Suche in Google Scholar PubMed

Petersen, C.M., Nielsen, M.S., Nykjær, A., Jacobsen, L., Tommerup, N., Rasmussen, H.H., Roigaard, H., Gliemann, J., Madsen, P., Moestrup SK. (1997). Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography.J. Biol. Chem. 272,3599–3605.10.1074/jbc.272.6.3599Suche in Google Scholar PubMed

Sheppard, M.C., Bailey, C.J., Flatt, P.R., Swanston-Flatt, S.K., and Shennan, K.I. (1985). Immunoreactive neurotensin in spontaneous syndromes of obesity and diabetes in mice. Acta Endocrinol. 108, 532–536.10.1530/acta.0.1080532Suche in Google Scholar PubMed

Sterl, K., Wang, S., Oestricker, L., Wallendorf, M.J., Patterson, B.W., Reeds, D.N., and Wice, B.M. (2016). Metabolic responses to xenin-25 are altered in humans with roux-en-Y gastric bypass surgery.Peptides 82, 76–84.10.1016/j.peptides.2016.06.001Suche in Google Scholar PubMed PubMed Central

Taylor, A.I., Irwin, N., McKillop, A.M., Patterson, S., Flatt, P.R., and Gault, V.A. (2010). Evaluation of the degradation and metabolic effects of the gut peptide xenin on insulin secretion, glycaemic control and satiety.J. Endocrinol.207,87–93.10.1677/JOE-10-0085Suche in Google Scholar PubMed

Thiriet, N., Deng, X., Solinas, M., Ladenheim, B., Curtis, W., Goldberg, S.R., Palmiter, R.D., and Cadet, J.L. (2005). Neuropeptide Y protects against methamphetamine-induced neuronal apoptosis in the mouse striatum. J. Neurosci. 25, 5273–5279.10.1523/JNEUROSCI.4893-04.2005Suche in Google Scholar PubMed PubMed Central

Trandaburu, T., Trandaburu, I., and Olaru, L. (2003). Immunohistochemical survey of neurotensin distribution in the gastro-entero-pancreatic neuroendocrine system of several european species of amphibians and reptiles. Proc. Rom. Acad. B Chemi. Life Sci. Geosci. 5, 17–24.Suche in Google Scholar

Vasu, S., Moffett, R.C., Thorens, B., and Flatt, P.R. (2014). Role of endogenous GLP-1 and GIP in β-cell compensatory responses to insulin resistance and cellular stress.PloS One 9, e101005.10.1371/journal.pone.0101005Suche in Google Scholar

Vita, N., Oury-Donat, F., Chalon, P., Guillemot, M., Kaghad, M., Bachy, A., Thurneyssen, O., Garcia, S., Poinot-Chazel, C., Casellas, P., et al. (1998). Neurotensin is an antagonist of the human neurotensin NT2 receptor expressed in Chinese hamster ovary cells. Eur. J. Pharmacol. 360, 265–272.10.1016/S0014-2999(98)00678-5Suche in Google Scholar

Wang, J.G., Li, N.N., Li, H.N., Cui, L., and Wang, P. (2011). Pancreatic cancer bears overexpression of neurotensin and neurotensin receptor subtype-1 and SR 48692 counteracts neurotensin induced cell proliferation in human pancreatic ductal carcinoma cell line PANC-1. Neuropeptides 45, 151–156.10.1016/j.npep.2011.01.002Suche in Google Scholar PubMed

Wice, B.M., Wang, S., Crimmins, D.L., Diggs-Andrews, K.A., Althage, M.C., Ford, E.L., Tran, H., Ohlendorf, M., Griest, T.A., Wang, Q., et al. (2010). Xenin-25 potentiates glucose-dependent insulinotropic polypeptide action via a novel cholinergic relay mechanism. J. Biol. Chem. 285, 19842–19853.10.1074/jbc.M110.129304Suche in Google Scholar PubMed PubMed Central

Wice, B.M., Reeds, D.N., Tran, H.D., Crimmins, D.L., Patterson, B.W., Dunai, J., Wallendorf, M.J., Ladenson, J.H., Villareal, D.T., Polonsky, K.S. (2012). Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes. Diabetes 61, 1793–1800.10.2337/db11-1451Suche in Google Scholar PubMed PubMed Central

Wierup, N., Sundler, F., and Heller, R.S. (2014). The islet ghrelin cell. J. Mol. Endocrinol. 52, R35–R49.10.1530/JME-13-0122Suche in Google Scholar PubMed

Wood, J.G., Hoang, H.D., Bussjaeger, L.J., and Solomon, T.E. (1988). Neurotensin stimulates growth of small intestine in rats. Am. J. Physiol. 255, G813–7.10.1152/ajpgi.1988.255.6.G813Suche in Google Scholar PubMed

Received: 2017-3-31
Accepted: 2017-8-14
Published Online: 2017-8-19
Published in Print: 2017-12-20

©2018 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/hsz-2017-0136
Schlagwörter für diesen Artikel
apoptosis; β-cell; COPA; diabetes; islets; neurotensin (NT); neurotensin receptor (NTSR); xenin

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Maintaining protein composition in cilia
  4. Eremophilane-type sesquiterpenes from fungi and their medicinal potential
  5. How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways
  6. Minireviews
  7. Targeted degradomics in protein terminomics and protease substrate discovery
  8. Brain plasticity, cognitive functions and neural stem cells: a pivotal role for the brain-specific neural master gene |-SRGAP2–FAM72-|
  9. Research Articles/Short Communications
  10. Protein Structure and Function
  11. Domain topology of human Rasal
  12. The consequences of deglycosylation of recombinant intra-melanosomal domain of human tyrosinase
  13. Cell Biology and Signaling
  14. Locally produced xenin and the neurotensinergic system in pancreatic islet function and β-cell survival
  15. The long non-coding RNA CRNDE promotes cervical cancer cell growth and metastasis
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