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Diabetologia

Erschienen in:

01.05.2013 | Article

Role of endogenous IL-6 in the neonatal expansion and functionality of Wistar rat pancreatic alpha cells

verfasst von: E. Fernández-Millán, J. de Toro-Martín, E. Lizárraga-Mollinedo, F. Escrivá, C. Álvarez

Erschienen in: Diabetologia | Ausgabe 5/2013

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Abstract

Aims/hypothesis

Plasma glucagon concentrations rise sharply during the early postnatal period. This condition is associated with increased alpha cell mass. However, the trophic factors that regulate alpha cell turnover during the perinatal period have not been studied. Macrophage infiltrations are present in the neonatal pancreas, and this cell type releases cytokines such as IL-6. Alpha cells have been identified as a primary target of IL-6 actions. We therefore investigated the physiological relevance of IL-6 to neonatal pancreatic alpha cell maturation.

Methods

Histochemical analyses were performed to quantify alpha cell mass, replication and apoptosis. Pancreatic Il6 expression was determined by quantitative RT-PCR. The biological effect of IL-6 was tested in two in vivo rat models of IL-6 blockade and chronic undernutrition.

Results

Alpha cell mass increased sharply shortly after birth but decreased significantly after weaning. Pancreatic alpha cell proliferation was as high as 2.5% at the beginning of suckling but diminished with time to 1.2% in adulthood. Similarly, alpha cell neoformation was remarkably high on postnatal day (PN) 4, whereas alpha cell apoptosis was low throughout the neonatal period. Moreover, Il6 mRNA exhibited developmental upregulation in the pancreas of suckling rats, with the highest expression on PN2. Neutralisation of IL-6 reduced alpha cell mass expansion and glucagon production. IL-6 staining was detected within the islets, mainly in the alpha cells. Finally, undernourished neonates showed altered alpha cell number and function and delayed appearance of IL-6 in the pancreas.

Conclusions/interpretation

These data point to a potential role for local IL-6 in the regulation of alpha cell growth and function during suckling.

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Sachdeva MM, Stoffers DA (2009) Meeting the demand for insulin: molecular mechanisms of adaptive postnatal beta-cell mass expansion. Mol Endocrinol 23:747–758PubMedCrossRef

Nielsen JH, Galsgaard ED, Møldrup A et al (2001) Regulation of beta-cell mass by hormones and growth factors. Diabetes 1(Suppl 1):S25–S29CrossRef

Bonner-Weir S (2000) Life and death of the pancreatic beta cells. Trends Endocrinol Metabol 11:375–378CrossRef

Sperling MA, DeLamater PV, Phelps D, Fiser RH, Oh W, Fisher DA (1974) Spontaneous and amino acid-stimulated glucagon secretion in the immediate postnatal period. Relation to glucose and insulin. J Clin Invest 53:1159–1166PubMedCrossRef

Girard JR, Cuendet GS, Marliss EB, Kervran A, Rieutort M, Assan R (1973) Fuels, hormones, and liver metabolism at term and during the early postnatal period in the rat. J Clin Invest 52:3190–3200PubMedCrossRef

Aguayo-Mazzucato C, Sanchez-Soto C, Godinez-Puig V, Gutiérrez-Ospina G, Hiriart M (2006) Restructuring of pancreatic islets and insulin secretion in a postnatal critical window. PLoS One 1:e35PubMedCrossRef

Petrik J, Arany E, McDonald TJ, Hill DJ (1998) Apoptosis in the pancreatic islet cells of the neonatal rat is associated with a reduced expression of insulin-like growth factor II that may act as a survival factor. Endocrinology 139:2994–3004PubMedCrossRef

Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S (1997) Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 138:1736–1741PubMedCrossRef

Danilovs JA, Hofman FM, Taylor CR, Brown J (1982) Expression of HLA-DR antigens in human fetal pancreas tissue. Diabetes 31:23–29PubMed

10.

Motojima K, Matsuo S, Mullen Y (1989) DR antigen expression on vascular endothelium and duct epithelium in fresh or cultured human fetal pancreata in the presence of gamma-interferon. Transplantation 48:1022–1026PubMedCrossRef

11.

Charré S, Rosmalen JG, Pelegri C et al (2002) Abnormalities in dendritic cell and macrophage accumulation in the pancreas of nonobese diabetic (NOD) mice during the early neonatal period. Histol Histopathol 7:393–401

12.

Homo-Delarche F, Drexhage A (2004) Immune cells, pancreas development, regeneration and type 1 diabetes. Trends Immunol 25:222–229PubMedCrossRef

13.

Kristiansen OP, Mandrup-Poulsen T (2005) Interleukin-6 and diabetes: the good, the bad, or the indifferent? Diabetes 54(Suppl 2):S114–S124PubMedCrossRef

14.

Spranger J, Kroke A, Möhlig M et al (2003) Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)–Potsdam Study. Diabetes 52:812–817PubMedCrossRef

15.

Ehses JA, Perren A, Eppler E et al (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56:2356–2370PubMedCrossRef

16.

Choi SE, Choi KM, Yoon IH et al (2004) IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced cell death and functional impairment in vitro and in vivo. Transpl Immunol 13:43–53PubMedCrossRef

17.

Ellingsgaard H, Ehses JA, Hammar EB et al (2008) Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc Natl Acad Sci U S A 105:13163–13168PubMedCrossRef

18.

Park JH, Stoffers DA, Nicholls RD, Simmons RA (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 118:2316–2324PubMedCrossRef

19.

Martín MA, Fernández E, Pascual-Leone AM, Escrivá F, Alvarez C (2004) Protein calorie restriction has opposite effects on glucose metabolism and insulin gene expression in fetal and adult rat endocrine pancreas. Am J Physiol Endocrinol Metab 286:E542–E550PubMedCrossRef

20.

Fernández E, Martín MA, Fajardo S et al (2006) Undernutrition does not alter the activation of beta-cell neogenesis and replication in adult rats after partial pancreatectomy. Am J Physiol Endocrinol Metab 291:E913–E921PubMedCrossRef

21.

Fernández E, Martín MA, Fajardo S, Escrivá F, Alvarez C (2007) Increased IRS-2 content and activation of IGF-I pathway contribute to enhance beta-cell mass in fetuses from undernourished pregnant rats. Am J Physiol Endocrinol Metab 292:E187–E195PubMedCrossRef

22.

de Miguel-Santos L, Fernández-Millán E, Angeles Martín M, Escrivá F, Alvarez C (2010) Maternal undernutrition increases pancreatic IGF-2 and partially suppresses the physiological wave of beta-cell apoptosis during the neonatal period. J Mol Endocrinol 44:25–36PubMedCrossRef

23.

Holness CL, Da Silva RP, Fawcett J, Gordon S, Simmons DL (1993) Macrosialin, a mouse macrophage-restricted glycoprotein, is a member of the lamp/lgp family. J Biol Chem 268:9661–9666PubMed

24.

Girard J, Ferré P, Pégorier JP, Duée PH (1992) Adaptations of glucose and fatty acid metabolism during perinatal period and suckling-weaning transition. Physiol Rev 72:507–562PubMed

25.

Quesada I, Tudurí E, Ripoll C, Nadal A (2008) Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes. J Endocrinol 199:5–19PubMedCrossRef

26.

Houghtling RA, Bayer BM (2002) Rapid elevation of plasma interleukin-6 by morphine is dependent on autonomic stimulation of adrenal gland. J Pharmacol Exp Ther 300:213–219PubMedCrossRef

27.

Mohamed-Ali V, Flower L, Sethi J et al (2001) Beta-adrenergic regulation of IL-6 release from adipose tissue: in vivo and in vitro studies. J Clin Endocrinol Metab 86:5864–5869PubMedCrossRef

28.

Pousset F (1994) Developmental expression of cytokine genes in the cortex and hippocampus of the rat central nervous system. Brain Res Dev Brain Res 81:143–146PubMedCrossRef

29.

Sadowska GB, Threlkeld SW, Flangini A, Sharma S, Stonestreet BS (2012) Ontogeny and the effects of in utero brain ischemia on interleukin-1β and interleukin-6 protein expression in ovine cerebral cortex and white matter. Int J Dev Neurosci 30:457–463PubMedCrossRef

30.

Kontogeorgos G, Messini I, Kyrodimou E et al (2002) Immunohistochemical localisation of interleukin-6 in peripheral human endocrine glands. Endocrine 17:135–140PubMedCrossRef

31.

Chentouf M, Dubois G, Jahannaut C et al (2011) Excessive food intake, obesity and inflammation process in Zucker fa/fa rat pancreatic islets. PLoS One 6:e22954PubMedCrossRef

32.

Ehses JA, Lacraz G, Giroix MH et al (2009) IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc Natl Acad Sci U S A 106:13998–14003PubMedCrossRef

33.

Campbell IL, Hobbs MV, Dockter J, Oldstone MB, Allison J (1994) Islet inflammation and hyperplasia induced by the pancreatic islet-specific overexpression of interleukin-6 in transgenic mice. Am J Pathol 145:157–166PubMed

34.

Kaneko K, Shirotani T, Araki E et al (1999) Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9 cells. Diabetes Res Clin Pract 44:83–92PubMedCrossRef

35.

van Schravendijk CF, Foriers A, van den Brande JL, Pipeleers DG (1987) Evidence for the presence of type I insulin-like growth factor receptors on rat pancreatic A and B cells. Endocrinology 121:1784–1788PubMedCrossRef

36.

Jermendy A, Toschi E, Aye T et al (2011) Rat neonatal beta cells lack the specialised metabolic phenotype of mature beta cells. Diabetologia 54:594–604PubMedCrossRef

37.

Garofano A, Czernichow P, Bréant B (1998) Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat. Diabetologia 41:1114–1120PubMedCrossRef

38.

Lizarraga-Mollinedo E, Fernández-Millán E, Martín Jde T, Martínez-Honduvilla C, Escrivá F, Alvarez C (2012) Early undernutrition induces glucagon resistance and insulin hypersensitivity in the liver of suckling rats. Am J Physiol Endocrinol Metab 302:E1070–E1077PubMedCrossRef

39.

Escrivá F, Rodríguez C, Cacho J, Alvarez C, Portha B, Pascual-Leone AM (1992) Glucose utilization and insulin action in adult rats submitted to prolonged food restriction. Am J Physiol 263:E1–E7PubMed

40.

Gelling RW, Du XQ, Dichmann DS et al (2003) Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A 100:1438–1443PubMedCrossRef

41.

Vincent M, Guz Y, Rozenberg M et al (2003) Abrogation of protein convertase 2 activity results in delayed islet cell differentiation and maturation, increased alpha-cell proliferation, and islet neogenesis. Endocrinology 144:4061–4069PubMedCrossRef

42.

Furuta M, Yano H, Zhou A et al (1997) Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc Natl Acad Sci U S A 94:6646–6651PubMedCrossRef

43.

Vuguin PM, Kedees MH, Cui L et al (2006) Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation. Endocrinology 147:3995–4006PubMedCrossRef

44.

Ødegård RA, Vatten LJ, Nilsen ST, Salvesen KA, Vefring H, Austgulen R (2001) Umbilical cord plasma interleukin-6 and fetal growth restriction in preeclampsia: a prospective study in Norway. Obstet Gynecol 98:289–294PubMedCrossRef

45.

Street ME, Seghini P, Fieni S et al (2006) Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls. Eur J Endocrinol 155:567–574PubMedCrossRef

Titel: Role of endogenous IL-6 in the neonatal expansion and functionality of Wistar rat pancreatic alpha cells
verfasst von: E. Fernández-Millán
J. de Toro-Martín
E. Lizárraga-Mollinedo
F. Escrivá
C. Álvarez
Publikationsdatum: 01.05.2013
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 5/2013
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-013-2862-8

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Aims/hypothesis

Methods

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