nach oben

Diabetologia

Erschienen in:

01.10.2014 | Article

Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes

verfasst von: Yi-Chun Chen, E. Scott Colvin, Katherine E. Griffin, Bernhard F. Maier, Patrick T. Fueger

Erschienen in: Diabetologia | Ausgabe 10/2014

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

EGF and gastrin co-administration reverses type 1 diabetes in rodent models. However, the failure of this to translate into a clinical treatment suggests that EGF-mediated tissue repair is a complicated process and warrants further investigation. Thus, we aimed to determine whether EGF receptor (EGFR) feedback inhibition by mitogen-inducible gene 6 protein (MIG6) limits the effectiveness of EGF therapy and promotes type 1 diabetes development.

Methods

We treated Mig6 (also known as Errfi1) haploinsufficient mice (Mig6 ^+/−) and their wild-type littermates (Mig6 ^+/+) with multiple low doses of streptozotocin (STZ), and monitored diabetes development via glucose homeostasis tests and histological analyses. We also investigated MIG6-mediated cytokine-induced desensitisation of EGFR signalling and the DNA damage repair response in 832/13 INS-1 beta cells.

Results

Whereas STZ-treated Mig6 ^+/+ mice became diabetic, STZ-treated Mig6 ^+/− mice remained glucose tolerant. In addition, STZ-treated Mig6 ^+/− mice exhibited preserved circulating insulin levels following a glucose challenge. As insulin sensitivity was similar between Mig6 ^+/− and Mig6 ^+/+ mice, the preserved glucose tolerance in STZ-treated Mig6 ^+/− mice probably results from preserved beta cell function. This is supported by elevated Pdx1 and Irs2 mRNA levels in islets isolated from STZ-treated Mig6 ^+/− mice. Conversely, MIG6 overexpression in isolated islets compromises glucose-stimulated insulin secretion. Studies in 832/13 cells suggested that cytokine-induced MIG6 hinders EGFR activation and inhibits DNA damage repair. STZ-treated Mig6 ^+/− mice also have increased beta cell mass recovery.

Conclusions/interpretation

Reducing Mig6 expression promotes beta cell repair and abates the development of experimental diabetes, suggesting that MIG6 may be a novel therapeutic target for preserving beta cells.

Nur mit Berechtigung zugänglich

von Herrath M, Sanda S, Herold K (2007) Type 1 diabetes as a relapsing-remitting disease? Nat Rev Immunol 7:988–994CrossRef

Skyler JS (2013) The year in immune intervention for type 1 diabetes. Diabetes Technol Ther 15(Suppl 1):S88–S95PubMed

Akirav E, Kushner JA, Herold KC (2008) Beta-cell mass and type 1 diabetes: going, going, gone? Diabetes 57:2883–2888PubMedCentralPubMedCrossRef

Eizirik DL, Sandler S, Palmer JP (1993) Repair of pancreatic beta-cells. A relevant phenomenon in early IDDM? Diabetes 42:1383–1391PubMedCrossRef

Group TDCaCTR (1998) Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. Ann Intern Med 128:517–523CrossRef

Karges B, Durinovic-Bello I, Heinze E, Boehm BO, Debatin KM, Karges W (2004) Complete long-term recovery of beta-cell function in autoimmune type 1 diabetes after insulin treatment. Diabetes Care 27:1207–1208PubMedCrossRef

Bottino R, Criscimanna A, Casu A et al (2009) Recovery of endogenous beta-cell function in nonhuman primates after chemical diabetes induction and islet transplantation. Diabetes 58:442–447PubMedCentralPubMedCrossRef

Sherry NA, Kushner JA, Glandt M, Kitamura T, Brillantes AM, Herold KC (2006) Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes. Diabetes 55:3238–3245PubMedCrossRef

Lupi R, Marselli L, Dionisi S et al (2004) Improved insulin secretory function and reduced chemotactic properties after tissue culture of islets from type 1 diabetic patients. Diabetes Metab Res Rev 20:246–251PubMedCrossRef

10.

Fiorentino L, Pertica C, Fiorini M et al (2000) Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain. Mol Cell Biol 20:7735–7750PubMedCentralPubMedCrossRef

11.

Anastasi S, Baietti MF, Frosi Y, Alema S, Segatto O (2007) The evolutionarily conserved EBR module of RALT/MIG6 mediates suppression of the EGFR catalytic activity. Oncogene 26:7833–7846PubMedCrossRef

12.

Zhang X, Pickin KA, Bose R, Jura N, Cole PA, Kuriyan J (2007) Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface. Nature 450:741–744PubMedCentralPubMedCrossRef

13.

Frosi Y, Anastasi S, Ballaro C et al (2010) A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation. J Cell Biol 189:557–571PubMedCentralPubMedCrossRef

14.

Makkinje A, Quinn DA, Chen A et al (2000) Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress. J Biol Chem 275:17838–17847PubMedCentralPubMedCrossRef

15.

Xu D, Patten RD, Force T, Kyriakis JM (2006) Gene 33/RALT is induced by hypoxia in cardiomyocytes, where it promotes cell death by suppressing phosphatidylinositol 3-kinase and extracellular signal-regulated kinase survival signaling. Mol Cell Biol 26:5043–5054PubMedCentralPubMedCrossRef

16.

Xu D, Makkinje A, Kyriakis JM (2005) Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function. J Biol Chem 280:2924–2933PubMedCrossRef

17.

Colvin ES, Ma HY, Chen YC, Hernandez AM, Fueger PT (2013) Glucocorticoid-induced suppression of beta-cell proliferation is mediated by Mig6. Endocrinology 154:1039–1046PubMedCentralPubMedCrossRef

18.

Chen YC, Colvin ES, Maier BF, Mirmira RG, Fueger PT (2013) Mitogen-inducible gene 6 triggers apoptosis and exacerbates ER stress-induced beta-cell death. Mol Endocrinol 27:162–171PubMedCentralPubMedCrossRef

19.

Zhang YW, Su Y, Lanning N et al (2005) Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease. Proc Natl Acad Sci U S A 102:11740–11745PubMedCentralPubMedCrossRef

20.

Demirci C, Ernst S, Alvarez-Perez JC et al (2012) Loss of HGF/c-Met signaling in pancreatic beta-cells leads to incomplete maternal beta-cell adaptation and gestational diabetes mellitus. Diabetes 61:1143–1152PubMedCentralPubMedCrossRef

21.

Fueger PT, Hernandez AM, Chen YC, Colvin ES (2012) Assessing replication and beta cell function in adenovirally-transduced isolated rodent islets. J Vis Exp 64:e4080

22.

Collier JJ, Fueger PT, Hohmeier HE, Newgard CB (2006) Pro- and antiapoptotic proteins regulate apoptosis but do not protect against cytokine-mediated cytotoxicity in rat islets and beta-cell lines. Diabetes 55:1398–1406PubMedCrossRef

23.

Hohmeier HE, Mulder H, Chen G, Henkel-Rieger R, Prentki M, Newgard CB (2000) Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes 49:424–430PubMedCrossRef

24.

Evans-Molina C, Garmey JC, Ketchum R, Brayman KL, Deng S, Mirmira RG (2007) Glucose regulation of insulin gene transcription and pre-mRNA processing in human islets. Diabetes 56:827–835PubMedCentralPubMedCrossRef

25.

Mohn KL, Laz TM, Melby AE, Taub R (1990) Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families. J Biol Chem 265:21914–21921PubMed

26.

Zhang YW, Vande Woude GF (2007) Mig-6, signal transduction, stress response and cancer. Cell Cycle 6:507–513PubMedCrossRef

27.

Lenzen S (2008) The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51:216–226PubMedCrossRef

28.

Hakonen E, Ustinov J, Eizirik DL, Sariola H, Miettinen PJ, Otonkoski T (2014) In vivo activation of the PI3K-Akt pathway in mouse beta cells by the EGFR mutation L858R protects against diabetes. Diabetologia 57:970–979PubMedCrossRef

29.

Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107PubMedCrossRef

30.

Murillo-Carretero M, Ruano MJ, Matarredona ER, Villalobo A, Estrada C (2002) Antiproliferative effect of nitric oxide on epidermal growth factor-responsive human neuroblastoma cells. J Neurochem 83:119–131PubMedCrossRef

31.

Ruano MJ, Hernandez-Hernando S, Jimenez A, Estrada C, Villalobo A (2003) Nitric oxide-induced epidermal growth factor-dependent phosphorylations in A431 tumour cells. Eur J Biochem 270:1828–1837PubMedCrossRef

32.

Wang M, Racine JJ, Song X et al (2012) Mixed chimerism and growth factors augment beta cell regeneration and reverse late-stage type 1 diabetes. Sci Transl Med 4:133ra159

33.

Rooman I, Bouwens L (2004) Combined gastrin and epidermal growth factor treatment induces islet regeneration and restores normoglycaemia in C57B16/J mice treated with alloxan. Diabetologia 47:259–265PubMedCrossRef

34.

Suarez-Pinzon WL, Lakey JR, Rabinovitch A (2008) Combination therapy with glucagon-like peptide-1 and gastrin induces beta-cell neogenesis from pancreatic duct cells in human islets transplanted in immunodeficient diabetic mice. Cell Transplant 17:631–640PubMedCrossRef

35.

Baeyens L, Lemper M, Leuckx G et al (2014) Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat Biotechnol 32:76–83PubMedCentralPubMedCrossRef

36.

Meier JJ, Ritzel RA, Maedler K, Gurlo T, Butler PC (2006) Increased vulnerability of newly forming beta cells to cytokine-induced cell death. Diabetologia 49:83–89PubMedCrossRef

37.

Hopkins S, Linderoth E, Hantschel O et al (2012) Mig6 is a sensor of EGF receptor inactivation that directly activates c-Abl to induce apoptosis during epithelial homeostasis. Dev Cell 23:547–559PubMedCentralPubMedCrossRef

38.

Meyn RE, Munshi A, Haymach JV, Milas L, Ang KK (2009) Receptor signaling as a regulatory mechanism of DNA repair. Radiother Oncol J Eur Soc Ther Radiol Oncol 92:316–322CrossRef

39.

Yacoub A, McKinstry R, Hinman D, Chung T, Dent P, Hagan MP (2003) Epidermal growth factor and ionizing radiation up-regulate the DNA repair genes XRCC1 and ERCC1 in DU145 and LNCaP prostate carcinoma through MAPK signaling. Radiat Res 159:439–452PubMedCrossRef

40.

Ko JC, Hong JH, Wang LH et al (2008) Role of repair protein Rad51 in regulating the response to gefitinib in human non-small cell lung cancer cells. Mol Cancer Ther 7:3632–3641PubMedCrossRef

41.

Bandyopadhyay D, Mandal M, Adam L, Mendelsohn J, Kumar R (1998) Physical interaction between epidermal growth factor receptor and DNA-dependent protein kinase in mammalian cells. J Biol Chem 273:1568–1573PubMedCrossRef

42.

Golding SE, Rosenberg E, Neill S, Dent P, Povirk LF, Valerie K (2007) Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res 67:1046–1053PubMedCrossRef

43.

Keenan HA, Sun JK, Levine J et al (2010) Residual insulin production and pancreatic ss-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes 59:2846–2853PubMedCentralPubMedCrossRef

44.

Gianani R, Campbell-Thompson M, Sarkar SA et al (2010) Dimorphic histopathology of long-standing childhood-onset diabetes. Diabetologia 53:690–698PubMedCrossRef

45.

Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC (2005) Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 48:2221–2228PubMedCrossRef

46.

Menge BA, Breuer TG, Ritter PR, Uhl W, Schmidt WE, Meier JJ (2012) Long-term recovery of beta-cell function after partial pancreatectomy in humans. Metabolism 61:620–624PubMedCrossRef

Titel: Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes
verfasst von: Yi-Chun Chen
E. Scott Colvin
Katherine E. Griffin
Bernhard F. Maier
Patrick T. Fueger
Publikationsdatum: 01.10.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 10/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3311-z

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 10/2014

Central prolactin receptors (PRLRs) regulate hepatic insulin sensitivity in mice via signal transducer and activator of transcription 5 (STAT5) and the vagus nerve

Cerebrospinal fluid levels of Alzheimer’s disease biomarkers in middle-aged patients with type 1 diabetes

Potential viral pathogenic mechanism in human type 1 diabetes

Estimates of insulin sensitivity from the intravenous-glucose-modified-clamp test depend on suppression of lipolysis in type 2 diabetes: a randomised controlled trial

Fermentable fibres condition colon microbiota and promote diabetogenesis in NOD mice