Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes

dc.contributor.authorChen, Yi-Chun
dc.contributor.authorColvin, E. Scott
dc.contributor.authorGriffin, Katherine E.
dc.contributor.authorMaier, Bernhard F.
dc.contributor.authorFueger, Patrick T.
dc.contributor.departmentDepartment of Cellular and Integrative Physiology, IU School of Medicineen_US
dc.date.accessioned2016-07-07T16:35:15Z
dc.date.available2016-07-07T16:35:15Z
dc.date.issued2014-10
dc.description.abstractAIMS/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 cellsen_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationChen, Y.-C., Colvin, E. S., Griffin, K. E., Maier, B. F., & Fueger, P. T. (2014). Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes. Diabetologia, 57(10), 2066–2075. http://doi.org/10.1007/s00125-014-3311-zen_US
dc.identifier.urihttps://hdl.handle.net/1805/10314
dc.language.isoen_USen_US
dc.publisherSpringeren_US
dc.relation.isversionof10.1007/s00125-014-3311-zen_US
dc.relation.journalDiabetologiaen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectCytokinesen_US
dc.subjectEGFRen_US
dc.subjectERRFI1en_US
dc.subjectIsletsen_US
dc.subjectMig6en_US
dc.subjectType 1 diabetesen_US
dc.titleMig6 haploinsufficiency protects mice against streptozotocin-induced diabetesen_US
dc.typeArticleen_US
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
nihms610890.pdf
Size:
3.83 MB
Format:
Adobe Portable Document Format
Description:
Main Article
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.88 KB
Format:
Item-specific license agreed upon to submission
Description: