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Diabetologia
Published in: Diabetologia 10/2014

01-10-2014 | Article

Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes

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

Published in: Diabetologia | Issue 10/2014

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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.
Appendix
Available only for authorised users
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Metadata
Title
Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes
Authors
Yi-Chun Chen
E. Scott Colvin
Katherine E. Griffin
Bernhard F. Maier
Patrick T. Fueger
Publication date
01-10-2014
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 10/2014
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-014-3311-z

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