Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes

Yi Chun Chen, E. Scott Colvin, Katherine E. Griffin, Bernhard Maier, Patrick T. Fueger

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 EGFmediated tissue repair is a complicated process and warrants further investigation. Thus, we aimed to determine whether EGF receptor (EGFR) feedback inhibition by mitogeninducible 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 glucosestimulated 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.

Original languageEnglish (US)
Pages (from-to)2066-2075
Number of pages10
JournalDiabetologia
Volume57
Issue number10
DOIs
StatePublished - 2014

Fingerprint

Haploinsufficiency
Experimental Diabetes Mellitus
Streptozocin
Epidermal Growth Factor Receptor
Glucose
Proteins
Type 1 Diabetes Mellitus
Epidermal Growth Factor
DNA Repair
DNA Damage
Insulin
Cytokines
Gastrins
Insulin Resistance
Rodentia
Homeostasis
Messenger RNA
Therapeutics

Keywords

  • Cytokines
  • EGFR
  • ERRFI1
  • Islets
  • Mig6
  • Type 1 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes. / Chen, Yi Chun; Colvin, E. Scott; Griffin, Katherine E.; Maier, Bernhard; Fueger, Patrick T.

In: Diabetologia, Vol. 57, No. 10, 2014, p. 2066-2075.

Research output: Contribution to journalArticle

Chen, Yi Chun ; Colvin, E. Scott ; Griffin, Katherine E. ; Maier, Bernhard ; Fueger, Patrick T. / Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes. In: Diabetologia. 2014 ; Vol. 57, No. 10. pp. 2066-2075.
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