title: Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Chen
authors.forename: E Scott
authors.initials: ES
authors.lastname: Colvin
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Griffin
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Maier
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Fueger
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000517:prevention & control*; D057895:Haploinsufficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins