title: PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis.
abstract: Mutations in PERK (EIF2AK3) result in permanent neonatal diabetes as well as several other anomalies that underlie the human Wolcott-Rallison syndrome, and these anomalies are mirrored in Perk knockout mice. To identify the cause of diabetes in PERK-deficient mice, we generated a series of tissue- and cell-specific knockouts of the Perk gene and performed a developmental analysis of the progression to overt diabetes. We discovered that PERK is specifically required in the insulin-secreting beta cells during the fetal and early neonatal period as a prerequisite for postnatal glucose homeostasis. However, PERK expression in beta cells is not required at the adult stage to maintain beta cell functions and glucose homeostasis. We show that PERK-deficient mice exhibit severe defects in fetal/neonatal beta cell proliferation and differentiation, resulting in low beta cell mass, defects in proinsulin trafficking, and abrogation of insulin secretion that culminate in permanent neonatal diabetes.
authors.affiliation: Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Daorong
authors.initials: D
authors.lastname: Feng
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.forename: Kaori
authors.initials: K
authors.lastname: Iida
authors.forename: Barbara
authors.initials: B
authors.lastname: McGrath
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Cavener
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005333:Fetus / Q000201:enzymology / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007231:Infant, Newborn; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000172:deficiency / Q000378:metabolism*
chemical_list: D005947:Glucose; D011384:Proinsulin; D019892:eIF-2 Kinase