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PERK EIF2AK3 control of pancreatic β cell differentiation and proliferation is required for postnatal glucose homeostasis

2006; Cell Press; Volume: 4; Issue: 6 Linguagem: Inglês

10.1016/j.cmet.2006.11.002

1932-7420

Wei Zhang, Daorong Feng, Yulin Li, Kaori Iida, Barbara C. McGrath, Douglas R. Cavener,

Diabetes and associated disorders

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 β cells during the fetal and early neonatal period as a prerequisite for postnatal glucose homeostasis. However, PERK expression in β cells is not required at the adult stage to maintain β cell functions and glucose homeostasis. We show that PERK-deficient mice exhibit severe defects in fetal/neonatal β cell proliferation and differentiation, resulting in low β cell mass, defects in proinsulin trafficking, and abrogation of insulin secretion that culminate in permanent neonatal diabetes.