PERK EIF2AK3 control of pancreatic β 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.

Insulin Secretion and Ca2+ Dynamics in β-Cells Are Regulated by PERK (EIF2AK3) in Concert with Calcineurin

“…Acute Inhibition of PERK Activity Impairs Glucose-dependent Insulin Secretion-Previously we showed that glucose-stimulated insulin secretion was ablated in islets isolated from neonatal PKO mice (19). In the present study, this result was confirmed by genetic knockdown of Perk in INS1 832/13 ␤-cells bearing a tetracycline-operated shPerk transgene (denoted as INS1 832/13 shPerk cells).…”

“…Seen in Genetic Ablation of Perk-Previously we showed that loss of function mutations of Perk in mice (PKO) led to an impacted ER phenotype in a substantial fraction of ␤-cells (30 -40%) characterized by accumulation of proinsulin and other client proteins in the ER and failure of anterograde trafficking to the Golgi (19,20,27). This phenotype can be readily detected using immunohistochemical labeling of insulin and proinsulin in mouse islets of Langerhans (Fig.…”

“…PERK has also been shown to play a key role in regulating the ER stress and the unfolded protein response in cultured cells that are subjected to severe stress conditions (16,17). However, the relevance of the ER stress response pathway to the normal developmental and physiological functions of PERK in ␤-cells has been questioned and remains controversial (18,19). Previous attempts to identify the primary functions of PERK were confounded by the myriad dysfunctions within ␤-cells including ablated insulin synthesis and secretion, delayed development and proliferation of the ␤-cells, and a massive accumulation of proinsulin in the ER (14,19,20) as well as dysfunctions in other organs and tissues (13,14,21).…”

“…However, the relevance of the ER stress response pathway to the normal developmental and physiological functions of PERK in ␤-cells has been questioned and remains controversial (18,19). Previous attempts to identify the primary functions of PERK were confounded by the myriad dysfunctions within ␤-cells including ablated insulin synthesis and secretion, delayed development and proliferation of the ␤-cells, and a massive accumulation of proinsulin in the ER (14,19,20) as well as dysfunctions in other organs and tissues (13,14,21). Recently a highly selective PERK inhibitor (denoted throughout as PERKi in text and PI in figure legends) was developed by GlaxoSmithKline, Inc. (22).…”

Connective tissue growth factor acts within both endothelial cells and β cells to promote proliferation of developing β cells

“…Only a few factors, however, have been shown to regulate embryonic β-cell proliferation in vivo. The eIF2α kinase PERK is important for β-cell proliferation in embryos and neonates but not in the adult (14). The transcription factor Pdx-1 is essential for pancreas organogenesis and β-cell proliferation (15)(16)(17).…”