Perk Gene Dosage Regulates Glucose Homeostasis by Modulating Pancreatic β-Cell Functions

Abstract

BackgroundInsulin synthesis and cell proliferation are under tight regulation in pancreatic β-cells to maintain glucose homeostasis. Dysfunction in either aspect leads to development of diabetes. PERK (EIF2AK3) loss of function mutations in humans and mice exhibit permanent neonatal diabetes that is characterized by insufficient β-cell mass and reduced proinsulin trafficking and insulin secretion. Unexpectedly, we found that Perk heterozygous mice displayed lower blood glucose levels.MethodologyLongitudinal studies were conducted to assess serum glucose and insulin, intracellular insulin synthesis and storage, insulin secretion, and β-cell proliferation in Perk heterozygous mice. In addition, modulation of Perk dosage specifically in β-cells showed that the glucose homeostasis phenotype of Perk heterozygous mice is determined by reduced expression of PERK in the β-cells.Principal FindingsWe found that Perk heterozygous mice first exhibited enhanced insulin synthesis and secretion during neonatal and juvenile development followed by enhanced β-cell proliferation and a substantial increase in β-cell mass at the adult stage. These differences are not likely to entail the well-known function of PERK to regulate the ER stress response in cultured cells as several markers for ER stress were not differentially expressed in Perk heterozygous mice.ConclusionsIn addition to the essential functions of PERK in β-cells as revealed by severely diabetic phenotype in humans and mice completely deficient for PERK, reducing Perk gene expression by half showed that intermediate levels of PERK have a profound impact on β-cell functions and glucose homeostasis. These results suggest that an optimal level of PERK expression is necessary to balance several parameters of β-cell function and growth in order to achieve normoglycemia.

Insulin demand regulates β cell number via the unfolded protein response

“…Inducing UPR by transgenic overexpression of mutant proinsulin or the islet amyloid polypeptide (49,50), or by deletion of ER stress cell-death mediators CHOP or DP5 (30,51), was noted to increase islet size or β cell proliferation. In adult mice, reducing PERK expression increased β cell proliferation (52,53). This is consistent with our observation that the PERK pathway is not responsible for the pro-proliferative UPR signal and supports the possibility that ATF6, responding to loss of PERK, might drive proliferation.…”

Attenuation of PERK enhances glucose-stimulated insulin secretion in islets

“…As a result, low-dose PERKi contributed to GSIS. Although we did not examine it, β cell proliferation could be another contributor, based on previous results from Perk heterozygous mice (Wang et al 2014). PERK is well known as an ER stress sensor that triggers the UPR, but it seems to have another role in insulin secretion through BiP in pancreatic islets.…”

“…Increased Bip expression has been observed not only in insulin-producing cells in which Perk was acutely ablated in vitro (Feng et al 2009) but also in islets from Perk +/− mice (Wang et al 2014). In the Perk +/− mice, the Bip induction was transient during the early post-natal period (day 17) and accompanied by a transient increase in serum insulin (Wang et al 2014). The mechanisms by which PERK insufficiency induces BiP expression are yet to be elucidated; however, PERK activation was reported to induce BiP expression through ATF6 (Luo et al 2003).…”

“…In addition, in the case of increased ER stress such as that in DM, even low-dose PERKi might profoundly affect the UPR, which can deteriorate cell viability. Favorable effects might be observed depending on the phenotype of Perk +/− mice, which showed enhanced β cell proliferation and substantially increased β cell mass in the adult stage (Wang et al 2014).…”

Peptide-based sequestration of the adaptor protein Nck1 in pancreatic β cells enhances insulin biogenesis and protects against diabetogenic stresses

“…However, the role of PERK in ␤-cell proliferation is far from being clearly understood. Indeed, although deficiencies in PERK expression or signaling in mice are associated with decreased ␤-cell mass (9, 10), half-dosage of PERK associated with Perk heterozygosity in mice increases ␤-cell proliferation and mass in the adult stage (11), and deletion of PERK in adult mice also increases ␤-cell proliferation (12). In contrast, it is clear that PERK deficiency in mice leads to defective insulin biogenesis and secretion (1,13).…”