PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis.
Germ line PERK mutations are associated with diabetes mellitus and growth retardation in both rodents and humans. In contrast, late embryonic excision of PERK permits islet development and was found to prevent onset of diabetes, suggesting that PERK may be dispensable in the adult pancreas. To definitively establish the functional role of PERK in adult pancreata, we generated mice harboring a conditional PERK allele in which excision is regulated by tamoxifen administration. Deletion of PERK in either young adult or mature adult mice resulted in hyperglycemia associated with loss of islet and β cell architecture. PERK excision triggered intracellular accumulation of proinsulin and Glut2, massive endoplasmic reticulum (ER) expansion, and compensatory activation of the remaining unfolded-protein response (UPR) signaling pathways specifically in pancreatic tissue. Although PERK excision increased β cell death, this was not a result of decreased proliferation as previously reported. In contrast, a significant and specific increase in β cell proliferation was observed, a result reflecting increased cyclin D1 accumulation. This work demonstrates that contrary to expectations, PERK is required for secretory homeostasis and β cell survival in adult mice.
The Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Yan
Y
Gao
Daniel J
DJ
Sartori
Changhong
C
Li
Qian-Chun
QC
Yu
Jake A
JA
Kushner
M Celeste
MC
Simon
J Alan
JA
Diehl
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006943:Hyperglycemia / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D019938:Cyclin D1; D005947:Glucose; D012333:RNA, Messenger; D019892:eIF-2 Kinase; C530105:Ccnd1 protein, mouse