title: Glucose-mediated repression of menin promotes pancreatic β-cell proliferation.
abstract: Menin, encoded by the Men1 gene, is responsible for β-cell tumor formation in patients with multiple endocrine neoplasia type 1. Recently, menin has been proven to negatively regulate β-cell proliferation during pregnancy. However, it is unclear whether menin is involved in pancreatic β-cell proliferation in response to other physiological replication stimuli, such as glucose. In this study, we found that the menin level was significantly reduced in high glucose-treated INS1 cells and primary rat islets, both with increased proliferation. A similar observation was found in islets isolated from rats subjected to 72-h continuous glucose infusion. The glucose-induced proliferation was inhibited by menin overexpression. Further molecular studies showed that glucose-induced menin suppression was blocked by PI3K/Akt pathway inhibitors. A major PI3K/Akt substrate, Foxo1, was shown to enhance menin transcription levels by binding the promoter region of the Men1 gene. Therefore, we conclude that glucose inhibits menin expression via the PI3K/Akt/Foxo1 pathway and hence promotes pancreatic β-cell proliferation. Our study suggests that menin might serve as an important intracellular target of glucose to mediate the mitogenic effect that glucose exerts in pancreatic β-cells.
authors.affiliation: Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology, Ruijin Hospital, Shanghai Jiaotong University Medical School, 197 Ruijin 2nd Road, 200025, Shanghai, PR China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Zhang
authors.forename: Wenyi
authors.initials: W
authors.lastname: Li
authors.forename: Qidi
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Fengying
authors.initials: F
authors.lastname: Li
authors.forename: Cuiping
authors.initials: C
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.forename: Hongmei
authors.initials: H
authors.lastname: Long
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
chemical_list: D051858:Forkhead Transcription Factors; D005947:Glucose; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C532041:Men1 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1