title: Altered insulin receptor signalling and β-cell cycle dynamics in type 2 diabetes mellitus.
abstract: Insulin resistance, reduced β-cell mass, and hyperglucagonemia are consistent features in type 2 diabetes mellitus (T2DM). We used pancreas and islets from humans with T2DM to examine the regulation of insulin signaling and cell-cycle control of islet cells. We observed reduced β-cell mass and increased α-cell mass in the Type 2 diabetic pancreas. Confocal microscopy, real-time PCR and western blotting analyses revealed increased expression of PCNA and down-regulation of p27-Kip1 and altered expression of insulin receptors, insulin receptor substrate-2 and phosphorylated BAD. To investigate the mechanisms underlying these findings, we examined a mouse model of insulin resistance in β-cells--which also exhibits reduced β-cell mass, the β-cell-specific insulin receptor knockout (βIRKO). Freshly isolated islets and β-cell lines derived from βIRKO mice exhibited poor cell-cycle progression, nuclear restriction of FoxO1 and reduced expression of cell-cycle proteins favoring growth arrest. Re-expression of insulin receptors in βIRKO β-cells reversed the defects and promoted cell cycle progression and proliferation implying a role for insulin-signaling in β-cell growth. These data provide evidence that human β- and α-cells can enter the cell-cycle, but proliferation of β-cells in T2DM fails due to G1-to-S phase arrest secondary to defective insulin signaling. Activation of insulin signaling, FoxO1 and proteins in β-cell-cycle progression are attractive therapeutic targets to enhance β-cell regeneration in the treatment of T2DM.
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, United States of America. folli@uthscsa.edu
authors.forename: Franco
authors.initials: F
authors.lastname: Folli
authors.forename: Terumasa
authors.initials: T
authors.lastname: Okada
authors.forename: Carla
authors.initials: C
authors.lastname: Perego
authors.forename: Jenny
authors.initials: J
authors.lastname: Gunton
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.forename: Masaru
authors.initials: M
authors.lastname: Akiyama
authors.forename: Anna
authors.initials: A
authors.lastname: D'Amico
authors.forename: Stefano
authors.initials: S
authors.lastname: La Rosa
authors.forename: Claudia
authors.initials: C
authors.lastname: Placidi
authors.forename: Roberto
authors.initials: R
authors.lastname: Lupi
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
authors.forename: Marc
authors.initials: M
authors.lastname: Hellerstein
authors.forename: Lucia
authors.initials: L
authors.lastname: Perego
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D016193:G1 Phase / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000172:deficiency / Q000378:metabolism*; D016196:S Phase / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014019:Tissue Donors
chemical_list: D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D007328:Insulin; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D011972:Receptor, Insulin