title: mTORC1 pathway mediates beta cell compensatory proliferation in 60 % partial-pancreatectomy mice.
abstract: Beta cell replication is the major component for maintenance of beta cell mass in adult rodents; however, little is known about what is the earliest signals that initiate rodent beta cell proliferation. The mTORC1 pathway integrates signals from growth factors and nutrients and regulates cell growth and survival. Here, we used normoglycemic 60 % partial-pancreatectomy (60 % Px) mouse model to determine whether mTORC1 pathway was required for compensatory beta cell proliferation. C57BL/6 J male mice were subjected to 60 % Px or sham operation, and subsequently treated with either rapamycin or vehicle for 7 days. Metabolic profile, pancreatic beta cell mass, and proliferation were examined, and expression levels of cell cycle regulators were determined. Beta cell proliferation was increased by 2.5-fold, and mTORC1 signaling was activated in islets post-Px. Rapamycin treatment impaired glucose tolerance and glucose stimulating insulin secretion in 60 % Px mice, but did not affect their insulin sensitivity in peripheral tissue. Rapamycin inhibited mTORC1 activity in beta cells, suppressed compensatory beta cell proliferation and growth, and reduced beta cell mass and insulin content in 60 % Px mice. Px caused an increase of the cyclin D2 at protein level and promoted cyclin D2 nuclear localization in an mTOR-dependent manner. Disrupting mTORC1 signaling suppressed cell proliferation and simultaneously diminished cyclin D2 protein abundance in RINm5F cells. Our data demonstrated that mTORC1 plays an essential role in beta cell adaption to significant beta cell mass loss in 60 % Px model and in early compensatory beta cell proliferation via cyclin D2 pathway.
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Li
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China.
authors.forename: Aifang
authors.initials: A
authors.lastname: Nie
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China.
authors.forename: Qicheng
authors.initials: Q
authors.lastname: Ni
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China.
authors.forename: Fengying
authors.initials: F
authors.lastname: Li
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China. qidiwang@yahoo.com.
authors.forename: Qidi
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology*; D056742:Cyclin D2 / Q000378:metabolism; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D010180:Pancreatectomy; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D056742:Cyclin D2; D007328:Insulin; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: 60 % Partial-pancreatectomy; Beta cell proliferation; Cyclin D2; mTORC1
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