title: Insulin and glucagon regulate pancreatic α-cell proliferation.
abstract: Type 2 diabetes mellitus (T2DM) results from insulin resistance and β-cell dysfunction, in the setting of hyperglucagonemia. Glucagon is a 29 amino acid peptide hormone, which is secreted from pancreatic α cells: excessively high circulating levels of glucagon lead to excessive hepatic glucose output. We investigated if α-cell numbers increase in T2DM and what factor (s) regulate α-cell turnover. Lepr(db)/Lepr(db) (db/db) mice were used as a T2DM model and αTC1 cells were used to study potential α-cell trophic factors. Here, we demonstrate that in db/db mice α-cell number and plasma glucagon levels increased as diabetes progressed. Insulin treatment (EC50 = 2 nM) of α cells significantly increased α-cell proliferation in a concentration-dependent manner compared to non-insulin-treated α cells. Insulin up-regulated α-cell proliferation through the IR/IRS2/AKT/mTOR signaling pathway, and increased insulin-mediated proliferation was prevented by pretreatment with rapamycin, a specific mTOR inhibitor. GcgR antagonism resulted in reduced rates of cell proliferation in αTC1 cells. In addition, blockade of GcgRs in db/db mice improved glucose homeostasis, lessened α-cell proliferation, and increased intra-islet insulin content in β cells in db/db mice. These studies illustrate that pancreatic α-cell proliferation increases as diabetes develops, resulting in elevated plasma glucagon levels, and both insulin and glucagon are trophic factors to α-cells. Our current findings suggest that new therapeutic strategies for the treatment of T2DM may include targeting α cells and glucagon.
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Liu
authors.forename: Wook
authors.initials: W
authors.lastname: Kim
authors.forename: Zhike
authors.initials: Z
authors.lastname: Chen
authors.forename: Yu-Kyong
authors.initials: YK
authors.lastname: Shin
authors.forename: Olga D
authors.initials: OD
authors.lastname: Carlson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Fiori
authors.forename: Li
authors.initials: L
authors.lastname: Xin
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Napora
authors.forename: Ryan
authors.initials: R
authors.lastname: Short
authors.forename: Juliana O
authors.initials: JO
authors.lastname: Odetunde
authors.forename: Qizong
authors.initials: Q
authors.lastname: Lao
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000097:blood / Q000502:physiology*; D050416:Glucagon-Secreting Cells / Q000166:cytology*; D006984:Hypertrophy / Q000209:etiology; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains
chemical_list: D007328:Insulin; D005934:Glucagon