title: Research Resource: A Dual Proteomic Approach Identifies Regulated Islet Proteins During β-Cell Mass Expansion In Vivo.
abstract: Diabetes is characterized by insulin insufficiency due to a relative paucity of functional β-cell mass. Thus, strategies for increasing β-cell mass in situ are sought-after for therapeutic purposes. Pregnancy is a physiological state capable of inducing robust β-cell mass expansion, however, the mechanisms driving this expansion are not fully understood. Thus, the aim of this study was to characterize pregnancy-induced changes in the islet proteome at the peak of β-cell proliferation in mice. Islets from pregnant and nonpregnant littermates were compared via 2 proteomic strategies. In vivo pulsed stable isotope labeling of amino acids in cell culture was used to monitor de novo protein synthesis during the first 14.5 days of pregnancy. In parallel, protein abundance was determined using ex vivo dimethyl labelling at gestational day 14.5. Comparison of the 2 datasets revealed 170 islet proteins to be up regulated as a response to pregnancy. These included several proteins, not previously associated with pregnancy-induced islet expansion, such as CLIC1, STMN1, MCM6, PPIB, NEDD4, and HLTF. Confirming the validity of our approach, we also identified proteins encoded by genes known to be associated with pregnancy-induced islet expansion, such as CHGB, IGFBP5, MATN2, EHHADH, IVD, and BMP1. Bioinformatic analyses demonstrated enrichment and activation of the biological functions: "protein synthesis" and "proliferation," and predicted the transcription factors HNF4α, MYC, MYCN, E2F1, NFE2L2, and HNF1α as upstream regulators of the observed expressional changes. As the first characterization of the islet-proteome during pregnancy, this study provides novel insight into the mechanisms involved in promoting pregnancy-induced β-cell mass expansion and function.
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Signe
authors.initials: S
authors.lastname: Horn
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Jeannette S
authors.initials: JS
authors.lastname: Kirkegaard
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Soraya
authors.initials: S
authors.lastname: Hoelper
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Seymour
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Claude
authors.initials: C
authors.lastname: Rescan
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Jens H
authors.initials: JH
authors.lastname: Nielsen
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Ole D
authors.initials: OD
authors.lastname: Madsen
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Jan N
authors.initials: JN
authors.lastname: Jensen
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Mads
authors.initials: M
authors.lastname: Grønborg
authors.affiliation: Global Research (S.Hor., J.S.K., C.R., O.D.M., J.N.J., M.G., J.A.-R.), Novo Nordisk A/S, 2870 Maaloev, Denmark; Department of Biomedical Sciences (S.Hor., J.S.K., J.H.N.), University of Copenhagen, 2200 Copenhagen N, Denmark; Max Planck Institute for Heart and Lung Research (S.Hoe.), 61231 Bad Nauheim, Germany; The Danish Stem Cell Center (P.A.S., O.D.M.), University of Copenhagen, 2200 Copenhagen N, Denmark; and Institute of Genetics (M.K.), Cluster of Excellence in Cellular Stress Responses, University of Cologne, 50931 Cologne, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Ahnfelt-Rønne
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D005260:Female; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D011247:Pregnancy; D040901:Proteomics / Q000379:methods*