title: Adipsin is an adipokine that improves β cell function in diabetes.
abstract: A hallmark of type 2 diabetes mellitus (T2DM) is the development of pancreatic β cell failure, which results in insulinopenia and hyperglycemia. We show that the adipokine adipsin has a beneficial role in maintaining β cell function. Animals genetically lacking adipsin have glucose intolerance due to insulinopenia; isolated islets from these mice have reduced glucose-stimulated insulin secretion. Replenishment of adipsin to diabetic mice treated hyperglycemia by boosting insulin secretion. We identify C3a, a peptide generated by adipsin, as a potent insulin secretagogue and show that the C3a receptor is required for these beneficial effects of adipsin. C3a acts on islets by augmenting ATP levels, respiration, and cytosolic free Ca(2+). Finally, we demonstrate that T2DM patients with β cell failure are deficient in adipsin. These findings indicate that the adipsin/C3a pathway connects adipocyte function to β cell physiology, and manipulation of this molecular switch may serve as a therapy in T2DM.
authors.affiliation: Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Lo
authors.affiliation: Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sanda
authors.initials: S
authors.lastname: Ljubicic
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: Leibiger
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig 04103, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kern
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Leibiger
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Tilo
authors.initials: T
authors.lastname: Moede
authors.affiliation: Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Molly E
authors.initials: ME
authors.lastname: Kelly
authors.affiliation: Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Diti
authors.initials: D
authors.lastname: Chatterjee Bhowmick
authors.affiliation: Department of Experimental and Clinical Medicine, University of Ancona, 60020 Ancona, Italy.
authors.forename: Incoronata
authors.initials: I
authors.lastname: Murano
authors.affiliation: Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Cohen
authors.affiliation: Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Banks
authors.affiliation: Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Melin J
authors.initials: MJ
authors.lastname: Khandekar
authors.affiliation: Department of Surgery, University of Leipzig, Leipzig 04103, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Dietrich
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Flier
authors.affiliation: Department of Experimental and Clinical Medicine, University of Ancona, 60020 Ancona, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig 04103, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nika N
authors.initials: NN
authors.lastname: Danial
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bruce_spiegelman@dfci.harvard.edu.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015926:Complement C3a / Q000378:metabolism; D011416:Complement Factor D / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice
chemical_list: D007328:Insulin; D015926:Complement C3a; C493488:CFD protein, human; D011416:Complement Factor D; C493491:complement factor D, mouse; D005947:Glucose