title: Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic β-cell function via glycogen synthase kinase-3β.
abstract: Individuals with schizophrenia and their first-degree relatives have higher rates of type 2 diabetes (T2D) than the general population (18-30 vs. 1.2-6.3%), independent of body mass index and antipsychotic medication, suggesting shared genetic components may contribute to both diseases. The cause of this association remains unknown. Mutations in disrupted in schizophrenia 1 (DISC1) increase the risk of developing psychiatric disorders [logarithm (base 10) of odds = 7.1]. Here, we identified DISC1 as a major player controlling pancreatic β-cell proliferation and insulin secretion via regulation of glycogen synthase kinase-3β (GSK3β). DISC1 expression was enriched in developing mouse and human pancreas and adult β- and ductal cells. Loss of DISC1 function, through siRNA-mediated depletion or expression of a dominant-negative truncation that models the chromosomal translocation of human DISC1 in schizophrenia, resulted in decreased β-cell proliferation (3 vs. 1%; P < 0.01), increased apoptosis (0.1 vs. 0.6%; P < 0.01), and glucose intolerance in transgenic mice. Insulin secretion was reduced (0.5 vs. 0.1 ng/ml; P < 0.05), and critical β-cell transcription factors Pdx1 and Nkx6.1 were significantly decreased. Impaired DISC1 allowed inappropriate activation of GSK3β in β cells, and antagonizing GSK3β (SB216763; IC50 = 34.3 nM) rescued the β-cell defects. These results uncover an unexpected role for DISC1 in normal β-cell physiology and suggest that DISC1 dysregulation contributes to T2D independently of its importance for cognition.
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Agata
authors.initials: A
authors.lastname: Jurczyk
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Anetta
authors.initials: A
authors.lastname: Nowosielska
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Przewozniak
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Ken-Edwin
authors.initials: KE
authors.lastname: Aryee
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: DiIorio
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: David
authors.initials: D
authors.lastname: Blodgett
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Chaoxing
authors.initials: C
authors.lastname: Yang
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Shultz
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Rittenhouse
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: David
authors.initials: D
authors.lastname: Harlan
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Greiner
authors.affiliation: *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA rita.bortell@umassmed.edu.
authors.forename: Rita
authors.initials: R
authors.lastname: Bortell
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014178:Translocation, Genetic
chemical_list: C412476:DISC1 protein, human; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: T2D; diabetes; insulin; secretion