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FASEB J. 2016 Feb;30(2):983-93. doi: 10.1096/fj.15-279810. Epub 2015 Nov 6.

Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic β-cell function via glycogen synthase kinase-3β.

Author information

1
*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.
2
*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.

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.

KEYWORDS:

T2D; diabetes; insulin; secretion

PMID:
26546129
PMCID:
PMC4714549
DOI:
10.1096/fj.15-279810
[Indexed for MEDLINE]
Free PMC Article

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