1FASEB J. 2016 Feb 30: 983-93
TitleBeyond the brain: disrupted in schizophrenia 1 regulates pancreatic ?-cell function via glycogen synthase kinase-3?.
AbstractIndividuals 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 ?-cell proliferation and insulin secretion via regulation of glycogen synthase kinase-3? (GSK3?). DISC1 expression was enriched in developing mouse and human pancreas and adult ?- 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 ?-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 ?-cell transcription factors PDX1 and Nkx6.1 were significantly decreased. Impaired DISC1 allowed inappropriate activation of GSK3? in ? cells, and antagonizing GSK3? (SB216763; IC50 = 34.3 nM) rescued the ?-cell defects. These results uncover an unexpected role for DISC1 in normal ?-cell physiology and suggest that DISC1 dysregulation contributes to T2D independently of its importance for cognition.
SCZ Keywordsschizophrenia