Jurczyk Agata, Nowosielska Anetta, Przewozniak Natalia, Aryee Ken-Edwin, DiIorio Philip, Blodgett David, Yang Chaoxing, Campbell-Thompson Martha, Atkinson Mark, Shultz Leonard, Rittenhouse Ann, Harlan David, Greiner Dale, Bortell Rita
*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.
*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
FASEB J. 2016 Feb;30(2):983-93. doi: 10.1096/fj.15-279810. Epub 2015 Nov 6.
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.
精神分裂症患者及其一级亲属患2型糖尿病（T2D）的比例高于普通人群（18 - 30% 对比1.2 - 6.3%），且不受体重指数和抗精神病药物的影响，这表明共同的遗传成分可能导致了这两种疾病。这种关联的原因尚不清楚。精神分裂症相关1基因（DISC1）的突变会增加患精神疾病的风险[优势对数（以10为底）= 7.1]。在此，我们发现DISC1是通过调节糖原合酶激酶 - 3β（GSK3β）来控制胰腺β细胞增殖和胰岛素分泌的主要因子。DISC1在发育中的小鼠和人类胰腺以及成年β细胞和导管细胞中表达丰富。通过小干扰RNA介导的消耗或表达模拟精神分裂症患者中人类DISC1染色体易位的显性负性截短体来丧失DISC1功能，会导致转基因小鼠的β细胞增殖减少（3% 对比1%；P < 0.01）、细胞凋亡增加（0.1% 对比0.6%；P < 0.01）以及葡萄糖不耐受。胰岛素分泌减少（0.5 ng/ml对比0.1 ng/ml；P < 0.05），关键的β细胞转录因子Pdx1和Nkx6.1显著降低。DISC1功能受损会导致β细胞中GSK3β的不适当激活，而拮抗GSK3β（SB216763；IC50 = 34.3 nM）可挽救β细胞缺陷。这些结果揭示了DISC1在正常β细胞生理学中的意外作用，并表明DISC1失调与T2D有关，且与其对认知的重要性无关。
