我们很早就知道，精神疾病例如精神分裂症与2型糖尿病的高发有密切联系。发表在《美国实验生物学学会联合会杂志》一项新的研究发现，一个共同基因可能促成两种疾病的同时出现。本研究首次提出了证据表明DISC1基因也是一种新的基因，在胰腺β细胞生存和功能中起到意想不到的作用。它也首次提供了精神疾病患者与2型糖尿病之间的关系。
为了证实这一发现，Bortell博士从基因层面操控一组小鼠来干扰破坏小鼠体内的胰腺β细胞的DISC1基因。与正常小鼠相比，DISC1基因受损的小鼠显示β细胞死亡增加，胰岛素分泌减少，糖耐量降低。当这些研究人员培养的β细胞中DISC1基因表达被抑制时，他们发现通过抑制特异性蛋白GSK3β的活性才能使DISC1继续作用。降低GSK3β活性是已知β细胞功能和生存的关键。研究小组通过直接抑制GSK3β的功能来进一步测试有效性。这可改善β细胞生存状况并能恢复DISC1受损小鼠的正常糖耐量。这些结果显示正常β细胞中DISC1一个意想不到的作用，表明DISC1可以独立调节血糖功能。
“众所周知， 由于几个因素的相互作用患有精神疾病的患者可能倾向于发展2型糖尿病，这些因素包括遗传、生活方式和药物治疗。基于我们对小鼠的研究，数据预测DISC1受损能对疾病起关键性作用，”Bortell补充说，它对人类的作用还有待证实。“DISC1受损对糖尿病和精神疾病的影响可能会揭示一种机制，该机制可提高治疗缓解这两种疾病造成的痛苦。”
Bortell说，评估新的抗精神病药物对胰腺β细胞影响具有潜在重要性。经常监测有精神疾病的糖尿病患者能及时发现异况，许多抗精神病药物也与糖尿病的风险增加有关。“我们也很感兴趣，糖尿病人为何有较高的风险患抑郁症，这表明连接大脑和胰腺β细胞的特殊分子可能会被发现。”Bortell说。
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Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic β-cell function via glycogen synthase kinase-3β
Agata Jurczyk*, Anetta Nowosielska†, Natalia Przewozniak*, Ken-Edwin Aryee*, Philip DiIorio‡,1, David Blodgett*, Chaoxing Yang*, Martha Campbell-Thompson§, Mark Atkinson§, Leonard Shultz¶, Ann Rittenhouse‖, David Harlan*, Dale Greiner* and Rita Bortell*,2
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.—Jurczyk, A., Nowosielska, A., Przewozniak, N., Aryee, K.-E., DiIorio, P., Blodgett, D., Yang, C., Campbell-Thompson, M., Atkinson, M., Shultz, L., Rittenhouse, A. Harlan, D., Greiner, D., Bortell, R. Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic β-cell function via glycogen synthase kinase-3β.