Nguyen K Hoa, Ande Sudharsana R, Mishra Suresh
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada; Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, Canada.
Biochem Biophys Res Commun. 2016 Jan 29;470(1):94-100. doi: 10.1016/j.bbrc.2016.01.001. Epub 2016 Jan 5.
The incidence of adult-onset T1D in low-risk non-HLA type has increased several folds, whereas the contemporaneous incidence in high-risk HLA-type remains stable. Various factors behind this selective increase in T1D in young adults remain unclear. Obesity and its associated abnormalities appear to be an important determinant; however, the underlying mechanism involved is not understood. Recently, we have developed two novel transgenic obese mice models, Mito-Ob and m-Mito-Ob, by expressing a pleiotropic protein prohibitin (PHB) and a phospho mutant form of PHB (Y114F-PHB or m-PHB) from the aP2 gene promoter, respectively. Both mice models develop obesity in a sex-neutral manner, independent of diet; but obesity associated chronic low-grade inflammation and insulin resistance in a male sex-specific manner. Interestingly, on a high fat diet (HFD) only male m-Mito-Ob mice displayed marked mononuclear cell infiltration in pancreas and developed insulitis that mimic adult-onset T1D. Male Mito-Ob mice that share the metabolic phenotype of male m-Mito-Ob mice, and female m-Mito-Ob that harbor m-PHB similar to male m-Mito-Ob mice, did not develop insulitis. Thus, insulitis development in male m-Mito-Ob in response to HFD requires both, obesity-related abnormalities and m-PHB. Collectively, this data provides a proof-of-concept that obesity-associated abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D and reveals PHB as a potential susceptibility gene for T1D.
低风险非HLA类型的成人发病1型糖尿病发病率增加了数倍，而高风险HLA类型的同期发病率保持稳定。年轻成年人中1型糖尿病这种选择性增加背后的各种因素仍不清楚。肥胖及其相关异常似乎是一个重要决定因素；然而，其中涉及的潜在机制尚不清楚。最近，我们分别通过从aP2基因启动子表达一种多效性蛋白抑制素（PHB）和一种PHB的磷酸化突变形式（Y114F-PHB或m-PHB），开发了两种新型转基因肥胖小鼠模型，即Mito-Ob和m-Mito-Ob。两种小鼠模型均以性别中性方式发生肥胖，与饮食无关；但以雄性特异性方式出现与肥胖相关的慢性低度炎症和胰岛素抵抗。有趣的是，在高脂饮食（HFD）条件下，只有雄性m-Mito-Ob小鼠在胰腺中表现出明显的单核细胞浸润，并发展为类似成人发病1型糖尿病的胰岛炎。具有与雄性m-Mito-Ob小鼠相同代谢表型的雄性Mito-Ob小鼠，以及与雄性m-Mito-Ob小鼠一样携带m-PHB的雌性m-Mito-Ob小鼠，均未发生胰岛炎。因此，雄性m-Mito-Ob小鼠在高脂饮食下发生胰岛炎既需要与肥胖相关的异常，也需要m-PHB。总体而言，这些数据提供了一个概念验证，即肥胖相关异常将环境触发因素与成人发病1型糖尿病的遗传易感性联系起来，并揭示PHB是1型糖尿病的一个潜在易感基因。
