Laboratory for Molecular Medicine and Israeli Rat Genome Center, Barzilai University Medical Center, Ashkelon 7830604, Israel.
Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 8410501, Israel.
Int J Mol Sci. 2023 Jan 10;24(2):1355. doi: 10.3390/ijms24021355.
The Cohen Diabetic rat is a model of type 2 diabetes mellitus that consists of the susceptible (CDs/y) and resistant (CDr/y) strains. Diabetes develops in CDs/y provided diabetogenic diet (DD) but not when fed regular diet (RD) nor in CDr/y given either diet. We recently identified in CDs/y a deletion in , a gene that has been attributed a role in the unfolded protein response (UPR) and in the prevention of endoplasmic reticulum (ER) stress. We hypothesized that this deletion prevents expression of SDF2L1 and contributes to the pathophysiology of diabetes in CDs/y by impairing UPR, enhancing ER stress, and preventing CDs/y from secreting sufficient insulin upon demand. We studied SDF2L1 expression in CDs/y and CDr/y. We evaluated UPR by examining expression of key proteins involved in both strains fed either RD or DD. We assessed the ability of all groups of animals to secrete insulin during an oral glucose tolerance test (OGTT) over 4 weeks, and after overnight feeding (postprandial) over 4 months. We found that SDF2L1 was expressed in CDr/y but not in CDs/y. The pattern of expression of proteins involved in UPR, namely the PERK (EIF2α, ATF4 and CHOP) and IRE1 (XBP-1) pathways, was different in CDs/y DD from all other groups, with consistently lower levels of expression at 4 weeks after initiation of DD and coinciding with the development of diabetes. In CDs/y RD, insulin secretion was mildly impaired, whereas in CDs/y DD, the ability to secrete insulin decreased over time, leading to the development of the diabetic phenotype. We conclude that in CDs/y DD, UPR participating proteins were dysregulated and under-expressed at the time point when the diabetic phenotype became overt. In parallel, insulin secretion in CDs/y DD became markedly impaired. Our findings suggest that under conditions of metabolic load with DD and increased demand for insulin secretion, the lack of SDF2L1 expression in CDs/y is associated with UPR dysregulation and ER stress which, combined with oxidative stress previously attributed to the concurrent mutation, are highly likely to contribute to the pathophysiology of diabetes in this model.
科恩糖尿病大鼠是一种 2 型糖尿病模型，包括易感（CDs/y）和抗性（CDr/y）两种品系。CDs/y 大鼠在给予致糖尿病饮食（DD）时会发生糖尿病，但在给予常规饮食（RD）时不会，CDr/y 大鼠无论给予哪种饮食都不会发生糖尿病。我们最近在 CDs/y 大鼠中发现了一个缺失，该基因被认为在未折叠蛋白反应（UPR）和预防内质网（ER）应激中起作用。我们假设这种缺失阻止了 SDF2L1 的表达，并通过损害 UPR、增强 ER 应激以及阻止 CDs/y 大鼠按需分泌足够的胰岛素，导致 CDs/y 大鼠的糖尿病病理生理学发生。我们研究了 CDs/y 和 CDr/y 大鼠中 SDF2L1 的表达。我们通过检查两种品系大鼠在给予 RD 或 DD 时参与 UPR 的关键蛋白的表达来评估 UPR。我们评估了所有动物组在 4 周的口服葡萄糖耐量试验（OGTT）期间和 4 个月的 overnight feeding（餐后）期间分泌胰岛素的能力。我们发现 SDF2L1 在 CDr/y 大鼠中表达，但在 CDs/y 大鼠中不表达。在开始给予 DD 后 4 周，参与 UPR 的蛋白质（即 PERK（EIF2α、ATF4 和 CHOP）和 IRE1（XBP-1）途径）的表达模式在 CDs/y DD 与所有其他组不同，表达水平始终较低，这与糖尿病的发生一致。在 CDs/y RD 大鼠中，胰岛素分泌轻度受损，而在 CDs/y DD 大鼠中，随着时间的推移，胰岛素分泌能力下降，导致糖尿病表型的发展。我们得出结论，在 CDs/y DD 大鼠中，在糖尿病表型明显出现之前的时间点，UPR 参与蛋白被失调且表达不足。同时，CDs/y DD 大鼠的胰岛素分泌明显受损。我们的发现表明，在给予 DD 导致代谢负荷增加和对胰岛素分泌需求增加的情况下，CDs/y 大鼠缺乏 SDF2L1 表达与 UPR 失调和 ER 应激有关，这与之前归因于并发 突变的氧化应激一起，很可能导致该模型糖尿病的病理生理学发生。
