Mattocks Dwight A L, Ommi Naidu B, Malloy Virginia L, Nichenametla Sailendra N
Animal Science Laboratory, Orentreich Foundation for the Advancement of Science Inc., 855, Route 301, Cold Spring-on-Hudson, NY, 10516, USA.
Geroscience. 2025 Apr;47(2):1653-1668. doi: 10.1007/s11357-024-01326-6. Epub 2024 Sep 19.
Protein folding in the endoplasmic reticulum (ER) requires a high ratio of oxidized to reduced glutathione (GSSG/rGSH). Since the GSSG/rGSH depends on total glutathione (tGSH = GSSG + rGSH) levels, we hypothesized that limiting GSH biosynthesis will ameliorate protein misfolding by enhancing the ER oxidative milieu. As a proof-of-concept, we used DL-buthionine-(S,R)-sulfoximine (BSO) to inhibit GSH biosynthesis in Akita mice, which are prone to proinsulin misfolding. We conducted a 2-week intervention to investigate if BSO was safe and a 6-week intervention to find its effect on glucose intolerance. In both cohorts, male heterozygous Akita (AK) and wild-type (WT) mice were continuously administered 15 mM BSO. No adverse effects were observed on body weight, food intake, and water intake in either cohort. Unaltered levels of plasma aspartate and alanine aminotransferases, and cystatin-C, indicate that BSO was safe. BSO-induced decreases in tGSH were tissue-dependent with maximal effects in the kidneys, where it altered the expression of genes associated with GSH biosynthesis, redox status, and proteostasis. BSO treatment decreased random blood glucose levels to 80% and 67% of levels in untreated mice in short-term and long-term cohorts, respectively, and 6-h fasting blood glucose to 82% and 74% of levels in untreated mice, respectively. BSO also improved glucose tolerance by 37% in AK mice in the long-term cohort, without affecting insulin tolerance. Neither glucose tolerance nor insulin tolerance were affected in WT. Data indicate that BSO might treat misfolded proinsulin-induced glucose intolerance. Future studies should investigate the effect of BSO on proinsulin misfolding and if it improves glucose intolerance in individuals with Mutant Insulin Diabetes of Youth.
内质网（ER）中的蛋白质折叠需要较高比例的氧化型谷胱甘肽与还原型谷胱甘肽（GSSG/rGSH）。由于GSSG/rGSH取决于总谷胱甘肽（tGSH = GSSG + rGSH）水平，我们推测限制谷胱甘肽生物合成将通过增强内质网氧化环境来改善蛋白质错误折叠。作为概念验证，我们使用DL-丁硫氨酸-（S，R）-亚砜亚胺（BSO）抑制易发生胰岛素原错误折叠的阿基塔小鼠的谷胱甘肽生物合成。我们进行了为期2周的干预以研究BSO是否安全，并进行了为期6周的干预以确定其对葡萄糖不耐受的影响。在两个队列中，雄性杂合阿基塔（AK）和野生型（WT）小鼠持续给予15 mM BSO。在任一队列中，均未观察到对体重、食物摄入量和饮水量的不良影响。血浆天冬氨酸和丙氨酸转氨酶以及胱抑素-C水平未改变，表明BSO是安全的。BSO诱导的tGSH降低具有组织依赖性，在肾脏中影响最大，它改变了与谷胱甘肽生物合成、氧化还原状态和蛋白质稳态相关的基因表达。短期和长期队列中，BSO处理分别使未处理小鼠的随机血糖水平降至80%和67%，6小时空腹血糖降至82%和74%。长期队列中，BSO还使AK小鼠的葡萄糖耐量提高了37%，而不影响胰岛素耐量。WT小鼠的葡萄糖耐量和胰岛素耐量均未受影响。数据表明，BSO可能治疗错误折叠的胰岛素原诱导的葡萄糖不耐受。未来的研究应调查BSO对胰岛素原错误折叠的影响，以及它是否能改善青年突变型胰岛素糖尿病患者的葡萄糖不耐受。
