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阴性脂质催化了细胞毒性胰岛素寡合体的产生

Jhinuk Saha^1,2,3, Audrey Wolszczak^1,2, Navneet Kaur^1,2

¹National High Magnetic Field Laboratory, Florida State University, 1800 E. Paul Dirac Drive, Tallahassee, FL 32310, USA.

|July 29, 2025

概括

像DMPG这样的阴性脂质会影响人体胰岛素聚合途径,在纤维细胞旁边形成可溶性,细胞毒性中间体. 这会影响胰岛素治疗的有效性和糖尿病患者的生物可用性.

科学领域:

生物化学生物化学
材料科学材料科学材料科学
医学科学医学科学医学科学

背景情况:

蛋白质错误折叠和聚合成粉样结构与代谢和神经退行性疾病有关.
人类胰岛素粉样纤维素可以在各种条件下形成,影响生物可用性,并在糖尿病治疗中提出挑战.
胰岛素聚合受到pH,温度,动以及脂质或其他蛋白质的存在等因素的影响.

研究的目的:

调查非状阴性1,2-二米里斯托伊尔-sn-甘油-3-糖醇 (DMPG) 脂质对人体胰岛素聚合途径的影响以及由此产生的聚合物的特征.
为了比较DMPG脂质存在或不存在时的聚合途径和中间形成.
评估DMPG形成的胰岛素聚合物和中间体的细胞毒性.

主要方法:

提奥夫拉T (ThT) 光测定用于监测聚合.
传输电子显微镜 (TEM) 和动态光散射 (DLS) 用于描述聚合物形态和尺寸.
核磁共振 (NMR) 光谱 (包括13C魔形旋转固态NMR) 和富里埃变换红外光谱 (FTIR) 来分析结构变化和分子动力学.
细胞毒性测试用于评估聚合物和中间体的生物影响.

主要成果:

DMPG诱导了不同的胰岛素聚合途径,导致可溶性中间体和大纤维的形成.
鉴定结果显示,当胰岛素与DMPG化时,可溶性中间体与纤维一起存在,与没有脂质形成的聚合物不同.
固态NMR和FTIR表明,DMPG不会改变胰岛素纤维的核心形状,但会影响侧链的动态.
可溶性胰岛素-DMPG中间体表现出较高的细胞毒性,与与脂质或没有脂质形成的纤维相比.

结论:

像DMPG这样的阴性脂质在指导胰岛素聚合中间体的途径和性质方面发挥着至关重要的作用.
在DMPG的存在下形成更多的细胞毒性溶解中间体突显了对胰岛素治疗的潜在担忧.
了解这些脂质介导的聚合机制对于开发提高胰岛素治疗效果和最大限度地降低毒性的策略至关重要.

关键词:

聚合方式聚合方式聚合方式粉样蛋白是什么粉样蛋白胰岛素的胰岛素胰岛素是什么脂质脂质脂质是一种

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