Revealing the role of increased SK3 expression in sulfonylurea resistance triggered by prolonged exposure.

IF 4.6 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Jung Gyu Park, Minseok Kim, Sungje Yoo, Sun Wook Hwang, Jongsoo Mok, Joonghoon Park, Keon Wook Kang
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引用次数: 0

Abstract

Background: Sulfonylureas have long been utilized in the management of type-2 diabetes mellitus (T2DM) due to their insulin-secretagogue properties. However, their clinical efficacy is hindered by the risk of severe hypoglycemia and secondary sulfonylurea failure. While the mechanisms underlying sulfonylurea-induced hypoglycemia are well-documented, the precise factors contributing to sulfonylurea resistance (SR) remain poorly understood. This study aims to elucidate the molecular basis of SR in insulinoma cells and an animal model.

Methods: INS-1E, rat insulinoma cells, were exposed to 10 μM glibenclamide for 7 days to induce sulfonylurea resistance (SR). Sprague-Dawley (SD) rats were fed a diet containing 0.01% glibenclamide for 3 weeks to induce sulfonylurea resistance.

Results: Insulinoma cells resistant to sulfonylureas exhibited elevated resting membrane potentials compared to sensitive cells. Transcriptome analysis revealed differential expression of genes, notably highlighting the significance of kcnn3 (Potassium Calcium-Activated Channel Subfamily N Member 3) in SR insulinoma cells. Western blot analysis confirmed the upregulation of SK3 protein in correlation with the duration of sulfonylurea exposure. Long-term administration of sulfonylureas in SD rats led to a diminished anti-diabetic response and increased SK3 expression in islets.

Conclusion: This study elucidates the molecular mechanisms underlying SR, with a specific focus on the overexpression of the SK3 channel in insulinoma cells. These findings enhance our understanding of the challenges associated with prolonged sulfonylurea therapy in the management of T2DM.

揭示SK3表达增加在长时间暴露引发的磺脲抗性中的作用。
背景:磺脲类药物由于其胰岛素分泌特性,长期以来被用于治疗2型糖尿病(T2DM)。然而,严重低血糖和继发性磺脲类药物失效的风险阻碍了其临床疗效。虽然磺脲类药物诱发低血糖的机制已被充分证实,但导致磺脲类药物耐药(SR)的确切因素仍知之甚少。本研究旨在阐明SR在胰岛素瘤细胞中的分子基础和动物模型。方法:将大鼠胰岛素瘤细胞in - 1e暴露于10 μM格列苯脲中7 d,诱导其产生磺酰脲耐药。采用0.01%格列苯脲喂养SD大鼠3周,诱导其对磺脲类药物产生耐药性。结果:与敏感细胞相比,对磺脲类药物耐药的胰岛素瘤细胞表现出更高的静息膜电位。转录组分析揭示了基因的差异表达,特别强调了kcnn3(钾钙激活通道亚家族N成员3)在SR胰岛素瘤细胞中的意义。Western blot分析证实,SK3蛋白的上调与磺酰脲暴露时间有关。SD大鼠长期服用磺脲类药物导致抗糖尿病反应降低,胰岛中SK3表达增加。结论:本研究阐明了SR的分子机制,特别关注胰岛素瘤细胞中SK3通道的过表达。这些发现增强了我们对长期磺脲类药物治疗T2DM相关挑战的理解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Nutrition & Diabetes
Nutrition & Diabetes ENDOCRINOLOGY & METABOLISM-NUTRITION & DIETETICS
CiteScore
9.20
自引率
0.00%
发文量
50
审稿时长
>12 weeks
期刊介绍: Nutrition & Diabetes is a peer-reviewed, online, open access journal bringing to the fore outstanding research in the areas of nutrition and chronic disease, including diabetes, from the molecular to the population level.
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