Sharma Khushboo, Rai Pooja, Maurya Shashank Kumar, Tapadia Madhu G
Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2025 May;398(5):6031-6041. doi: 10.1007/s00210-024-03632-4. Epub 2024 Dec 5.
Amyloid-proteinopathy is observed in type 2 diabetes, where Islet amyloid polypeptide is secreted atypically and impedes cellular homeostasis. The thiazolidinediones family is reported to influence amyloid-beta aggregations. However, research on drug-based stimulation of insulin signaling to alleviate Islet amyloid aggregations is lacking. To understand the impact of pioglitazone on islet amyloid aggregation, we conducted an in vivo and in silico analysis. For in vivo analysis, we generated a transgenic Drosophila harboring the preproform of human Islet amyloid polypeptide (IAPP) that can be ectopically expressed in a spatio-temporal manner. We show that the unprocessed form of IAPP also has the propensity to form aggregates and cause degeneration. Pioglitazone feeding effectively reduces the burden of Islet amyloid aggregations in the larval brain. In silico analysis shows that there is a higher protein-ligand binding energy for IAPP with pioglitazone than amyloid-beta. These results suggests that pioglitazone might be repurposed as a drug to cure islet amyloidogenesis.
在2型糖尿病中可观察到淀粉样蛋白病变，其中胰岛淀粉样多肽分泌异常并阻碍细胞稳态。据报道，噻唑烷二酮类药物会影响β淀粉样蛋白的聚集。然而，缺乏关于基于药物刺激胰岛素信号传导以减轻胰岛淀粉样蛋白聚集的研究。为了了解吡格列酮对胰岛淀粉样蛋白聚集的影响，我们进行了体内和计算机模拟分析。对于体内分析，我们构建了一种转基因果蝇，其携带人胰岛淀粉样多肽（IAPP）的前体形式，该前体形式可以时空方式异位表达。我们发现未加工形式的IAPP也有形成聚集体并导致退化的倾向。喂食吡格列酮可有效减轻幼虫大脑中胰岛淀粉样蛋白聚集的负担。计算机模拟分析表明，与β淀粉样蛋白相比，IAPP与吡格列酮的蛋白质-配体结合能更高。这些结果表明，吡格列酮可能被重新用作治疗胰岛淀粉样变的药物。
