Shrestha Swikriti, Jennings Lauren T, Knofczynski Kyle, Shivakumar Sharath B, Peterson Quinn P
Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, 200 1st Street SW, Rochester, MN 55902, USA.
Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st Street SW, Rochester, MN 55902, USA.
Stem Cell Reports. 2025 Jun 10;20(6):102504. doi: 10.1016/j.stemcr.2025.102504. Epub 2025 May 8.
Dysfunction of pancreatic alpha cells contributes to the pathophysiology of diabetes. Features of diabetic alpha cell dysfunction include glucagon hypersecretion, defects in proglucagon processing, and altered transcriptomic profile. The lack of an in vitro human alpha cell model has prevented the investigation, and potential correction, of these dysfunctional phenotypes. Here, we show that induction of endoplasmic reticulum (ER) stress in stem cell-derived alpha (SC-α) cells induces hypersecretion of glucagon. ER stress also increases the secretion of glicentin and the expression of glucagon-like peptide-1 (GLP-1), peptides produced by alternate cleavage of proglucagon by the prohormone convertase 1 (PC1/3) enzyme. Additionally, ER stress establishes a diabetic transcriptional state in SC-α cells characterized by downregulation of MAFB, as well as glycolysis and oxidative phosphorylation pathways. We show that sunitinib, a tyrosine kinase inhibitor, protects SC-α cells against the ER stress-induced glucagon hypersecretion phenotype. Thus, SC-α cell model can advance our knowledge of islets in health and diabetes.
胰腺α细胞功能障碍参与了糖尿病的病理生理过程。糖尿病α细胞功能障碍的特征包括胰高血糖素分泌过多、胰高血糖素原加工缺陷以及转录组谱改变。缺乏体外人α细胞模型阻碍了对这些功能障碍表型的研究及潜在纠正。在此，我们表明在内质网（ER）应激诱导下，干细胞衍生的α（SC-α）细胞会诱导胰高血糖素分泌过多。ER应激还会增加甘丙肽的分泌以及胰高血糖素样肽-1（GLP-1）的表达，GLP-1是由激素原转化酶1（PC1/3）对胰高血糖素原进行交替切割产生的肽。此外，ER应激在SC-α细胞中建立了一种糖尿病转录状态，其特征是MAFB以及糖酵解和氧化磷酸化途径下调。我们表明，酪氨酸激酶抑制剂舒尼替尼可保护SC-α细胞免受ER应激诱导的胰高血糖素分泌过多表型的影响。因此，SC-α细胞模型可以增进我们对健康状态和糖尿病状态下胰岛的认识。
