胰岛素原
内科学
内分泌学
胰岛素
胰高血糖素
医学
激素原
生物
2型糖尿病
免疫染色
糖尿病
化学
激素
免疫组织化学
作者
Yumeng Huang,Jinyang Zhen,Tengli Liu,Yunlong Wang,Na Li,Jing Yang,Rui Liang,Shusen Wang,Ming Liu
出处
期刊:European journal of endocrinology
[Bioscientifica]
日期:2021-10-01
卷期号:185 (4): 565-576
被引量:7
摘要
Objective Progressive beta-cell dysfunction is a hallmark of type 2 diabetes (T2D). Increasing evidence indicates that over-stimulating proinsulin synthesis causes proinsulin misfolding and impairs insulin maturation and storage in db/db mice. However, defective insulin maturation in patients with T2D remains unknown. Methods We examined intra-islet and intra-cellular distributions of proinsulin and insulin and proinsulin to insulin ratio in the islets of patients with T2D. The expression of transcription factor NKX6.1 and dedifferentiation marker ALDH1A3, as well as glucagon, were detected by immunofluorescence. Results We identified a novel subgroup of beta cells expressing only proinsulin but not insulin. Importantly, significantly increased proinsulin positive and insulin negative (PI + /INS − ) cells were evident in T2D, and this increase was strongly correlated with levels of hemoglobin A1C (HbA1c) in T2D and prediabetes. The percentages of beta cells expressing prohormone convertase 1/3 and carboxypeptidase E were not reduced. Indeed, while proinsulin displayed a higher degree of co-localization with the golgi markers GM130/TGN46 in control beta cells, it appeared to be more diffused within the cytoplasm and less co-localized with GM130/TGN46 in PI + /INS − cells. Furthermore, the key functional transcription factor NKX6.1 markedly decreased in the islets of T2D, especially in the cells with PI + /INS − . The decreased NKX6.1 + /PI + /INS + was strongly correlated with levels of HbA1c in T2D. Almost all PI + /INS − cells showed absence of NKX6.1. Moreover, the percentages of PI + /INS − cells expressing ALDH1A3 were elevated along with an increased acquisition of glucagon immunostaining. Conclusion Our data demonstrate defective insulin maturation in patients with T2D.
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