Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes
Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes
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DOI：
10.1016/j.molmet.2020.101014
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发表时间：
2020-09-01
影响因子：
8.1
通讯作者：
Light, Peter E.
中科院分区：
文献类型：
--
作者：
Campbell, Scott A.;Golec, Dominic P.;Light, Peter E.
目的：我们的研究表明胰高血糖素样肽-1 （glucagon-like peptide-1, GLP-1）在人类胰岛内分泌，并可能在胰岛生理和病理生理中发挥意想不到的重要旁分泌作用。众所周知，啮齿动物和人类胰岛细胞能够分泌GLP-1，但关于胰岛源性GLP-1在人类胰岛中所起的功能作用知之甚少。方法：我们使用流式细胞术、免疫组织化学、灌注和钙成像技术分析GLP-1在患有或不患有2型糖尿病的人尸体供体中分离的胰岛中的表达和功能。我们还使用免疫组织化学分析了活体供体胰腺活检组织中胰岛中GLP-1的表达。结果：我们已经证明，人类胰岛分泌的GLP-1比小鼠胰岛多50倍，并且40%的人类a细胞含有GLP-1。我们的结果也证实了二肽基肽酶-4 （DPP4）在细胞中表达。西格列汀增加了培养的人胰岛的GLP-1分泌，但没有增加非糖尿病（ND）或2型糖尿病（T2D）供体胰岛的葡萄糖刺激胰岛素分泌（GSIS），这表明b细胞GLP-1受体（GLP-1R）可能已经被最大限度地激活。因此，我们测试了exendin-9，一种GLP-1R拮抗剂的作用。Exendin-9可使ND和T2D胰岛的GSIS分别降低39%和61%。我们还观察到，与从尸体供体获得的ND胰岛相比，T2D胰岛中GLP-1thorn a细胞明显更多。此外，在手术活体供体胰岛切片中也发现了GLP-1thorn a细胞。结论：总之，我们证明了人类胰岛从一个细胞亚群中分泌大量的GLP-1， GLP-1R信号传导可能在更大程度上支持T2D胰岛的GSIS。(C) 2020作者。Elsevier GmbH出版。
Objectives: Our study shows that glucagon-like peptide-1 (GLP-1) is secreted within human islets and may play an unexpectedly important paracrine role in islet physiology and pathophysiology. It is known that a cells within rodent and human pancreatic islets are capable of secreting GLP-1, but little is known about the functional role that islet-derived GLP-1 plays in human islets.Methods: We used flow cytometry, immunohistochemistry, perifusions, and calcium imaging techniques to analyse GLP-1 expression and function in islets isolated from cadaveric human donors with or without type 2 diabetes. We also used immunohistochemistry to analyse GLP-1 expression within islets from pancreatic biopsies obtained from living donors.Results: We have demonstrated that human islets secretew50-fold more GLP-1 than murine islets and thatw40% of the total human a cells contain GLP-1. Our results also confirm that dipeptidyl peptidase-4 (DPP4) is expressed in a cells. Sitagliptin increased GLP-1 secretion from cultured human islets but did not enhance glucose-stimulated insulin secretion (GSIS) in islets from non-diabetic (ND) or type 2 diabetic (T2D) donors, suggesting that b cell GLP-1 receptors (GLP-1R) may already be maximally activated. Therefore, we tested the effects of exendin-9, a GLP-1R antagonist. Exendin-9 was shown to reduce GSIS by 39% and 61% in ND islets and T2D islets, respectively. We also observed significantly more GLP-1thorn a cells in T2D islets compared with ND islets obtained from cadaveric donors. Furthermore, GLP-1thorn a cells were also identified in pancreatic islet sections obtained from living donors undergoing surgery.Conclusions: In summary, we demonstrated that human islets secrete robust amounts of GLP-1 from an a cell subpopulation and that GLP-1R signalling may support GSIS to a greater extent in T2D islets. (C) 2020 The Author(s). Published by Elsevier GmbH.