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 α 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 secrete ∼50-fold more GLP-1 than murine islets and that ∼40% of the total human α cells contain GLP-1. Our results also confirm that dipeptidyl peptidase-4 (DPP4) is expressed in α 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 β 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-1+ α cells in T2D islets compared with ND islets obtained from cadaveric donors. Furthermore, GLP-1+ α 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 α cell subpopulation and that GLP-1R signalling may support GSIS to a greater extent in T2D islets.

中文翻译：

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人的胰岛含有分泌胰高血糖素样肽-1的亚细胞，该亚细胞在2型糖尿病中会增加。

目标

我们的研究表明，胰高血糖素样肽1（GLP-1）在人的胰岛内分泌，可能在胰岛生理学和病理生理学中发挥出乎意料的重要旁分泌作用。已知啮齿动物和人胰岛中的α细胞能够分泌GLP-1，但是关于胰岛来源的GLP-1在人胰岛中发挥的功能作用知之甚少。

方法

我们使用流式细胞仪，免疫组化，灌注和钙成像技术来分析GLP-1的表达和功能从尸体人类捐赠者分离的胰岛中有或没有2型糖尿病。我们还使用免疫组织化学分析了从活体供体获得的胰腺活检组织中胰岛内的GLP-1表达。

结果

我们已经证明，与胰岛相比，人类胰岛分泌的GLP-1约多50倍，并且人类α细胞总数的约40％含有GLP-1。我们的结果还证实了二肽基肽酶-4（DPP4）在α细胞中表达。西他列汀增加了培养的人胰岛的GLP-1分泌，但未增强非糖尿病（ND）或2型糖尿病（T2D）供体的胰岛中葡萄糖刺激的胰岛素分泌（GSIS），表明β细胞GLP-1受体（GLP） -1R）可能已经被最大程度地激活了。因此，我们测试了GLP-1R拮抗剂exendin-9的作用。Exendin-9在ND胰岛和T2D胰岛中分别显示GSIS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胰岛中的GLP-1 +α细胞明显增多。此外，

结论

总而言之，我们证明了人类胰岛从α细胞亚群中分泌大量GLP-1，并且GLP-1R信号传导可能在T2D胰岛中更大程度地支持GSIS。