Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany.
German Center for Diabetes Research, Neuherberg, Germany.
J Clin Endocrinol Metab. 2018 Dec 1;103(12):4373-4383. doi: 10.1210/jc.2018-00791.
Reduced β-cell mass, impaired islet function, and dedifferentiation are considered causal to development of hyperglycemia and type 2 diabetes. In human cohort studies, changes of islet cell-specific expression patterns have been associated with diabetes but not directly with in vivo insulin secretion.
This study investigates alterations of islet gene expression and corresponding gene variants in the context of in vivo glycemic traits from the same patients.
Fasting blood was collected before surgery, and pancreatic tissue was frozen after resection from 18 patients undergoing pancreatectomy. Islet tissue was isolated by laser capture microdissection. Islet transcriptome was analyzed using microarray and quantitative RT-PCR. Proteins were examined by immunohistochemistry and western blotting. The association of gene variants with insulin secretion was investigated with oral glucose tolerance test (OGTT)-derived insulin secretion measured in a large cohort of subjects at increased risk of type 2 diabetes and with hyperglycemic clamp in a subset.
Differential gene expression between islets from normoglycemic and hyperglycemic patients was prominent for the glycolytic enzyme ALDOB and the obesity-associated gene FAIM2. The mRNA levels of both genes correlated negatively with insulin secretion and positively with HbA1c. Islets of hyperglycemic patients displayed increased ALDOB immunoreactivity in insulin-positive cells, whereas α- and δ-cells were negative. Exposure of isolated islets to hyperglycemia augmented ALDOB expression. The minor allele of the ALDOB variant rs550915 associated with significantly higher levels of C-peptide and insulin during OGTT and hyperglycemic clamp, respectively.
Our analyses suggest that increased ALDOB expression in human islets is associated with lower insulin secretion.
β细胞质量减少、胰岛功能受损和去分化被认为是导致高血糖和 2 型糖尿病发生的原因。在人类队列研究中，胰岛细胞特异性表达模式的变化与糖尿病有关，但与体内胰岛素分泌无关。
本研究旨在调查同一患者体内血糖特征相关的胰岛基因表达变化及其相应的基因变异。
18 例行胰腺切除术的患者在术前采集空腹血，术后切除胰腺组织，用激光捕获显微切割分离胰岛组织。采用微阵列和定量 RT-PCR 分析胰岛转录组。通过免疫组织化学和 Western blot 检测蛋白质。通过口服葡萄糖耐量试验（OGTT）衍生的胰岛素分泌，在 2 型糖尿病风险增加的大队列中以及在亚组中通过高血糖钳夹试验，研究基因变异与胰岛素分泌的相关性。
正常血糖和高血糖患者之间的胰岛差异表达基因主要为糖酵解酶 ALDOB 和肥胖相关基因 FAIM2。这两个基因的 mRNA 水平与胰岛素分泌呈负相关，与 HbA1c 呈正相关。高血糖患者的胰岛中 ALDOB 免疫反应性在胰岛素阳性细胞中增加，而在α和δ细胞中为阴性。分离的胰岛暴露于高血糖会增加 ALDOB 的表达。ALDOB 变体 rs550915 的次要等位基因与 OGTT 和高血糖钳夹期间的 C 肽和胰岛素水平分别显著相关。
我们的分析表明，人类胰岛中 ALDOB 表达增加与胰岛素分泌减少有关。
