Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Department of Molecular Diabetology, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Nat Metab. 2021 Jul;3(7):1017-1031. doi: 10.1038/s42255-021-00420-9. Epub 2021 Jun 28.
Most research on human pancreatic islets is conducted on samples obtained from normoglycaemic or diseased brain-dead donors and thus cannot accurately describe the molecular changes of pancreatic islet beta cells as they progress towards a state of deficient insulin secretion in type 2 diabetes (T2D). Here, we conduct a comprehensive multi-omics analysis of pancreatic islets obtained from metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum, from normoglycemia to T2D. We find that islet pools isolated from surgical samples by laser-capture microdissection display remarkably more heterogeneous transcriptomic and proteomic profiles in patients with diabetes than in non-diabetic controls. The differential regulation of islet gene expression is already observed in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive, but disharmonic, remodelling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or transdifferentiation stages in T2D. Furthermore, through integration of islet transcriptomics with preoperative blood plasma lipidomics, we define the relative importance of gene coexpression modules and lipids that are positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.
大多数关于人类胰腺胰岛的研究都是在血糖正常或患有脑死亡疾病的供体获得的样本上进行的，因此不能准确描述胰岛β细胞在 2 型糖尿病（T2D）中向胰岛素分泌不足状态发展的分子变化。在这里，我们对从代谢特征明确的胰腺切除术活体供体中获得的胰岛进行了全面的多组学分析，这些供体沿着血糖连续体分层，从血糖正常到 T2D。我们发现，通过激光捕获显微切割从手术样本中分离的胰岛池在糖尿病患者中的转录组和蛋白质组谱比非糖尿病对照组显著更为异质。在糖耐量受损的糖尿病前期个体中，胰岛基因表达的差异调节已经被观察到。我们的研究结果表明，成熟的β细胞发生了渐进但不协调的重塑，这对 T2D 中向前体细胞或转分化阶段的线性轨迹的现有假说提出了挑战。此外，通过将胰岛转录组学与术前血浆脂质组学相结合，我们定义了与 HbA1c 水平呈正相关或负相关的基因共表达模块和脂质的相对重要性，这为潜在的预后标志物指明了方向。
