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.

大多数关于人类胰岛的研究都是在从血糖正常或患病的脑死亡供体获得的样本上进行的，因此无法准确描述胰岛β细胞在 2 型糖尿病 (T2D) 中向胰岛素分泌不足状态发展时的分子变化。在这里，我们对胰岛进行了全面的多组学分析，这些胰岛是从血糖连续体（从正常血糖到 T2D）分层的代谢分析的胰腺切除活体供体获得的。我们发现，通过激光捕获显微切割从手术样本中分离出的胰岛池在糖尿病患者中的转录组和蛋白质组学特征显着高于非糖尿病对照组。在糖耐量受损的糖尿病前期个体中已经观察到胰岛基因表达的差异调节。我们的研究结果证明了成熟β细胞的渐进但不和谐的重塑，挑战了当前关于T2D前体或转分化阶段线性轨迹的假设。此外，通过整合胰岛转录组学与术前血浆脂质组学，我们定义了与 HbA1c 水平正或负相关的基因共表达模块和脂质的相对重要性，指出了潜在的预后标志物。