Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes
Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes
复制标题
对在世的人类胰岛供体进行多组学分析，揭示了2型糖尿病中β细胞的异质性发展轨迹
DOI：
10.1038/s42255-021-00420-9
复制
发表时间：
2021-06-28
影响因子：
20.8
通讯作者：
Solimena, Michele
中科院分区：
文献类型：
--
作者：
Wigger, Leonore;Barovic, Marko;Solimena, Michele
Wigger、Barovic和Brunner等人对来自经历胰腺切除术的代谢特征患者的胰岛进行了多维分析，观察到来自患有2型糖尿病的个体的样品之间的显著异质性，大多数关于人类胰岛的研究是在从正常血糖或患病的大脑中获得的样本上进行的，死亡供体，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时的分子变化。在此，我们对胰岛进行了全面的多组学分析，这些胰岛是从代谢特征为胰腺切除的活体人类供体中获得的，这些供体沿着血糖连续体分层，从血糖正常到T2D。我们发现，激光捕获显微切割手术样本分离的胰岛池显示糖尿病患者比非糖尿病对照组的转录组学和蛋白质组学特征显着更异质。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。我们的研究结果表明，一个渐进的，但不和谐的，重塑成熟β细胞，挑战目前的假设，线性轨迹走向前体或转分化阶段的T2D。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水平正相关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。
Wigger, Barovic and Brunner et al. perform a multidimensional analysis of islets from metabolically characterized patients who had undergone pancreatectomy, observing remarkable heterogeneity between samples from individuals with type 2 diabetes, thus arguing against models of linear beta-cell dedifferentiation in diabetes.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.