Department of Pathology, Immunology, and Laboratory Medicine, The University of Florida Diabetes Institute, Gainesville, FL, USA.
Department of Neuroscience, The University of Florida Diabetes Institute, Gainesville, FL, USA.
Cell Metab. 2017 Sep 5;26(3):568-575.e3. doi: 10.1016/j.cmet.2017.08.013.
The canonical notion that type 1 diabetes (T1D) results following a complete destruction of β cells has recently been questioned as small amounts of C-peptide are detectable in patients with long-standing disease. We analyzed protein and gene expression levels for proinsulin, insulin, C-peptide, and islet amyloid polypeptide within pancreatic tissues from T1D, autoantibody positive (Ab+), and control organs. Insulin and C-peptide levels were low to undetectable in extracts from the T1D cohort; however, proinsulin and INS mRNA were detected in the majority of T1D pancreata. Interestingly, heterogeneous nuclear RNA (hnRNA) for insulin and INS-IGF2, both originating from the INS promoter, were essentially undetectable in T1D pancreata, arguing for a silent INS promoter. Expression of PCSK1, a convertase responsible for proinsulin processing, was reduced in T1D pancreata, supportive of persistent proinsulin. These data implicate the existence of β cells enriched for inefficient insulin/C-peptide production in T1D patients, potentially less susceptible to autoimmune destruction.
长期以来，人们一直认为 1 型糖尿病（T1D）是由于β细胞完全破坏所致，但最近这一观点受到了质疑，因为在长期患病的患者中仍能检测到少量 C 肽。我们分析了 T1D、自身抗体阳性（Ab+）和对照器官的胰腺组织中胰岛素原、胰岛素、C 肽和胰岛淀粉样多肽的蛋白和基因表达水平。T1D 队列的提取物中胰岛素和 C 肽水平较低甚至无法检测到；然而，大多数 T1D 胰腺中均检测到胰岛素原和 INS mRNA。有趣的是，胰岛素和 INS-IGF2 的异质核 RNA（hnRNA）均源自 INS 启动子，在 T1D 胰腺中几乎无法检测到，这表明 INS 启动子处于沉默状态。负责胰岛素原加工的转化酶 PCSK1 的表达在 T1D 胰腺中减少，支持持续存在的胰岛素原。这些数据表明，T1D 患者中存在β细胞，这些β细胞富含效率低下的胰岛素/C 肽生成，可能对自身免疫破坏的敏感性较低。
