Persistence of Pancreatic Insulin mRNA Expression and Proinsulin Protein in Type 1 Diabetes Pancreata

• Published in: Cell metabolism Vol. 26; no. 3; pp. 568 - 575.e3
• Main Authors: Wasserfall, Clive, Nick, Harry S., Campbell-Thompson, Martha, Beachy, Dawn, Haataja, Leena, Kusmartseva, Irina, Posgai, Amanda, Beery, Maria, Rhodes, Christopher, Bonifacio, Ezio, Arvan, Peter, Atkinson, Mark
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.09.2017
• Subjects: Adult; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - pathology; Female; Gene Expression Regulation; Glucagon - metabolism; Humans; Insulin - genetics; Insulin - metabolism; insulin mRNA; insulin promoter; insulin-positive single cells; Male; pancreas; Pancreas - metabolism; Pancreas - pathology; Pancreas, Exocrine - metabolism; Pancreas, Exocrine - pathology; PCSK1; PCSK2; proconvertases; proinsulin; Proinsulin - metabolism; Proprotein Convertase 1 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; type 1 diabetes; Young Adult; insulin mRNA; PCSK2; proinsulin; PCSK1; type 1 diabetes; pancreas; proconvertases; insulin-positive single cells; insulin promoter
• ISSN: 1550-4131; 1932-7420
• 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. [Display omitted] •Proinsulin is detectable, whereas insulin and C-peptide are reduced in T1D pancreas•Insulin mRNA is evident in T1D pancreas, while insulin hnRNA is undetectable•PCSK1 is reduced in T1D pancreas, suggesting incomplete processing of proinsulin•Intra-islet insulin+ cells are lost with T1D evolution; single insulin+ cells remain Wasserfall et al. analyze rare pancreatic samples from T1D patients. They find proinsulin protein and persistence of insulin mRNA but decreased proconvertase PCSK1 and undetectable INS hnRNA. These findings indicate the presence, in long-term T1D subjects, of a population of β cells with impaired insulin gene transcription and inefficient proinsulin processing.