Type 1 diabetes (T1D) incidence is increased after COVID-19 infection in children under 18 years of age. Interferon-α-activated oligoadenylate synthetase and downstream RNAseL activation degrade pathogen RNA, but can also damage host RNA when RNAseL activity is poorly regulated. One such regulator is PDE12 which degrades 2′-5′ oligoadenylate units, thereby decreasing RNAseL activity. We analyzed PDE12 expression in islets from non-diabetic donors, individuals with newly (median disease duration 35 days) and recently (5 years) diagnosed T1D, and individuals with type 2 diabetes (T2D). We also analyzed PDE12 single-nucleotide polymorphisms (SNPs) relative to T1D incidence. PDE12 expression was decreased in individuals with recently diagnosed T1D, in three of five individuals with newly diagnosed T1D, but not in individuals with T2D. Two rare PDE12 SNPs were found to have odds ratios of 1.80 and 1.74 for T1D development. We discuss whether decreased PDE12 expression after COVID-19 infection might be part of the up to 2.5-fold increase in T1D incidence.

Human tissue: Pancreatic tissue from donors was collected in the Diabetes Virus Detection (DiViD) and Network for Pancreatic Organ Donors with Diabetes (nPOD) studies, with informed consent obtained from all participants. Briefly, DiViD donors with diabetes had a surgical resection of the pancreatic tail, between three and nine weeks after their type 1 diabetes diagnosis, while nPOD material originates from cadaveric organ donors. The procedures were approved by The Norwegian Government’s Regional Ethics Committee (reference 2009/1907); nPOD donors with approval by the University of Tennessee Health Science Center (UTHSC) local Institutional Review Board [reference 10-00848-XM]). All experiments were performed in accordance with relevant guidelines and regulations.

Microdissection of pancreatic islets: Acquired pancreatic samples were laser microdissected as described previously. Briefly, frozen tissue sections from nPOD and DiViD were microdissected with the Arcturus Pixcell II laser capture microdissection system (Arcturus Bioscience, Mountain View, CA, USA). Islets from 2-5 sections per donor were detected by autofluorescence and pooled together, and afterwards subjected to RNA extraction with the Arcturus PicoPure RNA Isolation Kit (Applied Biosystems, Grand Island, NY, USA). RNA quality and quantity were validated with the Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA, USA), and samples underwent gene expression analysis with the Affymetrix expression arrays (Thermo Fisher, Santa Clara, CA, USA) as described previously.

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