PDE12 in type 1 diabetes

Abstract

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.

Figure 1

Phosphodiesterase 12 (PDE12) gene expression. CTR: non-diabetic controls (n = 18); AB + : non-diabetic autoimmune antibody-positive donors (n = 12); T1D (median disease duration, 35 days): donors with newly diagnosed type 1 diabetes (n = 5); T1D (median 5 years): donors with recently diagnosed type 1 diabetes (n = 20); T2D (median 2 years): donors with type 2 diabetes (n = 8); T1D Tx: biopsies from donors with recurrent T1D (n = 4). Boxes indicate 25% and 75% quartiles, whiskers 1.5 × interquartile ranges, and squares mark outliers. The p-values shown were calculated using unpaired two-sided t-tests relative to CTR. Test statistics for CTR vs T1D (5 years): t-statistic 6.054, 95%CI 7.74;15.59, degrees of freedom 31.997, mean of CTR 35.95, mean of T1D (5 years) 24.29. Test statistics for CTR vs T1D Tx: t-statistic 3.43, degrees of freedom 5.87, 95%CI 2.78;16.81, mean of T1D Tx 26.16.