Predicting The Onset Of Apeced Diabetes

Background: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic autosomal recessive disorder and diabetes (DM) one of its rare and less studied manifestations. Determinants of time to onset and clinical progression to DM seem currently unpredictable. Materials and Methods: We explored change in pre-diagnosis (dg) glycemic parameters (glucose, insulin, C-peptide), including 60’ intravenous glucose tolerance tests (ivGTT) and homeostasis indices (HOMA-β, -IR) over 20 years (y) with descriptive statistics. Fractional glucose turnover rate (KG) during ivGTT was calculated as 0.693/T1/2Gluc*100 with Pearson correlation coefficient (r) and 2-sided p value. Results: Between 1972 and 1996, 68 ivGTTs were conducted in 13 pediatric and adult individuals with APECED and DM. The mean age (SD) at DM dg was 27.78y (11.73) among those 22% of our cohort (n=100) with DM. Including one man with ‘latent DM’, with no clinical DM symptoms 20y post-dg. HbA1c was rarely measured, fasting plasma glucose (FPG) values were normoglycemic prior and up to DM dg: mean (SD) FPG 4.4 (0.6) mmol/l (-20y to -6 months [m]) and 5.7 (0.9) mmol/l (<6m to dg). Mean 60’ glucose values were only elevated for those with <6m to dg: 12.1 (0.7) mmol/l. Hyperinsulinemia was present 5-20y prior to dg while rapid 1st phase insulin secretion (combined 1+3 min value; normal >46 mIU/ml) was lost or delayed in some, but not all, 5y prior to dg. Up to and at dg, adequate fasting insulin (>2 mIU/ml) and C-peptide (>0.5 ng/ml) production was observed in most (85%) patients. KG displayed intra- and inter-individual variability, was normal (>1.2%/min) in latent DM, while it predicted DM onset over time (-20y to dg): r= -0.568 (p= 4E-06). Neither HOMA indices were sensitive enough to detect any change over time. Conclusion: Identification of reduced glucose removal rate over time, indicative of increased peripheral insulin resistance in the presence of pre-diagnostic hyperinsulinemia, provides first insights into progression of atypical diabetes in APECED patients. Disclosure P. M. Paldanius: Consultant; Self; UPM Biomedicals, Speaker’s Bureau; Self; Novartis AG. O. Makitie: None. S. Laakso: None.