Distinct secretion pattern of serum proinsulin in different types of diabetes

Background: Latent autoimmune diabetes in adults (LADA) is characterized by autoimmunity, late-onset and intermediate beta-cell deprivation rate between type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM). Herein, we investigated proinsulin (PI) secretion patterns and the endoplasmic reticulum (ER) dysfunction biomarker, PI-to-C-peptide (PI:CP) ratio, to elucidate beta-cell intrinsic pathogenesis mechanisms in different types of diabetes. Methods: Total serum fasting PI (FPI) were measured in adult-onset and newly-diagnosed diabetes patients, including 60 T1DM, 60 LADA and 60 T2DM. Thirty of each type underwent mixed meal tolerance tests (MMTTs), and hence 120 min postprandial PI (PPI) were detected. PI:CP ratio = PI (pmol/L) ÷ CP (pmol/L) × 100%. PI-related measurements among types of diabetes were compared. Correlation between PI-related measurements and beta-cell autoimmunity were analyzed. The possibility of discriminating LADA from T1DM and T2DM with PI-related measurements were tested. Results: FPI and PPI were significantly higher in LADA than T1DM (P<0.001 for both comparisons), but lower than those in T2DM (P<0.001 and P=0.026, respectively). Fasting PI:CP ratio was significantly higher in T1DM than both LADA and T2DM (median 3.25% vs. 2.13% and 2.32%, P=0.011 and P=0.017, respectively). In LADA, positive autoantibody numbers increased by both fasting and postprandial PI:CP ratio (P=0.007 and P=0.034, respectively). Areas under receiver operation characteristic curves (AUCROC) of FPI and PPI for discriminating LADA from adult-onset T1DM were 0.751 (P<0.001) and 0.838 (P<0.001), respectively. Between LADA and T2DM, AUCROC of FPI and PPI were 0.685 (P<0.001) and 0.741 (P=0.001), respectively. Conclusions: In the development of autoimmune diabetes, interplays between ER stress and beta-cell autoimmunity are potentially responsible for severer beta-cell destruction. PI-related measurements could help in differentiating LADA from adult-onset T1DM and T2DM.