Association of soluble apoptotic biomarkers (FAS,TNFR1 and TRAIL-R2) with β-cell dysfunction in early glucose dysregulation.

Objective: This study aimed to investigate the association of soluble death receptors (FAS, TNFR1, and TRAIL-R2) with β-cell function in individuals with naïve prediabetes and newly diagnosed, treatment - naïve type 2 diabetes, and to assess the strength of this association to determine the independent variable that contributes to the variance of HOMA-B.

Methods and materials: This was a cross-sectional study done at the Endocrine Clinics of National Hospital. There were two groups: group 1 included 49 newly diagnosed, drug-naive prediabetic patients, and group 2 consisted of 29 newly diagnosed, drug-naive,T2DM patients. Written informed consent was obtained from all participants. This study was approved by the Medical Ethics Committee of Damascus University (No. m/471 -12/5/2021) and registered with the Australian New Zealand Clinical Trials Registry (Trial ID: ACTRN12624001135505). Inclusion criteria included newly diagnosed prediabetic or T2DM subjects who had received no treatment, based on the 2015 American Diabetes Association criteria. Exclusion criteria entailed past histories of severe cardiovascular, renal, tumor, or autoimmune diseases and use of drug therapies including oral hypoglycemic agents. General and demographic information (Sex, age, BMI) was obtained, and blood samples were taken after fasting for 12 h. Fasting plasma glucose (FPG) levels were measured using an automatic analyzer (AMS, Italy). HbA1c levels were measured photometrically using the HemoCue (HbA1c 501 analyzer,America).Insulin levels were determined via an ELISA kit (Diametra, Italy), and soluble death receptors (TNFR1, Fas, TRAIL-R2) were measured using ELISA kits (Raybiotech, USA). The following formula calculates Homeostatic Model Assessment of Beta Cell Function( HOMA-B), HOMA-B (%) = [360 × basal insulin (µIU/mL)] / [basal glucose (mg/dL) - 63]. Statistical analyses were carried out in SPSS version 25. Distribution of the data was carried out using the Kolmogorov-Smirnov test for normality. Student t test for independent samples were done for normally distributed data, while Mann-Whitney U test was used for nonnormal variables. The relationships between HOMA-B and FBG in addition to other variables with significance level were performed using linear regressions with p values < 0.05 were deemed to be statistically significant.

Results: The levels of TNFR1, Fas, and TRAIL-R2 were significantly higher in T2DM compared with prediabetes (p < 0.0001). TNFR1 and Fas exhibited a strong negative correlation with HOMA-B in both groups. Regression analysis indicated that Fas, followed by TRAIL-R2, was the main predictor of β-cell function. They combined accounted for 60% and 42% of the HOMA-B variance in prediabetes and T2DM, respectively.

Conclusion: Elevated soluble death receptor levels, particularly Fas, are a marker of impaired β-cell function in prediabetes and T2DM. These observations suggest that death receptors-mediated apoptosis may play a role in the progression of β-cell dysfunction from prediabetes to T2DM and point toward possible use of these markers as early indicators of β-cell dysfunction.