Investigation of the effects of TNF-related apoptosis-inducing ligand (TRAIL) on the process of obesity and type 2 diabetes in C57BL6 animal models

Aim: To investigate the mechanism of the possible protective role of TNF-related apoptosis-inducing ligand (TRAIL) in diabetes, we studied the antidiabetic, antiinflammatory, proliferative, and regenerative roles of the lentiviral vector-mediated and/or soluble form of TRAIL in mouse obesity and type 2 diabetes (T2D) models. Methods: Expression profiles of the TRAIL ligand and receptors throughout obesity and T2D development were investigated by immunohistochemical analysis in C57BL6 obesity models generated via a high-fat diet (HFD), and T2D models established via additional Streptozotocin (STZ) injection. The antidiabetic and antiinflammatory effects of TRAIL application via lentiviral vectors (LV-TRAIL) and/or in the form of soluble TRAIL (sTRAIL) were investigated via periodic blood glucose and weight measurements, intraperitoneal glucose tolerance test (IPGTT), intraperitoneal insulin tolerance test (IPITT), and IL-6 ELISA test. The effect of TRAIL on insulin secretion was tested in NIT-1 mouse beta cell lines. The effects of TRAIL application on liver and kidney functions were examined via functional tests. Immunohistochemical analyses for Ki67 and MCM7 were performed to investigate TRAIL's proliferative effect in the pancreas, while PDX-1 and CK20 expressions were analyzed to study its regenerative effect. Results: Expression levels of the TRAIL ligand and DR5 and DcR2 receptors decreased throughout the development of obesity and T2D. TRAIL administration reduced non-fasting blood sugar in HFD-fed animals, had a reducing effect on insulin resistance by increasing glucose tolerance, suppressed systemic inflammation, and reduced serum alkaline phosphatase, glucose and total cholesterol levels. Furthermore, an increase in insulin expression, proliferative Ki67 and MCM7 and regenerative PDX1 expressions in the pancreas were observed following TRAIL application. Conclusion: We believe that our results will contribute to the elucidation of the not yet clearly identified role of TRAIL in obesity and T2D, and to the evaluation of TRAIL as a candidate therapeutic molecule in obesity and diabetes. Keywords: TRAIL, Obesity, Type 2 Diabetes, Beta cell replication, Beta cell regeneration, Lentiviral vectors, Gene therapy