Diabetes and other autoimmune endocrine diseases
Sushi domain containing protein 4 (SUSD4) is a newly discovered, but poorly characterized transmembrane protein. The structure of SUSD4 shows a high degree of homology among species, including 91% identity between mouse and man. SUSD4 is broadly expressed in human and mouse tissues including pancreatic islets. Therefore, in this study, we investigate the possible role of SUSD4 in the major function of pancreatic islets, which is insulin secretion. We found that SUSD4 KO mice displayed significantly impaired blood glucose clearance, which was aggravated with age and by a high fat diet. This defect was not due to increased insulin resistance of SUSD4 KO mice. Isolated islets from SUSD4 KO mice secreted less insulin upon stimulation with glucose and high KCl. No developmental malformation or morphological defect of pancreas or islets in SUSD4 KO mice was detected via Optical Projection Tomography (OPT), which allows the three-dimensional imaging of the spatial and quantitative distribution of the islets in the whole pancreas. RNA sequencing analysis of islets isolated from SUSD4 KO mice revealed significantly increased expression of IL-1R2, a decoy receptor for IL-1, which was confirmed by qPCR. Accordingly, blood glucose clearance was improved in WT but not SUSD4 KO mice by treatment with low levels of IL-1β that augments glucose induce insulin secretion. We propose that IL-1β signaling is impaired in SUSD4 KO mice due to increased expression of the IL-1R2 decoy receptor, which therefore prevents postprandial insulin secretion induced by low level of IL-1β.