The lysosome membrane protein, Sidt2: A novel insulin granule membrane protein regulates β cell dedifferentiation by a new pathway involving insulin secretion

Abstract β-cell dedifferentiation is important in the pathogenesis of type 2 diabetes, and the relationship between lysosome membrane proteins and pancreatic β-cell dedifferentiation is still unknown. Sidt2 is a lysosomal membrane protein identified in our previous study. After Sidt2 elimination, mice exhibited a diabetic phenotype. In the present study, we found that Sidt2 also can be considered a new insulin granule membrane protein. Sidt2 deficiency resulted in islet dysfunction and inhibited insulin secretion. The absence of Sidt2 also led to increased β cell dedifferentiation in mice. Further experiments showed that defects in insulin secretion caused dedifferentiation in the absence of Sid2. In summary, our study has found a new dedifferentiation regulatory mechanism mediated by a lysosomal membrane protein. This new secretory regulation pathway will enrich our understanding of the regulatory mechanisms involved in β cell dedifferentiation and provide new insights into the pathogenesis of diabetes.