Synaptotagmin IV and Myt factors promote β-cell functional maturation and maintenance

Abstract

Both type I and type II diabetes are related to β-cell defects in the pancreatic islet of Langerhans. Deriving β-cells from stem cells and other mature cell types provides an important cell source for transplantation-based therapy to treat diabetes. Mechanistic studies of β-cell maturation and functional maintenance are crucial in providing novel insights for the generation of glucose-responsive and long-term sustainable β-cells. In this study, I found that two gene/gene families, synaptotagmin IV (Syt4) and Myt factors are essential to promote β-cell maturation and functional maintenance. Mouse studies provided evidence that Syt4 modulates insulin Ca2+ vesicle sensitivity to facilitate β-cell maturation the neonatal stage. Loss of Syt4 in mice resulted in Ca2+ hypersensitivity of insulin vesicles in β-cells and compromised glucose-stimulated insulin secretion. Conversely, Syt4 overexpression reduced insulin Ca2+ vesicle sensitivity and established the mature insulin secretion profile in the newborn β-cells. Moreover, Myt factors are essential to generate functional β-cells. Postnatal β-cells in a Myt knockout mouse model were characterized by functional failure, cell apoptosis and loss of mature β-cell identity. Loss of Myt factors in β-cells disrupted the expression of genes involved in insulin secretion, β-cell survival and identity maintenance. These combined results suggest that Syt4 and Myt factors can be exploited as molecular targets to promote β-cell maturity and long-term functional maintenance for better clinical β-cell regeneration.