Deletion of the T1D risk gene Ormdl3 in β-cells does not impact disease progression
TL;DR
Findings indicate that ORMDL3 function in β-cells is dispensable in this preclinical model of T1D and underscore the need to investigate the role of ORMDL3 in immune cells, as well as the contribution of other genes within the 17q12–q21 locus to T1D susceptibility.
Abstract
Orosomucoid-like (ORMDL) proteins are a component of the serine palmitoyltransferase complex and a negative regulator of ceramide synthesis. Among these ORMDL3 in addition to its role in lipid homeostasis, plays a key role in inflammation, endoplasmic reticulum stress, and immune regulation. Single nucleotide polymorphisms in the 17q12–q21 locus, which harbors ORMDL3, have been associated with multiple autoimmune diseases, including type 1 diabetes (T1D). T1D results from dysregulation of both β-cells and immune cells; yet the role of ORMDL3 in disease pathogenesis remains unclear. Here, we deleted Ormdl3 specifically in β-cells of the T1D-prone non-obese diabetic mice. Our analyses demonstrate that loss of ORMDL3 in β-cells prior to the initiation of immune infiltration does not affect diabetes incidence, islet morphology, circulating insulin/proinsulin levels, or islet inflammation, and immune cell profiles. These findings indicate that ORMDL3 function in β-cells is dispensable in this preclinical model of T1D and underscore the need to investigate the role of ORMDL3 in immune cells, as well as the contribution of other genes within the 17q12–q21 locus to T1D susceptibility.