Diabetes and other autoimmune endocrine diseases
Activation of β-cell endoplasmic reticulum (ER) stress has been implicated in the progression of Type 1 Diabetes (T1D). Markers of β-cell ER stress were increased in mouse models of T1D and in islets from humans with T1D. ER stress is increased by the loss of ER Ca2+, leading to decreased β-cell function and increased apoptosis. Intraluminal ER Ca2+ stores are maintained by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2) pump. Our group has found that SERCA2 expression is reduced in islets from mouse models of T1D prior to disease onset and in human islets from donors with T1D. Thus, we hypothesized that SERCA2-mediated ER Ca2+ dyshomeostasis could be a major contributor to T1D development. To test this, we generated a mouse model haploinsufficient for SERCA2 on the NOD background (NOD-S2+/-). Compared to wild type littermates (NOD-WT), NOD-S2+/- mice have higher incidence of diabetes (p<0.0001) and incidence occurs earlier on average (14.5 wks vs 19 wks, p<0.0001). NOD-S2+/- islets also had increased MHC-I expression. To test whether SERCA2 activation may have beneficial therapeutic effects, we mimicked T1D β-cell loss with multiple-low-dose streptozotocin (MLD-STZ) in WT and SERCA2 haploinsufficent (S2+/-) C57BL/6 mice. Following MLD-STZ treatment, S2+/- mice exhibited impaired glucose tolerance and higher fasting glucose levels versus WT mice. MLD-STZ mice treated with CDN1163, an allosteric activator of SERCA2, exhibited improved glucose tolerance and fasting glucose levels. Taken together, our data suggests loss of SERCA2 exacerbates T1D development and SERCA2 is a novel therapeutic target for diabetes reversal.