Examination of Skeletal and Senescence Phenotypes in Young Mice with Juvenile Onset Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) and T2D are associated with skeletal fragility, contributing to increased fracture risk. Whereas decreased bone mineral density (BMD) is common in T1D, individuals with T2D tend to have normal or elevated BMD. These differences are incompletely understood but may stem from distinct mechanisms. Previously, we showed that obese male C57BL/6 mice (7-month-old) with T2D exhibit poor bone quality and accelerated osteocyte senescence with a unique senescence-associated secretory phenotype (SASP). We hypothesized that, similar to T2D, senescent osteocytes and additional senescent bone-resident cells (e.g., immune cells) accumulate in T1D. Consistent with previous studies, we studied a juvenile onset (2-month-old) T1D model, where following 8 weeks, male C57BL/6 mice with T1D displayed deteriorated bone microarchitecture, increased cortical porosity, and reduced bone strength. Unexpectedly, osteocytes, myeloid cells, T cells, and B cells in T1D mice showed no significant changes in key senescence/SAPS markers. Therefore, although T1D mice display several aspects of poor bone quality, consistent with juvenile-onset T1D in humans, senescent cells have yet to accumulate at substantial levels in bone at this young age. Future studies should include female mice and test whether senescence requires a later onset of T1D, a longer disease duration, or worse glycemic control.

Keywords: Bone disease; Cellular senescence; Diabetes; Osteocyte; SASP.