Wednesday, January 15, 2025
1/15/2025
Humans with type 1 diabetes mellitus (T1D) experience several disorders of skeletal health, including decreased bone mineral density (BMD) and increased risk for fragility fractures (i.e., osteoporosis). These features are the primary clinical characteristics of diabetic bone disease (DBD). Evidence suggests that DBD occurs early in the progression of T1D; involves impaired bone formation; results in micro-architectural abnormalities and poor bone matrix quality; and coincides with hyperglycemia and a decline in endogenous insulin and insulin-like growth factor-1 production. While many have postulated that skeletal deficits in diabetes occur as a direct result of glucose dysregulation, our pre-clinical studies in mouse models, supported by observational studies in humans, show that impairment in the production and action of insulin and insulin-like growth factor-1 (IGF-1) may be root causes of DBD. Specifically, our laboratory and others have demonstrated that in rodent models of T1D: 1) deficits in bone formation occur in the context of insulin-deficiency; 2) near- normalization of serum glucose alone is not sufficient to prevent DBD; 3) insulin and IGF-1 therapy improve fracture resistance and new bone formation; and 4) both insulin and IGF-1 utilize similar down-stream pathways to promote osteoblastogenesis and bone formation. To clarify the mechanisms and signaling pathways by which insulin and/or IGF-1 modulate osteogenesis; to understand how deficiencies or impaired signaling of each may contribute to DBD; and to delineate how each may contribute to therapeutic approaches to prevent or treat DBD, we propose to 1) determine how insulin and IGF-1 deficiencies contribute to DBD at the tissue, cellular, and molecular level, and 2) how each hormone may perform overlapping and independent effects through specific downstream signaling pathways that may ultimately become therapeutic targets for preventing and/or reversing DBD.
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