John L. Fowlkes, Clay Bunn R and Kathryn M. Thrailkill
Recent studies in diabetic humans and rodent models of diabetes have identified osteopathy as a serious complication of type 1 (T1D) and type 2 (T2D) diabetes. Accumulating evidence suggests that disruption of insulin and insulin-like growth factor 1 (IGF-1) homeostasis in the diabetic condition may be responsible for the observed skeletal deficits. Indeed, replacement of insulin or IGF-1 in rodent models of T1D results in significant improvement in bone healing despite ongoing moderate to severe hyperglycemia. Insulin and IGF-1 act through distinct receptors. Mice in which the receptor for insulin or IGF-1 is selectively deleted from osteoblast lineages show skeletal deficits. Despite acting through distinct receptors, insulin and IGF-1 exert their cellular activities via conserved intracellular signaling proteins. Genetic manipulation of these signaling proteins, such as insulin receptor substrate (IRS)-1 and -2, Protein Kinase B (Akt), and MAPK/ERK kinase (MEK), has uncovered a significant role for these signal transduction pathways in skeletal homeostasis. In addition to effects on skeletal physiology via canonical signaling pathways, insulin and IGF- 1 may crosstalk with wingless-int. (Wnt) and bone morphogenic protein 2 (BMP-2) signaling pathways in cells of the osteoblast lineage and thereby promote skeletal development. In this review, a discussion is presented regarding the role of insulin and IGF-1 in skeletal physiology and disruptions of this axis that occur in the diabetic condition which could underlie many of the skeletal pathologies observed.
