The disruption of insulin signalling (due to insulin deficiency or resistance) results in significant skeletal complications via several tightly coordinated key pathways, including PI3K/Akt, canonical Wnt/β-catenin, and RANK/RANKL/OPG signal transduction cascades. The gene discussed is TNFRSF11A; the disease is hyperinsulinemic hypoglycemia, familial, 4.