Contributions of the Insulin/Insulin-Like Growth Factor-1 Axis to Diabetic Osteopathy

Abstract

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.

Figure 1

Pro-osteoblastogenic signal transduction by insulin and IGF1 receptors. Receptors at the plasma membrane bind ligands within extracellular domains, triggering receptor autophosphorylation on tyrosine residues within the cytoplasmic domain. Phosphorylated receptors recruit scaffolding proteins [src homology 2 domain-containing transforming protein C (Shc), IRS], which are subsequently phosphorylated by the receptor kinase domain. Recruitment of growth factor receptor bound protein 2 (GRB2) to the receptor-Shc complex initiates phosphorylation and activation of the MEK/ERK pathway. MEK/ERK signaling culminates with phosphorylation of osteoblastogenic transcription factors in the nucleus. IRS proteins recruit phosphatidylinositol 3-kinase to the receptor complex, resulting in kinase activation, which generates phosphatidylinositol (3,4,5) triphosphate (PIP3). PIP3 recruits AKT to the plasma membrane, resulting in AKT activation. Activated AKT phosphorylates numerous proteins, among them FoxO1, resulting in retention of FoxO1 in the cytosol, where it is unable to perform its function as a transcription factor.

Figure 2

Insulin and IGF1 signal transduction is functional in osteoblast precursors in vitro. IR mRNA levels measured by quantitative RT-PCR in MC3T3-E1 cells after 1, 2, 3, or 4 weeks of differentiation with ascorbate and β-glycerol phosphate (A) and in primary calvariae, C3H10T1/2, MC3T3-E1, and bone marrow stromal cell cultures (B). Western blot detection of Akt and ERK1/2 phosphorylation in C3H10T1/2 (C) or MC3T3-E1 (D) cell lysates prepared after treating cells with 10 ng/ml of insulin or IGF-1 for the indicated times.

Figure 3

Potential cross-talk between insulin/IGF-1, BMP2, and Wnt signaling pathways. BMP2 receptor signaling and the MEK/ERK branch of the insulin/IGF-1 signaling pathway converge on ERK1/2 kinase, which can modulate the activity of the master osteoblastogenic transcription factor, Runx2. Wnt and the PI3-K/Akt branch of the insulin/IGF-1 signaling pathway converge on GSK-3b, inhibiting GSK-3b kinase activity and reducing its constitutive phosphorylation of β-catenin. Unphosphorylated β-catenin is not readily degraded and can accumulate in the nucleus, where it acts as a pro-osteoblastogenic transcription factor by regulating transcription of Runx2 and other genes.