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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.

Rabson-Mendenhall syndrome is a rare genetic disorder characterized by severe insulin resistance and hyperinsulinemia due to defects in signaling through the insulin receptor. Herein, we describe a new case of Rabson-Mendenhall syndrome in which investigations of the growth hormone (GH) - insulin-like growth factor (IGF) axis - reveal severe deficiencies in total and free insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 (IGFBP-3), and the acid labile subunit (ALS). Based on these findings, we anticipated significant bone deficits, as have been described in other clinical scenarios in which the IGF axis is significantly perturbed. Long-bone studies revealed no gross malformations. Paradoxically, DXA scanning revealed a total body bone density Z-score of +2.0 (0.8 gm/cm(2)), suggesting an overall high-normal BMD for age and a high BMD corrected for bone or height age. The mechanisms by which BMD is protected from severe deficiencies in the IGF-axis are unknown, yet may involve enhanced IGF sensitivity, increased local production of IGFs, and/or supra-physiological concentrations of insulin substituting for the actions of IGFs in bone.

The actinin-associated LIM protein, ALP, is the prototype of a large family of proteins containing an N-terminal PDZ domain and a C-terminal LIM domain. These PDZ-LIM proteins are components of the muscle cytoskeleton and occur along the Z lines owing to interaction of the PDZ domain with the spectrin-like repeats of alpha-actinin. Because PDZ and LIM domains are typically found in proteins that mediate cellular signaling, PDZ-LIM proteins are suspected to participate in muscle development. Interestingly the ALP gene occurs at 4q35 near the heterochromatic region mutated in facioscapulohumeral muscular dystrophy, indicating a possible role for ALP in this disease. Here, we describe the generation and analysis of mice lacking the ALP gene. Surprisingly, the ALP knockout mice show no gross histological abnormalities and maintain sarcolemmal integrity as determined by serum pyruvate kinase assays. The absence of a dystrophic phenotype in these mice suggests that down-regulation of ALP does not participate in facioscapulohumeral muscular dystrophy. These data suggest that ALP does not participate in muscle development or that an alternative PDZ-LIM protein can compensate for the lack of ALP.

Subcellular targeting and the activity of facilitative glucose transporters are likely to be regulated by interactions with cellular proteins. This report describes the identification and characterization of a protein, GLUT1 C-terminal binding protein (GLUT1CBP), that binds via a PDZ domain to the C terminus of GLUT1. The interaction requires the C-terminal four amino acids of GLUT1 and is isoform specific because GLUT1CBP does not interact with the C terminus of GLUT3 or GLUT4. Most rat tissues examined contain both GLUT1CBP and GLUT1 mRNA, whereas only small intestine lacked detectable GLUT1CBP protein. GLUT1CBP is also expressed in primary cultures of neurons and astrocytes, as well as in Chinese hamster ovary, 3T3-L1, Madin-Darby canine kidney, Caco-2, and pheochromocytoma-12 cell lines. GLUT1CBP is able to bind to native GLUT1 extracted from cell membranes, self-associate, or interact with the cytoskeletal proteins myosin VI, alpha-actinin-1, and the kinesin superfamily protein KIF-1B. The presence of a PDZ domain places GLUT1CBP among a growing family of structural and regulatory proteins, many of which are localized to areas of membrane specialization. This and its ability to interact with GLUT1 and cytoskeletal proteins implicate GLUT1CBP in cellular mechanisms for targeting GLUT1 to specific subcellular sites either by tethering the transporter to cytoskeletal motor proteins or by anchoring the transporter to the actin cytoskeleton.