Insulin-Like Growth Factor 1, Glycation and Bone Fragility: Implications for Fracture Resistance of Bone

Abstract

Despite our extensive knowledge of insulin-like growth factor 1 (IGF1) action on the growing skeleton, its role in skeletal homeostasis during aging and age-related development of certain diseases is still unclear. Advanced glycation end products (AGEs) derived from glucose are implicated in osteoporosis and a number of diabetic complications. We hypothesized that because in humans and rodents IGF1 stimulates uptake of glucose (a glycation substrate) from the bloodstream in a dose-dependent manner, the decline of IGF1 could be associated with the accumulation of glycation products and the decreasing resistance of bone to fracture. To test the aforementioned hypotheses, we used human tibial posterior cortex bone samples to perform biochemical (measurement of IGF1, fluorescent AGEs and pentosidine (PEN) contents) and mechanical tests (crack initiation and propagation using compact tension specimens). Our results for the first time show a significant, age-independent association between the levels of IGF1 and AGEs. Furthermore, AGEs (fAGEs, PEN) predict propensity of bone to fracture (initiation and propagation) independently of age in human cortical bone. Based on these results we propose a model of IGF1-based regulation of bone fracture. Because IGF1 level increases postnatally up to the juvenile developmental phase and decreases thereafter with aging, we propose that IGF1 may play a protective role in young skeleton and its age-related decline leads to bone fragility and an increased fracture risk. Our results may also have important implications for current understanding of osteoporosis- and diabetes-related bone fragility as well as in the development of new diagnostic tools to screen for fragile bones.

Fracture Risk in Type 2 Diabetes: Current Perspectives and Gender Differences

“…IGF-I is also synthesized by osteoblasts and it is a regulator of bone cells metabolism [34]. Several studies showed a reduced IGF-1 activity when glucose and AGEs levels are high, suggesting an osteoblastic resistance to IGF-1 effects [35, 36].…”

“…A recent review evaluating the risk of fall-related fracture in T2DM subjects on sulfonylureas concluded that available studies suffer methodological limitations and may have underestimated the risk [80, 81]. Further studies are needed to define the effect of these drugs on falls and fractures, although the overall beneficial effects of this class of drugs are currently debated [34, 82]. …”

The Relationship of Fat Distribution and Insulin Resistance with Lumbar Spine Bone Mass in Women

“…In animal models of type 2 diabetes mellitus (WBN/Kob rats), the appearance of hyperglycemia coincides with the increase of non-enzymatic cross-links (pentosidine) and the reduction of bone strength[23]. In support of these data, there is also evidence of the effects of advanced glycation end products as mechanisms for the emergence of osteoporosis in clinical investigations[24]. In the present study we observed a positive correlation of HbA1c and serum glucose levels with BMAT, suggesting another potential mechanism for bone weakening related to hyperglycemia.…”

Diabetes Perturbs Bone Microarchitecture and Bone Strength through Regulation of Sema3A/IGF-1/β-Catenin in Rats

“…IGF-1, highly expressed in osteoblast and chondrocytes [34], exhibits its bone anabolic effect through promoting osteoblasts differentiation and bone mineralization [35]. Deficiency of IGF-1 in the course of diabetes may contribute to skeletal abnormalities and lead to impaired bone formation, and increased bone fragility [36]. Clinically, serum level of IGF-1 is positively associated with increased bone mass [37] and inversely associated with the number of vertebral fractures in postmenopausal women with T2DM [5, 38].…”