Published online Jun 10, 2015. doi: 10.4239/wjd.v6.i5.673
Peer-review started: January 15, 2015
First decision: February 7, 2015
Revised: February 12, 2015
Accepted: March 5, 2015
Article in press: March 9, 2015
Published online: June 10, 2015
Processing time: 158 Days and 17.7 Hours
It was previously understood that body weight gain and obesity observed in type 2 diabetes mellitus (T2DM) could be beneficial since body weight increase elevated bone mineral density and thus helped maintain the skeletal framework. However, a number of recent findings in humans and rodents have revealed that T2DM is not only associated with trabecular defects but also increases cortical porosity, and compromised bone cell function and bone mechanical properties. Hyperglycemia and insulin resistance in T2DM may further induce osteoblast apoptosis and uncoupling bone turnover. Prolonged accumulation of advanced glycation end products and diminished activity of lysyl oxidase, an essential enzyme for collagen cross-link, can lead to structural abnormalities of bone collagen fibrils, brittle matrix, and fragility fractures. Our studies in T2DM rats showed that dyslipidemia, which often occurs in T2DM, could obscure the T2DM-associated changes in bone microstructure and osteopenia. Longitudinal bone growth regulated by the growth plate chondrocytes is also impaired by T2DM since differentiation of growth plate chondrocytes is arrested and retained in the resting state while only a small number of cells undergo hypertrophic differentiation. Such a delayed chondrocyte differentiation may have also resulted from premature apoptosis of the growth plate chondrocytes. Nevertheless, the underlying cellular and molecular mechanisms of insulin resistance in osteoblasts, osteoclasts, osteocytes, and growth plate chondrocytes remain to be investigated.
Core tip: Type 2 diabetes mellitus (T2DM) negatively affects bone density and strength by inducing cellular and extracellular matrix failures. Insulin resistance in T2DM deteriorates osteoblast proliferation and activity, but enhances osteoclast activity, leading to uncoupled bone remodeling. Hyperglycemia also aggravates osteoblast dysfunction, thus contributing to cellular failure. Extracellular matrix failure is caused by abnormal collagen synthesis and aberrant collagen structure and alignment, the latter of which results, in part, from advanced glycation end products (AGEs). With hyperglycemia and AGEs, impaired bone strength may occur despite high bone mineral density. It is, therefore, concluded that T2DM can be considered a cause of osteoporosis and/or poor bone mechanical properties.