Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by hyperglycemia, hyperinsulinemia and complications, including obesity and osteoporosis. Rodents have been widely used to model human T2DM and investigate its effect on the skeleton. We aimed to investigate skeletal alterations in Yellow Kuo Kondo (KK-Ay) diabetic mice displaying high insulin and glucose levels. Bone mineral density (BMD), micro-architecture and bone metabolism-related genes were analyzed. The total femoral areal BMD (aBMD), cortical volumetric BMD (vBMD) and thickness were significantly increased in KK-Ay mice, while the trabecular vBMD and mineralized bone volume/tissue volume (BV/TV), trabecular thickness and number were decreased compared to C57BL mice. The expression of both osteoblast-related genes, such as osteocalcin (OC), bone sialoprotein, Type I Collagen, osteonectin, RUNX2 and OSX, and osteoclast-related genes, such as TRAP and TCIRG, were up-regulated in KK-Ay mice. Correlation analyses showed that serum insulin levels were positively associated with aBMD, cortical vBMD and thickness and negatively associated with trabecular vBMD and micro-architecture. In addition, serum insulin levels were positively related to osteoblast-related and osteoclast-related gene expression. Our data suggest that high insulin levels in KK-Ay diabetic mice may increase cortical bone mass and impair trabecular micro-structure by up-regulating osteoblast-and osteoclast-related gene expression.
Highlights
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by elevated blood glucose levels resulting from impaired glucose metabolism and insulin resistance, which transitions into insulin deficiency over time
Diabetes isassociated with complications [1], such as altered bone metabolism that may lead to osteopenia, an increased risk of fracture and osteoporosis [2]; the causal relationship between diabetes and bone loss has been controversial, and the bone diseases that develop in type 1 and type 2 diabetes may differ
We detected the up-regulation of bone metabolism-related genes. These findings suggest that high insulin levels are associated with increased bone metabolism-related gene expression in KK-Ay mice, which subsequently may increase bone mineral density (BMD) and impair trabecular micro-architecture
Summary
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by elevated blood glucose levels resulting from impaired glucose metabolism and insulin resistance, which transitions into insulin deficiency over time. A reduction in bone mass in Type 1 diabetes mellitus (T1DM) is generally accepted to be related to high fracture risk resulting from a lack of insulin [3]; patients with T2DM often have normal or slightly high bone mineral density (BMD), suggesting impaired bone quality rather than quantity [4,5,6]. Hyperglycemia has been implicated in the pathogenesis of diabetic bone disease. High glucose significantlyimpairs bone formation by inhibiting osteoblast proliferation and differentiation [7]
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