Analysis of bone metabolic alterations linked with osteoporosis progression in type 2 diabetic db/db mice

Type 2 diabetes (T2D) is a common chronic disease, characterized by persistent hyperglycemia and insulin resistance. This disorder is associated with decreased bone quality and an elevated risk of bone fractures. However, evidence on the relationship between systemic metabolic change and the development of type 2 diabetic osteoporosis (T2DOP) remains elusive. Herein, we investigate the changes of bone metabolites with bone loss in db/db mice (an animal model of T2DOP exhibited bone loss with age progression), and explore the potential metabolic mechanism underlying type 2 diabetes and osteoporosis. C57BKS male mice were distributed in four groups, consisting six mice in each group: 8w m/m, 24w m/m, 8w db/db and 24w db/db. Bone morphometric and biomechanical parameters of db/db mice were analyzed by micro-CT and materials tester, it was found that 24w db/db mice showed severe bone loss and decreased bone tissue hardness compared with misty/misty littermates. The tibia of misty/misty mice (8 weeks, 24 weeks) and db/db mice (8 weeks, 24 weeks) were screened for differential metabolites by UPLC-Orbitrap MS. Ninety-eight metabolites were identified (35 and 63 metabolites are associated with early staged and late staged, respectively), consisting of amino acids, fatty acyls, and nucleotides. Notably, fatty acyls (such as 18-HEPE, 16(17)-EpDPE, arachidonic acid) and glycerophospholipids (such as phosphocholines (PC) (O-10:1(9E)/0:0), PC (O-16:1(9E)/0:0) [U] and phosphatidylethanolamines (PE) (P-16:0/0:0)) were significantly increased, and metabolites of amino acid pathway (such as l-glutamine, proline, phenylalanine) showed a downregulation trend. Dysregulation of lipid and glutathione pathways is the major contributor to progression of T2DOP in C57BKS mice.