Bone fragility in Type 2 Diabetes Mellitus. Influence of sex and cardiovascular disease in a pilot study using metabolomics

Type 2 diabetes mellitus (T2DM) is one of the most common worldwide metabolic disorders, characterized by insulin resistance (IR) and defective insulin secretion by pancreatic β-cells which leads to multiple complications such as bone fragility. This complication might be influenced by other factors such as gender and cardiovascular disease (CVD). However, it is unclear why a certain T2DM group develops bone fragility, and what the molecular mechanism is. Metabolomics is a powerful approach to the study of human metabolism, especially in complex diseases such as T2DM. Thus, this study aimed to identify significant metabolites associated with bone fragility in T2DM patients. To achieve this, 81 individuals were enrolled and classified as T2DM patients (D, n=28), T2DM with bone fragility (D-Frag, n=25), or age-matched non-diabetic subjects (ND, n=28) as the control group. Serum samples were collected and analyzed using liquid chromatography and gas chromatography, both coupled to mass spectrometry (LC-MS and GC-MS, respectively). Samples were compared within four different scenarios: 1) the classical comparison of D vs ND to corroborate previous studies; 2) D-Frag vs D to explore the metabolites mainly associated with bone fragility; 3) the same comparison using male data (MD-Frag vs MD) to study as a more homogeneous model of bone fragility as in women, bone fragility could be mainly associated with hormonal stage and pregnancy; and 4) MD-Frag-CVD vs MD-CVD to explore the influence of bone fragility in the male-based model with CVD considering that most of the T2DM patients suffer from CVD. After analysis of these scenarios, our results suggest that acylcarnitines and glycerophospholipids, among other metabolites, are involved in the development of bone fragility in T2DM.