Researchers at New York University College of Dentistry (NYU Dentistry) have described a new target that may open the door to developing therapies for preventing bone fractures in individuals with type 2 diabetes. In a study published in Nature Communications, the investigators report that hyperglycemic mice (i.e., mice with type 2 diabetes) have a 24-fold higher accumulation of succinate—an intermediate metabolite—in the metabolic pathways of their bone marrow stromal cells. In comparison, succinate was barely detectable in healthy mice. An intermediate metabolite is a compound that represents one step in a biochemical pathway or cycle, and also serves as the substrate for the next step.
In the study, “Succinate and its G-protein-coupled receptor stimulate osteoclastogenesis,” the researchers took samples of bone marrow from hyperglycemic male mice and control mice. Studying the bone metabolism at the cellular level allowed them to identify 142 metabolites that were altered by more than 1.5 times in the diabetic mice. Of these, 126 metabolites were upregulated (or increased) and 16 were downregulated (or decreased).
Succinate was the first metabolite in the energy pathway, and with its more than 20-fold increased concentration, it overwhelmed the energy pathways. Additionally, the diabetic mice had considerably lower spongy bone mass—known as trabecular bone—making them susceptible to bone fractures.
“The results are important because individuals with diabetes have a significantly higher fracture risk and their healing process is delayed,” notes Xin Li, PhD, an associate professor of basic science and craniofacial biology at NYU Dentistry, and the study’s senior investigator. “In our study, the hyperglycemic mice had increased bone resorption, which outpaced the formation of new bone. This has implications for bone protection, as well as for the treatment of diabetes-associated collateral bone damage.”
The team utilized a relatively new field of research called metabolomics to examine the bone marrow. The technique examines the molecules, or metabolites, within cells, biofluids, tissue, or organisms and their interactions within the larger system (or metabolome). Metabolomics can depict the underlying biochemical activity and signaling between cells and tissues. It is proving invaluable in identifying biomarkers and pinpointing potential drug targets for various diseases.
This study builds on previous research by Li’s laboratory that showed significant accumulation of succinate in the bone marrow and serum of hyperglycemic mice. It opens the door to pursuing regulating succinate for protecting bone in patients with diabetes.