Researchers have found that the increased levels of succinate in the bone marrow of patients with type 2 diabetes may be responsible for their elevated risk for bone fracture, a discovery that paves the way for further studies on the efficacy of succinate regulation to protect bone in these patients, according to a study recently published in the journal Nature Communications.
Succinate is an intermediate metabolite, a product of one-step in a biochemical pathway or cycle and a substrate for the next step.
“The bottom line is that the high level of succinate combined with the finding of more fragile bone points to a new target to protect bone,” said Yuqi Guo, MD, associate research scientist, New York University College of Dentistry (NYU Dentistry), New York City, NY.
For this metabolomics study, Dr. Guo and colleagues obtained bone marrow samples from hyperglycemic male mice and healthy controls. With advanced imaging and computational techniques, they observed the bone metabolism at a cellular level, identifying 142 metabolites significantly altered (over 1.5 times) in the diabetic mice. Of these metabolites, 126 were increased, and 16 decreased.
They found that diabetic mice had a 24-fold higher accumulation of succinate in the metabolic pathways of stromal cells in the bone marrow. In normal mice, succinate was barely detectable. In the energy pathway, succinate was the first metabolite, and because it was so increased in concentration in the diabetic mice, energy pathways were overwhelmed.
Researchers from the Women’s Health Initiative had previously found that type 2 diabetes was associated with a 20% increase in risk of fractures.
“The results are important because diabetics have a significantly higher fracture risk and their healing process is always delayed,” said senior investigator Xin Li, PhD, associate professor, basic science and craniofacial biology, NYU Dentistry. “In our study, the hyperglycemic mice had increased bone resorption [the breakdown and absorption of old bone], 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.”
Previously, Dr. Li and fellow researchers at his laboratory showed, for the first time, that hyperglycemic mice had significant accumulations of succinate in bone marrow and serum. The study was built on this finding.
The National Institutes of Health (NIH) grants R01CA180277 and R03 CA 172894 and NYU Provost Office Mega Grant Seed Fund Initiative supported Dr. Li’s work. Funding to other coauthors came from the California Institute for Regenerative Medicine, the Ministry of Science and Technology of China, the National Science Foundation of China, and the National Science Foundation of Liaoning.