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Researchers Identify Multi-Action Drug Candidate For Type 2 Diabetes And Bone Disease

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Diabetes

Currently-available diabetes medications called glitazones (TZDs) are targeted towards the PPARγ protein, but these drugs can cause substantial bone loss and increase the risk of fractures.

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July 28, 2016 | by Sarah Massey, M.Sc.

Patients with type 2 diabetes face a significantly greater risk of bone fractures. Unfortunately, many drugs used to treat the condition further raise this risk – a side effect which limits the treatment options for postmenopausal diabetic women.

To help mitigate this problem, researchers at The Scripps Research Institute (TSRI) and the University of Toledo, set out to identify potential new drug candidates for the chronic condition. Their new class of drug candidates was found to both increase the rate of new bone formation, and speed the normal process of bone turnover by which old bone is replaced by new tissue.

These two processes are critical to the maintenance of strong and healthy bones, however they are often imbalanced in patients with type 2 diabetes. According to the researchers, their new dual-targeting drug candidate – known as SR10171 – could be effective at concurrently treating both diabetes and bone disease.

For ten years, the TSRI researchers have studied molecules capable of increasing insulin sensitivity – an important component of diabetes maintenance. Using this information, the researchers developed a new family of drug candidates targetting the peroxisome proliferator-activated receptor gamma (PPARγ). This receptor helps to regulate stem cells involved in new bone formation and bone resorption, and is also involved in the regulation of fat cells.



Currently-available diabetes medications called glitazones (TZDs) are targeted towards the PPARγ protein, but these drugs can cause substantial bone loss and increase the risk of fractures. Glitazones drive stem cells in the bone marrow to differentiate into fat cells, instead of bone cells.

SR10171 on the other hand, was able to block fat formation in the bone marrow in both healthy and diabetic animal models. The results of the study were published in the journal, EBioMedicine.

“Using structural biology techniques and rational design synthetic chemistry, SR10171 was constructed to engage the PPARγ protein in a unique way possessing an optimal balance with the receptor's other family member, PPARa, to treat diabetes and, at the same time, improve bone health,” said Patrick R. Griffin, a professor on the Florida campus of TSRI. “This targeted polypharmacological approach demonstrates that the target isn't the problem if you target it correctly.”

By promoting bone cells in various stages of development, the SR10171 drug candidate increases bone mass. The compound uses mechanisms common to those involved in energy metabolism across all cells in the body.

“SR10171 improves bone mass regardless of body mass index, normal to obese,” said Griffin. “So you could use such a drug to treat osteoporosis whether patients are diabetic or not.”

According to a 2012 report from the American Diabetes Association, over 29 million people in the US are affected by diabetes. In 2013, the agency estimates that the medical costs as a result of diabetes diagnosis totaled $176 billion.


Keywords: Type 2 Diabetes, Bone Disease, Drug Candidate


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