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Bone Plays Key Role In Insulin Regulation

New US research on mice suggests that bone plays a key role in insulin regulation and helps cells of the body take up glucose; as both these processes are impaired in people with type 2 diabetes the researchers suggest this discovery could lead to new diabetes drugs.

Dr Gerard Karsenty from Columbia University Medical Center, New York, and colleagues found that the process of bone resorption, when old bone breaks down to make way for new growth, releases a hormone called osteocalcin that turns on insulin production and also helps cells take up glucose.

You can read about the research that led to these findings in a paper published online on 23 July in the journal Cell.

There is great curiosity among scientists in the field about what influences the regulation of insulin, because the insulin receptor appears to be everywhere in the body, including osteoblasts, cells responsible for bone formation and releasing osteocalcin, which Karsenty and his team first linked with glucose regulation in 2007. Back then they found that once uncarboxylated (when the protein loses the COOH carboxyl terminus, a way of switching signals on and off), osteocalcin switches on insulin production in the pancreas and improves the ability of cells in the whole body to take in glucose: both of which are impaired in people with type 2 diabetes.

In this study they found that as osteoblasts begin the resorption process, the cell environment becomes more acidic which favors decarboxylation and thereby activates more osteocalcin, which in turn stimulates insulin production.

But they also found that insulin favored bone resorption, so the process appears to be a "feed-forward" loop where insulin signals osteoblasts to start resorption, which in turn releases more osteocalcin, which in turn releases more insulin. "Insulin is a street-smart molecule that takes advantage of the functional interplay between bone resorption and osteocalcin, to turn-on the secretion and synthesis of more insulin," said Karsenty.

The researchers suggest their finding strengthens the idea that diabetes could be treated by regulating levels of osteocalcin in the body. They also raised an important question that warrants further research: bisphosphonates, the most common drugs for treating osteoporosis, work by slowing down bone resorption, so could they also inhibit osteocalcin activation and cause some patients to become glucose intolerant?

"This research has important implications for both diabetes and osteoporosis patients," said Karsenty: "First, this research shows that osteocalcin is involved in diabetes onset; secondly, bone may become a new target in the treatment of type 2 diabetes, the most frequent form of diabetes, as it appears to contribute strongly to glucose intolerance; and, finally, osteocalcin could become a treatment for type 2 diabetes."

And secondly, said Karsenty, although more research is needed to study this further, there is a concern that an osteoporosis patient with borderline glucose intolerance who is then treated with bisphosphonates could be pushed into "fully-fledged" diabetes onset.

Another paper (Fulzele et al) in the same issue of Cell, describes how researchers found that insulin signalling helps bone formation by suppressing Twist2, a protein that inhibits osteoblast development and enhances expression of osteocalcin. Writing in a preview article about the significance of the two studies, Drs Clifford J. Rosen and Katherine J. Motyl of the Maine Medical Center Research Institute suggested that together they add to the growing evidence that the skeleton plays an important role in metabolic homeostasis: it would seem that bones are key players in keeping a steady throughput of energy through every cell of the body.

"Insulin Signaling in Osteoblasts Integrates Bone Remodeling and Energy Metabolism."
Mathieu Ferron, Jianwen Wei, Tatsuya Yoshizawa, Andrea Del Fattore, Ronald A. DePinho, Anna Teti, Patricia Ducy, Gerard Karsenty.
Cell, 142 (2) pp. 296 - 308, published online 23 July 2010.
DOI: 10.1016/j.cell.2010.06.003

Sources include:
http://www.bbc.co.uk/news/health-10727169
http://www.medicalnewstoday.com/articles/195837.php
http://www.bcm.edu/cnrc/faculty/oldkarsenty.htm
http://www.cell.com/abstract/S0092-8674%2810%2900621-5
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-50KKXCT-H&_user=10&_coverDate=07%2F23%2F2010&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=76af8e7fd776364cf485af335ceee728

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