Insulin, the well-known blood sugar hormone, may have a newly discovered function in the body that will rattle your bones—regulating skeletal growth and breakdown.

Two new studies published online July 22 in Cell show that insulin stimulates both bone building and breakdown in mice through the hormone's effects on two types of bone cells: bone-building osteoblasts and bone-resorbing osteoclasts. What's more, these cells are involved in an intricate hormonal loop that in turn regulates not only insulin production, but also blood sugar levels and energy metabolism. The studies suggest that the skeleton may be an important regulator of whole-body energy metabolism, joining the ranks of known metabolic regulators such as muscle and fat. The authors conclude that their findings have important implications for understanding and treating metabolic disorders such as type 2 diabetes as well as bone conditions like osteoporosis.

Our skeletons are continually being broken down and rebuilt through a mechanism known as bone remodeling. This seemingly wasteful process is absolutely necessary to maintain structural integrity of the skeleton, and also regulates blood levels of calcium, an essential nutrient used in muscle contraction and other cellular processes. Skeletal remodeling is controlled by the actions of many different hormones, including vitamin D and parathyroid hormone (PTH). Now scientists have identified insulin as a surprising new player in this process.

In order for a cell to respond directly to insulin it must display an insulin receptor on its surface. Scientists have known for some time that the bone-building osteoblasts have insulin receptors, although the effect of insulin on these cells was not well understood.

To better comprehend insulin's effects on bone, both research teams engineered mice so that their osteoblasts no longer displayed insulin receptors. Researchers led by Thomas Clemens of Johns Hopkins University School of Medicine discovered that those mice developed a bone-making deficiency, having thinner bones with fewer osteoblasts. Their results suggest that insulin is necessary for mice to maintain normal bone mass.

Clemens points out that people with type 1 diabetes, who are unable to make insulin, frequently have low bone mass, suggesting that the results may be relevant for humans.

The most surprising finding for Clemens's team: as the modified mice aged they became overweight even though they were losing bone and not eating more than the controls. The animals also developed insulin resistance and other biochemical hallmarks of type 2 diabetes.

Clemens explains that his team traced these metabolic effects to a critical hormone known as osteocalcin, which is produced by bone. Osteocalcin stimulates the pancreas to make more insulin and makes cells in the body more sensitive to insulin's actions. "The reason these mice are fat is because they're not making enough insulin, which is because they're not making osteocalcin," Clemens says. To confirm this, the researchers gave the insulin receptor-deficient mice osteocalcin, which improved their metabolic abnormalities.

But the insulin/osteoblast/osteocalcin/insulin loop does not appear to be the whole story. According to the second study, led by Gerard Karsenty of Columbia University, insulin stimulates osteoblasts to produce an "inactive" form of osteocalcin that "sticks" to bone and doesn't enter circulation to stimulate the pancreas. Accumulation of inactive osteocalcin instead nudges osteoclasts into action, causing them to gobble up bone. Therefore, insulin's effects on the bones favors bone resorption.

Karsenty's team further found that the bone resorption process creates an acidic environment that converts osteocalcin into an "active" form, which can escape bone and enter circulation. Karsenty calls this process a "feed-forward" loop, where insulin stimulates the production of osteocalcin, which in turn stimulates more insulin production. His team's findings suggest that the bone resorptive process is necessary to further stimulate of insulin generation.

"The significance of this is that bone is an integrated part of how whole body glucose equilibrium is regulated. Drugs that inhibit bone resorption [which are commonly used to treat osteoporosis] may, in certain patients, favor glucose intolerance," Karsenty says. He adds that this is a concern that also needs to be addressed in future studies.

Clifford Rosen, senior scientist at Maine Medical Center Research Institute who was not involved with either study, says the new findings have "huge implications" and "bring the skeleton into the metabolic arena." He points out that mice have very high metabolic rates, however, so future studies will need to address whether this loop exists in humans. Also, glucose is a major stimulator of insulin, and other compounds in the body can stimulate its production as well, so where in the hierarchy of metabolic regulation the skeleton fits in is not yet clear.

Together, the studies suggest that bone plays a part in energy expenditure, Clemens says. "It's a part we missed before. We knew that muscle and fat played a role in metabolism, but we didn't think of bone as a true metabolic organ. This puts the skeleton, specifically bone cells, in control of body composition, through insulin," he adds.