Bones and Diabetes
Wouldn't you like to have a drug that reduces insulin resistance, increases insulin production, makes your beta cells grow, and keeps you from getting fat?
Me too. And guess what. We may already have such a "drug" in our bodies, osteocalcin.
Osteocalcin is produced by your bones. More specifically, it's produced by bone cells called osteoblasts. Those are the bone cells that build new bone and make your bones stronger.
Osteocalcin is thought to be involved with laying down the new bone, although the mechanism is not entirely clear. In this case, osteocalcin works within the bone itself.
But until recently, no one had any idea that the bones could also produce a hormone, meaning a substance that is produced in one part of the body and travels through the bloodstream to affect other parts of the body, in this case beta cells and fat cells. But apparently that's what the bones are doing.
Osteocalcin produced by the bone seems to be regulating blood sugar levels. One surprising thing about the effects of osteocalcin is that it seems to increase insulin production at the same time it decreases insulin resistance. Usually when something reduces insulin resistance, it also reduces insulin production.
Not only does the osteocalcin regulate blood sugar levels, but it also keeps fatty acid levels in the blood low, makes animals use more energy, and keeps them from getting fat.
So far, this all sounds miraculous. However, the research, done by Gerard Karsenty of Columbia University and coworkers, was done in mice. And we all know how many times mice have been cured of diabetes without anyone being able to translate this research into useful treatments for humans.
Nevertheless, this is exciting research. I won't detail the many elegant experiments done by the Karsenty group to give good evidence of what is going on in the mice. If you want the science behind the results, you can read the full text of the paper here.
Their discoveries came about because they applied the concept of reciprocity, or feedback loops. In general, if one substance stimulates the production of another substance, when the second substance increases sufficiently, it feeds back and inhibits further synthesis.
For example, low blood glucose levels stimulate the synthesis and secretion of insulin. When insulin levels rise sufficiently, they feed back to inhibit further synthesis and secretion.
The Karsenty group were familiar with leptin, a hormone produced by fat cells. Leptin tells the rest of the body how much fat you're carrying around. Obviously, if you're carrying a lot of fat, you're heavier, and you need stronger bones. Hence leptin acts on the osteoblasts to make them produce stronger bones.
The Karsenty group reasoned that if a product of the fat cells stimulated bone cells, most likely the bone cells would produce a substance that fed back to inform the fat cells of their situation. So they started to look for such a compound. And they identified osteocalcin as the key. People with type 2 diabetes tend to have low levels of osteocalcin, and those levels increase as they get their blood glucose levels controlled.
Mice lacking osteocalcin are fat and glucose intolerant. Much of their fat is visceral fat, the "dangerous" kind that is supposed to be related to insulin resistance. They have higher blood glucose levels, lower levels of insulin production, and lower insulin sensitivity. They also use less energy than normal mice.
If you give these mice extra osteocalcin, their blood glucose levels become normal and they don't gain weight, even when they overeat.
Mice lacking another gene that reduces the activity of osteocalcin (so in effect they have more osteocalcin) show just the opposite effects. They have increased beta-cell proliferation, an increase in insulin levels, and an increase in the hormone adiponectin, which is produced by fat cells and increases insulin sensitivity. People with type 2 diabetes tend to have low levels of adiponectin.
(The mouse gene is called Esp and it produces a protein called tyrosine phosphatase, or OST-PTP, but don't worry about the names. I mention them just in case you see them in other stories.)
Osteocalcin exists in both carboxylated and uncarboxylated forms. Vitamin K is required to produce the carboxylated form, which binds calcium. In fact, for some time, people have used carboxylated osteocalcin as a test for people's vitamin K status.
Not surprisingly, when the news about osteocalcin was published, purveyors of vitamins called osteocalcin "vitamin K dependent" and urged people to buy their vitamin K, which is also found in green, leafy vegetables as well as being produced by bacteria in the gut.
However, it's the uncarboxylated form of osteocalcin that turns out to be the active form. Perhaps the carboxylated form is an inactive storage form of the compound and decarboxylation would activate it. This is true in some other systems.
Another vitamin that is important for osteocalcin production is vitamin D, which increases osteocalcin synthesis. People with type 2 diabetes tend to be low in vitamin D.
Does all this mean that supplementing with vitamins K and D would help people with type 2 diabetes? Possibly. And possibly not. Supplementation doesn't always fix deficiencies, which are sometimes the result of some underlying flaw that is the source of the problem.
However, I think it's interesting that many Americans eat very few green leafy vegetables. Some try to avoid fat, which is necessary for the absorption of the fat-soluble vitamins, including vitamins D and K. When they go outside, some people slather themselves with sunscreen, thus reducing their production of the active form of vitamin D. Is all this contributing to type 2 diabetes? Possibly and possibly not, but it's something to think about.
Finally, what interests us patients most, of course, is the practical implications of any research. Unfortunately, we'll have to wait to see if this research translates into human treatments. Although the researchers are testing osteocalcin injections in various animals, it's too early to recommend them for humans.
But from a theoretical point of view, this research is fascinating. Bone was thought to be mostly an inert skeleton holding up the rest of the body, although bone marrow, the soft tissue inside the bones, has many functions, including producing blood cells. Now it has been shown that bone is also an endocrine organ (meaning one that produces hormones) that controls metabolism.
This is not the first time in recent history that an "inert" organ has been found to be an endocrine organ. Not long ago, scientists thought fat cells were simply bags of fat, storing energy for lean times. Then they found that fat cells were also endocrine organs, producing a multiplicity of hormones they called adipokines.
If this trend continues, maybe some day they'll discover that the cure for type 2 diabetes rests in our hair and fingernails. Not likely, of course, but who knows?