Surprise: Diabetes clue found in bones

Original at: http://tinyurl.com/2m9pfd

By Alice Dembner, Globe Staff  |  August 13, 2007

As medicine struggles to halt the nation's diabetes epidemic,
scientists have found a potential new weapon in the most unlikely
place -- the skeleton.

Bone cells, they discovered, generate a hormone that helps regulate
the body's metabolism. And the lack of that hormone appears to
contribute to the development of diabetes.

The work, conducted in mice, has a long way to go before it could be
used to help diabetics. But a previous study showed that the
substance, called osteocalcin, is found in lower quantities in people
with untreated type 2 diabetes, scientists said.

"One could hope and certainly we will test if it could be a treatment
for type 2 diabetes," said Dr. Gerard Karsenty, senior author of the
paper in Cell magazine and chairman of the department of genetics and
development at Columbia University Medical Center. "What makes
osteocalcin attractive is that we all have it in our bodies and we
tolerate it very well."

The study, which is the first to provide evidence for a skeletal
hormone, is generating excitement among diabetes researchers. But they
cautioned that it is only one of a number of substances that appear to
interact to control blood sugar in the body, and scientists must learn
much more before osteocalcin could be considered a medicine.

"It has opened up a new area" of research, said Dr. C. Ronald Kahn,
head of obesity research at the Joslin Diabetes Center, who was not
involved in the work. "But it's so unexpected, it's going to take a
number of studies to figure out if this applies to humans."

In type 2 diabetes, sugar can rise to dangerous levels in the blood
because the body loses sensitivity to insulin and may eventually not
produce enough insulin. The body needs insulin to move digested food
into cells to fuel activities. About 20 million Americans have this
type of diabetes, which can lead to serious complications or death if
not properly treated.

Scientists have known for years that osteocalcin is produced by
osteoblasts, cells that help build bone. But the Columbia researchers
are the first to show that it is also an endocrine hormone -- a
substance that acts through the bloodstream to affect metabolism.

In their experiments, they inactivated mouse genes that produce
osteocalcin. The osteocalcin-deficient mice grew abnormally fat and
developed symptoms of diabetes, even when eating a normal diet. When
the researchers gave the mice osteocalcin, the rodents' blood sugar
normalized. Presence of the hormone also prevented mice from gaining
weight when they overate.

Karsenty said the hormone appears to work in multiple ways to counter
diabetes: it increases the body's production of the pancreatic cells
that make insulin, it directly increases the secretion of insulin, it
enhances the body's sensitivity to insulin, and it reduces storage of
fat. No drug on the market carries that kind of punch.

Kahn called that multiple effect "particularly striking" and one of
the goals for any new treatment. But another specialist, Dr. Michael
A. Lazar, director of the Institute for Diabetes, Obesity, and
Metabolism at the University of Pennsylvania, said two of those
effects seem contradictory and raise questions that need to be
explained.

Typically, he said, if the body becomes more sensitive to insulin,
other mechanisms would kick in to shut off insulin production and vice
versa. That makes it important to understand how osteocalcin interacts
with other hormones as a next step, he said.

The diabetes specialists said that mice have proved to be a useful
model for learning about human metabolism because of many similarities
in genes, hormones, and functions. In this case, one of the genes that
affects osteocalcin function in mice is not active in humans, but
Karsenty said he believes there are other genes that serve the same
purpose.

Karsenty, however, acknowledged "the possibility that osteocalcin
function has been lost in evolution" and is not present in people.

The next steps, he said, are to study its effect in monkeys and then
in humans over the next few years.

Karsenty's group discovered the new bone-based hormone because they
were looking for the symmetry that often exists in the body. They knew
that most hormones are part of a feedback loop and that a fat cell
hormone called leptin helps controls bone mass. So they searched for a
corresponding bone hormone that controls fat, and found osteocalcin.

"As proof of the concept that the skeleton makes molecules that act as
hormones, this is the first of its kind, convincing and interesting,"
said Lazar. "It adds another candidate to the list . . . that could
help us combat diabetes. But it's premature to be giving osteocalcin
injections at this time."