The more we learn, the less we know:

http://www.nytimes.com/ HEATLTH
NYT October 16, 2007
In Diabetes, a Complex of Causes By AMANDA SCHAFFER

An explosion of new research is vastly changing scientists’
understanding of diabetes and giving new clues about how to attack it.

The fifth leading killer of Americans, with 73,000 deaths a year,
diabetes is a disease in which the body’s failure to regulate glucose,
or blood sugar, can lead to serious and even fatal complications. Until
very recently, the regulation of glucose — how much sugar is present in
a person’s blood, how much is taken up by cells for fuel, and how much
is released from energy stores — was regarded as a conversation between
a few key players: the pancreas, the liver, muscle and fat.

Now, however, the party is proving to be much louder and more complex
than anyone had shown before.

New research suggests that a hormone from the skeleton, of all places,
may influence how the body handles sugar. Mounting evidence also
demonstrates that signals from the immune system, the brain and the gut
play critical roles in controlling glucose and lipid metabolism. (The
findings are mainly relevant to Type 2 diabetes, the more common kind,
which comes on in adulthood.)

Focusing on the cross-talk between more different organs, cells and
molecules represents a “very important change in our paradigm” for
understanding how the body handles glucose, said Dr. C. Ronald Kahn, a
diabetes researcher and professor at Harvard Medical School.

The defining feature of diabetes is elevated blood sugar. But the
reasons for abnormal sugar seem to “differ tremendously from person to
person,” said Dr. Robert A. Rizza, a professor at the Mayo Clinic
College of Medicine. Understanding exactly what signals are involved, he
said, raises the hope of “providing the right care for each person each
day, rather than giving everyone the same drug.”

Last summer, researchers at Columbia University Medical Center published
startling results showing that a hormone released from bone may help
regulate blood glucose.

When the lead researcher, Dr. Gerard Karsenty, first described the
findings at a conference, the assembled scientists “were overwhelmed by
the potential implications,” said Dr. Saul Malozowski, senior adviser
for endocrine physiology research at the National Institute of Diabetes
and Digestive and Kidney Diseases, who was not involved in the research.
“It was coming from left field. People thought, ‘Oof, this is really new.’

“For the first time,” he went on, “we see that the skeleton is actually
an endocrine organ,” producing hormones that act outside of bone.

In previous work, Dr. Karsenty had shown that leptin, a hormone produced
by fat, is an important regulator of bone metabolism. In this work, he
tested the idea that the conversation was a two-way street. “We
hypothesized that if fat regulates bone, bone in essence must regulate
fat,” he said.

Working with mice, he found that a previously known substance called
osteocalcin, which is produced by bone, acted by signaling fat cells as
well as the pancreas. The net effect is to improve how mice secrete and
handle insulin, the hormone that helps the body move glucose from the
bloodstream into cells of the muscle and liver, where it can be used for
energy or stored for future use. Insulin is also important in regulating
lipids.

In Type 2 diabetes, patients’ bodies no longer heed the hormone’s
directives. Their cells are insulin-resistant, and blood glucose levels
surge. Eventually, production of insulin in the pancreas declines as well.

Dr. Karsenty found that in mice prone to Type 2 diabetes, an increase in
osteocalcin addressed the twin problems of insulin resistance and low
insulin production. That is, it made the mice more sensitive to insulin
and it increased their insulin production, thus bringing their blood
sugar down. As a bonus, it also made obese mice less fat.

If osteocalcin works similarly in humans, it could turn out to be a
“unique new treatment” for Type 2 diabetes, Dr. Malozowski said. (Most
current diabetes drugs either raise insulin production or improve
insulin sensitivity, but not both. Drugs that increase production tend
to make insulin resistance worse.)

A deficiency in osteocalcin could also turn out to be a cause of Type 2
diabetes, Dr. Karsenty said. Another recent suspect in glucose
regulation is the immune system. In 2003, researchers from two
laboratories found that fat tissue from obese mice contained an
abnormally large number of macrophages, immune cells that contribute to
inflammation. The finding piqued the curiosity of researchers. “I
remember reading the paper and thinking: ‘Wow, look at all those
macrophages. What are they doing?’” said Dr. Jerrold M. Olefsky of the
University of California, San Diego, School of Medicine.

Scientists have long suspected that inflammation was somehow related to
insulin resistance, which precedes nearly all cases of Type 2 diabetes.
In the early 1900s, diabetics were sometimes given high doses of
aspirin, which is an anti-inflammatory, Dr. Olefsky said.

Only in the past few years has research into the relationship of
obesity, inflammation and insulin resistance become “really hot,” said
Dr. Alan R. Saltiel, director of the Life Sciences Institute at the
University of Michigan.

Many researchers agree that obesity is accompanied by a state of
chronic, low-grade inflammation in which some immune cells are
activated, and that that may be a primary cause of insulin resistance.
They also agree that the main type of cell responsible for the
inflammation is the macrophage, Dr. Saltiel said.

But major questions remain, he said: “Why are these macrophages
attracted to fat, liver and muscle in the first place? What are they
doing? What are they secreting? What other immune cells are in there?”

New research also suggests that “not all macrophages are created equal,”
added Dr. Saltiel. There appear to be “good ones and bad ones” competing
in fat tissue, with potentially large consequences for inflammation and
diabetes.

Meanwhile, the promise of anti-inflammatory compounds as treatment
continues to attract attention. “Certain cellular anti-inflammatory
proteins may now be important new targets for drug discovery for
diabetes treatment,” Dr. Olefsky said. But damping down the immune
system is also potentially risky, he noted, adding: “If you’re
inhibiting the macrophage inflammatory pathway, that’s good for insulin
resistance and diabetes. But it might not be so good for your
susceptibility to infections.” A major goal is to develop a drug that
quashes only the specific component of macrophage inflammation that
leads to insulin resistance, without causing other side effects.

One class of current medications, called thiazolidinediones, may work in
part by reducing inflammation, which may in turn improve insulin
sensitivity. But an example from this class, the drug Avandia, was also
found to increase the risk of heart attacks.

Another participant in the glucose conversation is the brain. Its role
has long been suspected. More than a century ago, the French
physiologist Claude Bernard suggested that the brain was important in
blood sugar regulation. He punctured the brains of experimental animals
in specific areas and managed to derange their blood sugar metabolism,
making them diabetic.

But for years, virtually no one followed up on this finding, said Dr.
Kahn, of Harvard.

People thought about glucose as a critical fuel for the brain, Dr. Kahn
said, but did not explore the brain’s role in glucose regulation.

Only recently, with more advanced laboratory techniques, has this role
been definitively established and expanded upon.

Today’s genetic techniques, said Dr. Rizza, at the Mayo Clinic, are what
have “really driven the process.”

For instance, once scientists developed the ability to manipulate mice
so that they lacked particular receptors in specific tissues, they could
show that mice without insulin receptors in the brain could not regulate
glucose properly and went on to develop diabetes, said Dr. Kahn, whose
laboratory published this groundbreaking work in 2000.

Other researchers have shown that free fatty acids, as well as the
hormone leptin, produced by fat tissue, signal directly to a part of the
brain called the hypothalamus, which also regulates appetite,
temperature and sex drive.

And several recent papers suggest that direct signaling by glucose
itself to neurons in the hypothalamus is also crucial to normal blood
sugar regulation in mice.

“If the brain is getting the message that you have adequate amounts of
these hormones and nutrients, it will constrain glucose production by
the liver and keep blood glucose relatively low,” said Dr. Michael W.
Schwartz, a professor at the University of Washington. But if the brain
senses inadequate amounts, he continued, it will “activate responses
that cause the liver to make more glucose, and new evidence suggests
that this contributes to diabetes and impaired glucose metabolism.”

The brain, therefore, appears to be listening to — and weighing and
making sense of — a chorus of signals from insulin, leptin, free fatty
acids and glucose itself. In response, it appears to send signals to
liver and muscle cells by way of several nerves, though additional
mechanisms are probably involved. The gut also seems to chime in, said
Dr. Rizza, adding that for him, this aspect of sugar regulation came as
“the biggest gee whiz of all.”

“Food comes in through the gut, so of course you should look there” for
molecules involved in glucose regulation, he said. “But few people
realized this until very recently.”

Hormones from the small intestine called incretins turn out to talk
directly with the brain and pancreas in ways that help reduce blood
sugar and cause animals and people to eat less and lose weight, Dr.
Rizza said.

Numerous molecules that mimic incretins or prevent them from being
degraded are in clinical trials. Two such drugs have been approved by
the Food and Drug Administration: Byetta, an incretin mimic, from Amylin
Pharmaceuticals and Eli Lilly; and Januvia, from Merck, which inhibits
the destruction of the incretin GLP1. (Dr. Rizza is an adviser to Merck
but says all consulting fees go to the Mayo Clinic for education and
research.)

Still, it can be hard to predict how different drugs will interact in
the body. And many promising candidates will turn out to have side
effects — chattering helpfully with one organ, but problematically with
another.

“The picture is becoming more and more complicated,” Dr. Saltiel said.
“And let’s face it, it was pretty complicated before.”
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