Found this article very interesting... file it under "NO
EASY ANSWERS"
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.”
--
Rudy - Remove the Z from my address to respond.
"It is better to die on your feet than to live on your knees!"
-Emiliano Zapata
Check out the a.s.d.l-c FAQ at:
http://www.grossweb.com/asdlc/faq.htm