Type 2 Diabetes;
Take Two Aspirin and Call Me In The Morning?
Evan David Rosen, M.D., Ph.D.
Assistant Professor of Medicine,
Harvard Medical School
Acrp30
is a molecule that is produced by fat cells and which is deficient
in the blood of people and animals with type 2 diabetes. When
this protein is given back to diabetic mice, it seems to restore
serum glucose and insulin levels, causes burning of fats accumulated
inappropriately in muscle and liver, and leads to weight loss.
One of the most interesting features of Acrp30 is that it looks
very similar to molecules used by the body to ward off infection.
In this edition of Viewpoint, I want to expand on this notion
of immune molecules being produced by fat tissue, and the role
these molecules may play in type 2 diabetes.
It turns out that adipose tissue
(fat) is far more versatile than we once supposed. In addition
to storing energy in the form of triglycerides, fat secretes
a variety of hormones that have effects on a wide variety of
bodily functions, ranging from bone density to blood pressure
control. In the last three to five years, the list of factors
known to be secreted by fat has swelled considerably, and at
least one interesting theme has emerged: the fact that fat secretes
a lot of things that are known to regulate the immune system.
This was first seen with a protein called adipsin, which was
identified as a fat cell product in 1986. Adipsin is also called
complement factor D, and like other complement proteins it participates
in a process that kills many forms of invading bacteria. A few
weeks ago a paper was published about a family with many members
carrying adipsin mutations; these unfortunate people are prone
to devastating infections by meningitis-causing bacteria, among
others.
But it's not just about adipsin.
It turns out that many molecules known for their role in the
immune system are produced by fat cells, including the inflammatory
hormones tumor necrosis factor-alpha (TNF-alpha) and interleukin-6
(IL-6), as well as a variety of proteins known to be a part
of the "acute phase response," such as serum amyloid
A, haptoglobin, and others. The acute-phase response is the
name given to a phenomenon seen when the body is subjected to
different kinds of stress, such as malignancy, infection, or
tissue injury. It describes the appearance or disappearance
of specific proteins in the blood, some of which I've just mentioned.
Presumably, these proteins participate in the inflammatory process
that helps the body deal with these events, although exactly
what each individual protein does is still a bit murky. In many
cases of chronic inflammation, there is often what looks like
a permanent state of acute-phase response (which points out
the silliness of the name "acute-phase", but tradition
dies hard in medicine and so the name has remained).
So what does all this have to
do with diabetes? Well, one idea that is gaining currency is
that type 2 diabetes is actually a form of chronic inflammation.
Fat cells, overabundant in obese patients and cranking out lots
of acute-phase proteins, may induce a state of persistent inflammation
that manifests itself as type 2 diabetes.
This is not as crazy as it sounds,
if you consider the following points:
Many inflammatory molecules,
like TNF-alpha and IL-6, can induce a state of insulin resistance
in muscle, fat, and liver. Blocking these molecules, at least
in diabetic rats and mice, improves blood sugar levels.
It has been known for almost 100 years that high doses of salicylates,
which include aspirin-like drugs and which have anti-inflammatory
activity, can improve diabetes. These drugs block an enzyme
called IKKbeta, and mice that lack this enzyme are resistant
to obesity-induced diabetes.
Levels of many acute-phase proteins are higher in diabetics
than non-diabetics.
Now, this last point can be interpreted two ways. On the one
hand, I am obviously suggesting that these proteins may play
a causative role in diabetes. On the other hand, you could just
as well argue that these proteins rise because of the diabetes,
rather than the other way round. A new study published in a
recent Journal of the American Medical Association (JAMA) tends
to support the former conclusion, however. In the Women's Health
Study, physicians collected blood from thousands of women beginning
almost a decade ago. They have followed these women over the
ensuing years, and have kept up with them to record how they
have fared. The results have been relevant to many diseases
and conditions, but in this particular paper the authors chose
hundreds of women who developed diabetes over the years and
compared them to women who remained diabetes-free. They then
went back to their freezers to look at the frozen blood samples
collected before the women developed diabetes. Interestingly,
they found that those women destined to have type 2 diabetes
had higher levels of acute-phase proteins and other inflammatory
markers than did those destined to remain healthy.
This observation, coupled with
the sort of other data that I mentioned above, is certain to
focus attention on inflammation as a way for diabetes to develop.
This in turn will lead people to test new potent anti-inflammatory
drugs in diabetes, a use that would not have been predicted
even a few years ago. Another spin-off of this type of study
might be the early identification of patients at risk for diabetes
later in life--this would allow doctors to focus their efforts
to change diet and exercise patterns on those patients most
likely to develop the disease. Many questions remain unanswered,
such as how the inflammation is triggered in the first place.
While these answers are being sought by scientists, practical
interventions can still be tested that may benefit the millions
of people that have or will soon have type 2 diabetes.
References:
1. Jason K. Kim, Yoon-Jung Kim,
Jonathan J. Fillmore, Yan Chen, Irene Moore, Jongsoon Lee, Minsheng
Yuan, Zhi Wei Li, Michael Karin, Pascale Perret, Steven E. Shoelson,
and Gerald I. Shulman. Prevention of fat-induced insulin resistance
by salicylate. Journal of Clinical Investigation 2001 108: 437-446.
2. Pradhan AD, Manson JE, Rifai
N, Buring JE, Ridker PM. C-reactive protein, interleukin 6,
and risk of developing type 2 diabetes mellitus. Journal of
the American Medical Association 2001 Jul 18;286(3):327-34.
3. Pickup JC, Crook MA. Is type
II diabetes mellitus a disease of the innate immune system?
Diabetologia. 1998 Oct;41(10):1241-8. Review.
Written by Evan D. Rosen, M.D.,
Ph.D.
Content created 8/14/01
Content last reviewed August 14, 2001
Print
This Article
Dr.
Rosens Archives
