is a growing trend in this country. An abundance of food and lack
of exercise have added pounds and inches to the waists of millions
of Americans. It is particularly notable among pre-school and
school-age Americans. State and federal lawmakers are now looking
for ways to end this trend by introducing more healthy foods into
schools and more gym days into the school week. What is all the
Obesity itself is not harmful, but it can
lead to many other serious conditions such as heart disease and
high blood pressure (see sidebar story). This month we’ll focus on obesity’s
possible connection with a related chronic condition that is growing
in prevalence in this country: diabetes. Diabetes is a disease
that can have many consequences. If obesity contributes
to diabetes, and we can figure out how, then we may have some
additional weapons against the disease.
There are three main kinds of diabetes, all
of which are characterized by hyperglycemia, or too much blood
sugar: gestational, type 1, and type 2. The onset of gestational
diabetes occurs in women during pregnancy. Type 1 diabetes can
be hereditary and results from the body’s inability to make
insulin, a hormone needed for sugar uptake from the blood. This
is because the cells in the pancreas that usually make insulin
get destroyed in people with Type 1 diabetes.
The body of a person with type 2 diabetes produces insulin, but
for some reason the insulin does not work normally. Researchers
are trying to understand why this occurs, but there are many unanswered
questions. A major factor that increases the risk for type 2 diabetes
is obesity. Both Type 1 and Type 2 diabetes are increasing
in prevalence. Type 2 diabetes accounts for more than 90 percent
of the cases in the U.S. Type 2 diabetes is caused by insulin resistance and the body’s limited ability to secrete insulin.
The simple sugar called glucose is arguably
the most important molecule in the body. It provides energy –
and thus existence – to the body’s cells by a process
called cellular respiration.
Every cell is surrounded by a
lipid membrane. Because glucose is a large, electrically charged
molecule, it cannot enter the cell by itself. Instead, it needs
to bind to a protein that will allow it to cross the membrane.
The major glucose transporter protein that responds to insulin
GLUT4. GLUT4 acts like a gate to allow glucose to leave the
bloodstream quickly when insulin levels go up, such as after a
meal. If there is not enough GLUT4, glucose will build up in the
blood stream, causing hyperglycemia. If enough insulin cannot
be secreted to overcome this build up of glucose in the blood
and the block in glucose transfer to cells, diabetes can occur.
As insulin levels rise, the insulin directs
two kinds of tissues to take glucose from the bloodstream: muscle
cells and fat cells. Glucose is also made by liver cells. Insulin
signals liver cells to stop producing glucose when it is not needed.
In people with obesity or type 2 diabetes, the levels of GLUT4
are decreased in fat cells but not in muscle or liver cells.
Dr. Barbara Kahn of Harvard Medical School
and Beth Israel Deaconess Medical Center wanted to find out if
there was a link between glucose transport in fat cells and diabetes.
To do this, she made “fat specific-GLUT4
knockout” mice, mice whose gene for GLUT4 in fat cells had been inactivated.
In this way, the fat cells of the mice would not be able to take
up glucose circulating in the bloodstream. Because muscle cells
are the major site of cells that take up glucose from the bloodstream,
Dr. Kahn and her colleagues expected that the mice would have
relatively normal blood glucose levels. To her surprise, the knockout
animals developed insulin resistance. But if she took muscle from
these mice and tested it in test tubes outside of the body, she
found the muscle cells showed no problems responding to insulin.
This led Dr. Kahn to the conclusion that there must be a molecule
secreted from fat cells that circulates throughout the body causing
insulin resistance. After many tests, she found a protein that
always increased when the mice were insulin resistant. This protein
is called retinol binding protein 4, or RBP4.
The next step was to determine the effect
of overproduction and underproduction of this protein. If increased
RBP4 correlated with greater insulin resistance, it would suggest
how obesity contributes to Type 2 diabetes.
Through many experiments, Dr. Kahn and her
team of researchers found that the over-production of RBP4 causes
insulin-resistance in normal and obese mice. Conversely, mice
with the RBP4 gene knocked out (and thus, less RBP4) had heightened
Dr. Kahn’s team then focused on RBP4
in humans. She and her collaborators found that obese people at
risk for diabetes and non-obese people with a genetic risk for
diabetes had higher levels of RBP4. The amount of RBP4 correlates
with the severity of insulin resistance. This means that RBP4
could be used as a marker for people at risk for diabetes. If
this was, for example, a blood test done in the doctor’s
office during your yearly check-up, the doctor could follow your
RBP4 levels. Increases in RBP4 levels would indicate a physiological
change in your body, which may indicate the start of insulin resistance.
Current treatment for diabetes ranges from
managing exercise and diet to insulin injections. The discovery
of RPB4 as a marker for diabetes has opened up the possibility
of an entirely new class of drugs for the treatment of diabetes
that is under investigation by several pharmaceutical companies.
These drugs could reduce RBP4 levels as a way of preventing or
treating insulin resistance.
Dr. Kahn’s research has also shown
that when insulin resistant people go on an exercise regime, their
RBP4 levels decrease. This decrease is associated with improved
insulin sensitivity. Dr. Kahn and her
colleagues have found similar results in children. Obese children
who walked four times a week, did not watch much TV, drank less
soda and had fewer snacks high in carbohydrates (such as potato
chips, donuts, or candy) lost weight and had lower RBP4 levels. (Want to learn more about your Body Mass Index ˆ BMI ˆ and how to calculate it? Click here.)
To date, the only known function of RBP4
is to transport retinol, or vitamin A, in the blood to cells.
It is unknown if this function is related to RBP4’s role
in insulin resistance.
is sobering information about obesity from the Centers for Disease
Control and Prevention:
and obese individuals are at increased risk for many diseases
and health conditions, including the following:
(high blood pressure)
(a degeneration of cartilage and its underlying bone within
example, high total cholesterol or high levels of triglycerides)
||Type 2 diabetes
||Sleep apnea and respiratory problems
||Some cancers (endometrial, breast, and colon)
Kahn Lab Team
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What A Year! is a project of the Massachusetts
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And it is funded by a grant from The William
Townsend Porter Foundation
Kahn is the George R. Minot Professor of Medicine at Harvard Medical
School and Chief of the Endocrinology, Diabetes and Metabolism
Division at the Beth Israel Deaconess Medical Center in Boston.
After completing her medical degree and training, Dr. Kahn realized
that she did not want to spend her life simply prescribing medicines
that were already on the market. Instead, she wanted to actually
do the research to create new therapies and preventative approaches.
Dr. Kahn found diabetes intriguing and began her career as a researcher.
She hopes to find better ways to treat chronic diseases, such
To Learn More:
- Abel, E. Dale, Odile Peroni, Jason Kim,
Young-Bum Kim, Olivier Boss, Ed Hadro, Timo Minnemann, Gerald
Shulman, and Barbara Kahn. Adipose-selective targeting of
the GLUT4 gene impairs insulin action in muscle and liver.
Nature. 409 (2001): 729-733.
- Balagopal, Prabhakaran, Timothy Graham,
Barbara Kahn, Astride Altomare, Vicky Funanage, and Donald
George. Reduction of elevated serum retinol binding protein
(RBP4) in obese children by lifestyle intervention: association
with sub-clinical inflammation. Journal of Clinical Endocrinology.
- Graham, Timothy, Qin Yang, Matthias
Bluher, Ann Hammarstedt, Theodore Ciaraldi, Robert Henry,
Christopher Wason, Andreas Oberbach, Per-Anders Jansson, Ulf
Smth, and Barbara Kahn. Retinol-binding protein 4 and insulin
resistance in lean, obese, and diabetic subjects. New
England Journal of Medicine 354 (2006): 2552-2563.
- Herman, Mark, and Barbara Kahn. Glucose
transport and sensing in the maintenance of glucose homeostasis
and metabolic harmony. Journal of Clinical Investigation
116 (2006): 1767-1775.
- Yang, Qin, Timothy Graham, Nimesh Mody,
Frederic Preitner, Odile Peroni, Janice Zabolotny, Ko Kotani,
Loredana Quadro, and Barbara Kahn. Serum retinol binding protein
4 contributes to insulin resistance in obesity and type 2
diabetes. Nature 436 (2005): 356-362.
For Information on Diabetes:
For Information on Obesity:
For Information on Insulin
and Insulin Resistance:
Written by Rebecca Kranz with Andrea R. Gwosdow, PhD
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