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05.07>> Obesity     
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Obesity 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 craze about?

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 semi-permeable 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 is 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 insulin sensitivity.

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.

 

Here is sobering information about obesity from the Centers for Disease Control and Prevention:

Health Consequences
Overweight and obese individuals are at increased risk for many diseases and health conditions, including the following:
Hypertension (high blood pressure)
Osteoarthritis (a degeneration of cartilage and its underlying bone within a joint)
Dyslipidemia (for example, high total cholesterol or high levels of triglycerides)
Type 2 diabetes
Coronary heart disease
Stroke
Gallbladder disease
Sleep apnea and respiratory problems
Some cancers (endometrial, breast, and colon)


Kahn Lab Team


Student Worksheet
May 2007
Teacher Guidance
May 2007

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Dr. 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 as diabetes.

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. 2006
  • 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

Gwosdow Associates

 

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