Diabetes Origin: Free Fatty Acids?

Last Editorial Review: 3/2/2005

What actually causes diabetes? Free fatty acids -- substances that circulate in the bloodstream -- may be part of the answer.

WebMD Feature

Reviewed By Charlotte Grayson

While the treatment of diabetes has improved greatly in recent years, its emphasis has changed from stabilizing and lowering blood sugar levels to prevention of complications and to prevention of the disease itself.

Even though diabetes care is still necessarily focused on maintenance, researchers and doctors have been attempting to get at the causes of the illness as a means of actually curing or preventing it. What really causes diabetes? And particularly important -- given the worrying surge of obesity in the U.S. and the world -- what is it about excess fat that puts people at greater risk of developing type 2 diabetes?

The answer might lie in free fatty acids, fat cells that circulate in the bloodstream. Experts have long known that levels of free fatty acids are higher in people who are obese and those who have diabetes. But are free fatty acids somehow responsible for the resistance to insulin seen in type 2 diabetes, or are they only another sign of the metabolic dysfunction that the disease causes? No one is entirely sure yet, but the research suggests that free fatty acid levels may be important.

What Are Free Fatty Acids?

"There's a lot of scientific emphasis on free fatty acids now," says Paul Jellinger, MD, past president of the American Association of Clinical Endocrinologists (AACE). "And free fatty acids seem to do a lot of bad things."

So what are free fatty acids? During the process of lipolysis -- the breakdown of fat stored in fat cells -- free fatty acids are released into the bloodstream and circulate throughout the body. Naturally, people who are obese have larger reservoirs of fat cells that can potentially become free fatty acids. When free fatty acid levels are too high, there's evidence they cause a number of problems.

To understand the potential risks of high levels of free fatty acids, it's important to know the mechanisms of diabetes and the condition that often precedes it, insulin resistance. Insulin is a hormone produced by the pancreas that allows blood sugar (glucose) to be used by cells in the body as energy or stored for later use. In insulin resistance, the cells of the body become resistant to insulin and less receptive to the blood sugar they need. Once insulin resistance develops, type 2 diabetes may follow.

The Potential Dangers

High free fatty acid levels decrease the ability of the liver to store sugars -- keeping sugars in the blood and away from muscles that use them for energy. They may also directly affect the functioning of beta cells in the pancreas, the cells that produce insulin. How free fatty acids do this is the subject of some debate.

One widely accepted hypothesis that goes back 40 years is that an excess of free fatty acids in the bloodstream blocks the normal absorption of glucose by other cells. However, that idea, called the Randle hypothesis, has been under scrutiny recently.

A different hypothesis is that an excess of fat cells results in fat being stored in places that it shouldn't, such as in the liver, skeletal muscles, and in the beta cells. This improper storage could result in insulin resistance. Another potentially complimentary hypothesis is that the excretion of other endocrine hormones -- such as leptin and resistin -- from fat tissue could have a marked effect on the body's metabolism, causing dysfunction.

Perils of the Potbelly

The connection between obesity and type 2 diabetes is well established. According to the American Diabetes Association, more than 90% of all people newly diagnosed with type 2 diabetes are overweight or obese.

But some fat is worse than other fat. Having fat in the abdomen (called visceral fat or central obesity) is believed to pose a greater health risk than fat elsewhere in the body, such as fat on the hips. Studies have associated abdominal fat with a greater risk of diabetes and heart disease. But why does it matter where the fat is located?

One theory is that free fatty acids released by visceral fat have a direct path to the liver. If too much is released, the liver is less capable of responding to insulin. The liver takes in glucose for storage and releases it when needed. In the presence of insulin, the liver takes glucose from the blood and stores it. In the absence of insulin, the liver releases stored glucose. When there is excess fat, the liver ignores insulin and releases more sugar into the blood -- hence, insulin resistance.

Sorting Through the Theories

The exact role of free fatty acids has not yet been determined, and no one is certain whether controlling their levels specifically will be important to diabetes treatment.

"We know that diabetes treatment is not just about glucose anymore," says Fran Kaufman, MD, president of the American Diabetes Association, who cites new focus on blood pressure and cholesterol and triglyceride levels in diabetics as an important shift in treatment. "And we know that when fat levels go up and visceral fat increases, that the medical situation can deteriorate."

However, she cautions that no one has yet been able to establish a causative role for high free fatty acid levels in the development of diabetes.

Regardless, certain diabetes drugs do seem to have an effect on free fatty acid levels and improve the body's sensitivity to insulin, such as the thiazolidinediones (TZDs) -- including Avandia and Actos -- and Glucophage.

"The good news is that there's evidence that both drugs reduce [free fatty acid] levels," Jellinger tells WebMD, "and rather robustly, too."

What Do I Need To Do?

So all of this invites a few obvious questions. Should you run out and have your free fatty acid levels checked? Do you need to take medication to control them?

The simple answer is no. While the study of free fatty acids is intriguing, it hasn't led to any practical recommendations about monitoring or lowering their levels.

"The role of free fatty acids in the development of diabetes is very important," says Om Ganda, MD, director of the lipid clinic at the Joslin Diabetes Center and Associate Clinical Professor at Harvard Medical School. "But I don't think that we need to measure them in order to assess the metabolic status of the patient. [Free fatty acids] are very tricky to measure in clinical situations anyway."

And even if it were simpler to monitor levels of free fatty acids, it's not clear yet what a doctor would do with the information.

"We now recognize that elevated levels of free fatty acids may cause resistance and deficient insulin secretion," David M. Nathan, MD, director of the diabetes center at Massachusetts General Hospital and a professor of medicine at Harvard Medical School. "But it isn't clear that this insight will change our therapeutic approach to the disease. Therapies that lower blood sugar also lower free fatty acid levels."

If you're concerned about your diabetes, or your risk of developing diabetes, the best thing you can do is talk to your doctor about aggressive treatment and prevention. If you're overweight, lose some weight and exercise regularly -- this improves the body's sensitivity to insulin and decreases the need for it. If you have diabetes, your doctor may prescribe medications that will help control your condition and lower your glucose levels.

While it may be too soon to have developed treatments for free fatty acids specifically, they may yet turn out to be an important new target in the battle against diabetes.

Originally published March 17, 2003.

Medically updated June 18, 2004.

SOURCES: Thomas Buchanan, MD, director of the clinical research center at the Keck School of Medicine; professor of medicine at the University of Southern California; leader of the Troglitazone in Prevention of Diabetes (TRIPOD) study * Om Ganda, MD, associate clinical professor of medicine at Harvard Medical School; senior physician and director of the lipid clinic at the Joslin Diabetes Center; attending physician at Beth Israel-Deaconess Medical Center, Boston * David E. Goldstein, MD, chair of the NGSP Steering Committee; professor of child health and principal investigator at the health sciences center at the University of Missouri School of Medicine * Paul Jellinger, MD, past president of the American Association of Clinical Endocrinologists (AACE); clinical professor in the department of medicine at the University of Miami School of Medicine * Fran Kaufman, MD, president of the American Diabetes Association (ADA); head of the division of endocrinology and metabolism and director of the comprehensive childhood diabetes center at the Children's Hospital in Los Angeles; professor of pediatrics at the Keck School of Medicine * David M. Nathan, MD, director of the general clinical research center and of the diabetes center at Massachusetts General Hospital; professor of medicine at Harvard Medical School; chairman of the Diabetes Prevention Project (DPP).

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