What is Insulin Resistance?

Insulin is a hormone that is produced by the beta cells, which are cells that are scattered throughout the pancreas. The insulin produced is released into the blood stream and travels throughout the body. Insulin is an important hormone that has many actions within the body. Most of the actions of insulin are directed at metabolism (control) of carbohydrates (sugars and starches), lipids (fats), and proteins. Insulin also is important in regulating the cells of the body including their growth.

Insulin resistance (IR) is a condition in which the cells of the body become resistant to the effects of insulin, that is, the normal response to a given amount of insulin is reduced. As a result, higher levels of insulin are needed in order for insulin to have its effects. The resistance is seen with both the body's own insulin (endogenous) and if insulin is given through injection (exogenous).

What causes insulin resistance?

There are probably several causes of insulin resistance and there is thought to be a strong genetic factor (an inherited component), Some medications also can lead to insulin resistance. In addition, insulin resistance is seen often in the following conditions:

• the metabolic syndrome
• obesity
• pregnancy
• infection or severe illness
• stress
• during steroid use
• What is the relationship between insulin resistance and diabetes?
• Type 2 diabetes is the type of diabetes that occurs later in life. Insulin resistance precedes the development of type 2 diabetes, sometimes by years. In individuals who will ultimately develop type 2 diabetes, it is believed that blood glucose and insulin levels are normal for many years; then at some point in time, insulin resistance develops.
• At this point, there is often an association of high insulin levels, central obesity, cholesterol abnormalities, and /or high blood pressure (hypertension). When this constellation of disease processes occur, it is known as the metabolic syndrome.
• One of the actions of insulin is to cause the cells of the body, particularly the muscle and fat cells, to remove and use glucose from the blood. This is one way in which insulin controls the level of glucose in blood. Insulin has this effect on the cells by binding to insulin receptors on the surface of the cells. You can think of it as insulin "knocking" on the doors of muscle and fat cells. The cells hear the knock, open up, and let glucose in to be used by the cell. With insulin resistance, the muscles don't hear the knock as well (they are resistant), and the pancreas is notified that it needs to make more insulin, which increases the level of insulin in the blood and causes a louder knock.
• The resistance of the cells continues to increase over time. As long as the pancreas is able to produce enough insulin to overcome this resistance, blood glucose levels remain normal. When the pancreas can no longer produce enough insulin, the blood glucose levels begin to rise, initially after meals when glucose levels are at their highest and more insulin is needed, but eventually in the fasting state too. At this point, type 2 diabetes is present.

What medical conditions are associated with insulin resistance?

While the metabolic syndrome links insulin resistance with abdominal obesity, elevated cholesterol and high blood pressure, there are several medical other conditions that are associated with insulin resistance specifically. It may be that insulin resistance is the cause of some of these conditions, but this has not yet been proven. Conditions associated with insulin resistance include:

Type 2 Diabetes

Overt diabetes may be the first sign that insulin resistance is present. While it can be noted long before diabetes develops, in cases where there is reluctance or inability to see a physician regularly, insulin resistance can present as type 2 diabetes.

Fatty liver

Fatty liver is strongly associated with insulin resistance. The accumulation of fat in the liver is a manifestation of the disordered control of lipids that occurs with insulin resistance. Fatty liver associated with insulin resistance may be mild or severe. Newer evidence suggests that fatty liver may even lead to cirrhosis of the liver and, possibly, liver cancer.

Arteriosclerosis

Arteriosclerosis, also known as atherosclerosis, is a process of progressive thickening and hardening of the walls of medium-sized and large arteries. Arteriosclerosis is responsible for:

• coronary artery disease (angina and heart attack ),
• strokes and
• peripheral vascular disease.

Other risk factors for arteriosclerosis include:

• high levels of "bad" (LDL) cholesterol,
• high blood pressure,
• smoking,
• diabetes, and a
• family history of arteriosclerosis.

Skin Lesion

Skin lesions include increased skin tags and a condition called acanthosis nigricans - a darkening and thickening of the skin especially in fold areas such as the neckline and axilla. This condition is directly related to the insulin resistance, though the exact mechanism is not known.

• Acanthosis nigricans: Acanthosis nigricans is a cosmetic condition strongly associated with insulin resistance in which there is darkening of the skin in areas where there are creases such as the neck and arm pits.
• Skin tags: Skin tags are also seen with increased frequency in patients with insulin resistance. A skin tag is a common, benign condition which consists of a bit of skin that projects from the surrounding skin and may appear attached to the skin. Skin tags can vary quite a bit in appearance. They may be smooth or irregular, flesh colored or more deeply pigmented, and either simply be raised above the surrounding skin or have a stalk (a peduncle) so that the skin tag hangs from the skin.

Reproductive abnormalities in women

Reproductive abnormalities include difficulty with ovulation and conception (infertility), irregular menses, or a cessation of menses. In contrast, there are no known reproductive abnormalities in men with insulin resistance.

Polycystic ovary disease

Polycystic ovary disease is a hormonal problem that affects young women. It is associated with irregular periods or no periods at all, obesity, and increased growth of body hair.

Hyperandrogenism

High male hormone levels, which are produced by the ovaries, can be seen in insulin resistance and may play a role in PCOS described above. Why this association occurs is not known, but it's thought that the insulin resistance somehow causes the abnormal ovarian hormone production.

Growth abnormalities

There may be growth affects in insulin resistance due to the high levels of circulating insulin that may be present. While insulin's effects on glucose metabolism may be impaired, its effects on other mechanisms may be intact (or at least less impaired). Insulin is an anabolic and can exert effects on growth, through a medicator known as insulin- like growth factor -1. Patients may have actual linear growth and a noticeable coarsening of features. The increase incidence of skin tags mentioned above may be through this mechanism as well.

Who is at risk for insulin resistance?

Individuals are more likely to have or develop insulin resistance if they:

• are overweight with a body mass index (BMI) more than 25
• are a man with a waist more than 40 inches or a woman with a waist more than 35 inches
• are over 40 years of age
• are Latino, African American, Native American or Asian American
• have close family members with type 2 diabetes, high blood pressure or arteriosclerosis
• have had gestational diabetes
• have high blood pressure, high blood triglycerides, low HDL cholesterol or arteriosclerosis (for example, have other components of the metabolic syndrome)
• have polycystic ovarian disease
• have acanthosis nigricans

How is insulin resistance diagnosed?

A physician can identify individuals who are likely to have insulin resistance with a detailed patient history, patient physical examination, and laboratory testing utilizing the risk factors. There are some very sophisticated tests for the diagnosis or confirmation of insulin resistance such as euglycemic insulin clamping or intravenous tolerance testing. However, these are expensive or complicated and are not necessary for managing patients. These tests are used primarily for research purposes.

In general clinical practice, glucose levels in conjunction with fasting insulin levels can give the physician a clue as to whether insulin resistance is present or not in patients without diabetes. A firm diagnosis cannot be made simply based on this, since the lab techniques for measuring insulin can vary, and there is no absolute value that meets a definition. However, a level above the upper quartile in the fasting state in someone without diabetes is considered abnormal.

How is insulin resistance managed?

Insulin resistance can be managed in two ways. First, the need for insulin can be reduced, and second, the sensitivity of cells to the action of insulin can be increased.

Life-style changes

The need for insulin can be reduced by altering the diet, particularly the carbohydrates in the diet. Carbohydrates are absorbed into the body after they are broken up into their component sugars. Some carbohydrates are broken up and absorbed faster than others and are referred to as having a high glycemic index. These carbohydrates increase the blood glucose level more rapidly and require the secretion of more insulin to control the level of glucose in the blood.

Examples of carbohydrates with a high glycemic index that rapidly raise blood glucose levels include:

• unrefined sugars,
• white breads, and
• unrefined corn and potato products (for example, bagels, mashed potatoes, doughnuts, corn chips, and french fries).

Examples of foods with a low glycemic index include:

• foods with higher fiber content such as whole grain breads and brown rice;
• non-starchy vegetables (for example, broccoli, green beans, asparagus, carrots, and greens).

Since foods are rarely eaten in isolation, it can be argued that the glycemic index of each food isn't as important as the overall profile of the whole meal itself.

Several studies have shown that weight loss and aerobic exercise (without weight loss) increase the rate at which glucose in the blood is taken up by muscle cells as a result of improved sensitivity of the cells to insulin.

There are two important studies that have looked at the prevention of type 2 diabetes. Both studies took patients who could not control their blood glucose levels, which, for the purposes of this discussion, can be considered the same as patients with insulin resistance. One study done in Finland, showed that changes in diet and exercise reduced the development of diabetes by 58%. Another study, done in the United States and referred to as the DPP study, showed a similar reduction in diabetes with diet and exercise.

Medications

Metformin (Glucophage) is a medication that is used for treating diabetes. It has two mechanisms of action that help to control blood glucose levels. It prevents the liver from releasing glucose into the blood, and it increases the sensitivity of muscle and fat cells to insulin so that they remove more glucose from the blood. Because of these actions, metformin reduces blood insulin levels.

The DPP studied the effects of metformin in addition to diet and exercise on the prevention of diabetes in insulin resistance. Metformin reduced the development of diabetes by 31%. (Note, however, that the benefit was not as great as with diet and exercise!) Metformin is a reasonably safe medication when used in the right population. Although there are gastrointestinal side effects with metformin, it is usually well-tolerated.

Another study, the STOP NIDDM (Study to Prevent Non-insulin Dependent Diabetes Mellitus) trial, studied individuals with insulin resistance by treating them with a medication called acarbose (Precose). Acarbose works in the intestines to slow the absorption of sugars, and this effect would reduce the need for insulin after meals. The study found that acarbose reduced the development of diabetes by 25%.

Other medications in a class of drugs called thiazolidinediones, for example, pioglitazone (Actos), rosiglitazone (Avandia), also increase sensitivity to insulin. At this time, however, these medications are not routinely used, in part because of liver toxicity that requires monitoring of blood liver tests. Avandia, however, has been associated with an increased risk of heart attack and stroke, and experts have debated the severity of these concerns since the risk was first reported. On September 23, 2010, the U.S. Food and Drug Administration (FDA) announced that it will significantly restrict the use of the diabetes drug rosiglitazone (Avandia) to patients with type 2 diabetes who cannot control their diabetes on other medications such as pioglitazone (Actos). These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia.

One study, the TRIPOD (Troglitazone in Prevention of Diabetes) study, treated patients with gestational diabetes, a precursor of insulin resistance and diabetes, with troglitazone (Rezulin), however, because of severe toxic liver effects; troglitazone has been taken off the market and is no longer available. Among the women treated with troglitazone, diabetes was prevented in 25%.

What's new in insulin resistance?

It is only in recent years that insulin resistance has been gaining importance its own right, and as a contributor to the metabolic syndrome. It now appears that intervention can delay the onset of overt diabetes. Future studies will need to be longer than the studies already done to determine for how long treatment can prevent the development of diabetes and its complications.

Lifestyle changes (for example, diet, exercise) clearly are important in delaying the development of diabetes in individuals with insulin resistance, and education about these changes needs to be directed to groups at risk for diabetes. Childhood obesity is on the rise in the United States as well as other countries, and changes need to be made in school cafeterias and in the food choices offered to children and teens at home.

The value of diet and exercise in combination with medication needs to be evaluated to determine if the combination is better than diet and exercise alone.

Insulin Resistance At A Glance

• Insulin resistance is a condition in which the cells of the body become resistant to the hormone, insulin.
• Insulin resistance may be part of the metabolic syndrome, and associated with the development of heart disease.
• Insulin resistance precedes the development of type 2 diabetes.
• Insulin resistance is associated with other medical conditions including fatty liver, arteriosclerosis, acanthosis nigricans, skin tags, and reproductive abnormalities in women.
• Individuals are more likely to have insulin resistance if they have any of the associated medical conditions listed above. They also are more likely to be insulin resistant if they are obese or are Latino, African-American, Native American, and Asian-American.
• While there is a genetic component, insulin resistance can be managed with diet, exercise, and medication.

REFERENCE: FDA Prescribing Information for Avandia.