Insulin Resistance

While insulin resistance is usually seen long before diabetes develops, in cases in which medical attention has lapsed, insulin resistance can present as type 2 diabetes.

• Insulin is a hormone that is produced by the beta cells found in the pancreas.
• Insulin is an important hormone that has many actions within the body including those involved in the metabolism (control) of carbohydrates (sugars and starches), lipids (fats), and proteins.
• When insulin resistance develops, tissues in the body – particularly muscle and fat tissues- do not respond appropriately to insulin. In fact, more insulin is needed to elicit the same response from these tissues.
• As a result, higher levels of insulin are needed in order for insulin to continue to exert its physiologic effect.
• Insulin resistance may cause these conditions including type 2 diabetes, fatty liver, arteriosclerosis, hyperandrogenism, and more
• Insulin resistance treatment includes lifestyle changes, medication, diet, and exercise.

There are many causes of insulin resistance, including a strong association with genetics (an inherited component). In addition, insulin resistance is often associated with the following conditions:

• infection or severe illness,
• the metabolic syndrome,
• obesity,
• pregnancy,
• steroid use and with other medications, and
• stress.

Aside from the well-known association of insulin resistance with metabolic syndrome, abdominal obesity, elevated cholesterol levels, and high blood pressure; there are several other medical conditions that are associated with insulin resistance specifically. While the associations are clear, whether insulin resistance is the cause of these conditions is not yet known.

Type 2 Diabetes

While insulin resistance is usually seen long before diabetes develops, in cases in which medical attention has lapsed, insulin resistance can present as type 2 diabetes.

Fatty liver

The accumulation of fat in the liver is a manifestation of the disordered control of lipids that occurs with insulin resistance. The extent of liver damage can range from mild to severe. Newer evidence suggests that fatty liver may even lead to cirrhosis of the liver, and possibly liver cancer.

Arteriosclerosis

Insulin resistance is one of the factors associated with 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.

Skin Lesions

Skin lesions include an increased number of 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 insulin resistance, though the exact causal mechanism is not known.

Reproductive abnormalities in women

Reproductive abnormalities include difficulty with ovulation and conception (infertility), irregular menses, or a cessation of menses. A condition that is significantly associated with insulin resistance is polycystic ovary syndrome (PCOS). PCOS is a problem that affects young women. It is associated with irregular periods or no periods at all, obesity, and increased growth of body hair. In contrast to women, there are no known reproductive abnormalities in men associated with insulin resistance.

Hyperandrogenism

High levels of male hormones in women, which are produced by the ovaries, can be seen in insulin resistance and may play a role in PCOS as described above. The high levels of insulin seen in insulin resistance cause the abnormal ovarian hormone production of testosterone and other hormones.

Growth abnormalities

There may be growth effects 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 can exert effects on growth, through a mediator known as insulin-like growth factor -1. Individuals may have actual linear growth in height and a noticeable coarsening of features. The increased incidence of skin tags mentioned above may be due to this mechanism as well.

An individual should consider being evaluated for insulin resistance if they:

• are overweight with a body mass index (BMI) of more than 25,
• are a man with a waist measurement of more than 40 inches or a woman with a waist of more than 35 inches,
• are over 40 years of age,
• are Latino, African American, Native American, or Asian American,
• have close blood-related 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 the polycystic ovarian syndrome, or
• have acanthosis nigricans.

A physician can identify individuals who are likely to have insulin resistance with detailed patient history, physical examination, and laboratory testing.

In general clinical practice, glucose levels in conjunction with fasting insulin levels provide the physician with information as to whether insulin resistance is present, or not present, 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 used for the definition. However, an insulin level above the upper quartile in the fasting state in someone without diabetes is considered abnormal.

In addition, an oral glucose tolerance test (OGTT) can be used to detect insulin resistance and is more sensitive for detecting milder/earlier diseases. It involves drinking a known amount of simple sugar and measuring blood glucose and insulin levels at baseline as well as one and two (and sometimes three) hours after drinking.

• Lifestyle changes are important in the treatment of insulin resistance, namely, reducing sugar and carbohydrate intake.
• Medical treatment includes a number of different medications to complement lifestyle changes.

Maintaining a healthy lifestyle is the cornerstone to managing insulin resistance, and lifestyle change begin at home.

By altering the diet, particularly the carbohydrates in the diet, the body can decrease the amount of insulin released by the pancreas. 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.

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 the improved sensitivity of the cells to insulin.

Medical treatment can be used as an adjunct to lifestyle modification and should be discussed as an option with the patient's physician.

Metformin (Glucophage) is a medication used to treat 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 effectively reduces blood insulin levels. Metformin is a reasonably safe medication when used as indicated. Although there are gastrointestinal side effects with metformin, the drug usually is well-tolerated.

Interestingly, a study known as the DPP study evaluated 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%.
• Acarbose (Precose) is another medication that can be used for the treatment of insulin resistance. It works in the intestines to slow the absorption of sugars, and this effect can reduce the need for insulin after meals. The Study to Prevent Non-insulin Dependent Diabetes Mellitus trial (also known as the STOP NIDDM Trial), treated individuals with insulin resistance with acarbose and found that acarbose reduced the development of diabetes by 25%.
• Other medications in a class of drugs called thiazolidinediones, for example, pioglitazone (Actos), and 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.

Individuals with insulin resistance should follow up with their physician on a routine basis to assure optimal lifestyle changes, and to monitor any side effects of the medications prescribed.

While there is a significant genetic component to the development of insulin resistance, many things can be done to prevent its onset and progression.

Lifestyle changes (for example, diet and exercise) clearly are important, 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.

Medications have been shown to delay the progression of insulin resistance to overt type 2 diabetes. To date, no study has shown the ability to prevent metabolic syndrome in a high-risk population.

It is only in recent years that insulin resistance has been gaining importance both in its own right and as a contributor to metabolic syndrome. It now appears that intervention can delay the onset of overt diabetes.

• With lifestyle modification and medication, if needed, those with insulin resistance can have some control over their disease progression.