Insulin Resistance

Exercise may help prevent insulin resistance.

• Insulin resistance is usually part of the metabolic syndrome, and it has been associated with a higher risk of developing heart disease.
• Insulin resistance precedes the development of type 2 diabetes (T2D).
• Causes of insulin resistance include both genetic (inherited) and lifestyle factors.
• Insulin resistance lacks specific signs and symptoms.
• Insulin resistance is associated with other medical conditions, including
  • fatty liver,
  • arteriosclerosis,
  • acanthosis nigricans (darkened skin usually around the neck, under the arms, along the waist, and in some skinfolds),
  • skin tags, and
  • reproductive abnormalities in women.
• Individuals are more likely to have insulin resistance if they have any of several associated medical conditions. They also are more likely to be insulin resistant if obese or of Latino, African-American, Native American, or Asian-American ancestry.
• While genetic risk factors exist, insulin resistance can be managed with diet, exercise, and proper medication.
• Measurements of fasting blood glucose and insulin levels test for insulin resistance.
• Insulin resistance is treated by lifestyle modifications and in some cases, medications.
• In some cases, insulin resistance cannot be prevented, yet modifiable risk factors include maintaining a healthy weight, diet, and getting regular exercise.

Insulin is a hormone produced by the beta cells of the pancreas, an organ near the stomach. Beta cells are scattered throughout the pancreas in small clusters known as the islets of Langerhans. The insulin produced is released into the bloodstream and travels throughout the body. Insulin is an essential hormone with many actions within the body. Most actions of insulin are directed at the metabolism (control) of carbohydrates (sugars and starches), lipids (fats), and proteins. Insulin also regulates the functions of the body's other cells, including their growth. Insulin is critical for the body's use of glucose as energy.

Insulin resistance (IR) is a condition in which the body's cells become resistant to the effects of insulin. That is, the normal response to a given amount of insulin is reduced. As a result, the pancreas must generate higher levels of insulin for insulin to have its proper effects. This resistance occurs in response to the body's own insulin (endogenous) or insulin administered by injection (exogenous).

With insulin resistance, the pancreas produces more and more insulin. When the pancreas can no longer produce sufficient insulin for the body's demands, then blood sugar rises. Insulin resistance is a risk factor for the development of type 2 diabetes and heart disease.

There are no specific symptoms of insulin resistance. Certain conditions make a person more likely to develop insulin resistance. An individual is more likely to have or develop insulin resistance if he or she:

• Is overweight with a body mass index (BMI) above 25 kg/m2. You can calculate your BMI by taking your weight (in kilograms) and dividing twice by your height (in meters).
• Is a man with a waist more than 40 inches or a woman with a waist more than 35 inches
• Is over 40 years of age
• Has a blood pressure reading of 130/80 or higher
• Is of Latino, African American, Native American, or Asian American ancestry
• Has close family members who have type 2 diabetes, high blood pressure, or arteriosclerosis
• Has had gestational diabetes
• Has a history of high blood pressure, high blood triglycerides, low HDL cholesterol, arteriosclerosis (or other components of the metabolic syndrome)
• Has polycystic ovarian syndrome (PCOS)
• Displays acanthosis nigricans
• Has a fasting glucose level over 100 mg/dL
• Has a fasting triglyceride level over 150 mg/dL
• Has an HDL cholesterol level under 40 mg/dL in men and 50 mg/dL in women

Among several causes of insulin resistance, genetic factors (inherited causes) are usually significant. Some medications can contribute to insulin resistance. In addition, insulin resistance is often seen with the following conditions:

• A metabolic syndrome is a group of conditions involving excess weight (particularly around the waist), high blood pressure, and elevated levels of cholesterol and triglycerides in the blood.
• Obesity
• Pregnancy
• Infection or severe illness
• Stress
• Inactivity and excess weight
• During steroid use

Other causes of insulin resistance or factors that may worsen it can include:

• Taking certain medications
• Older age
• Sleep problems (especially sleep apnea)
• Cigarette smoking

Type 2 diabetes mellitus (T2D) can occur with obesity at any age. Insulin resistance precedes the development of T2D, sometimes by years. In individuals who will ultimately develop T2D, research showed blood glucose and insulin levels are normal for many years until, at some point in time, insulin resistance develops.

High insulin levels are often associated with central obesity, cholesterol abnormalities, and/or high blood pressure (hypertension). When these disease processes occur together, it is called metabolic syndrome.

One action of insulin is to cause the body's cells (particularly the muscle and fat cells) to remove and use glucose from the blood. This is one way how insulin controls the glucose level in the blood. Insulin binds to insulin receptors on the surfaces of 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. With insulin resistance, the muscles don't hear the knock (they are resistant). So the pancreas is notified it needs to make more insulin, which increases the level of insulin in the blood and causes a louder knock.

Insulin resistance of 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, blood glucose levels begin to rise. Initially, this happens after meals -- when glucose levels are at their highest and more insulin is needed -- but eventually while fasting too (for example, upon waking in the morning). When blood sugar rises abnormally above certain levels, T2D is present.

Exact values for normal or high insulin levels vary according to the laboratory and the type of test performed. With insulin resistance, fasting insulin level is high with normal to high fasting blood glucose levels. High or elevated insulin levels can be seen with other medical conditions too, including

• insulin-producing tumors (insulinomas),
• Cushing syndrome, and
• fructose or galactose intolerance.

Metabolic syndrome links insulin resistance with abdominal obesity, elevated cholesterol, and high blood pressure. Several other medical conditions are specifically associated with insulin resistance. Insulin resistance may contribute to the following conditions:

Type 2 diabetes: Overt diabetes may be the first sign insulin resistance is present. Insulin resistance can be noted long before T2D develops. Individuals who are reluctant or unable to see a health care professional often seek medical attention after they have developed T2D.

Fatty liver: Fatty liver is strongly associated with insulin resistance. Accumulation of fat in the liver is a manifestation of the disordered control of lipids occurring with insulin resistance. Fatty liver associated with insulin resistance may be mild or severe. Newer evidence suggests 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 (leading to angina and heart attack)
• Strokes
• Peripheral vascular disease

Other risk factors for arteriosclerosis include:

• High levels of "bad" (LDL) cholesterol
• High blood pressure (hypertension)
• Smoking
• Diabetes mellitus from any cause
• Family history of arteriosclerosis

Skin lesions: Skin lesions include increased skin tags and a condition called acanthosis nigricans (AN). Acanthosis nigricans is a darkening and thickening of the skin, especially in folds such as the neck, under the arms, and in the groin. This condition is directly related to insulin resistance, though the exact mechanism is not clear.

• Acanthosis nigricans is a cosmetic condition strongly associated with insulin resistance. Here skin darkens and thickens in areas of skin creases (for example, the neck, armpits, and groin).
• Skin tags occur more frequently in patients with insulin resistance. A skin tag is a common, benign condition where a few skin projects from the surrounding skin. Skin tags vary significantly in appearance. A skin tag may appear smooth or irregular, flesh-colored or darker than the surrounding skin. A tag may be either simply raised above the surrounding skin or attached by a stalk (peduncle) so that it hangs from the skin.

Picture of skin tags on an adult armpit

Polycystic ovary syndrome (PCOS): Polycystic ovary syndrome is a common hormonal problem that affects menstruating women. It is associated with irregular periods or no periods at all (amenorrhea), obesity, and increased body hair in a male pattern of distribution (called hirsutism; for example, mustache, sideburns, beard, mid-chest, and central belly hair).

Hyperandrogenism: With PCOS, the ovaries can produce high levels of the hormone testosterone. This high testosterone level can be seen with insulin resistance and may play a role in causing PCOS. Why this association occurs is unclear, but it appears that insulin resistance somehow causes abnormal ovarian hormone production.

Growth abnormalities: High levels of circulating insulin can affect growth. While insulin's effects on glucose metabolism may be impaired, its effects on other mechanisms may remain intact (or at least less impaired). Insulin is an anabolic hormone that promotes growth. Patients may actually grow larger with a noticeable coarsening of features. Children with open growth plates in their bones may actually grow faster than their peers. However, neither children nor adults with insulin resistance become taller than predicted by their familial growth pattern. Indeed, most adults simply appear larger with coarser features. The increased incidence of acanthosis nigricans or skin tags mentioned earlier may also occur through this mechanism.

Reproductive abnormalities in women

An individual is more likely to have or develop insulin resistance if he or she:

• Is overweight with a body mass index (BMI) above 25 kg/m2. You can calculate your BMI by taking your weight (in kilograms) and dividing twice by your height (in meters).
• Is a man with a waist more than 40 inches or a woman with a waist more than 35 inches
• Is over 40 years of age
• Has a blood pressure reading of 130/80 or higher
• Is of Latino, African American, Native American, or Asian American ancestry
• Has close family members who have type 2 diabetes, high blood pressure, or arteriosclerosis
• Has had gestational diabetes
• Has a history of high blood pressure, high blood triglycerides, low HDL cholesterol, arteriosclerosis (or other components of the metabolic syndrome)
• Has polycystic ovarian syndrome (PCOS)
• Displays acanthosis nigricans
• Has a fasting glucose level over 100 mg/dL
• Has a fasting triglyceride level over 150 mg/dL
• Has an HDL cholesterol level under 40 mg/dL in men and 50 mg/dL in women

Insulin resistance may be treated by primary care professionals, including

• internists,
• family doctors, or
• pediatricians.
• Endocrinologists specialize in hormonal disorders and treat patients with insulin resistance.

A health care professional can identify individuals likely to have insulin resistance by taking a detailed history, performing a physical examination, and simple laboratory testing based on individual risk factors.

In general practice, the fasting blood glucose and insulin levels are usually adequate to determine whether insulin resistance and/or diabetes are present. The exact insulin level for diagnosis varies by assay (by the laboratory). However, a fasting insulin level above the upper quartile in a non-diabetic patient is considered abnormal.

Management of insulin resistance is through lifestyle changes (such as diet, exercise, and disease prevention) and medications. Weight loss may help reverse insulin resistance by and taking small steps, such as exercising and eating healthier foods. It also can prevent or delay type 2 diabetes in people with prediabetes.

The need for insulin can be reduced by altering the diet, particularly the carbohydrates in the diet. Carbohydrates are absorbed into the body as they are broken up into their component sugars. High glycemic index refers to some carbohydrates that break down and absorb faster than others. 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 (such as fruit juice and table sugar)
• White bread
• Unrefined corn and potato products (such as 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 bread and brown rice)
• Non-starchy vegetables (such as broccoli, green beans, asparagus, carrots, and greens). These are low in calories and in total carbohydrates and contain vitamins and fiber.

Since foods are rarely eaten in isolation, one could argue that the glycemic index of each food is less important than the overall profile of the whole meal and associated drinks.

Foods that are particularly helpful for people trying to prevent type 2 diabetes and maintain a healthy weight are similar to the low glycemic index foods described above:

• Vegetables and fruits provide fiber and vitamins.
• Fat-free or low-fat dairy products provide calcium and strengthen bones. Avoid full-fat dairy products, as high-fat foods can worsen insulin resistance.
• Whole-grain products have a lower glycemic index than refined grains and are rich in fiber.
• Nuts contain fiber, protein, and healthy fats.
• Some fish can be a source of "good" (heart-healthy) fats, such as salmon, herring, mackerel, or sardines.
• Lean meats or beans are an excellent source of protein.

Several studies have confirmed that weight loss -- and even aerobic exercise without weight loss -- increases the rate at which muscle cells take glucose from the blood as a result of improved sensitivity to insulin.

Multiple studies have shown that diet and exercise reduce the development of type 2 diabetes and can reduce insulin resistance.

Metformin (Glucophage) is a medication used for treating type 2 diabetes. It exerts two actions to help control blood glucose levels. Metformin prevents the liver from releasing glucose into the blood, and it also increases the sensitivity of muscle and fat cells to insulin, allowing them to remove more glucose from the blood. By these actions, metformin lowers blood insulin levels because lower blood sugar levels tell the pancreas to put out less insulin.

Metformin is a reasonably safe medication when used in the proper population. Though occasionally associated with gastrointestinal side effects, metformin is usually well tolerated. While no FDA-approved drugs exist to prevent type 2 diabetes or to treat pre-type 2 diabetes (insulin resistance), the American Diabetes Association has recommended that metformin be the only drug considered for the prevention of type 2 diabetes.

It's not always possible to prevent insulin resistance, but there are ways to modify risk factors, such as

• keeping a healthy weight and
• getting regular exercise.

Insulin resistance is associated with the development of type 2 diabetes. Effective measures can reverse insulin resistance.

• Weight loss,
• eating a healthy diet,
• not smoking,
• adequate sleep, and
• exercise can all help reverse insulin resistance.

Insulin resistance has gained awareness and significance, in its own right, as a contributor to metabolic syndrome. Timely intervention can delay the onset of overt type 2 diabetes. Future studies must assess longer intervals than existing research to determine the duration of treatment to prevent the development of type 2 diabetes and related complications.

Lifestyle changes (in nutrition and physical activity) are clearly important to delay the development of type 2 diabetes in individuals with insulin resistance. Lifestyle changes are the primary recommendation for the prevention of diabetes in high-risk individuals.

Metformin is the only drug recommended by guidelines for patients at the highest risk. Education about these changes must be directed to all groups at risk for type 2 diabetes.

Childhood obesity is an epidemic and on the rise in developed countries. Changes must be made in homes and school cafeterias to ensure healthier nutrition.