Disease: Insulin Resistance

    Insulin resistance facts

    • 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 it has been associated with higher risk of developing heart disease.
    • Insulin resistance precedes the development of type 2 diabetes (T2D).
    • 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 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 heritage.
    • While there are genetic risk factors, insulin resistance can be managed with diet, exercise, and proper medication.

    What is insulin resistance?

    Insulin is a hormone that is produced by the beta cells of the pancreas. These cells are scattered throughout the pancreas in small clusters known as the islets of Langerhans. The insulin produced is released into the blood stream and travels throughout the body. Insulin is an essential hormone that has many actions within the body. Most actions of insulin are directed at metabolism (control) of carbohydrates (sugars and starches), lipids (fats), and proteins. Insulin also regulates the functions of the body's 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, higher levels of insulin are needed in order for insulin to have its proper effects. So, the pancreas compensates by trying to produce more insulin. This resistance occurs in response to the body's own insulin (endogenous) or when insulin is administered by injection (exogenous).

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

    What causes insulin resistance?

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

    • The 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

    What is the relationship between insulin resistance and diabetes?

    Type 2 diabetes mellitus (T2D) is the type of diabetes that occurs later in life or with obesity at any age. Insulin resistance precedes the development of type 2 diabetes, sometimes by years. In individuals who will ultimately develop type 2 diabetes, it has been shown that blood glucose and insulin levels are normal for many years, until at some point in time, insulin resistance develops.

    At this point, 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 the metabolic syndrome.

    One action of insulin is to cause the body's cells (particularly the muscle and fat) to remove and use glucose from the blood. This is one way by 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. With insulin resistance, the muscles don't hear the knock (they are resistant). So, 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, 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, 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; several medical other conditions are specifically associated with insulin resistance. Insulin resistance may contribute to some of the conditions listed.

    Type 2 Diabetes

    Overt diabetes may be the first sign that insulin resistance is present. Insulin resistance can be noted long before type 2 diabetes develops. Individuals reluctant or unable to see a health care practitioner regularly often seek medical attention when they have already developed type 2 diabetes and insulin resistance.

    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 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 (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 the insulin resistance, though the exact mechanism is not clear.

    • Acanthosis nigricans is a cosmetic condition strongly associated with insulin resistance in which the skin darkens and thickens in creased areas (for example, the neck, ar pits, and groin).
    • Skin tags are occur more frequently in patients with insulin resistance. A skin tag is a common, benign condition where a bit of 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 surrounding skin, and either be simply raised above surrounding skin or attached by a stalk (peduncle) so that it hangs from the skin.
    Picture of skin tags on an adult armpit Reproductive abnormalities in women Polycystic ovary syndrome (PCOS)

    Polycystic ovary syndrome is a common hormonal problem which 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, moustache, 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 the 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 which 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 skin tags mentioned earlier may occur through this mechanism too.

    Who is at risk for insulin resistance?

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

    • Is overweight with a body mass index (BMI) more than 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
    • Is of Latino, African American, Native American or Asian American ancestry
    • Has close family members 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

    How is insulin resistance diagnosed?

    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 is present. The exact insulin level for diagnosis varies by assay (by laboratory). However, a fasting insulin level above the upper quartile in a non-diabetic patient is considered abnormal.

    How is insulin resistance managed?

    Management of insulin resistance is through lifestyle changes such as diet, exercise, and disease prevention; and medications.

    Lifestyle changes (diet, weight loss, exercise)

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

    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. Some carbohydrates break and absorb faster than others; these are referred to 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 (such as fruit juice and table sugar)
    • White bread
    • Unrefined corn and potato products (like 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 (like 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 is less important than the overall profile of the whole meal and associated drinks.

    Several studies have confirmed that weight loss - and even aerobic exercise without weight loss - increase the rate at which glucose is taken from the blood by muscle cells as a result of improved sensitivity.

    Two important studies have assessed ways to prevent type 2 diabetes. Both assessed 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, performed in Finland, showed that changes in diet and exercise reduced the development of type 2 diabetes by 58%. The Diabetes Prevention Program (DPP) study performed in the US, showed a similar reduction in type 2 diabetes with diet and exercise.

    Medications

    Metformin (Glucophage) is a medication that is used for treating type 2 diabetes. It exerts two actions that help to control blood glucose levels. Metformin prevents the liver from releasing glucose into the blood, and it increases the sensitivity of muscle and fat cells to insulin. So, the muscle and fat remove more glucose from the blood. By these actions, metformin lowers blood insulin levels.

    The DPP studied the effects of metformin, in addition to diet and exercise, for prevention of type 2 diabetes in insulin resistant people. Metformin reduced the development of type 2 diabetes by 31%. Note, however, that the benefit was not as great as with diet and intense exercise. Metformin is a reasonably safe medication when used in the proper population. Although occasionally associated with gastrointestinal side effects, metformin is usually well-tolerated. While there are no FDA-approved drugs 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.

    The STOP NIDDM (Study to Prevent Non-insulin Dependent Diabetes Mellitus) trial assessed individuals with insulin resistance by treating with acarbose (Precose). Acarbose slows the gut's absorption of sugars, which reduces the demand for insulin after a meal. This study suggested that acarbose could reduce the development of type 2 diabetes by 25%.

    Thiazolidinediones comprise another class of drugs which increase sensitivity to insulin, including pioglitazone (Actos) and rosiglitazone (Avandia). These medications are no longer used routinely, in part because of liver toxicity that requires monitoring of liver blood tests. Avandia has been associated with an increased risk of heart attack and stroke, but experts have debated the severity of these concerns since this risk was first reported. In September 2010, the U.S. Food and Drug Administration (FDA) significantly restricted the use of Avandia to patients who cannot control their type 2 diabetes on other medications (including pioglitazone). These restrictions responded to data suggesting an elevated risk of cardiovascular events (such as heart attack and stroke) in patients treated with Avandia.

    The TRIPOD (Troglitazone in Prevention of Diabetes) study assessed troglitazone (Rezulin) for treating women with gestational diabetes, a precursor of insulin resistance and type 2 diabetes. However, due to severe toxicity to the liver, troglitazone has been taken off the market and is no longer available. Type 2 diabetes was prevented in 25% of those women treated with troglitazone.

    What causes insulin resistance?

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

    • The 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

    What is the relationship between insulin resistance and diabetes?

    Type 2 diabetes mellitus (T2D) is the type of diabetes that occurs later in life or with obesity at any age. Insulin resistance precedes the development of type 2 diabetes, sometimes by years. In individuals who will ultimately develop type 2 diabetes, it has been shown that blood glucose and insulin levels are normal for many years, until at some point in time, insulin resistance develops.

    At this point, 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 the metabolic syndrome.

    One action of insulin is to cause the body's cells (particularly the muscle and fat) to remove and use glucose from the blood. This is one way by 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. With insulin resistance, the muscles don't hear the knock (they are resistant). So, 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, 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, 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; several medical other conditions are specifically associated with insulin resistance. Insulin resistance may contribute to some of the conditions listed.

    Type 2 Diabetes

    Overt diabetes may be the first sign that insulin resistance is present. Insulin resistance can be noted long before type 2 diabetes develops. Individuals reluctant or unable to see a health care practitioner regularly often seek medical attention when they have already developed type 2 diabetes and insulin resistance.

    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 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 (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 the insulin resistance, though the exact mechanism is not clear.

    • Acanthosis nigricans is a cosmetic condition strongly associated with insulin resistance in which the skin darkens and thickens in creased areas (for example, the neck, ar pits, and groin).
    • Skin tags are occur more frequently in patients with insulin resistance. A skin tag is a common, benign condition where a bit of 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 surrounding skin, and either be simply raised above surrounding skin or attached by a stalk (peduncle) so that it hangs from the skin.
    Picture of skin tags on an adult armpit Reproductive abnormalities in women Polycystic ovary syndrome (PCOS)

    Polycystic ovary syndrome is a common hormonal problem which 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, moustache, 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 the 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 which 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 skin tags mentioned earlier may occur through this mechanism too.

    Who is at risk for insulin resistance?

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

    • Is overweight with a body mass index (BMI) more than 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
    • Is of Latino, African American, Native American or Asian American ancestry
    • Has close family members 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

    How is insulin resistance diagnosed?

    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 is present. The exact insulin level for diagnosis varies by assay (by laboratory). However, a fasting insulin level above the upper quartile in a non-diabetic patient is considered abnormal.

    How is insulin resistance managed?

    Management of insulin resistance is through lifestyle changes such as diet, exercise, and disease prevention; and medications.

    Lifestyle changes (diet, weight loss, exercise)

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

    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. Some carbohydrates break and absorb faster than others; these are referred to 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 (such as fruit juice and table sugar)
    • White bread
    • Unrefined corn and potato products (like 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 (like 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 is less important than the overall profile of the whole meal and associated drinks.

    Several studies have confirmed that weight loss - and even aerobic exercise without weight loss - increase the rate at which glucose is taken from the blood by muscle cells as a result of improved sensitivity.

    Two important studies have assessed ways to prevent type 2 diabetes. Both assessed 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, performed in Finland, showed that changes in diet and exercise reduced the development of type 2 diabetes by 58%. The Diabetes Prevention Program (DPP) study performed in the US, showed a similar reduction in type 2 diabetes with diet and exercise.

    Medications

    Metformin (Glucophage) is a medication that is used for treating type 2 diabetes. It exerts two actions that help to control blood glucose levels. Metformin prevents the liver from releasing glucose into the blood, and it increases the sensitivity of muscle and fat cells to insulin. So, the muscle and fat remove more glucose from the blood. By these actions, metformin lowers blood insulin levels.

    The DPP studied the effects of metformin, in addition to diet and exercise, for prevention of type 2 diabetes in insulin resistant people. Metformin reduced the development of type 2 diabetes by 31%. Note, however, that the benefit was not as great as with diet and intense exercise. Metformin is a reasonably safe medication when used in the proper population. Although occasionally associated with gastrointestinal side effects, metformin is usually well-tolerated. While there are no FDA-approved drugs 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.

    The STOP NIDDM (Study to Prevent Non-insulin Dependent Diabetes Mellitus) trial assessed individuals with insulin resistance by treating with acarbose (Precose). Acarbose slows the gut's absorption of sugars, which reduces the demand for insulin after a meal. This study suggested that acarbose could reduce the development of type 2 diabetes by 25%.

    Thiazolidinediones comprise another class of drugs which increase sensitivity to insulin, including pioglitazone (Actos) and rosiglitazone (Avandia). These medications are no longer used routinely, in part because of liver toxicity that requires monitoring of liver blood tests. Avandia has been associated with an increased risk of heart attack and stroke, but experts have debated the severity of these concerns since this risk was first reported. In September 2010, the U.S. Food and Drug Administration (FDA) significantly restricted the use of Avandia to patients who cannot control their type 2 diabetes on other medications (including pioglitazone). These restrictions responded to data suggesting an elevated risk of cardiovascular events (such as heart attack and stroke) in patients treated with Avandia.

    The TRIPOD (Troglitazone in Prevention of Diabetes) study assessed troglitazone (Rezulin) for treating women with gestational diabetes, a precursor of insulin resistance and type 2 diabetes. However, due to severe toxicity to the liver, troglitazone has been taken off the market and is no longer available. Type 2 diabetes was prevented in 25% of those women treated with troglitazone.

    Source: http://www.rxlist.com

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

    • Is overweight with a body mass index (BMI) more than 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
    • Is of Latino, African American, Native American or Asian American ancestry
    • Has close family members 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

    Source: http://www.rxlist.com

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