Insulin resistance

Insulin Resistance 

Definition

Insulin resistance is not a disease as such but rather a state or condition in which a person's body tissues have a lowered level of response to insulin, a hormone secreted by the pancreas that helps to regulate the level of glucose (sugar) in the body. As a result, the person's body produces larger quantities of insulin to maintain normal levels of glucose in the blood. There is considerable individual variation in sensitivity to insulin within the general population, with the most insulin-sensitive persons being as much as six times as sensitive to the hormone as those identified as most resistant. Some doctors use an arbitrary number, defining insulin resistance as a need for 200 or more units of insulin per day to control blood sugar levels. Various researchers have estimated that 3-16 percent of the general population in the United States and Canada is insulin-resistant; another figure that is sometimes given is 70-80 million Americans.

Insulin resistance can be thought of as a set of metabolic dysfunctions associated with or contributing to a range of serious health problems. These disorders include type 2 diabetes (formerly called adult-onset or non-insulin-dependent diabetes), the metabolic syndrome (formerly known as syndrome X), obesity, and polycystic ovary syndrome. Some doctors prefer the term "insulin resistance syndrome" to "metabolic syndrome."

Description

To understand insulin resistance, it may be helpful for the reader to have a brief account of the way insulin works in the body. After a person eats a meal, digestive juices in the small intestine break down starch or complex sugars in the food into glucose, a simple sugar. The glucose then passes into the bloodstream. When the concentration of glucose in the blood reaches a certain point, the pancreas is stimulated to release insulin into the blood. As the insulin reaches cells in muscle and fatty (adipose) tissues, it attaches itself to molecules called insulin receptors on the surface of the cells. The activation of the insulin receptors sets in motion a series of complex biochemical signals within the cells that allow the cells to take in the glucose and convert it to energy. If the pancreas fails to produce enough insulin or the insulin receptors do not function properly, the cells cannot take in the glucose and the level of glucose in the blood remains high.

The insulin may fail to bind to the insulin receptors for any of several reasons. Some persons inherit a gene mutation that leads to the production of a defective form of insulin that cannot bind normally to the insulin receptor. Others may have one of two types of abnormalities in the insulin receptors themselves. In type A, the insulin receptor is missing from the cell surface or does not function properly. In type B, the person's immune system produces autoantibodies to the insulin receptor.

In the early stages of insulin resistance, the pancreas steps up its production of insulin in order to control the increased levels of glucose in the blood. As a result, it is not unusual for patients to have high blood sugar levels and high blood insulin levels (a condition known as hyperinsulinemia) at the same time. If insulin resistance is not detected and treated, however, the islets of Langerhans (the insulin-secreting groups of cells) in the pancreas may eventually shut down and decrease in number.

Causes & symptoms

Causes

The reasons for the development of insulin resistance are not completely understood as of the early 2000s, but several factors that contribute to it have been identified:

Symptoms

The symptoms of insulin resistance vary considerably from person to person. Some people may have no noticeable symptoms until they develop signs of heart disease or are diagnosed with high blood pressure during a routine checkup. Other patients may come to the doctor with extremely high levels of blood sugar (hyperglycemia) and such classical symptoms of diabetes as thirst, frequent urination, and weight loss. A small percentage of patients—most commonly women with polycystic ovary syndrome—develop a velvet-textured blackish or dark brown discoloration of the skin known as acanthosis nigricans. This symptom, which is most commonly found on the neck, groin, elbows, knees, knuckles, or armpits, is thought to appear when high levels of insulin in the blood spill over into the skin. This spillover activates insulin receptors in the skin and causes it to develop an abnormal texture and color. Acanthosis nigricans occurs more frequently in Hispanic and African American patients than in Caucasians.

Disorders associated with insulin resistance

Insulin resistance became an important field of research in the late 1980s, when doctors first began to understand it as a precondition of several common but serious threats to health. As of the early 2000s, insulin resistance is associated with the following disorders:

Diagnosis

Patient history and physical examination

Because insulin resistance is a silent condition in many people, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) recommends that all adults over the age of 45 be tested for type 2 diabetes. People younger than 45 who are overweight and have one or more of the following risk factors should also visit their doctor to be tested:

Some signs and symptoms associated with insulin resistance can be detected by a primary care physician during a routine office visit. Blood pressure, weight, body shape, and the condition of the skin can be checked, as well as determining whether the patient meets the criteria for obesity or is less severely over-weight. Obesity is determined by the patient's body mass index, or BMI. The BMI, which is an indirect measurement of the amount of body fat, is calculated in English units by multiplying a person's weight in pounds by 703.1, and dividing that number by the person's height in inches squared. A BMI between 19 and 24 is considered normal; 25-29 is overweight; 30-34 is moderately obese; 35-39 is severely obese; and 40 or higher is defined as morbidly obese. The doctor may also evaluate the patient for obesity in the office by measuring the thickness of the skinfold at the back of the upper arm.

The distribution of the patient's weight is also significant, as insulin resistance is associated with a so-called "apple-shaped" figure, in which much of the excess weight is carried around the abdomen. People whose excess weight is carried on the hips (the "pearshaped" figure) or distributed more evenly on the body are less likely to develop insulin resistance. One way of measuring weight distribution is the patient's waist-to-hip ratio; a ratio greater than 1.0 in men or 0.8 in women is strongly correlated with insulin resistance.

Laboratory tests

There is no single laboratory test that can be used to diagnose insulin resistance by itself as of 2005. Doctors usually evaluate individual patients on the basis of specific symptoms or risk factors. The tests most commonly used include the following:

A highly accurate technique for measuring insulin resistance is called the euglycemic clamp technique. The patient's blood insulin level is kept ("clamped") at a high but steady level by continual insulin infusion while the blood glucose level is monitored at frequent intervals. Glucose concentrations in the blood are maintained at a normal level by an adjustable-rate glucose drip. The amount of glucose needed to maintain a normal blood glucose level over a given unit of time indicates the degree of insulin resistance. This test, however, requires complex equipment and careful monitoring; it is considered too cumbersome to use in routine screening and is used mostly by researchers.

Treatment

Lifestyle modifications

Lifestyle modifications are the first line of treatment in dealing with insulin resistance:

Medications

There are several different types of medications that can be used to treat patients with abnormal blood sugar or insulin levels:

As of early 2005, however, the Food and Drug Administration (FDA) has not approved any drugs for the treatment of insulin resistance by itself. For this reason, the American Diabetes Association does not recommend treating insulin resistance with medications unless the patient has already been diagnosed with diabetes.

The patient's doctor may also prescribe medications to treat specific health problems associated with insulin resistance. These drugs may include diuretics and other medications to lower blood pressure; aspirin to reduce the risk of heart attack; medications to lower the levels of triglycerides and LDL cholesterol in the blood; and weight-control drugs. The drugs most frequently prescribed in the early 2000s to help patients lose weight are orlistat (Xenical) and sibutramine (Meridia).

Acanthosis nigricans may be treated with topical preparations containing Retin-A, 20% urea, or salicylic acid; however, many patients find that the skin disorder improves by itself following weight loss.

Surgery

Insulin resistance by itself does not require surgical treatment; however, patients who have already developed heart disease may require coronary artery bypass surgery. In addition, very obese patients—those with a BMI of 40 or higher—may benefit from bariatric surgery. Bariatric surgery includes such procedures as vertical banded gastroplasty and gastric bypass, which limit the amount of food that the stomach can contain.

Alternative treatment

Some alternative treatments for insulin resistance and type 2 diabetes have been studied by the Agency for Healthcare Research and Quality (AHRQ). One study reported in 2004 that omega-3 fatty acids, a dietary supplement commonly derived from fish, canola, or soybean oil, did not appear to have any significant effect on blood sugar levels or blood insulin levels in patients diagnosed with type 2 diabetes or the metabolic syndrome. An earlier study of Ayurvedic medicine, the traditional medical system of India, reported in 2001 that certain herbs used to make Ayurvedic medicines, such as fenugreek, holy basil, Coccinia indica, and Gymnema sylvestre appear to be effective in lowering blood sugar levels and merit further study. The AHRQ report also noted that the Ayurvedic practice of combining herbal medicines with yoga and other forms of physical activity should be investigated further.

Other alternative treatments for insulin resistance and type 2 diabetes include chromium supplements, ginseng, biofeedback, and acupuncture. The connection between chromium supplementation and insulin resistance is that the body needs chromium to produce a substance called glucose tolerance factor, which increases the effectiveness of insulin. Further studies need to be done, however, before recommendations about dietary chromium as a treatment for insulin resistance can be made.

Prognosis

Since insulin resistance is a condition that precedes the appearance of symptoms of a number of different disorders, its prognosis depends in part on the patient's age, ethnicity, family history, and severity of any current health problems. Some patients diagnosed with insulin resistance eventually develop type 2 diabetes, but it is not yet known why the others do not; for example, some patients do not develop diabetes in spite of a high degree of insulin resistance. What is known at present is that weight reduction and exercise can control or even reverse insulin resistance in many people.

Prevention

Genetic factors contributing to insulin resistance cannot be changed as of the early 2000s.

Key terms

Acanthosis nigricans — A dark brownish or blackish discoloration of the skin related to overweight and high levels of insulin in the blood. Acanthosis nigricans is most likely to develop in the groin or armpits, or around the back of the neck.

Bariatrics — The branch of medicine that deals with the prevention and treatment of obesity and related disorders.

Body mass index (BMI) — A measurement that has replaced weight as the preferred determinant of obesity. The BMI can be calculated (in English units) as 703.1 times a person's weight in pounds divided by the square of the person's height in inches.

Glucose — A simple sugar produced when carbohydrates are broken down in the small intestine. It is the primary source of energy for the body. Various tests that measure blood glucose levels are used in diagnosing insulin resistance.

Hyperandrogenism — Excessive secretion of androgens (male sex hormones).

Hyperinsulinemia — The medical term for high levels of insulin in the blood.

Insulin — A protein hormone secreted by the islets of Langerhans in the pancreas in response to eating. Insulin carries glucose and amino acids to muscle and adipose cells and promotes their efficient use and storage.

Islets of Langerhans — Special structures in the pancreas responsible for insulin secretion among other functions. They are named for Paul Langerhans, the German researcher who first identified them in 1869.

Lipids — A group of fats and fat-like substances that are not soluble in water, are stored in the body, and serve as a source of fuel for the body.

Metabolic syndrome — A group of risk factors for heart disease, diabetes, and stroke. It includes abdominal obesity, high blood pressure, high blood glucose levels, and low levels of high-density lipoprotein (HDL) cholesterol. The metabolic syndrome is sometimes called the insulin resistance syndrome.

Metabolism — The sum of an organism's physical and chemical processes that produce and maintain living tissue, and make energy available to the organism. Insulin resistance is a disorder of metabolism.

Obesity — Excessive weight gain due to accumulation of fat in the body, sometimes defined as a BMI of 30 or higher, or body weight greater than 30 percent above one s desirable weight on standard height-weight tables.

Pancreas — A large gland located behind the stomach near the spleen that secretes digestive enzymes into the small intestine and insulin into the bloodstream.

Syndrome — In general, a set of symptoms that occur together as signs of a disease or disorder.

Syndrome X — A term that was sometimes used for metabolic syndrome when the syndrome was first identified in the 1960s.

Triglycerides — Fatty compounds synthesized from carbohydrates during the process of digestion and stored in the body's adipose (fat) tissues. High levels of triglycerides in the blood are associated with insulin resistance.

Type 2 diabetes mellitus — One of the two major types of diabetes mellitus, characterized by late age of onset (30 years or older), insulin resistance, high levels of blood sugar, and little or no need for supple-mental insulin. It was formerly known as adult-onset or non-insulin-dependent diabetes.

With regard to lifestyle factors, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) reported the findings of a study of the effects of lifestyle changes or metformin on the incidence of diabetes in a group of over 3200 overweight people with impaired glucose tolerance, which is a risk factor for developing type 2 diabetes. The researchers found that the subjects in the lifestyle modification group, who lowered their food intake and took 30-minute walks five days a week, had a 58-percent lower incidence of diabetes. The subjects who received metformin had a 31-percent lower incidence of diabetes. Lifestyle changes were most effective in volunteers over the age of 60, while metformin was most effective in younger subjects. In short, the 2002 study confirmed the beneficial effects of lowered food intake and increased activity as preventive measures against type 2 diabetes.

Another important part of preventing insulin resistance is patient education. A number of resources on weight control and exercise written for the general public are available from the Weight-Control Information Network (WIN) on the NIDDK website at http://win.niddk.nih.gov/publications/physical.htm. Some pamphlets are available in Spanish as well as English. Patient education materials on insulin resistance in relation to heart disease and diabetes can be downloaded free of charge from the American Heart Association and American Diabetes Associan websites.

Resources

Books

"Diabetes Mellitus." Section 2, Chapter 13 in The Merck Manual of Diagnosis and Therapy, edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Flancbaum, Louis, MD, with Erica Manfred and Deborah Biskin. The Doctor's Guide to Weight Loss Surgery. West Hurley, NY: Fredonia Communications, 2001.

"Nutritional Disorders: Obesity." Section 1, Chapter 5 in The Merck Manual of Diagnosis and Therapy, edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Pelletier, Kenneth R., MD. The Best Alternative Medicine. New York: Simon & Schuster, 2002.

Periodicals

Boney, C. M., A. Verma, R. Tucker, and B. R. Vohr. "Metabolic Syndrome in Childhood: Association with Birth Weight, Maternal Obesity, and Gestational Diabetes Mellitus." Pediatrics 115 (March 2005): 290-296.

Diabetes Prevention Program Research Group. "Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin." New England Journal of Medicine 346 (February 7, 2002): 393-403.

Ford, Earl S., MD, MPH, Wayne H. Giles, MD, MSc, and William H. Dietz, MD, PhD. "Prevalence of the Metabolic Syndrome Among US Adults." Journal of the American Medical Association 287 (January 16, 2002): 356-359.

Litonjua, P., A. Pinero-Pilona, L. Aviles-Santa, and P. Raskin. "Prevalence of Acanthosis Nigricans in Newly-Diagnosed Type 2 Diabetes." Endocrine Practice 10 (March-April 2004): 101-106.

Olatunbosun, Samuel, MD, and Samuel Dagogo-Jack, MD. "Insulin Resistance." eMedicine, 3 June 2004. http://www.emedicine.com/med/topic1173.htm.

Rao, Goutham, MD. "Insulin Resistance Syndrome." American Family Physician 63 (March 15, 2001): 1159-1166.

Scheinfeld, N. S. "Obesity and Dermatology." Clinical Dermatology 22 (July-August 2004): 303-309.

Sivitz, William I., MD. "Understanding Insulin Resistance: What Are the Clinical Implications?" Postgraduate Medicine 116 (July 2004): 41-48.

Organizations

American Academy of Dermatology (AAD). P. O. Box 4014, Schaumburg, IL 60168-4014. (847) 330-0230. Fax: (847) 330-0050. http://www.aad.org.

American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 342-2383. http://www.diabetes.org.

American Heart Association National Center. 7272 Greenville Avenue, Dallas, TX 75231. (800) 242-8721. http://www.americanheart.org.

American Obesity Association (AOA). 1250 24th Street NW, Suite 300, Washington, DC 20037. (202) 776-7711 or (800) 98-OBESE. www.obesity.org.

National Diabetes Information Clearinghouse (NDIC). 1 Information Way, Bethesda, MD 20892-3560. (800) 860-8747. Fax: (703) 738-4929.

Other

Agency for Healthcare Research and Quality (AHRQ). Evidence Report/Technology Assessment: Number 41. Ayurvedic Interventions for Diabetes Mellitus. Rockville, MD: AHRQ, 2001. http://www.ahrq.gov/clinic/epcsums/ayurvsum.htm.

Agency for Healthcare Research and Quality (AHRQ). Evidence Report/Technology Assessment: Number 89. Effects of Omega-3 Fatty Acids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis. Rockville, MD: AHRQ, 2004. http://www.ahrq.gov/clinic/epcsums/o3lipidsum.htm.

Mayo Clinic Staff. Metabolic Syndrome. http://www.mayoclinic.com/invoke.cfm?id=DS00522.

National Diabetes Information Clearinghouse (NDIC). Insulin Resistance and Pre-Diabetes. NIH Publication No. 04-4893. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 2004. http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) News Brief, 6 February 2002. "Diet and Exercise Delay Diabetes and Normalize Blood Glucose." http://www.niddk.nih.gov/welcome/releases/02-06-02.htm.

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insulin resistance

n.

A state of diminished effectiveness of insulin in lowering the levels of blood sugar, usually resulting from insulin binding by antibodies, and associated with such conditions as obesity, ketoacidosis, and infection.