insulin resistance


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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:
  • Genetic factors. Insulin resistance is known to run in families. Genetic mutations may affect the insulin receptor, the signaling proteins within cells, or the mechanisms of glucose transport.
  • Obesity. Being overweight keeps the muscles from using insulin properly, as it decreases the number of insulin receptors on cell surfaces.
  • Low level of physical activity. Because muscle tissue takes up 95 percent of the glucose that insulin helps the body utilize (brain cells and blood cells do not depend on insulin to help them use glucose), inactivity further reduces the muscles ability to use insulin effectively.
  • Aging. The aging process affects the efficiency of glucose transport.
  • Other diseases and disorders. Some disorders—most notably Cushing syndrome and cirrhosis—and such stresses on the body as trauma, surgery, malnutrition, or severe infections speed up the breakdown of insulin or interfere with its effects.
  • Certain medications. Some drugs, including cyclosporine, niacin, and the protease inhibitors used to treat HIV infection, may contribute to insulin resistance.

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:
  • Obesity. Obesity is not only the most common cause of insulin resistance but is a growing health concern in its own right. According to the National Institutes of Health (NIH), the percentage of American adults who meet the criteria for obesity rose from 25 percent to 33 percent between 1990 and 2000—an increase of a third within the space of a decade. Obesity is a risk factor for the development of type 2 diabetes, high blood pressure, and coronary artery disease.
  • Pre-diabetes and type 2 diabetes. The NIH estimates that about 6.3 percent of the American population has diabetes. Of these 18.3 million people, 5.2 million are undiagnosed. Type 2 diabetes is much more common than type 1, accounting for 90-95 percent of patients with diabetes. Diabetes increases a person's risk of blindness, kidney disease, heart disease and stroke, disorders of the nervous system, complications during pregnancy, and dental problems; it also worsens the prognosis for such infectious diseases as influenza or pneumonia. About 41 million Americans are thought to have pre-diabetes, which is a condition marked by elevated levels of blood glucose after fasting or after a 2-hour test for glucose tolerance. According to the NIH, a majority of pre-diabetic people will develop type 2 diabetes within 10 years unless they lose between 5 and 7 percent of their body weight.
  • Heart disease. Insulin resistance has been linked to a group of risk factors for heart disease and stroke known as the metabolic syndrome (formerly called syndrome X). The metabolic syndrome, like obesity, has become increasingly prevalent in the United States since the 1990s; as of the early 2000s, about a quarter of the general adult population is thought to have it, with the rate rising to 40 percent for adults over the age of 60. To be diagnosed with the metabolic syndrome, a person must have three or more of the following risk factors: a waist circumference greater than 40 in (102 cm) in men or 35 in (88 cm) in women; a level of blood triglycerides of 150 milligrams per deciliter (mg/dL) or higher; blood pressure of 130/85 Hg or higher; fasting blood sugar level of 110 mg/dL or higher; and a blood level of high-density lipoprotein (HDL) cholesterol (the so-called "good" cholesterol) lower than 50 mg/dL for men or 40 mg/dL for women.
  • Polycystic ovary syndrome (PCOS). PCOS is an endocrine disorder that develops in 3-10 percent of premenopausal women as a result of the formation of cysts (small fluid-filled sacs) in the ovaries. Women with PCOS do not have normal menstrual periods; they are often infertile and may develop hirsutism (excess body hair) or other indications of high levels of androgens (male sex hormones) in the blood. This condition is called hyperandrogenism, and has been linked to insulin resistance in women with PCOS. Weight loss in these patients usually corrects hyperandrogenism and often restores normal ovulation patterns and fertility.

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:
  • One or more family members with diabetes.
  • High levels of triglycerides and low levels of HDL cholesterol as defined by the criteria for metabolic syndrome.
  • Hypertension (high blood pressure).
  • A history of smoking.
  • A history of diabetes during pregnancy (gestational diabetes).
  • Giving birth to a baby weighing more than 9 pounds. In addition to increasing the mother's risk of developing type 2 diabetes, children who are large for their gestational age (LGA) at birth have an increased risk of developing insulin resistance and metabolic syndrome in later life.
  • Having African American, Hispanic, Native American, or Asian American/Pacific Islander heritage.
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:
  • Blood glucose tests. A high level of blood glucose may indicate either that the body is not producing enough insulin or is not using it effectively. Two common tests used to screen for insulin resistance are the fasting glucose test and the glucose tolerance test. In the fasting glucose test, the person takes no food after midnight and has their blood glucose level measured early in the morning. Normal blood glucose levels after several hours without food should be below 100 milligrams per deciliter (mg/dL). If the level is between 100 and 125 mg/dL, the person has impaired fasting glucose (IFG) or pre-diabetes. If the level is over 126 and is confirmed by a second test, the person has diabetes. In the glucose tolerance test, the person is given a sugar solution to drink and their blood glucose level is measured 2 hours later. A normal level is 140 mg/dL; 140-199 mg/dL indicates impaired glucose tolerance (IGT) or pre-diabetes, while a level of 200 mg/dL or higher indicates diabetes.
  • Tests of blood insulin levels. These help to determine whether high blood glucose levels are the result of insufficient production of insulin or inefficient use of insulin.
  • Lipid profile test. This test measures the amount of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. Patients with insulin resistance will have high levels of LDL cholesterol and triglycerides with low levels of HDL cholesterol.
  • Measurement of blood electrolytes and uric acid. Many patients with the metabolic syndrome have high blood levels of uric acid.
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:
  • Weight reduction. Losing weight increases the body's sensitivity to insulin. It is not necessary, however, for patients to reduce their weight to the ideal levels listed on life insurance charts. In recent years, researchers have found that even a modest weight loss—usually defined as 10 percent of the patient's pretreatment weight—is enough to control or at least improve insulin resistance and other health complications of obesity. Weight reduction is usually accomplished by a combination of reduced calorie intake and increased physical activity. Insulin sensitivity is reported to improve within a few days of lowered calorie intake, even before the patient loses a measurable amount of weight.
  • Exercise. Regular exercise improves the body's sensitivity to insulin by increasing the muscles' uptake of glucose from the bloodstream, by increasing the efficiency of the circulatory system and glucose transport, and by reducing the amount of fat around the patient's abdomen. The American Academy of Family Practice (AAFP) recommends 30 minutes of moderately intense physical activity on most or all days of the week for people diagnosed with insulin resistance. Walking is a very good form of exercise because it does not require any special equipment other than comfortable walking shoes, can be combined with doing errands, and can be done either alone or with a group of friends. Riding a bicycle is another form of exercise recommended for weight control.
  • Adding foods high in fiber to the diet. A diet high in natural fiber, found in whole grains and vegetables, lowers the levels of blood insulin as well as lowering the patient's risk of developing high blood pressure.
  • Quitting smoking. Giving up smoking lowers the risk of heart disease, stroke, or lung cancer as well as increasing the body's sensitivity to insulin.
  • Limiting alcohol consumption. Alcohol is a source of "empty" calories with little nutritional value of its own.

Medications

There are several different types of medications that can be used to treat patients with abnormal blood sugar or insulin levels:
  • Biguanides. Biguanides are drugs that improve the body's sensitivity to insulin by lowering the absorption of glucose in the small intestine, decreasing the liver's production of glucose, and increasing the uptake of glucose in muscle and fatty tissues. Metformin (Glucophage), a drug used in the treatment of type 2 diabetes, is the most commonly used biguanide in treating insulin resistance. It has also been studied as a possible treatment in preventing or delaying the onset of type 2 diabetes.
  • Thiazolidinediones. These drugs stimulate glucose uptake in the muscles and fatty tissues by activating specific receptors in the cell nucleus. They also lower blood insulin levels in patients with hyperinsulinemia. The thiazolidinediones include pioglitazone (Actos) and rosiglitazone (Avandia).
  • Glucocorticoids. These drugs may be given to patients with insulin resistance caused by anti-insulin antibodies produced by their immune system. Prednisone (Deltasone) is the most commonly used glucocorticoid.
  • Insulin itself. Some patients with insulin resistance benefit from injectable insulin to reduce their blood sugar 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.

insulin

 [in´su-lin]
1. the major fuel-regulating hormone of the body, a double-chain protein formed from proinsulin in the beta cells of the islets of Langerhans in the pancreas. Insulin promotes the storage of glucose and the uptake of amino acids, increases protein and lipid synthesis, and inhibits lipolysis and gluconeogenesis. Secretion of insulin is a response of the beta cells to a stimulus; the primary stimulus is glucose, and others are amino acids and hormones such as secretin, pancreozymin, and gastrin. These chemicals play an important role in maintaining normal blood glucose levels by triggering insulin release after a meal. After insulin is released from the beta cells, it enters the blood stream and is transported to cells throughout the body. The cell membranes have insulin receptors to which the hormone becomes bonded or “fixed.” An interaction between the insulin and its receptors leads to biochemical processes that include (1) the transport of glucose, amino acids, and certain ions across the membrane and into the cell body; (2) the storage of glycogen in liver and muscle cells; (3) the synthesis of triglycerides and storage of fat; (4) the synthesis of protein, RNA, and DNA, and (5) inhibition of gluconeogenesis, degradation of glycogen and protein, and lipolysis. Although insulin increases the transport of glucose across the cell membrane of most cells, in the brain glucose enters the cells by simple diffusion through the blood--brain barrier.
2. a preparation of the hormone, first discovered in 1921, used in treatment of diabetes mellitus; it may be bovine or porcine in origin (prepared from the pancreas of the animals) or a recombinant human type, although insulin of bovine origin is no longer available in the United States. Recombinant human types may duplicate exactly the human insulin protein sequence, or may be analogues with small differences in sequence. Commercially prepared insulin is available in various types that differ in the speed with which they act and in the duration of their effectiveness. There are several different types of insulin, usually classified by their onset and duration of action. (See table.)

Patients with diabetes react differently in the rate at which they absorb and utilize exogenous insulin; therefore, the duration of action varies from person to person. Moreover, the site of injection, volume of injection, and the condition of the tissues into which the insulin is injected can alter its rate of absorption and peak action times, and exercising the limb which has been injected immediately after injection can increase the speed of absorption. Insulin is measured in units.
Problems of Insulin Therapy. The problem of either too much or too little insulin is always a potential hazard for the person on insulin therapy. The causes, symptoms, and treatment of hypoglycemic or insulin reaction and hyperglycemia are discussed under diabetes mellitus. Other problems of insulin therapy include insulin allergy, insulin resistance, insulin rebound due to the somogyi effect, and lipodystrophies or other localized tissue changes at injection sites.

Lipodystrophies are localized manifestations of disordered fat metabolism at the sites of insulin injection. Tissue hypertrophy can be seen as a mass of fibrous scar tissue and is sometimes called “insulin tumor.” atrophy of the tissues at the injection site appears as dimpling and pitting of the skin and underlying tissues. These problems are more common in adult females and in children. Atrophy of the tissues is relatively harmless, but hypertrophy can cause malabsorption of the insulin and a possible misdiagnosis of insulin resistance. Measures that can help prevent lipodystrophies include (1) systematic rotation of injection sites, (2) warming insulin to room temperature before injection, (3) pinching the skin when injecting the insulin so that it is deposited between fat and muscle tissue, and (4) use of human insulin.
insulin allergy a hypersensitivity reaction to insulin, usually a reaction to its protein components. More purified insulins have now been developed that are less likely to cause an allergic reaction and other complications. Human insulin, prepared by recombinant genetic engineering, eliminates many problems associated with repeated insulin injections, because of reduced antibody concentrations.
insulin pump a device consisting of a syringe filled with a predetermined amount of short-acting insulin, a plastic cannula and a needle, and a pump that periodically delivers the desired amount of insulin. The basal rate of insulin delivery usually is one pulse every 8 minutes, but the pump can deliver as many as 60 pulses at a time. Before each meal or snack the patient manually administers a bolus of insulin by adjusting the pump setting to the desired one-time dose. Some insulin pumps will automatically reset themselves to the basal rate of infusion after each bolus. Research is ongoing regarding implantable pumps that release insulin in response to the pump's glucose sensor. This method could potentially administer insulin in a manner resembling the normal absorption from the pancreas.
Insulin pumps are worn externally and connected to an indwelling subcutaneous needle, usually inserted in the abdomen. From Black and Matassarin-Jacobs, 2001.
insulin rebound extreme fluctuations in blood sugar levels owing to overreaction of the body's homeostatic feedback mechanisms for control of glucose metabolism. When exogenous insulin is given, the hypoglycemia triggers an outpouring of glucagon and epinephrine, both of which raise the blood sugar concentration markedly. Although the patient may actually have periods of hypoglycemia, urine and blood glucose tests will show hyperglycemia. Treatment is aimed at modifying the extremes by gradually lowering the insulin dosage so as to reduce stimulation of the feedback system of glucose regulation. The patient may need to take smaller doses of insulin or take it at more frequent intervals and at different times during the day
insulin resistance impairment of the normal biologic response to insulin, which may result from abnormalities in the B-cell products, binding of insulin to antagonists such as anti-insulin antibodies, defects in or reduced numbers of receptors, and defects in the insulin action cascade in the target cell. Diabetic persons with this problem require more than 100 units daily, and some may need as much as 500 or 1000 units daily. Besides diabetes, the condition has also been associated with diseases such as obesity, acromegaly, uremia, and certain rare, possibly genetic, autoimmune diseases.
insulin sensitivity test a test used to differentiate diabetes mellitus from pituitary and adrenal diabetes. A test dose of exogenous insulin will produce a rapid and marked decrease in blood glucose if the pancreas is not secreting sufficient quantities of insulin. A much less dramatic response is produced if hyperglycemia is due to excessive secretion of either pituitary or adrenocortical hormones rather than insufficient insulin production.

resistance

 [re-zis´tans]
1. opposition, or counteracting force, as opposition of a conductor to passage of electricity or other energy or substance.
2. the natural ability of a normal organism to remain unaffected by noxious agents in its environment; see also immunity.
3. in psychology or psychiatry, conscious or unconscious defenses against change, preventing repressed material from coming into awareness; they can take such forms as forgetfulness, evasions, embarrassment, mental blocks, denial, anger, superficial talk, intellectualization, or intensification of symptoms. It occurs because the blocked association or understanding would be too threatening to face at this point in the therapy; identification of what point the resistance comes at can be an important indicator of the patient's unconscious patterns.
airway resistance the opposition of the tissues of the air passages to air flow: the mouth-to-alveoli pressure difference divided by the rate of air flow. Symbol RA or RAW.
androgen resistance resistance of target organs to the action of androgens, resulting in any of a spectrum of defects from a normal male phenotype in which men have normal genitalia but infertility to complete androgen resistance in which the individual has a female phenotype. Complete androgen resistance is an extreme form of male pseudohermaphroditism in which the individual is phenotypically female but is of XY chromosomal sex; there may be rudimentary uterus and tubes, but the gonads are typically testes, which may be abdominal or inguinal in position. Called also testicular feminization and testicular feminization syndrome. Incomplete androgen resistance is any of various forms less than the complete type, manifested by a male phenotype with various degrees of ambiguous genitalia such as hypospadias and a small vaginal pouch, a hooded phallus, or a bifid scrotum that may or may not contain gonads.
drug resistance the ability of a microorganism to withstand the effects of a drug that are lethal to most members of its species.
insulin resistance see insulin resistance.
multidrug resistance (multiple drug resistance) a phenomenon seen in some malignant cell lines: cells that have developed natural resistance to a single cytotoxic compound are also resistant to structurally unrelated chemotherapy agents. Called also cross-resistance.
peripheral resistance resistance to the passage of blood through the small blood vessels, especially the arterioles.
pulmonary vascular resistance the vascular resistance of the pulmonary circulation; the difference between the mean pulmonary arterial pressure and the left atrial filling pressure divided by the cardiac output. Called also total pulmonary vascular resistance.
total peripheral resistance the vascular resistance of the systemic circulation: the difference between the mean arterial pressure and central venous pressure divided by the cardiac output.
total pulmonary resistance (total pulmonary vascular resistance) pulmonary vascular resistance.
vascular resistance the opposition to blood flow in a vascular bed; the pressure drop across the bed divided by the blood flow, conventionally expressed in peripheral resistance units. Symbol R or R.

in·su·lin re·sis·tance

diminished effectiveness of insulin in lowering plasma glucose levels, arbitrarily defined as a daily requirement of at least 200 units of insulin to prevent hyperglycemia or ketosis; usually due to binding of insulin or insulin receptor sites by antibodies; associated with obesity, ketoacidosis, and infection.
See also: metabolic syndrome.

Impairment of the normal response of muscle and other cells to endogenous or exogenous insulin often complicates the deficiency of endogenous insulin that is characteristic of Type 2 diabetes mellitus. It is a peripheral phenomenon and can occur even when the quality and quantity of insulin produced by the pancreas are normal. It apparently results from a decrease in the number of insulin receptor sites on cells, from a malfunction of the biochemical glucose transport system, or both. Insulin resistance is often associated with high levels of circulating antibody to insulin receptors. The phenomenon of insulin resistance explains why some patients with Type 2 diabetes have hyperinsulinemia in the fasting state, often coexisting with elevated plasma glucose levels. Insulin resistance correlates closely with obesity in diabetes. It occurs less frequently in lean patients with diabetes, whose principal problem is usually primary failure of insulin production. Insulin resistance is a prominent feature of the metabolic syndrome, which also includes obesity, dyslipidemias, hypertension, and hyperuricemia. Some women with polycystic ovaries, hirsutism, and anovulation also have insulin resistance and hyperinsulinemia. Thiazolidinediones (pioglitazone, rosiglitazone) improve insulin sensitivity in type 2 diabetes mellitus.

insulin resistance

n.
Impaired ability of an organism or of its cells or tissues to respond effectively to insulin, as in type 2 diabetes.

insulin resistance

a cause of type 2 diabetes mellitus characterized by a need for an increased amount of insulin per day to control hyperglycemia and ketosis. It is associated with decreased or ineffective glucose transporter proteins with insulin-sensitive cells or insulin-binding by high levels of antibody. Insulin-resistant states also may occur with acanthosis nigrans, Werner's syndrome, ataxia telangiectasia, Alström syndrome, pineal hyperplasia syndrome, and various lipodystrophic disorders.

insulin resistance

Endocrinology A suboptimal hypoglycemic response to physiologic insulin, which may be due to local allergy to insulin, acute exacerbation of chronic leukemia, DKA; IR–measured by oral GTT, and hyperinsulinemia are risk factors for type 2 DM; IR may also be due to ↑ circulating glucagon or a relative insulin receptor deficiency, where plasma insulin is high relative to glucose; in uremia, IR may be due to nonspecific receptor antagonism, as insulin binds poorly to receptors and hypocalcemia with ↑ proinsulin secretion. See Subcutaneous insulin-resistance syndrome. Cf Syndrome X.
Insulin resistance
Type A 'Pre-receptor', due to defects in synthesis and secretion of insulin, seen in the HAIR-IN syndrome, with hyperandrogenism (to a degree suggesting hyperthecosis, ovarian neoplasia, or polycystic ovaries), which is of pubertal onset, with ↑ levels of endogenous insulin, overt DM and resistance to exogenous insulin, related to anti-insulin antibodies.
Type B 'Receptor', related to ↓ insulin binding to receptors, ↓ number of receptors, or to insulin resistance, which may be associated with acanthosis nigricans, autoimmune disease, and overt DM due to circulating anti-receptor antibodies
Type C 'Post-receptor', related to defects arising after the insulin-receptor complex has formed, eg a defect in the cascade that follows receptor-ligand interaction

in·su·lin re·sis·tance

(in'sŭ-lin rĕ-zis'tăns)
Diminished effectiveness of insulin in lowering blood sugar levels; arbitrarily defined as requiring 200 units or more of insulin per day to prevent hyperglycemia or ketosis; usually due to insulin binding by antibodies, but abnormalities in insulin receptors on cell surfaces also occur; associated with obesity, ketoacidosis, infection, and some less common conditions.

insulin resistance

A state in which normal levels of insulin in the blood fail to produce the normal biological response. A feedback mechanism results in higher than normal levels of insulin and the blood sugar levels may be normal or raised. Insulin resistance is commonly associated with type II DIABETES (non-insulin dependent diabetes mellitus), obesity and essential HYPERTENSION. It may be exacerbated by various drugs including corticosteroids, beta blockers, and high dosage of thiazide diuretics.

insulin resistance

non-effectiveness of insulin at peripheral tissues, characteristic of presentations of type 2 diabetes; due to failure of insulin binding at cell membrane or reduced numbers of membrane insulin receptors (receptor numbers are lowered in obesity and in chronic exposure to raised insulin levels); subjects show hyperinsulinaemia + characteristics of diabetes (hyperglycaemia, glycosuria, polyuria and polydypsia) see Table 1
Table 1: Presentations of diabetes mellitus
Presentation of DMCharacteristics
Type 1 DM (formerly termed IDDM)Tends to affect younger people; acute-onset disease with weight loss and marked dehydration; untreated leads to ketoacidosis, coma and death; treated by diet control and lifelong insulin
Type 2 DM (formerly termed NIDDM)Tends to affect older people (>35 years old); chronic-onset disease with gradual weight gain and symptom onset; untreated leads to PVD, MI, CVA, and possibly ketoacidosis, coma and death; treated by diet control ± oral hypoglycaemic agents, and possibly insulin therapy in the long term
MODYAffects young people, but shows the characteristics of type 2 DM
Gestational DMCharacteristics of type 2 DM, which resolve after parturition
Low-birth-weight DMAs type 2 DM, presenting in adulthood in patients who were of low birth weight and/or those who were undernourished as children (including anorexics)
Pre-diabetes (insulin resistance)Subjects, such as those with obesity, lichen planus, acromegaly, polycystic ovary syndrome, history of anorexia, may show a poor response to a glucose tolerance test, and tend to go on to develop type 1 or type 2 diabetes later in life

IDDM, insulin-dependent diabetes mellitus; NIDDM, non-insulin-dependent diabetes mellitus; PVD, peripheral vascular disease; MI, myocardial infarct; CVA, cerebrovascular accident.

in·su·lin re·sis·tance

(in'sŭ-lin rĕ-zis'tăns)
Diminished effectiveness of insulin in lowering plasma glucose levels, arbitrarily defined as a daily requirement of at least 200 units to prevent hyperglycemia or ketosis; associated with obesity, ketoacidosis, and infection.
References in periodicals archive ?
Inactive adults lose roughly 5% of their lean body mass every decade and lean mass is inversely associated with body fat and insulin resistance.
Alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population.
Simply put, insulin resistance is a condition wherein insulin becomes less effective at lowering blood sugar.
In PCOS group, there were no significant associations between CRP, C3 and insulin resistance as defined according to HOMA index (r=0.
Major finding: The adjusted incidence of insulin resistance was 14% higher and the incidence of metabolic syndrome was 12% higher in patients with PTSD, compared with those without PTSD.
The researchers used standard statistical methods to identify factors linked to higher (worse) or lower insulin resistance.
Prof Raffaella Buzzetti, from Sapienza University in Rome, said: "If our work is confirmed by future studies, wrist circumference could be used to predict insulin resistance and cardiovascular disease risk.
This damage showed up, he says, even though the mice didn't have high blood sugar, suggesting that insulin resistance plays a role in kidney disease brought on by diabetes, called diabetic nephropathy.
In all, 23% of the men and 26% of the women were estimated to have insulin resistance, as measured indirectly by the homeostasis model assessment (HOMA).
In non-obese subjects without diabetes, insulin resistance has predicted the development of CHD independently of the other known risk factors (16).
Metabolic syndrome is not pre-diabetes, insulin resistance or glucose intolerance.
has begun high- throughput screening against another target from Metabolex's proprietary database of human genes associated with insulin resistance and obesity in order to identify potential drug candidates.

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