Monday, 19 August 2013

479. INSULIN - 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
1.    type 2 diabetes (formerly called adult-onset or non-insulin-dependent diabetes),
2.    the metabolic syndrome (formerly known as syndrome X),
3.    obesity, and

        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.
        1]      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.
        2]      The glucose then passes into the bloodstream.
        3]      When the concentration of glucose in the blood reaches a certain point, the pancreas is stimulated to release insulin into the blood.
        4]      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.
        5]      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.
        6]      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.
        1] 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.
        2] Others may have one of two types of abnormalities in the insulin receptors themselves.
        3]  In type A, the insulin receptor is missing from the cell surface or does not function properly.
        4]  In type B, the person's immune system produces auto-antibodies to the insulin receptor.
        In the early stages of insulin resistance,
        1]  The pancreas steps up its production of insulin in order to control the increased levels of glucose in the blood.
        2]  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.
        3]  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

        1]    The symptoms of insulin resistance vary considerably from person to person.
        2]    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.
        3]    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.
        4]    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.
        5]    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.
        6]    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. 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 hyper-androgenism, 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.

1.    A BMI between 19 and 24 is considered normal;
2.    25-29 is overweight;
3.    30-34 is moderately obese;
4.    35-39 is severely obese; and
5.    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.

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.

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