Insulin Resistance and Prediabetes

Insulin resistance is one of the main features of type 2 diabetes and prediabetes. The term refers to a change in how the body responds to insulin, one of the main hormone produced by the pancreas, such that a given concentration of insulin produces an abnormally low effect in the body. In insulin resistance, tissues and organs such as fat, muscle, and liver become less efficient at taking up glucose from the blood, resulting in high circulating blood glucose levels, especially after meals. The pancreas may attempt to compensate by releasing more insulin, or insulin secretion may be low or in the normal range.

Insulin resistance has no symptoms, but is an important indicator of prediabetes and raises a person's risk of cardiovascular disease. It is highly prevalent, especially in the industrialized world. Several inexpensive options exist to lower the risk of progression from insulin resistance to overt type 2 diabetes.

Insulin structure. Pink=sulfur, blue=nitrogen, green=oxygen, red=carbon. Source: Wikimedia Commons

Overview

Insulin resistance and Pre-diabetes is a condition in which the body produces insulin but does not use it properly. Insulin, a hormone made by the pancreas, helps the body use glucose for energy. Glucose is a form of sugar that is the body’s main source of energy.

The body’s digestive system breaks food down into glucose, which then travels in the bloodstream to cells throughout the body. Glucose in the blood is called blood glucose, also known as blood sugar. As the blood glucose level rises after a meal, the pancreas releases insulin to help cells take in and use the glucose.

When people are insulin resistant, their muscle, fat, and liver cells do not respond properly to insulin. As a result, their bodies need more insulin to help glucose enter cells. The pancreas tries to keep up with this increased demand for insulin by producing more. Eventually, the pancreas fails to keep up with the body’s need for insulin. Excess glucose builds up in the bloodstream, setting the stage for diabetes. Many people with insulin resistance have high levels of both glucose and insulin circulating in their blood at the same time.

When the blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes, the word Prediabetes is used. This condition is sometimes called impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), depending on the test used to diagnose it. The U.S. Department of Health and Human Services estimates that about one in four U.S. adults aged 20 years or older—or 57 million people—had pre-diabetes in 2007.

People with pre-diabetes are at increased risk of developing type 2 diabetes, formerly called adult-onset diabetes or noninsulin-dependent diabetes. Type 2 diabetes is sometimes defined as the form of diabetes that develops when the body does not respond properly to insulin, as opposed to type 1 diabetes, in which the pancreas makes little or no insulin.

Studies have shown that most people with pre-diabetes develop type 2 diabetes within 10 years, unless they lose 5 to 7 percent of their body weight—about 10 to 15 pounds for someone who weighs 200 pounds—by making changes in their diet and level of physical activity. People with pre-diabetes also are at increased risk of developing cardiovascular disease.

Insulin resistance increases the chance of developing type 2 diabetes and heart disease. Learning about insulin resistance is the first step toward making lifestyle changes that can help prevent diabetes and other health problems.

Signs and Symptoms

Insulin resistance and pre-diabetes usually have no symptoms. The person may have one or both conditions for several years without noticing anything. If the person has a severe form of insulin resistance, he or she may get dark patches of skin, usually on the back of the neck. Sometimes people get a dark ring around their neck. Other possible sites for these dark patches include elbows, knees, knuckles, and armpits. This condition is called acanthosis nigricans.

If the patient has a mild or moderate form of insulin resistance, blood tests may show normal or high blood glucose and high levels of insulin at the same time.

Diagnosis

Insulin resistance has been defined somewhat arbitrarily as the need for 200 or more units of insulin per day to maintain normal blood glucose values.^[1] This is in contrast to the normal insulin requirement (in people who have had the pancreas surgically removed) of about 40 units/day.^[2] The test that most accurately measures insulin resistance—the euglycemic clamp—is a complicated and expensive research tool that helps scientists learn more about sugar metabolism problems. Insulin resistance can also be assessed with measurement of fasting insulin.

Exams and tests

On a more practical level, diabetes and pre-diabetes can be detected with one of the following tests:

A fasting glucose test measures the blood glucose after the person has gone overnight without eating. Fasting glucose levels of 100 to 125 mg/dL are above normal, but not high enough to be called diabetes. This condition is called pre-diabetes or impaired fasting glucose, and it suggests that the person has probably had insulin resistance for some time. IFG is considered a pre-diabetic state, meaning that the person more likely to develop diabetes but do not have it yet.

A glucose tolerance test measures the blood glucose after an overnight fast and 2 hours after drinking a sugar-containing liquid provided by the doctor or laboratory. If the blood glucose falls between 140 and 199 mg/dL 2 hours after drinking the liquid, the glucose tolerance is above normal but not high enough for diabetes. This condition, also a form of pre-diabetes, is called impaired glucose tolerance and, like IFG, it points toward a history of insulin resistance and a risk for developing diabetes.

• Blood Glucose. High blood glucose may be a sign that the body does not have enough insulin or does not use it well. However, a fasting measurement or oral glucose tolerance test gives more precise information.
• Insulin. An insulin measurement helps determine whether a high blood glucose reading is the result of insufficient insulin or poor use of insulin.
• Fasting Glucose. The blood glucose level should be lower after several hours without eating. After an overnight fast, the normal level is below 100 mg/dL. If it is in the 100 to 125 mg/dL range, the person may have impaired fasting glucose or pre-diabetes. A result of 126 or higher, if confirmed on a repeat test, indicates diabetes.
• Glucose Tolerance. The blood glucose level will be higher after drinking a sugar solution, but it should still be below 140 mg/dL 2 hours after the drink. If it is higher than normal (in the 140 to 199 mg/dL range) 2 hours after drinking the solution, the person has IGT or pre-diabetes, which is another strong indication that the body has trouble using glucose. A level of 200 or higher, if confirmed, means diabetes is already present.

People whose test results indicate they have pre-diabetes should have their blood glucose levels checked again in 1 to 2 years.

Causes

Scientists have identified specific genes that make people more likely to develop insulin resistance and diabetes. Excess weight and lack of physical activity also contribute to insulin resistance because too much fat interferes with muscles' ability to use insulin.

Many people with insulin resistance and high blood glucose have excess weight around the waist, high LDL (bad) blood cholesterol levels, low HDL (good) cholesterol levels, high levels of triglycerides (another fat in the blood), and high blood pressure, all conditions that also put the heart and blood vessels at risk (also called cardiovascular disease). This combination of problems is referred to as the metabolic syndrome, or the insulin resistance syndrome (formerly called Syndrome X). The American Diabetes Association recommends that testing to detect pre-diabetes and type 2 diabetes be considered in adults without symptoms who are overweight or obese and have one or more additional risk factors for diabetes. In those without these risk factors, testing should begin at age 45.

Risk Factors

Risk factors for pre-diabetes and diabetes—in addition to being overweight or obese or being age 45 or older—include the following:

• being physically inactive
• having a parent or sibling with diabetes
• having a family background that is African American, Alaska Native, American Indian,Asian American, Hispanic/Latino, or Pacific Islander
• giving birth to a baby weighing more than 9 pounds or being diagnosed with gestational diabetes—diabetes first found during pregnancy
• having high blood pressure—140/90 or above—or being treated for high blood pressure
• having an HDL, or “good,” cholesterol level below 35 mg/dL or a triglyceride level above 250 mg/dL
• having polycystic ovary syndrome, also called PCOS
• having impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) on previous testing
• having other conditions associated with insulin resistance, such as severe obesity or acanthosis nigricans
• having a history of cardiovascular disease

If test results are normal, testing should be repeated at least every 3 years. Health care providers may recommend more frequent testing depending on initial results and risk status.

Treatment

The main goal in treating insulin resistance and pre-diabetes is to help the body relearn to use insulin normally. A person can do several things to help reach this goal.

Physical activity and weight loss help the body respond better to insulin. By losing weight and being more physically active, people with insulin resistance or pre-diabetes may avoid developing type 2 diabetes.

The Diabetes Prevention Program (DPP) and other large studies have shown that people with pre-diabetes can often prevent or delay diabetes if they lose a modest amount of weight by cutting fat and calorie intake and increasing physical activity—for example, walking 30 minutes a day 5 days a week. Losing just 5 to 7 percent of body weight prevents or delays diabetes by nearly 60 percent. In the DPP, people aged 60 or older who made lifestyle changes lowered their chances of developing diabetes by 70 percent. Many participants in the lifestyle intervention group returned to normal blood glucose levels and lowered their risk for developing heart disease and other problems associated with diabetes. The DPP also showed that the diabetes drug metformin reduced the risk of developing diabetes by 31 percent.

People with insulin resistance or pre-diabetes can help their body use insulin normally by being physically active, making wise food choices, and reaching and maintaining a healthy weight. Physical activity helps muscle cells use blood glucose for energy by making the cells more sensitive to insulin.

Activity and diet

Physical activity helps the muscle cells use blood glucose because they need it for energy. Exercise makes those cells more sensitive to insulin.

The DPP confirmed that people who follow a low-fat, low-calorie diet and who increase activities such as walking briskly or riding a bike for 30 minutes, five times a week, have a far smaller risk of developing diabetes than people who do not exercise regularly. The DPP also reinforced the importance of a low-calorie, low-fat diet. Following such a diet can provide two benefits. If the person is overweight, one benefit is that limiting the calorie and fat intake can help that person lose weight. DPP participants who lost weight were far less likely to develop diabetes than others in the study who remained at an unhealthy weight. Increasing activity and following a low-calorie, low-fat diet can also improve blood pressure and cholesterol levels and has many other health benefits. Scientists have established some numbers to help people set goals that will reduce their risk of developing glucose metabolism problems.

• Weight. Body mass index (BMI) is a measure used to evaluate body weight relative to height, calculated as weight (in kg) divided by height squared (in m²).
• Blood Pressure. Blood pressure is expressed as two numbers that represent pressure in the blood vessels when the heart is beating (systolic pressure) and when it is resting (diastolic pressure). The numbers are usually written with a slash—for example, 140/90, which is expressed as "140 over 90." For the general population, blood pressure below 130/85 is considered normal, although people whose blood pressure is slightly elevated and who have no additional risk factors for heart disease may be advised to make lifestyle changes—that is, diet and exercise—rather than take blood pressure medicines. People who have diabetes, however, should take whatever steps necessary, including lifestyle changes and medicine, to reach a blood pressure goal of below 130/80.
• Cholesterol. Cholesterol is usually reported with three values: low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and total cholesterol. LDL cholesterol is sometimes called "bad" cholesterol, while HDL cholesterol is called "good" cholesterol. To lower the risk of cardiovascular problems if diabetes is present, try to keep the LDL cholesterol below 100 and the total cholesterol below 200.

If the person has metabolic syndrome, the doctor may recommend weight loss with diet and exercise, as well as medication to lower cholesterol and blood pressure levels.

Quitting smoking

In addition to increasing the risk of cancer and cardiovascular disease, smoking contributes to insulin resistance. Quitting smoking reduces the risk for respiratory problems, lung cancer, and diabetes.

Medications

Clinical trials have shown that people at high risk for developing diabetes can be given treatments that delay or prevent onset of diabetes. The first therapy should always be an intensive lifestyle modification program because weight loss and physical activity are much more effective than any medication at reducing diabetes risk.

Several drugs have been shown to reduce diabetes risk to varying degrees. No drug is approved by the U.S. Food and Drug Administration to treat insulin resistance or pre-diabetes or to prevent type 2 diabetes. The American Diabetes Association recommends that metformin is the only drug that should be considered for use in diabetes prevention. Other drugs that have delayed diabetes have side effects or haven’t shown long-lasting benefit. Metformin use was recommended only for very high-risk individuals who have both forms of pre-diabetes (IGT and IFG), have a BMI of at least 35, and are younger than age 60. In the DPP, metformin was shown to be most effective in younger, heavier patients.

Two classes of drugs can improve the body's response to insulin and are used by prescription for type 2 diabetes—biguanides and Thiazolidinedione (thigh-uh-ZOLE-uh-deen-DYE-own]]. Other medicines used for diabetes act by other mechanisms. Alpha-glucosidase inhibitors restrict or delay the absorption of carbohydrates after eating, resulting in a slower rise of blood glucose levels. Sulfonylureas and meglitinides increase insulin production.

The Diabetes Prevention Program (DPP) showed that the diabetes drug metformin, a biguanide, reduced the risk of diabetes in those with pre-diabetes but was much less successful than losing weight and increasing activity. In another study, treatment with troglitazone, a Thiazolidinedione later withdrawn from the market following reports of liver toxicity, delayed or prevented type 2 diabetes in Hispanic women with a history of gestational diabetes. Acarbose, an alpha-glucosidase inhibitor, has been effective in delaying development of type 2 diabetes. Additional studies using other diabetes medicines and some types of blood pressure medicines to prevent diabetes are under way. No drug has been approved by the Food and Drug Administration (FDA) specifically for insulin resistance or pre-diabetes.

Epidemiology

Incidence

People with blood glucose levels that are higher than normal but not yet in the diabetic range have “pre-diabetes.” Doctors sometimes call this condition impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), depending on the test used to diagnose it. Pre-diabetes is becoming more common in the United States, according to new estimates provided by the U.S. Department of Health and Human Services. About 40 percent of U.S. adults ages 40 to 74—or 41 million people—had pre-diabetes in 2000. New data suggest that at least 54 million U.S. adults had pre-diabetes in 2002.

People having pre-diabetes also have a higher risk of developing type 2 diabetes, formerly called adult-onset diabetes or noninsulin-dependent diabetes. Studies have shown that most people with pre-diabetes go on to develop type 2 diabetes within 10 years, unless they lose 5 to 7 percent of their body weight—which is about 10 to 15 pounds for someone who weighs 200 pounds—by making modest changes in their diet and level of physical activity. People with pre-diabetes also have a higher risk of heart disease.

Type 2 diabetes is sometimes defined as the form of diabetes that develops when the body does not respond properly to insulin, as opposed to type 1 diabetes, in which the pancreas makes no insulin at all. At first, the pancreas keeps up with the added demand by producing more insulin. In time, however, it loses the ability to secrete enough insulin in response to meals.

Insulin resistance can also occur in people who have type 1 diabetes, especially if they are overweight.

Research

Researchers continue to follow DPP participants to learn about the long-term effects of the study. Other research sponsored by the National Institutes of Health builds on the findings from the DPP, including research focusing on lowering diabetes risk in children. Once considered an adult disease, type 2 diabetes is becoming more common in children, and researchers are seeking ways to reverse this trend.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsors the HEALTHY study, which is part of a broad research initiative called STOPP T2D (Studies to Treat or Prevent Pediatric Type 2 Diabetes). The study seeks to improve the treatment and prevention of type 2 diabetes in youth, exploring the roles of nutrition, physical activity, and behavior change in lowering risk for type 2 diabetes in children. The participating 42 middle schools are randomly assigned to a program group implementing changes or a comparison group. Students in the program group have healthier choices from the cafeteria and vending machines; longer, more intense periods of physical activity; and activities and awareness campaigns that promote long-term healthy behaviors. Results from the HEALTHY study are expected in 2009.

The NIDDK also sponsors the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study, which focuses on treatment of type 2 diabetes in children and teens at 13 sites. The TODAY study will evaluate the effects of three treatment approaches on control of blood glucose levels, insulin production, insulin resistance, and other outcomes. Each approach involves medication, but one of the three treatment groups will also receive an intensive lifestyle intervention to help the participants lose weight and increase physical fitness. More information about the TODAY study is available at http://www.todaystudy.org.

Video: Findings from The Diabetes Prevention Program

In this video from BigThink, David L. Katz MD MPH, Director of Yale University’s Prevention Research Center, discusses how to put the findings of the DPP to work in every town in America:

Clinical Trials

Several clinical trials are actively searching for more effective ways to treat insulin resistance. Examples include "Exercise Training and Glucose Metabolism in Aging", ^[3] and the "Healthy Living Partnership to Prevent Diabetes".^[4]

Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research. For information about current studies, visit http://www.medpedia.com/clinical-trials.

Points to Remember

• Insulin resistance is a condition in which the body’s cells do not use insulin properly. Insulin helps cells use blood glucose for energy.
• Insulin resistance increases the risk of developing pre-diabetes, type 2 diabetes, and cardiovascular disease.
• Pre-diabetes is a condition in which blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes.
• Causes of insulin resistance and pre-diabetes include genetic factors, excess weight, and lack of physical activity.
• Being physically active, making wise food choices, and reaching and maintaining a healthy weight can help prevent or reverse insulin resistance and pre-diabetes.
• The Diabetes Prevention Program (DPP) study confirmed that people at risk for developing type 2 diabetes can prevent or delay the onset of diabetes by losing 5 to 7 percent of their body weight through regular physical activity and a diet low in fat and calories.

For More Information

American Diabetes Association

1701 North Beauregard Street

Alexandria, VA 22311

Phone: 1–800–DIABETES (342–2383)

Email: AskADA@diabetes.org

Internet: http://www.diabetes.org

National Diabetes Education Program

1 Diabetes Way

Bethesda, MD 20814–9692

Phone: 1–888–693–NDEP (6337)

TTY: 1–866–569–1162

Fax: 703–738–4929

Email: ndep@mail.nih.gov

Internet: http://www.ndep.nih.gov

National Heart, Lung, and Blood Institute Information Center

P.O. Box 30105

Bethesda, MD 20824–0105

Phone: 301–592–8573

Fax: 301–592–8563

Email: nhlbiinfo@nhlbi.nih.gov

Internet: http://www.nhlbi.nih.gov

National Diabetes Information Clearinghouse

1 Information Way

Bethesda, MD 20892–3560

Phone: 1–800–860–8747

TTY: 1–866–569–1162

Fax: 703–738–4929

Email: ndic@info.niddk.nih.gov

Internet: http://www.diabetes.niddk.nih.gov