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•	In-Depth Reports Home

In This Report

•	Highlights
•	Introduction
•	Causes
•	Risk Factors
•	Symptoms
•	Emergency Complications
•	Screening Tests
•	Treatment
•	Lifestyle Changes
•	Medications
•	Long-Term Complications
•	Resources
•	References

Related Reports

•	Diabetes - type 1
•	Diabetes diet

Encyclopedia

•	Diabetes
•	Type 2 diabetes

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Diabetes - type 2

Highlights

Drug Approvals

• Exenatide (Byetta) is a new type of injectable drug for patients who cannot control their blood sugar with oral drugs. Approved in 2005, Exenatide is used in combination with oral medication.
• Exubera, an inhaled insulin, was approved in 2006. It is the first non-injected form of insulin.
• Pramlintide (Symlin) is a new injectable drug that is taken in combination with insulin. Approved in 2005, it is only for patients who cannot control their blood sugar with insulin therapy alone.

Drug Warning

Rosiglitazone (Avandia) may cause or worsen swelling in the macular region of the eye’s retina. Most patients who experienced this problem also had swelling in their legs and feet. The condition usually improves once the drug is stopped.

Investigational Drugs

Gliptins such as vildagliptin (Galvus) and sitagliptin (Januvia) are a new type of drug showing promise in late-stage clinical trials. Researchers are studying them in combination with metformin or thiazolidinediones.

Diabetes and High Blood Pressure

• A thiazide-type diuretic works as well as an ACE inhibitor or calcium channel blocker for controlling blood pressure in patients with diabetes and high blood pressure, according to results from the 2005 Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). However, ACE inhibitors and angiotensin-receptor blockers (ARBs) have special benefits for protecting the kidneys in patients with diabetes.
• Some types of high blood pressure drugs may increase the risk for developing diabetes in patients with pre-diabetes, suggests several 2006 studies.

Diabetes and Cholesterol

• Patients with diabetes and heart disease should aim for LDL (“bad”) cholesterol levels below 70 mg/dL, recommends the American Diabetes Association.
• A 2006 study suggested that high-dose atorvastatin (Lipitor) therapy may help these patients reduce their risk of heart attack and stroke by 25%.

Introduction

The two major forms of diabetes are type 1 (previously called insulin-dependent diabetes mellitus, IDDM, or juvenile-onset diabetes) and type 2 (previously called noninsulin-dependent diabetes mellitus, NIDDM, or maturity-onset diabetes).

Insulin

Both diabetes type 1 and type 2 share one central feature: elevated blood sugar (glucose) levels due to insufficiencies of insulin, a hormone produced by the pancreas. Insulin is a key regulator of the body's metabolism. It works in the following way:

• During and immediately after a meal the process of digestion breaks down carbohydrates into sugar molecules (including glucose) and proteins into amino acids.
• Right after the meal, glucose and amino acids are absorbed directly into the bloodstream, and blood glucose levels rise sharply.
• The rise in blood glucose levels signals important cells in the pancreas, called beta cells, to secrete insulin, which pours into the bloodstream. Within 10 minutes after a meal, insulin rises to its peak level.
• Insulin enables glucose and amino acids to enter cells in the body, particularly muscle and liver cells. Here, insulin and other hormones direct whether these nutrients will be burned for energy or stored for future use. (The brain and nervous system are not dependent on insulin; they regulate their glucose needs through other mechanisms.)
• When insulin levels are high, the liver stops producing glucose and stores it in other forms until the body needs it again.
• As blood glucose levels reach their peak, the pancreas reduces the production of insulin.
• About 2 to 4 hours after a meal, both blood glucose and insulin are at low levels, with insulin being slightly higher. The blood glucose levels are then referred to as fasting blood glucose concentrations.

The pancreas is located behind the liver and is where the hormone insulin is produced. Insulin is used by the body to store and utilize glucose.

Type 2 Diabetes

Type 2 diabetes is the most common form of diabetes, accounting for 90% of cases. An estimated 19 million Americans have type 2 diabetes and half are unaware they have it. The disease mechanisms in type 2 diabetes are not wholly known, but some experts suggest that it may involve the following three stages in most patients:

• The first stage in type 2 diabetes is the condition called insulin resistance. Although insulin can attach normally to receptors on liver and muscle cells, certain mechanisms prevent insulin from moving glucose (blood sugar) into these cells where it can be used. Most patients with type 2 diabetes produce variable, even normal or high, amounts of insulin. In the beginning, this amount is usually sufficient to overcome such resistance.
• Over time, the pancreas becomes unable to produce enough insulin to overcome resistance. In type 2 diabetes, the initial effect of this stage is usually an abnormal rise in blood sugar right after a meal (called postprandial hyperglycemia). This effect is now believed to be particularly damaging to the body.
• Eventually, the cycle of elevated glucose further impairs and possibly destroys beta cells, thereby stopping insulin production completely and causing full-blown diabetes. This is made evident by fasting hyperglycemia, in which elevated glucose levels are present most of the time.

Type 1 Diabetes

In type 1 diabetes, the disease process is more severe and onset is usually in childhood:

• Beta cells in the pancreas that produce insulin are gradually destroyed. Eventually insulin deficiency is absolute.
• Without insulin to move glucose into cells, blood glucose levels become excessively high, a condition known as hyperglycemia.
• Because the body cannot utilize the sugar, it spills over into the urine and is lost.
• Weakness, weight loss, and excessive hunger and thirst are among the consequences of this "starvation in the midst of plenty."
• Patients become dependent on administered insulin for survival. [See In-Depth Report # 9: Diabetes - type 1.]

Click the icon to see an image of the pancreas.

Diabetes Secondary to Other Conditions

Conditions that damage or destroy the pancreas, such as pancreatitis, pancreatic surgery, or certain industrial chemicals can cause diabetes. Polycystic ovaries are highly associated with diabetes. Certain drugs can also cause temporary diabetes, including corticosteroids, beta-blockers, and phenytoin. Rare genetic disorders (Klinefelter's syndrome, Huntington's chorea, Wolfram's syndrome, leprechaunism, Rabson-Mendenhall syndrome, lipoatrophic diabetes) and hormonal disorders (acromegaly, Cushing's syndrome, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma) are associated with or increase the risk for diabetes.

Causes

Type 2 diabetes is caused by a complicated interplay of genes, environment, insulin abnormalities, increased glucose production in the liver, increased fat breakdown, and possibly defective hormonal secretions in the intestine. The recent dramatic increase indicates that lifestyle factors (obesity and sedentary lifestyle) may be particularly important in triggering the genetic elements that cause this type of diabetes.

Insulin Abnormalities

The characteristic features of most patients with type 2 diabetes are:

• Insulin resistance in muscle cells
• Normal or even excessive levels of insulin (to compensate for this resistance), eventually followed by a drop in insulin production

In addition, researchers are trying to determine the factors that might promote insulin resistance:

• Both obesity and insulin resistance at different phases are marked by elevated levels of free fatty acids and the hormones resistin and leptin. It is not known yet if elevated levels are simply a product of obesity or play some causal role in diabetes.
• Insulin resistance is associated with a chronic low inflammatory response, which involves a number of immune factors, such as TGH-beta 1 and C-reactive protein. Such factors can cause damage over time and may be responsible for the association between insulin resistance and heart disease.

Genetic Factors

Genetic factors play an important role in type 2 diabetes, but the pattern is complicated, since both impairment of beta cell function and an abnormal response to insulin are involved. Researchers have identified a number of genetic factors that may be responsible for selected or more general cases of diabetes:

• Genes responsible for maturity-onset diabetes in youth (MODY), a rare genetic form of type 2 diabetes that develops only in Caucasian teenagers. (This is not the diabetes associated with obesity that is now being seen increasingly in young people.)
• A defective fatty-acid binding protein 2 (FABP2) gene, which may result in higher levels of unhealthy fat molecules (particularly triglycerides) that may be critical in the link between obesity and insulin resistance in some people with type 2 diabetes.
• Alterations in five genes that regulate beta cell and pancreas function may play an important role in inherited cases of type 2 diabetes.
• Variations in a gene that regulates a protein called calpain-10 affects insulin secretion and action and may play a role in type 2 diabetes in certain populations. There is some disagreement, however, about its significance. Calpains are enzymes that play a wide role in many essential cellular functions. Evidence suggests that genetic activation of these enzymes may be important in many aging-related diseases.
• Defective genes that regulate a molecule called peroxisome proliferator-activated receptor (PPAR) gamma may contribute to both type 2 diabetes and high blood pressure in some patients.
• A defective gene that reduces activity of a protective substance called beta3-adrenergic receptor, which is found in visceral fat cells (those occurring around the abdominal region), may be responsible for a slow-down in metabolism and an increase in obesity.

The Thrifty Gene. One theory suggests that some cases of type 2 diabetes and obesity are derived from normal genetic actions that were once important for survival. Some experts postulate the existence of a so-called "thrifty" gene, which regulates hormonal fluctuations to accommodate seasonal changes. In certain nomadic populations, hormones are released during seasons when food supplies have traditionally been low, which results in resistance to insulin and efficient fat storage. The process is reversed in seasons when food is readily available. Because modern industrialization has made high-carbohydrate and fatty foods available all year long, the gene no longer serves a useful function and is now harmful because fat, originally stored for famine situations, is not used up. Such a theory could help explain the high incidence of type 2 diabetes and obesity found in Pima people and other Native American tribes with nomadic histories and Western dietary habits.

Risk Factors

Over 19 million Americans have diabetes; up to 95% of these cases are type 2. In addition, 26% of Americans age 20 and older (and 40% of Americans age 65 and older) have impaired fasting glucose, a pre-diabetes condition that increases the risk for diabetes. According to a 2006 study, a total of 73 million Americans either have diabetes or are at risk of developing it.

Historically, type 2 diabetes usually developed after the age of 40, but it is now also increasing in children. Given the current epidemic of obesity, experts are now estimating that over a third of all people born in 2002 will eventually develop diabetes. Furthermore, the dramatic increase in diabetes is occurring worldwide as American lifestyles become global. Evidence strongly suggests that healthy lifestyles can prevent most cases of type 2 diabetes. People with pre-diabetes can substantially lower their risk by losing weight through diet and exercise.

Healthy adults age 45 and older should get tested for diabetes. Patients who are younger than age 45 and who are overweight or have other risk factors should also ask their doctors about testing. According to the National Institutes of Health, the following are major risk factors for diabetes and pre-diabetes:

• Age 45 or older
• Family history of diabetes
• Overweight· Inactive lifestyle (exercise less than 3 times a week)
• African American, Hispanic/Latin American, American Indian and Alaska Native, Asian American, or Pacific Islander ethnicity
• High blood pressure (140/90 mm/Hg or higher)
• HDL (“good”) cholesterol less than 35 mg/dL or triglyceride level 250 mg/dL or higher
• Have had diabetes during pregnancy (gestational diabetes) or have given birth to a baby that weighed more than 9 pounds
• Polycystic ovary syndrome (metabolic disorder that affects female reproductive system
• Acanthosis nigricans (dark, thickened skin around neck or armpits)
• History of disease of blood vessels to the heart, brain, or legs
• Diabetes test history of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)

Obesity and Metabolic Syndrome

Obesity is the number one risk factor for type 2 diabetes. It is estimated that 80 - 95% of the current dramatic increases in type 2 diabetes are due to obesity. Excess body fat appears to play a strong role in insulin resistance, but the way the fat is distributed is also significant. Weight concentrated around the abdomen and in the upper part of the body (apple-shaped) is associated with insulin resistance and diabetes, heart disease, high blood pressure, stroke, and unhealthy cholesterol levels. Waist circumferences greater than 35 inches in women and 40 inches in men have been specifically associated with a greater risk for heart disease and diabetes. (People with a "pear-shape" -- fat that settles around the hips and flank -- appear to have a lower risk for with these conditions.) However, obesity does not explain all cases of type 2 diabetes. It is also common among people in countries where weights tend to be low, such as Asia or India.

Metabolic Syndrome. A set of conditions referred to as metabolic syndrome (also called syndrome X) is a pre-diabetic condition that is significantly associated with heart disease and higher mortality rates from all causes. The syndrome consists of obesity marked by abdominal fat, unhealthy cholesterol levels, high blood pressure, and insulin resistance. A 2002 study estimated that nearly a quarter of the U.S. population now has this condition. Even worse, according to a 2003 study, nearly a million American teenagers have this syndrome.

Family History

Between 25 - 33% of patients with type 2 diabetes have family members with diabetes. Having a first-degree relative with the disease poses a 40% risk of developing diabetes. One study reported that people with diabetic family histories have a higher risk for developing the disease at an earlier stage and with more severe features. Because families share many lifestyle features (eating and exercise habits) it is difficult to determine when genetics or environment play the major role. When clusters of diabetes type 1 and 2 appear within families, genetic factors should be strongly suspected.

Ethnicity

The risk for type 2 diabetes varies among population groups. Diabetes also seems to pose higher or lower risks for specific complications among ethnic groups. Genetic and socioeconomic factors, or both, seem to be involved in some ethnic differences, but in most cases the observed increase in ethnic groups in Americans is due to changes in traditional lifestyles.

• African Americans. African American men have twice the risk of developing type 2 diabetes as Caucasian men. African Americans with diabetes are also at higher risk for amputations than Caucasians. This is most likely due to a higher incidence of high blood pressure and smoking as well as poorer health care in African Americans. Genetic factors may also play a role. For example, there is some evidence that African Americans process insulin in the liver differently from Caucasians, which may make them more susceptible to diabetes when other risk factors are present.
• Native Americans. The Pima tribe in Arizona has an incidence of type 2 diabetes that is 19 times higher than that of the white population. The risk for diabetic complications among young Pima adults is also very high. Other Native American tribes in North America are also at high risk for type 2 diabetes. The association between diet and diabetes among this population remains critical, however, in assessing the reason for their higher risk. For example, Pimas who live in Mexico exercise more and eat less fat (but consume more calories) than Pima tribes in Arizona. Mexican Pimas have a prevalence of diabetes of only 6%, while half of their Arizona Pima neighbors have diabetes.
• Hispanic Americans. The rate of type 2 diabetes is also very high among Mexican Americans, approximately double that for Caucasians. This group may also be at higher risk for heart problems than other ethnic groups with diabetes.
• Asian Americans. Overweight Asian Americans and Pacific Islanders are at increased risk for developing type 2 diabetes. The risk for some Asian ethnic groups, (such as Native Hawaiians and Filipinos), is twice that of Caucasians.

Smoking

Smoking increases the risk for diabetes. According to a 2006 study, smokers are more than twice as likely to develop diabetes as people who have never smoked. Another 2006 study found that exposure to second-hand cigarette smoke also increases the risk for diabetes in non-smokers

Low Birth Weight

Low birth weight is now a recognized risk factor for type 2 diabetes and heart disease in adulthood. The reasons are unclear, although studies suggest it may represent a genetic factor. Studies have observed that babies of fathers with type 2 diabetes and of women who later developed type 2 diabetes tend to weigh less than babies of parents without diabetes. Such studies suggest that some parents may have some specific gene that affects insulin factors, putting both themselves and their children at risk for future diabetes. Theoretically, such a gene might also affect insulin factors in the developing fetus, causing low birth weight. (Of note, mothers of very high-weight babies are also at risk for diabetes -- although in these cases it is most often associated with gestational diabetes.)

Diabetes in Children and Adolescents

Obesity-Related Type 2 Diabetes in Children. Until recent years, diabetes in children was almost always type 1 (an autoimmune disease). Between 1982 and 1994, however, the incidence of type 2 diabetes in children increased 10-fold. By 1996, a study reported that a third of all new diabetes cases in children were type 2. This increase parallels the rising epidemic in childhood obesity that has occurred both in the U.S. and worldwide, notably Europe and Japan. In some areas of Japan, type 2 diabetes has now become the dominant form of diabetes in children and adolescents. Obesity in children is also related to abnormalities in cholesterol, blood pressure, and insulin levels in adults. Administering glucose tolerance tests in overweight children may be helpful in identifying those at high risk for diabetes.

Maturity-Onset Diabetes in Caucasian Youth. Maturity-onset diabetes in youth (MODY) is a rare genetic form of type 2 diabetes that develops only in Caucasian teenagers. It accounts for 2 - 5% of type 2 cases. (This form of type 2 diabetes is not associated with obesity.)

Diabetes in the Pregnant Woman (Gestational Diabetes)

An estimated 5% of pregnant women develop a form of type 2 diabetes, usually temporary, in their third trimester called gestational diabetes.

The placenta provides the fetus with oxygen and nutrients and takes away waste such as carbon dioxide via the umbilical cord.

Other Medical Conditions

Polycystic Ovary Syndrome. Polycystic ovary syndrome (PCOS) is a condition that affects about 6% of women and results in the ovarian production of high amounts of androgens (male hormones), particularly testosterone. It appears to be an important cause of many menstrual disorders. Women with PCOS are at higher risk for insulin resistance, and about half of PCOS patients also have diabetes.

Click the icon to see an image of polycystic ovary syndrome.

Schizophrenia. While no definitive association has been established, research has suggested an increased background risk of diabetes among people with schizophrenia. In addition, many of the new generation of antipsychotic medications may elevate blood glucose levels. Patients taking antipsychotic medications, (such as clozapine, olanzapine, risperidone, aripiprazole, quetiapine fumarate, ziprasidone), should receive a baseline blood glucose level test and be monitored for any increases during therapy.

Hepatitis C. Patients with hepatitis C have a higher incidence of type 2 diabetes. The reasons for this are unclear.

Symptoms

Type 2 diabetes usually begins gradually and progresses slowly. Symptoms in adults include:

• Excessive thirst
• Increased urination
• Fatigue
• Blurred vision
• Weight loss
• In women, vaginal yeast infections or fungal infections under the breasts or in the groin
• Severe gum problems
• Itching
• Erectile dysfunction in men
• Unusual sensations, such as tingling or burning, in the extremities

Symptoms in children are often different:

• Most children are obese or overweight
• Increased urination is mild or even absent
• Many children develop a skin problem called acanthosis, which is characterized by velvety, dark colored patches of skin

Emergency Complications

Hypoglycemia

People with diabetes who need to intensively control glucose levels are at risk for low blood sugar (hypoglycemia). Hypoglycemia, also called insulin shock, develops if blood sugar levels fall below normal. It may also be caused by insufficient intake of food, excess exercise, or alcohol intake. The condition is usually manageable, but occasionally it can be severe or even life threatening, particularly if the patient fails to recognize the symptoms. Mild hypoglycemia is common among people with type 2 diabetes, but severe episodes are rare, even among those who are taking insulin. Still, all patients who intensively control blood sugar (glucose) levels should be aware of warning symptoms.

Risk Factors for Severe Hypoglycemia. People at highest risk for severe hypoglycemia are those who intensively control blood glucose and also have one or more of the following conditions:

• Long-term diabetes
• Less education on their condition
• A previous history of severe hypoglycemia
• Hypoglycemia unawareness

Hypoglycemia unawareness is a condition in which people become insensitive to hypoglycemic symptoms. It affects about 25% of patients who use insulin, nearly always people with type 1 diabetes. In such cases, hypoglycemia appears suddenly, without warning, and can escalate to a severe level. Even a single recent episode of hypoglycemia may make it more difficult to detect the next episode. With vigilant monitoring and by rigorously avoiding low blood glucose levels, patients can often regain the ability to sense the symptoms. However, even very careful testing may fail to detect a problem, particularly one that occurs during sleep.

Symptoms. Mild hypoglycemia symptoms usually occur at moderately low and easily correctable levels of blood glucose. They include:

• Sweating
• Trembling
• Hunger
• Rapid heartbeat

Severely low blood glucose levels can cause neurologic symptoms such as:

• Confusion
• Weakness
• Disorientation
• Combativeness
• In rare and worst cases, coma, seizure, and death

Preventive Measures. The following tips may help avoid hypoglycemia or prepare for attacks:

• Patients are at highest risk for hypoglycemia at night. Bedtime snacks may be helpful.
• Patients who intensively control their blood sugar should monitor blood levels as often as possible, four times or more per day. This is particularly important for patients with hypoglycemia unawareness.
• In adults, it is also particularly critical to monitor blood glucose levels before driving, when hypoglycemia can be very hazardous.
• Patients who use medications that put them at risk for hypoglycemia should always carry hard candy, juice, sugar packets, or commercially available glucose substitutes designed for individuals with diabetes.

Family and friends should be aware of the symptoms and be prepared:

• If the patient is helpless (but not unconscious), family or friends should administer three to five pieces of hard candy, two to three packets of sugar, half a cup (four ounces) of fruit juice, or a commercially available glucose solution.
• If there is inadequate response within 15 minutes, additional oral sugar should be provided or the patient should receive emergency medical treatment, including intravenous administration of glucose.
• Family members and friends can learn to inject glucagon, a hormone, which, in contrast to insulin, raises blood glucose.

Click the icon to see a glucagon kit.

Diabetic Ketoacidosis (DKA)

Diabetic ketoacidosis (DKA) is a life-threatening complication caused by insulin depletion. Until recently, it was a complication almost exclusively of type 1 diabetes. In such cases, it is nearly always due to noncompliance with insulin treatments. However, DKA is being reported increasingly in type 2 diabetes, especially among Hispanic and African Americans. It is not clear what causes total insulin depletion in these patients. Researchers are trying to learn which individuals are at particular risk.

Diabetic ketoacidosis often develop as follows:

• The process is usually triggered in insulin-deficient patients by a stressful event, most often pneumonia or urinary tract infections. Other triggers include alcohol abuse, physical injury, pulmonary embolism, heart attacks, or other illnesses.
• Severely low insulin levels cause excessive amounts of glucose in the bloodstream (hyperglycemia).
• Fat breakdown then accelerates and increases the production of fatty acids.
• These fatty acids are converted into chemicals called ketone bodies, which are toxic at high levels.

Symptoms and complications may include:

• Nausea and vomiting
• Abnormally deep and rapid breathing with frequent sighing
• Rapid heartbeat
• If the condition persists, coma and, eventually, death, may occur; however, over the past 20 years, death from DKA has decreased to about 2% of all cases
• Other serious complications from DKA include aspiration pneumonia and adult respiratory distress syndrome

Life-saving treatment uses rapid rehydration with a saline solution followed by low-dose insulin and potassium replacement.

Screening Tests

There are no clear-cut guidelines for when to screen for diabetes. Some experts recommend that everyone over age 45 be tested regularly for diabetes, although others do not feel this necessary in people without symptoms or risk factors. In fact, early screening may identify some people with impaired glucose levels that would eventually normalize. Such people might be treated unnecessarily with medications that pose a risk for high blood sugar (hypoglycemia).

Still, given the risk for serious complications with diabetes and the potential value of early treatments, most experts recommend that all adults over 45 be screened and that younger adults be screened if they have one or more of the following conditions:

• A weight that is 20% more than ideal body weight
• Risk factors for heart disease (high blood pressure, unhealthy cholesterol levels -- especially for patients with low HDL cholesterol and high triglyceride levels
• A close relative with diabetes
• A high-risk ethnic group background
• In women, having delivered a baby weighing over 9 pounds or having a history of gestational diabetes

Some experts recommend that children over age 10 should be tested for type 2 diabetes (even if they have no symptoms), if they are overweight and have at least two of the above mentioned risk factors.

Testing for Diabetes

Fasting Plasma Glucose. The fasting plasma glucose (FPG) test is the standard test for diabetes. It is a simple blood test taken after 8 hours of fasting. Results indicate:

• FPG levels are considered normal up to 100 mg/dL (or 5.5 mmol/L).
• Levels between 100 and 125 mg/dL (5.5 to 7.0 mmol/L) are referred to as impaired fasting glucose or pre-diabetes. These levels are considered to be risk factors for type 2 diabetes and its complications.
• Diabetes is diagnosed when FPG levels are 126 mg/dL (7.0 mmol/L) or higher.

The FPG test is not always reliable, so a repeat test is recommended if the initial test suggests the presence of diabetes, or if the test is normal in people who have symptoms or risk factors for diabetes. For example, people who take the test in the afternoon and show normal results may actually have abnormal levels that would be revealed if they were tested in the morning.

A 2005 study suggested that even people with FPG levels in the high end of the normal range (high 90s) may be at increased risk for developing type 2 diabetes. Obesity further increases this risk. Patients with FPG levels in the upper 90s should strive to exercise and lose weight to help lower their FPG levels.

Glucose Tolerance Test. The oral glucose tolerance test (OGTT) is more complex than the FPG and may overdiagnose diabetes in people who do not have it. Some experts recommend it as a follow-up after FPG, if the latter test results are normal but the patient has symptoms or risk factors of diabetes. The test uses the following procedures:

• It first uses an FPG test.
• A blood test is then taken 2 hours later after drinking a special glucose solution.

The following results suggest different conditions:

• OGTT levels are considered normal up to 140 mg/dL.
• Levels between 140 mg/dL and 199 mg/dL are referred to as impaired glucose tolerance or pre-diabetes.
• Diabetes is diagnosed when OGTT levels are 200 mg/dL or higher.

Both the FPG and OGTT require that the patient not eat for at least 8 hours prior to the test.

Test for Glycated Hemoglobin. Tests for blood levels of glycated hemoglobin, also known as hemoglobin A1c (HbA1c) are not currently used for an initial diagnosis, but they are useful for determining the severity of diabetes. Some experts think this test can help predict complications in people who have FPG levels between 110 and 139, which are above normal but do not indicate full-blown diabetes.

The basis for its use as a diagnostic measurement in diabetes is as follows:

• Hemoglobin is a protein molecule found in red blood cells. When glucose binds to it, the hemoglobin becomes modified, a process called glycosylation.
• Glycosylation affects a number of proteins, and elevated levels of glycolated hemoglobin are strongly associated with complications of diabetes.
• A glycated hemoglobin level of 1% above normal range identifies diabetes in 98% of patients. Normal HbA1c levels do not necessarily rule out diabetes, but if diabetes is present and levels are normal, the risk for complications is low.

The test is not affected by food intake so it can be taken at any time. A home test has been developed that might make it easier to measure HbA1c. In general, measurements suggest the following:

• Normal HbA1c levels should be below 7%.
• Levels of 11 - 12% glycolated hemoglobin indicate poor control of carbohydrates. High levels are also markers for kidney trouble.

Testing for Insulin Resistance. Investigators hope that some day a simple test for insulin resistance will be available that will be able to identify people at risk for diabetes. The presence of insulin resistance may also be a predictor of heart disease, independent of the presence of diabetes. Some research suggests that measuring insulin and triglyceride levels during a fasting period may predict a person's sensitivity to insulin.

Screening Tests for Complications

Screening for Heart Disease. All patients with diabetes should be tested for hypertension and unhealthy cholesterol and lipid levels and given an electrocardiogram. For cholesterol, people with diabetes should aim for LDL levels below 100 mg/dL, HDL levels over 50 mg/dL, and triglyceride levels below 150 mg/dL. Blood pressure goals should be 130/80 mmHg or lower. Other tests may be needed in patients with signs of heart disease.

The electrocardiogram (ECG, EKG) is used extensively in the diagnosis of heart disease, from congenital heart disease in infants to myocardial infarction and myocarditis in adults. Several different types of electrocardiogram exist.

Screening for Kidney Damage. The earliest manifestation of kidney damage is microalbuminuria, in which tiny amounts (30 to 300 mg per day) of protein called albumin are found in the urine. About 20% of type 2 patients show evidence of microalbuminuria upon diagnosis of diabetes. (However, only a small percentage of people with type 2 diabetes eventually develop kidney disease.) Microalbuminuria typically shows up in patients with type 2 diabetes who have high blood pressure.

The American Diabetes Association recommends that people with diabetes receive an annual microalbuminuria urine test. Patients should also have their blood creatinine tested at least once a year. Creatinine is a waste product that is removed from the blood by the kidneys. High levels of creatinine may indicate kidney damage. A doctor uses the results from a creatinine blood test to calculate the glomerular filtration rate (GFR). The GFR is an indicator of kidney function; it estimates how well the kidneys are cleansing the blood.

Screening for Thyroid Abnormalities. Thyroid function tests should be administered.

Treatment

The major treatment goals for people with type 2 diabetes are:

• Treat all conditions that place the patients at risk for heart disease and stroke, which are the major killers of people with type 2 diabetes.
• Control blood glucose levels. The goal is to achieve fasting blood glucose levels of less than 110 mg/dL and glycolated hemoglobin (HbA1c) levels of less than 7%. The objective is to reduce complications in small blood vessels and the nerve damage associated with diabetes.

An intensive multi-pronged approach is critical for reducing complications and improving survival rates in patients with diabetes. Intensive therapy includes:

• Healthy lifestyle changes: Regular exercise; heart-healthy diet; quitting smoking.
• Controlling blood sugar levels. Monitor blood sugar and hemoglobin A1C levels. Oral anti-hyperglycemic drugs such as metformin are first-line drug treatments. Insulin may eventually be needed.
• Heart-protective drugs. These medications include various drugs to control high blood pressure (ACE inhibitors, diuretics, others) and cholesterol (statins, fibrates). Controlling high blood pressure is a proven factor in reducing mortality rates. Aspirin may help prevent blood clots and heart attack.

Treating Special Populations

Different goals may be required for specific individuals, including pregnant women, very old and very young people, and those with accompanying serious medical conditions. Treating children with type 2 diabetes depends on the severity of the condition at diagnosis. Metformin is now approved for children. Until recently, only insulin was approved for treating children with diabetes.

Lifestyle Changes

A simple heart-healthy diet with weight control and exercise may be sufficient for some people with type 2 diabetes. Some patients may be able to control their blood sugar with lifestyle measures and not need medication. Even for patients who do need to take drugs, lifestyle plays an essential role in controlling diabetes. Lifestyle changes can be difficult to initiate and sustain, however. Patients should surround themselves with a solid network of doctors, dietitians, family, and friends who understand both their condition and their needs.

Heart-Healthy Diet

Although there are many major dietary approaches for protecting health, experts generally agree on the following recommendations for heart protection:

• Choose fiber-rich food (whole grains, legumes, nuts) as the main source of carbohydrates, along with a high intake of fresh fruits and vegetables. Walnuts in particular have cholesterol-lowering properties and are a good source of antioxidants and alpha-linolenic acid.
• Avoid saturated fats (found mostly in animal products) and trans fatty acids (found in hydrogenated fats and many commercial products and fast foods). Choose unsaturated fats (particularly omega-3 fatty acids found in vegetable and fish oils).
• In selecting proteins, choose soy protein, poultry, and fish over meat. A 2006 study found that soy does not help improve cholesterol. However, experts still recommend it as a heart healthy food choice.
• Weight control, quitting smoking, and exercise are essential companions of any diet program.

[For detailed information, see In-Depth Report #43: Heart-healthy diet.]

Diabetes Diet

There is no such thing as a single diabetes diet. Patients should meet with a professional dietitian to plan an individualized diet within the general guidelines that takes into consideration their own health needs.

Healthy eating habits along with good control of blood glucose are the basic goals, and several good dietary methods are available to meet them. General dietary guidelines for diabetes recommend:

• Carbohydrates should provide 45 – 65% of total daily calories. The type and amount of carbohydrate are both important. Best choices are vegetables, fruits, beans, and whole grains. These foods are also high in fiber. Patients with diabetes should monitor their carbohydrate intake either through carbohydrate counting or meal planning exchange lists.
• Fats should provide 25 – 35% of daily calories. Monounsaturated (olive, peanut, canola oils; avocados; nuts) and omega-3 polyunsaturated (fish, flaxseed oil, walnuts) fats are the best types. Limit saturated fat (red meat, butter) to less than 7% of daily calories. Choose nonfat or low-fat dairy instead of whole milk products. Limit trans-fats (hydrogenated fat found in snack foods, fried foods, commercially baked goods) to less than 1% of total calories.
• Protein should provide 12 – 20% of daily calories, although this may vary depending on a patient’s individual health requirements. Patients with kidney disease should limit protein intake to less than 10% of calories. Fish, soy, and poultry are better protein choices than red meat.

[For detailed information, including diabetic exchange lists and carbohydrate counting, see In-Depth Report #42: Diabetes diet.]

Weight Loss

Being overweight is the number one risk factor for type 2 diabetes. Even modest weight loss can help prevent type 2 diabetes from developing. It can also help control or even stop progression of type 2 diabetes in people with the condition and reduce risk factors for heart disease. Patients should aim to lose weight if their body mass index (BMI) is 25 – 29 (overweight) or higher (obese).

The American Diabetes Association recommends that patients aim for a small but consistent weight loss of 1 to 2 pounds per week. Most patients should follow a diet that supplies at least 1,000–1,200 kcal/day for women and 1,200–1,600 kcal/day for men.

Unfortunately, not only is weight loss difficult to sustain, but many of the oral medications used in type 2 diabetes cause weight gain as a side effect. For obese patients who cannot control weight using dietary measures alone, weight-loss drugs, such as orlistat (Xenical) or sibutramine (Meridia), may be helpful. Orlistat may have specific benefits for people with diabetes. It may not only help achieve weight but also improve glucose, cholesterol, and lipid levels. A new weight-loss drug called rimonabant (Acomplia) has been approved in Europe and is being considered for approval in the United States. [For detailed information, see In-Depth Report #53: Obesity.]

Exercise

Sedentary habits, especially TV watching, are associated with significantly higher risks for obesity and type 2 diabetes. Regular exercise, even of moderate intensity (such as brisk walking), improves insulin sensitivity and may play a significant role in preventing type 2 diabetes -- regardless of weight loss. An important study reported a 58% lower risk for type 2 diabetes in adults who performed moderate exercise for as little as 2.5 hours a week.

Aerobic Exercise. Aerobic exercise has significant and particular benefits for people with diabetes. Regular aerobic exercise, even of moderate intensity, improves insulin sensitivity. People with diabetes are at particular risk for heart disease, so the heart-protective effects of aerobic exercise are especially important. Moderate exercise protects the heart in people with type 2 diabetes, even if they have no risk factors for heart disease other than diabetes itself. (In general, patients with diabetes should aim for a heart rate target of 55 - 75% of their maximum heart rate when exercising.)

Strength Training. Strength training, which increases muscle and reduces fat, may also be helpful for people with diabetes.

Exercise Precautions. The following are precautions for all people with diabetes, both type 1 and type 2:

• Because people with diabetes are at higher than average risk for heart disease, they should always check with their doctors before undertaking vigorous exercise. For fastest results, frequent high-intensity (not high-impact) exercises are best for people who are cleared by their doctors. For people who have been sedentary or have other medical problems, lower-intensity exercises are recommended.
• Strenuous strength training or high-impact exercise is not recommended for people with uncontrolled diabetes. Such exercises can strain weakened blood vessels in the eyes of patients with retinopathy. High-impact exercise may also injure blood vessels in the feet.

Patients who are taking medications that lower blood glucose, particularly insulin, should take special precautions before embarking on a workout program:

• Monitor glucose levels before, during, and after workouts (glucose levels swing dramatically during exercise)
• Avoid exercise if glucose levels are above 300 mg/dL or under 100 mg/dL
• Inject insulin in sites away from the muscles used during exercise; this can help avoid hypoglycemia
• Drink plenty of fluids before and during exercise; avoid alcohol, which increases the risk of hypoglycemia
• Insulin-dependent athletes may need to decrease insulin doses or take in more carbohydrates prior to exercise, but may need to take an extra dose of insulin after exercise (stress hormones released during exercise may increase blood glucose levels)
• Wear good, protective footwear to help avoid injuries and wounds to the feet
• Some blood pressure drugs can interfere with exercise capacity. Patients who use blood pressure medication should consult their doctors on how to balance medications and exercise. Patients with high blood pressure should also aim to breathe as normally as possible during exercise. Holding the breath can increase blood pressure.

[For more information, see In-Depth Report #29: Exercise.]

Monitoring Glucose (Blood Sugar) and Hemoglobin A1C

According to the American Diabetes Association, people with diabetes should aim for preprandial (before eating) plasma glucose levels of 90 to 130 mg/dL and postprandial (after eating) plasma glucose levels less than 180 mg/dL. Hemoglobin A1C levels should be less than 7%.

Measuring Blood Glucose. In patients being treated with insulin or insulin-producing or sensitizing drugs, it is important to monitor blood glucose levels carefully to avoid hypoglycemia. Different goals may be required for specific individuals, including pregnant women, very old and very young people, and those with accompanying serious medical conditions.

Blood glucose levels are generally more stable in type 2 diabetes than in type 1, so experts usually recommend measuring blood levels only once or twice a day. For patients who have become insulin-dependent, more intensive monitoring is necessary. Usually, a drop of blood obtained by pricking the finger is applied to a chemically treated strip. The glucose level is read on a standard meter or a small, portable digital display device.

Measuring Hemoglobin A1C. Hemoglobin A1c (HbA1c or HA1c), also called glycated hemoglobin, is measured periodically to determine the average blood-sugar level over the life span of the red blood cell, which is about 8 to 10 weeks. Home tests (DRx, Metrika A1c Now) are available for measuring HA1c that may allow even better monitoring of glucose levels. Patients should keep a chart of their HA1c levels to track any changes that may occur over time.

To monitor the amount of glucose within the blood a person with diabetes should test their blood regularly. The procedure is quite simple and can often be done at home.

Improving Sleep

Some research suggests that not getting enough sleep may impair insulin use and increase the risk for obesity. More research is needed, but it is always wise to improve sleep habits.

Medications

The American Heart Association now recommends that patients should aim for the following test results for intensive control of glucose levels:

• Fasting plasma glucose concentrations below 110 mg/dL.
• Glycolated hemoglobin (HbA1c) levels of less than 7%. Controlling HbA1c is the most important factor for reducing the risk of complications in patients with diabetes. According to one 2000 study, a 1% reduction in people with elevated glycolated hemoglobin levels lowers the risk for complications by 21%.

Evidence clearly supports strict glycemic control for reducing complications in the nervous system and blood vessels that occur in both type 1 and type 2 diabetes. Research shows that tight glucose control can help prevent heart disease and complications.

It may be difficult for patients with type 2 diabetes to control their blood sugar levels--particularly if they are overweight. Metformin (Glucophage), an oral anti-hypoglycemic drug, helps control blood glucose levels, does not produce weight gain, and also has heart benefits. In comparison with other diabetic drugs, including insulin, it is the only drug proven to improve survival rates. A number of other oral drugs are also available that are beneficial, alone or in combinations. Insulin therapy may eventually be required when natural insulin reserves become depleted.

Managing risk factors for heart disease and stroke, particularly strict control of blood pressure, may be more important for improving survival than strict control of blood glucose levels for some patients. Such goals also seem to be more attainable for many patients with type 2 diabetes.

Oral Anti-Hyperglycemic Drugs. Many oral anti-hyperglycemic drugs are available to help patients with type 2 diabetes control their blood sugar levels. Most of these drugs are aimed at using or increasing sensitivity to the patient's own natural stores of insulin. Metformin is the only drug to date that achieves lower mortality rates:

• Biguanides (metformin). Metformin increases tissue sensitivity to available insulin. Metformin also has beneficial effects on cholesterol, blood pressure, and clotting factors. It does not cause weight gain or hypoglycemia. Metformin produces lower mortality rates than other drugs, including insulin, and should be considered as first-line therapy for most patients with type 2 diabetes.
• Sulfonylureas (glyburide, glipizide, and glimepiride). Stimulate insulin secretion.
• Meglitinides (repaglinide, nateglinide). Stimulate insulin secretion. These newer drugs are better than sulfonylureas in controlling glucose spikes after meals.
• Thiazolidinediones (pioglitazone and rosiglitazone). Reduce insulin resistance. These drugs improve cholesterol levels and may reduce the risk for blood clots. However, they can cause swelling from fluid build-up, which can worsen heart failure or even possibly precipitate it. They also may injure the liver.
• Alpha-glucosidase inhibitors (acarbose and miglitol). Slow intestinal absorption of carbohydrates. Have only modest effects on diabetes and have gastrointestinal side effects.

Combinations of these drugs, particularly with metformin, are often used to increase effectiveness. For example, combinations of rosiglitazone and metformin (Avandamet) and glyburide and metformin (Glucophage) are proving to be very effective. Metformin may be particularly helpful for patients with unhealthy cholesterol levels and poor control of their blood sugar levels. Some experts recommend a metformin combination as first-line treatment.

Injectable Anti-Hyperglycemic Drugs. In 2005, the FDA approved two new injectable drugs to help patients improve blood sugar control:

• Exenatide (Byetta). Exenatide is the first drug in a new class of drugs called incretin mimetics. It lowers blood glucose levels by increasing insulin secretion. Exenatide is used in combination with oral antihyperglycemics such as metformin or a sulfonylurea drug.
• Pramlintide (Symlin). Pramlintide is a first-in-class drug that is a synthetic form of the hormone amylin. The drug is meant for patients who take insulin but still have difficulty controlling their glucose levels.

Insulin Replacement. Insulin replacement may be required when natural insulin reserves are depleted. It is typically started in combination with an oral drug. Eventually, some patients may need to go on full insulin replacement. In addition to injectable forms of insulin, an inhaled insulin product (Exubera) is now available.

Biguanides (Metformin)

Metformin (Glucophage) is a biguanide, which works by reducing glucose production in the liver and by making tissues more sensitive to insulin. It is now considered by many experts to be the first choice for most type 2 patients who are insulin resistant, particularly if they are overweight. Metformin achieves lower mortality rates from diabetes and all causes than other drugs. In one comparison study, it achieved the lowest mortality rates (8%) compared to insulin (28%), a sulfonylurea (16%), and a thiazolidinedione (14%). Combinations with insulin-secreting drugs, other insulin-sensitizing drugs, or insulin itself are particularly effective.

Metformin does not cause hypoglycemia or add weight, so it is particularly well-suited for obese patients with type 2 diabetes. (In some studies, in fact, patients lost weight.) Metformin also appears to have beneficial effects on cholesterol and lipid levels and may help protect the heart. Some research has suggested that it significantly reduces the risk for heart attack. It is also the first choice for children who need oral drugs and is proving to be very effective for women with polycystic ovary syndrome and insulin resistance.

Side Effects. Side effects include:

• A metallic taste
• Gastrointestinal problems, including nausea, and diarrhea
• Interference with absorption of vitamin B12 and folic acid, (which are important for protection against heart disease)
• Rare reports of lactic acidosis, a potentially life-threatening condition, particularly in people with risk factors for it. Major studies, however, found no greater risk with metformin than with any of the other drugs used for type 2 diabetes.

Certain people should not use this drug, including anyone with heart failure or kidney or liver disease. It is rarely suitable for adults over age 80.

Sulfonylureas

Sulfonylureas are oral drugs that stimulate the pancreas to release insulin. They are also first-line oral drugs. For adequate control of blood glucose levels, the drugs should only be taken 20 - 30 minutes before a meal. A number of brands are available, including chlorpropamide (Diabinese), tolazamide (Tolinase), acetohexamide (Dymelor), glipizide (Glucotrol), tolbutamide (Orinase), and glimepiride (Amaryl).

Most patients can take sulfonylureas for 7 to 10 years before they lose effectiveness. Combinations with small amounts of insulin or with other oral anti-hyperglycemic drugs (such as metformin or a thiazolidinedione) may extend their benefits. In fact, a combination of glyburide and metformin in one pill (Glucovance) is now available. Glucovance may be particularly beneficial for patients with unhealthy cholesterol levels and poor control of their blood sugar levels. Some doctors recommend the combination as first-line treatment.

An encouraging 2000 study of patients with severe type 2 diabetes reporting that combinations of insulin with either chlorpropamide or glipizide (two different sulfonylureas) achieved better glucose control over the long term than insulin alone.

Side Effects and Complications. In general, sulfonylureas should not be used by women who are pregnant or nursing or by individuals who are allergic to sulfa drugs. Side effects may include:

• Weight gain (some sulfonylureas, such as glimepiride, may produce less weight gain than others)
• Water retention
• Although sulfonylureas pose a lower risk for hypoglycemia than insulin does, the hypoglycemia produced by sulfonylureas may be prolonged and dangerous. The newer sulfonylureas, such as glimipiride, have much less risk of hypoglycemia than older sulfonylureas.
• Some sulfonylureas may pose a slight risk for cardiac events.

Sulfonylureas interact with many other drugs, and patients should be sure to inform their doctor of any medications they are taking, including alternative or over-the-counter drugs.

Meglitinides

Meglitinides stimulate beta cells to produce insulin. They include repaglinide (Prandin), nateglinide (Starlix), and mitiglinide. These drugs are rapidly metabolized and short-acting. If taken before every meal, they actually mimic the normal effects of insulin after eating. Patients, then, can vary their meal times with this drug. (Nateglinide appears to work more quickly and is shorter-acting than repaglinide). These drugs may be particularly helpful in combination with metformin or other drugs. They may also be a good choice for people with potential kidney problems.

Side Effects. Side effects include diarrhea and headache. As with the sulfonylureas, repaglinide poses a slightly increased risk for cardiac events. (Newer drugs, such as nateglinide, may pose less of a risk.) People with heart failure or liver disease should use them with caution and be monitored.

Thiazolidinedione

Thiazolidinediones include rosiglitazone (Avandia) and pioglitazone (Actos). They improve insulin sensitivity by activating certain genes involved in fat synthesis and carbohydrate metabolism. These drugs are usually taken once or twice per day; however, it may take several days before the patient notices any results from them and several weeks before they take full effect. Thiazolidinediones are usually taken in combination with other oral drugs or insulin.

In some studies, thiazolidinediones have produced favorable effects on the heart, including reducing blood pressure and preventing blood clots. A 2006 study found that pioglitazone reduced the risk of heart attack, stroke, and acute coronary syndrome. Research presented at the 2005 American Heart Association meeting indicated that pioglitazone may be especially helpful in preventing a second heart attack for patients with type 2 diabetes who have suffered a previous heart attack. Evidence suggests that pioglitazone is superior to rosiglitazone in improving triglyceride and HDL levels. In addition, some evidence suggests that these drugs may preserve beta-cell function and, if used early, may help prevent progression of diabetes. This effect has not been observed with other oral drugs.

Side Effects. Thiazolidinediones can have serious side effects. They tend to increase fluid-build up, which can cause or worsen heart failure in some patients. Combinations with insulin increase the risk. They should not be used by patients with existing heart failure and should be used cautiously in those with risk factors for heart failure. They may cause more weight gain than other antidiabetic medications or insulin. Any patient who experiences sudden weight gain, water retention, or shortness of breath should immediately call their doctors.

There have been rare reports of rosiglitazone causing or worsening diabetic macular edema. This is an eye condition associated with diabetic retinopathy that causes swelling in the macular area of the retina. Symptoms include blurred vision and decreased color sensitivity. Most patients who had this side effect also had swelling in the feet and legs (peripheral edema). The condition resolved or improved when patients stopped taking the drug.

Thiazolidinediones can also cause liver damage. Patients who take these drugs should have their liver enzymes checked regularly.

Alpha-Glucosidase Inhibitors

Alpha-glucosidase inhibitors, including acarbose (Precose, Glucobay) and miglitol (Glyset) reduce glucose levels by interfering with the absorption of starch in the small intestine. Acarbose tends to lower insulin levels after meals, a particular advantage, since higher levels of insulin after meals are associated with an increased risk for heart disease. Some evidence suggests that early use of these drugs may reduce heart risk factors, including high blood pressure. A 2002 study of acarbose suggested that these drugs may even delay the development of type 2 diabetes in high-risk individuals. Alpha-glucosidase inhibitors are not as effective alone as other single oral drugs, but combinations, such as with metformin, insulin, or a sulfonylurea, increase their effectiveness.

Side Effects. These medications need to be taken with meals. Unfortunately, about a third of patients stop taking the drug because of flatulence and diarrhea, particularly after high-carbohydrate meals. The drug may also interfere with iron absorption.

Alpha-glucosidase inhibitors do not cause hypoglycemia when used alone, but combinations with other drugs do. In such cases, it is important that the patient receive a solution that contains glucose or lactose, not table sugar. This is because acarbose inhibits the breakdown of complex sugar and starches, which includes table sugar.

Incretin Mimetics (Exenatide)

Incretin mimetics belong to a new class of drugs that help improve blood sugar control. In 2005, the FDA approved exenatide (Byetta), the first of these drugs. Exenatide is an injectable drug that is a synthetic version of the hormone found in the saliva of the Gila monster, a venomous desert lizard. Exenatide is injected twice a day, 1 hour before morning and evening meals. It is prescribed for patients with type 2 diabetes who have not been able to control their glucose with metformin or a sulfonylurea drug. It can be taken in combination with these drugs or alone.

Side Effects. Exenatide stimulates insulin secretion only when blood sugar levels are high and so has less risk for causing low blood sugar (hypoglycemia) when it is taken alone. However, the risk for hypoglycemia increases when exenatide is taken along with a sulfonylurea drug. There does not appear to be a risk for hypoglycemia when exenatide is used along with metformin. Other side effects may include nausea, vomiting, and diarrhea.

A 2005 study compared exenatide to insulin for improving glucose control in patients taking metformin and a sulfonylurea. Both insulin and exenatide worked well for glucose control. Patients lost weight with exenatide and gained weight with insulin. However, patients who received exenatide had significantly more problems with nausea, vomiting, and diarrhea than those who received insulin.

Insulin Replacement

Insulin replacement is the best treatment for strict control of blood glucose and is required once natural insulin reserves are depleted. Because type 2 diabetes is progressive, most patients eventually require insulin, typically starting it in combination with an oral anti-hyperglycemic drug. However, when a single oral drug fails to control blood sugar it is not clear whether it is better to add insulin replacement or to add a second or third oral drug.

Some experts advocate using insulin as early as possible for optimal control. However, in patients who still have insulin reserves, there is concern that extra natural insulin will have adverse effects. Low blood sugar (hypoglycemia) and weight gain are the main side effects of insulin therapy. Some research suggests that insulin may also cause heart complications. A 2006 study reported that insulin therapy increases the risk of developing high blood pressure (hypertension). It is still not clear if insulin replacement improves survival rates compared to oral drugs, notably metformin.

One approach is to combine insulin with metformin, which achieves blood glucose control without added weight gain. Newer forms of insulin analogues, such as glargine, may be especially helpful for people with type 2 diabetes and reduce the risk for hypoglycemia.

Fortunately, studies to date have not reported any adverse cardiac effects in patients with type 2 diabetes who take insulin. In fact, insulin has been associated, in some cases, with improvement in heart risk factors. More research is needed to clarify these important issues.

Forms of Insulin. Experts are working toward administering insulin so that it closely mimics the daily pattern of insulin, which responds to blood sugar levels by surging after meals and then falling to a steady base level afterward. To achieve this, doctors may use two insulin types:

• Fast-Acting Insulins for Surges. Insulin lispro and aspart are fast-acting insulins. They mimic insulin's response to food intake. They are taken before meals, and their short action reduces the risk for hypoglycemia afterward.
• Slower Insulins for Base Levels. Intermediate forms (including NPH and lente) and long-acting forms (glargine, ultralente) were developed to provide a steady level of insulin throughout the day. To date, glargine (Lantus) seems to be the most successful in achieving this goal in type 2 diabetes.

In 2006, the FDA approved the first non-injected form of insulin. Exubera is an inhaled form of insulin. It is approved for adults but should not be used by patients who smoke or have quit smoking within the past 6 months. Patients with asthma, bronchitis, or emphysema should also not use inhaled insulin. Clinical trials indicate that Exubera can provide sustained blood sugar control over a 2-year period. Patients in the trials who took Exubera experienced half as much weight gain as those who took injected insulin. Scientists are also developing other types of non-injected insulin, including spray formulas.

In a 2005 trial, Exubera improved blood sugar control when it was added to or substituted for combination oral drug therapy (sulphonylurea and thiazolidenedione). However, as with other forms of insulin, Exubera caused more hypoglycemia and weight gain than the oral anti-hyperglycemic drugs.

Pramlintide (Symlin) is a new type of injectable drug that may help patients who take insulin but still need better blood sugar control. The FDA approved this drug in 2005. Pramlintide is a synthetic form of amylin, a hormone that is related to insulin. Pramlintide is used in combination with insulin to lower blood sugar levels in the 3 hours after meals.

[For more detailed information on insulin therapy, see In-Depth Report #9: Diabetes - type 1.]

Investigational Drugs

Gliptins. Gliptins are a new class of drug that is showing promise for improving blood sugar control. These drugs raise the levels of glucagons-like-peptide-1 (GLP-1), a hormone that helps the pancreas produce more insulin but prevents the liver from producing sugar. Scientists hope that gliptins may eventually replace sulfonylurea drugs. Several types of gliptins are currently in late-stage clinical trials. Vildagliptin (Galvus) and sitagliptin (Januvia) are classified as dipeptidyl peptidase-4 (DPP-4) inhibitors. Liraglutide is a GLP-1 analog. Researchers are investigating these drugs in combination with metformin or thiazolidinediones.

Long-Term Complications

Patients with diabetes have higher mortality rates than nondiabetics regardless of sex, age, or other factors. Heart disease and stroke are the leading causes of death in these patients. All lifestyle and medical efforts should be made to reduce the risk for these conditions.

People with type 2 diabetes are also at risk for nerve damage (neuropathy) and abnormalities in both small and large blood vessels (vascular injuries) that occur as part of the diabetic disease process. Such abnormalities produce complications over time in many organs and structures in the body. Although these complications tend to be more serious in type 1 diabetes, they still are of concern in type 2 diabetes. All people with diabetes should aim for fasting blood glucose levels of less than 110 mg/dL and hemoglobin A1C of less than 7%.

There are two important approaches to preventing complications from diabetes:

• Intensive control of blood glucose and keeping glycosylated hemoglobin (HbA1c) levels below 7%. Tight blood glucose and HbA1c control can prevent complications due to vascular (blood vessel) abnormalities and nerve damage (neuropathy) that can cause major damage to organs, including the eyes, kidneys, and heart.
• Managing risk factors for heart disease. Control of blood glucose also helps the heart, but its benefits occur over time. It is very important that people with diabetes control blood pressure, cholesterol levels, and other factors associated with heart disease.

Heart Disease

Heart attacks account for 60% and strokes for 25% of deaths in patients with diabetes. Diabetes affects the heart in many ways:

• Both type 1 and 2 diabetes speed the progression of atherosclerosis (hardening of the arteries). Diabetes can adversely affect blood lipid levels by lowering HDL ("good cholesterol") and increasing triglycerides. This can lead to coronary artery disease, heart attack, or stroke.
• In type 1 diabetes, high blood pressure usually develops if the kidneys become damaged. High blood pressure (hypertension) is another major cause of heart attack, stroke, and heart failure. Children with diabetes are also at risk for hypertension.
• Impaired nerve function (neuropathy) associated with diabetes also causes heart abnormalities. Some experts estimate that the mortality rates from neuropathy-related heart conditions range between 15 - 53%.

Tight blood sugar control may help protect blood vessels and reduce the risk for blood clotting. It is still not known whether intensive control will have a major protective effect on the heart, however. People with diabetes must be sure to use other measures as well to protect the heart.

Aspirin for Reducing the Risk for Blood Clots. Taking a daily aspirin reduces the risk for blood clotting and may help protect against heart attacks. In a 2000 study, low-dose aspirin was associated with a 30% lower risk for death from heart disease in adults with type 2 diabetes.

Controlling Blood Pressure. Strict control of blood pressure is critical for preventing complications of diabetes and has proven to improve survival rates. Patients should strive for blood pressure levels of less than 130/80 mm Hg (systolic/diastolic). (Controlling systolic pressure may be especially important for reducing the risk for kidney complications.)

Dozens of anti-hypertensive drugs are available. Most fall into the following categories:

• Diuretics rid the body of extra sodium (salt) and water. There are three main types of diuretics: Potassium-sparing, thiazide, and loop.
• Angiotensin-converting enzyme (ACE) inhibitors reduce the production of angiotensin, a chemical that causes arteries to narrow.
• Angiotensin-receptor blockers (ARBs) block angiotensin.· Beta-blockers block the effects of adrenaline and ease the heart’s pumping action.
• Calcium-channel blockers (CCBs) decrease the contractions of the heart and widen blood vessels.

The American Diabetes Association (ADA) recommends any of these classes of drugs as first-line treatment for hypertension. New research suggests, however, that beta-blockers are less effective at preventing strokes and heart attacks than other types of blood pressure medications. Many patients require more than one type of drug to control blood pressure. For patients with diabetes who have microalbuminuria, the ADA strongly recommends ACE inhibitors or ARBs. Microalbuminuria is an accumulation of protein in the blood, which can signal the onset of kidney disease (nephropathy).

Anti-hypertensive drugs that block or reduce angiotensin are the first option for many people with diabetes. Angiotensin is a natural chemical that influences all aspects of blood pressure control and also interferes with insulin's normal metabolic signaling. In fact, angiotensin may be the common factor linking diabetes and high blood pressure.

The 2005 landmark Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) indicated that a thiazide-type diuretic works as well as an ACE inhibitor or CCB for patients with diabetes and high blood pressure. Compared with ACE inhibitors or CCBs, diuretics appeared to be better at lowering systolic blood pressure and preventing heart failure. In addition, the trial suggested that diuretics are especially helpful for African Americans, by offering greater protection than ACE inhibitors or CCBS in preventing strokes.

Several 2006 studies suggested that anti-hypertensive drugs may increase the risk of developing diabetes. One study found more risk for thiazide diuretics and beta-blockers than ACE inhibitors and CCBs. However, another study indicated that the ACE inhibitor ramipril had a lower risk of causing diabetes in African Americans than a CCB or beta-blocker. Research in this subject is important for patients with pre-diabetes who have high blood pressure. Results of future research may help doctors decide which treatment is most appropriate for patients with high blood pressure who are at high risk for diabetes.

[For more information, see In-Depth Report #14: High blood pressure.]

Improving Cholesterol and Lipid Levels. Abnormal cholesterol and lipid levels are common in diabetes. High LDL (“bad”) cholesterol should always be lowered, but people with diabetes also often have additional harmful imbalances including low HDL (“good”) cholesterol and high triglycerides. Patients should aim for LDL levels below 100 mg/dL, HDL levels over 50 mg/dL and triglyceride levels below 150 mg/dL. Patients with diabetes and existing heart disease should strive for even lower LDL levels; the American Diabetes Association recommends LDL levels below 70 mg/dL for these patients.

Statins are the best cholesterol-lowering drugs. They include atorvastatin (Lipitor), lovastatin (Mevacor, generics), pravastatin (Pravachol), simvastatin (Zocor, generics), fluvastatin (Lescol), and rosuvastatin (Crestor). These drugs are very effective for lowering LDL cholesterol levels. Recent studies indicate that aggressive high-dose statin therapy may be an important treatment approach for high-risk patients who need to substantially lower their LDL levels. A 2006 study found that patients with diabetes and heart disease who were treated with 80 mg daily of atorvastatin had a 25% lower risk of heart attack and stroke than patients who received the standard 10 mg daily dose.

The primary safety concern with statins has involved myopathy, an uncommon condition that can cause muscle damage and, in some cases, muscle and joint pain. A specific myopathy called rhabdomyolysis can lead to kidney failure. People with diabetes and risk factors for myopathy should be monitored for muscle symptoms

Although lowering LDL is beneficial, statins are not as effective as other medications -- such as fibrates, niacin, ezetimbe, or bile acid sequesters -- in addressing HDL and triglyceride imbalances. This is a common problem in type 2 diabetes. Combinations of statins with one these drugs may be helpful for people with diabetes who have heart disease, low HDL, and near-normal LDL levels. Although combinations of statins and fibrates or niacin increase the risk of myopathy, both combinations are considered safe if used with extra care.

Fibrates, such as gemfibrozil (Lopid) and fenofibrate (Tricor), are usually the first choice. Niacin has the most favorable effect on raising HDL and lowering triglycerides of all the cholesterol drugs. However, about 30% of patients who take high-dose niacin experience increased blood glucose levels. Moderate doses of niacin can achieve lipid control without causing serious blood glucose problems.

[For more information, see In-Depth Report #23: Cholesterol.]

Kidney Damage (Nephropathy)

Kidney disease (nephropathy) is a very serious complication of diabetes. With this condition, the tiny filters in the kidney (called glomeruli) become damaged and leak protein into the urine. Over time this can lead to kidney failure. Urine tests showing microalbuminuria (small amounts of protein in the urine) are important markers for kidney damage.

Prevention and Treatment of Nephropathy. Tight control of blood sugar and blood pressure is essential for preventing the onset of kidney disease. Long-term studies report that strict control of these two conditions produces a 60% reduction in new cases of nephropathy and a delay in progression of the disease. ACE inhibitors and ARBs, two classes of blood pressure medication, are very helpful for preventing or slowing the progression of diabetic kidney disease.

A doctor may recommend a low-protein diet for patients whose kidney disease is progressing despite tight blood sugar and blood pressure control. Protein-restricted diets can help slow disease progression and delay the onset of end-stage renal disease (kidney failure). [For more information, see In-Depth Report #42: Diabetes diet.]

Diabetic nephropathy occurs in about 20 – 40% of patients with diabetes and is the leading cause of end-stage renal disease. If the kidneys fail, dialysis is required. Symptoms of kidney failure may include swelling in the feet and ankles, itching, fatigue, and pale skin color.

Click the icon to see an image of the pancreas and kidneys.

Neuropathy

Diabetes reduces or distorts nerve function causing a condition called neuropathy. Neuropathy refers to a group of disorders that affect nerves. The two main types of neuropathy are:

• Peripheral (affects nerves in the toes, feet, legs, hand, and arms)
• Autonomic (affects nerves that help regulate digestive, bowel, bladder, heart, and sexual function)

Peripheral neuropathy particularly affects sensation. It is a common complication that affects nearly half of people with type 1 or type 2 diabetes after 25 years. The most serious consequences of neuropathy occur in the legs and feet and pose a risk for ulcers and, in very severe cases, amputation. Peripheral neuropathy usually starts in the fingers and toes and moves up to the arms and legs (called a stocking-glove distribution). Symptoms include:

• Tingling
• Weakness
• Burning sensations
• Loss of the sense of warm or cold
• Numbness (if the nerves are severely damaged, the patient may be unaware that a blister or minor wound has become infected)
• Deep pain

Autonomic neuropathy can cause digestive problems (constipation, diarrhea, nausea, vomiting), bladder infections, and erectile dysfunction. In some cases, neuropathy may mask angina, the warning chest pain for heart disease and heart attack. Patients with diabetes should be aware of other warning signs of a heart attack including sudden fatigue, sweating, shortness of breath, nausea, and vomiting.

Blood sugar control is the only treatment for neuropathy. Studies show that tight control of blood glucose levels delays the onset and slows progression of neuropathy. A 2005 study also suggested that heart disease risk factors can increase the likelihood of developing neuropathy. Lowering triglycerides, losing weight, reducing blood pressure, and quitting smoking may help prevent the onset of neuropathy.

Pain Relief for Peripheral Neuropathy. A number of different drugs are used for peripheral neuropathy pain relief. They include:

• Nonprescription analgesics such as aspirin, acetaminophen, and non-steroidal anti-inflammatory drugs (NSAIDs). (Patients with stomach or kidney problems should check with their doctors before using these drugs.)
• Prescription painkillers such as tramadol (Ultram). Tramadol is a drug that is similar to opioids. It can help relieve pain but has significant side effects, including nausea, constipation, and headache.
• Topical medications, particularly capsaicin (the active ingredient in hot peppers), are applied to the skin to relieve minor local pain. A 5% lidocaine patch has also shown good results in clinical trials.
• Tricyclic antidepressants, such as amitriptyline (Elavil) or doxepin (Sinequan), are effective in reducing pain from neuropathy in up to 75% of patients. A combination of doxepin and capsaicin (applied to the skin) may be particularly beneficial. Unfortunately, tricyclics may cause heart rhythm problems.
• Duloxetine (Cymbalta) is a serotonin and norepinephrine reuptake inhibitor, a newer type of antidepressant, which was approved in 2004 for treatment of pain associated with diabetic peripheral neuropathy.
• The anti-convulsant drug pregabalin (Lyrica) was approved in 2004 for neuropathic pain management. It is classified as a controlled substance (like narcotics), which indicates a potential risk for abuse. Other anti-seizure drugs used for peripheral neuropathy pain relief include gabapentin (Neurontin) and valproate (Depakote).

Treatments under investigation include acetyl-l-carnitine and intravenous alpha-lipoic acid. Patients may also benefit from transcutaneous electrostimulation (TENS), a treatment that involves administering mild electrical pulses to painful areas. Alternative treatments such as hypnosis, biofeedback, relaxation techniques, and acupuncture have helped some patients manage pain. Doctors also recommend lifestyle measures such as walking and wearing elastic stockings.

Treatments for Other Complications of Neuropathy. Neuropathy also impacts other functions, and treatments are needed to reduce their effects. If diabetes affects the nerves in the autonomic nervous system, then abnormalities of blood pressure control and bowel and bladder function may occur. Erythromycin, domperidone (Motilium), or metoclopramide (Reglan) may be used to relieve delayed stomach emptying caused by neuropathy.

Erectile dysfunction is also associated with neuropathy. Sildenafil (Viagra), vardenafil (Levitra, Nuviva, and tadalafil (Cialis)) are proving to be effective treatments for impotence in about half of the men with either type 1 or type 2 diabetes. Side effects and usually minimal.

Foot Ulcers and Amputations

Perhaps the most serious consequences of diabetic neuropathy occur in the lower limbs. An estimated 15% of patients with diabetes experience serious foot problems. They are the leading cause of hospitalizations for these patients.

Diabetes is responsible for more than half of all lower limb amputations performed in the U.S. Each year there are about 88,000 non-injury amputations, 50 - 75% of them due to diabetes. The number is increasing as the prevalence in diabetes type 2 rises. According to a 2005 study in the Lancet, every 30 seconds someone in the world receives a lower limb amputation due to diabetes. About 85% of amputations start with foot ulcers, which develop in about 12% of people with diabetes.

In general, foot ulcers develop from infections, such as those resulting from blood vessel injury. A 2006 study reported that people with diabetes who develop foot infections are 155 times more likely to have an amputation than people who did not develop infections. Foot infections often develop from injuries. Even minor infections can develop into severe complications. Numbness from nerve damage, which is common in diabetes, compounds the danger since the patient may not be aware of injuries. About one-third of foot ulcers occur on the big toe.

A 2003 government survey found that those at higher risk for foot ulcers tend to be people with diabetes who are overweight, smokers, and those with a long history of diabetes. People who have the disease for more than 20 years and are insulin-dependent are at the highest risk. Related conditions that put people at risk include peripheral neuropathy, peripheral artery disease, foot deformities, and a history of ulcers. [For more information, see In-Depth Report #102: Peripheral artery disease and intermittent claudication.]

Charcot Foot. Charcot foot or Charcot joint (medically referred to as neuropathic arthropathy) occurs in about 2.5% of people with diabetes. Early changes appear like an infection, with the foot becoming swollen, red, and warm. A seriously affected foot can become deformed. The bones may crack, splinter, and erode, and the joints may shift, change shape, and become unstable. It typically develops in people who have neuropathy to the extent that they cannot feel sensation in the foot and are not aware of an existing injury. Instead of resting an injured foot or seeking medical help, the patient often continues to normal activity, causing further damage.

Charcot foot is initially treated with strict immobilization of the foot and ankle; some centers use a cast that allows the patient to move and still protects the foot. A 2001 study in the U.K. concluded that a single dose of pamidronate, a bisphosphonate, reduces bone turnover, symptoms, and disease activity. When the acute phase has passed, patients usually need lifelong protection of the foot using a brace initially and custom footwear.

Measures to Prevent Foot Ulcers. Preventive foot care can significantly reduce the risk of ulcers and amputation. Some tips for preventing problems include:

• Patients should inspect their feet daily and watch for changes in color or texture, odor, and firm or hardened areas, which may indicate infection and potential ulcers.
• When washing the feet, the water should be warm (not hot) and the feet and areas between the toes should be thoroughly dried afterward. Check water temperature with the hand or a thermometer before stepping in.
• Moisturizers should be applied, but not between the toes.
• Corns and calluses should be gently pumiced and toenails trimmed short and the edges filed to avoid cutting adjacent toes.
• Patients should not use medicated pads or try to shave the corns or calluses themselves.
• Well-fitting footwear is very important. People should be sure the shoe is wide enough; according to a 2001 study, 30% of patients with diabetes wear shoes that are too narrow. Patients should also avoid high heels, sandals, thongs, and going barefoot. Shoes with a rocker sole (LucRo) reduce pressure under the heel and front of the foot by 35 - 65% and may be particularly helpful. Custom-molded boots increase the surface area over which foot pressure is distributed. This reduces stress on the ulcers and allows them to heal.
• Shoes should be changed often during the day.
• Wear socks, particularly with extra padding (which can be specially purchased).
• Patients should avoid tight stockings or any clothing that constricts the legs and feet.
• Foot pain, numbness, or tingling is worse at night; diphenhydramine (Benadryl) may help.
• A specialist in foot care should be consulted for any problems.

People with diabetes are prone to foot problems because the disease can cause damage to the blood vessels and nerves, which may result in decreased ability to sense a trauma to the foot. The immune system is also altered, so that the patient cannot efficiently fight infection.

Treating Foot Ulcers in Diabetes. About one-third of foot ulcers will heal within 20 weeks with good wound care treatments. Treatments include:

• Antibiotics are generally given. In some cases, hospitalization and intravenous antibiotics for up to 28 days may be needed for severe foot ulcers.
• In virtually all cases, wound care requires debridement, which is the removal of injured tissue until only healthy tissue remains. Debridement may be accomplished using chemical (enzymes), surgical, or mechanical (irrigation) means.
• Hydrogels (Nu-Gel, Intrasite Gel, Scherisorb, Clearsite, Duoderm, Geliperm) are helpful in healing ulcers and are noninvasive and soothing.
• Felted foam may be helpful in healing ulcers on the sole of the foot. Felted foam uses a multi-layered foam pad over the bottom of the foot with an opening over the ulcer.

Other Treatments for Foot Ulcers. Doctors are also using or investigating other treatments to heal ulcers. These include:

• Administering hyperbaric oxygen (oxygen given at high pressure) is showing promise in promoting healing. In one study, patients who had had ulcers that had not responded to treatment for over 3 months received daily treatments that lasted 90 minutes for 2 weeks. About 15 days after completion, patients who received oxygen had significant reduction in ulcers, sometimes with complete healing. Other studies are also demonstrating good results.
• Monochromatic near-infrared photo energy (MIRE) uses light therapy to improve sensation in the feet of patients with peripheral neuropathy.
• Total-contact casting (TCC) uses a cast that is designed to match the exact contour of the foot and to distribute weight along the entire length of the foot. It is usually changed weekly. It may be helpful for ulcer healing and for Charcot foot. Although it is very effective in healing ulcers, recurrence is common.

Retinopathy and Eye Complications

Diabetes accounts for 12,000 - 24,000 of new cases of blindness annually and is the leading cause of new cases of blindness in adults ages 20 to 74. The most common eye disorder in diabetes is retinopathy. People with diabetes are also at higher risk for developing cataracts and certain types of glaucoma. [For more information, see In-Depth Report #26: Cataracts and Report #25: Glaucoma.]

Description of Retinopathy. Retinopathy is a condition in which the retina in the eye becomes damaged. The two primary abnormalities that occur are a weakening of the blood vessels in the retina and the obstruction in the capillaries--probably from very tiny blood clots. Retinopathy generally occurs in one or two phases:

Click the icon to see an image of diabetic retinopathy.

• The early and more common type of this disorder is called nonproliferative or background retinopathy. The blood vessels in the retina are abnormally weakened. They rupture and leak, and waxy areas may form. If these processes affect the central portion of the retina, swelling may occur, causing reduced or blurred vision.
• If the capillaries become blocked and blood flow is cut off, soft, "woolly" areas may develop in the retina's nerve layer. These woolly areas may signal the development of proliferative retinopathy. Often there are no symptoms of progressing retinopathy. In this more severe condition, new abnormal blood vessels form and grow on the surface of the retina. They may spread into the cavity of the eye or bleed into the back of the eye. Major hemorrhage or retinal detachment can result, causing severe visual loss or blindness. The sensation of seeing flashing lights may indicate retinal detachment.

Click the icon to see an animation on diabetic retinopathy.

According to a 2003 study, about 40% of young adults with type 1 diabetes had developed retinopathy within 10 years of diagnosis. (Although this rate is high, it is significantly lower than in previous years when blood glucose control was not as strict.) The risk is lower in patients with type 2, although in one study over 20% had signs of retinopathy 6 years after diagnosis. In general, all patients with diabetes should have a yearly eye examination. Patients with no signs of retinal damage or low risk factors for retinopathy may only require screening every 3 years.

Prevention of Retinopathy. Fortunately, severe and even moderate vision loss is largely preventable with tight control of blood glucose levels. (Intense glucose control can cause early worsening of retinopathy, although this is nearly always counterbalanced by long-term benefits.) Drugs and other measures that help lower blood pressure, improve cholesterol, and protect the heart may also have preventive benefits for the eyes. Whereas low-dose aspirin is used to prevent heart disease, high doses may prevent retinopathy. Patients at risk for retinopathy should discuss this therapy with their doctors.

Treatment of Retinopathy. Once damage to the eye develops, eye surgery may be needed. Argon or diode laser photocoagulation is proving to be particularly effective in reducing severe visual loss from retinopathy, and is useful for patients with macular edema when fluid build-up threatens the retina. The FDA is currently reviewing a new drug, ruboxistaurin (Arxxant), to treat diabetic retinopathy. Studies presented at the 2006 American Diabetes Association meeting indicated that the drug reduced vision loss by 41% in patients with moderate-to-severe diabetic retinopathy.

Mental Function and Dementia

Studies indicate that patients with type 2 diabetes face a higher than average risk of developing dementia caused either by Alzheimer's disease or problems in blood vessels in the brain. Problems in attention and memory can occur even in people under age 55 who have had diabetes for a number of years. In one study of people with type 1 diabetes, high glucose levels (hyperglycemia) were associated with slower brain function, including less verbal fluency and slower ability to do mental arithmetic.

Infections

Respiratory Infections. People with diabetes face a higher risk for influenza and its complications, including pneumonia, possibly because the disorder neutralizes the effects of protective proteins on the surface of the lungs. In fact, deaths among people with diabetes increase by 5 - 15% during flu epidemics and they are six times more likely to be hospitalized with complications from flu than nondiabetic patients who have flu. Everyone with diabetes should have annual influenza vaccinations and a vaccination against pneumococcal pneumonia.

Urinary Tract Infections. Women with diabetes face a significantly higher risk for urinary tract infections, which are likely to be more complicated and difficult to treat than in the general population.

Depression

Diabetes doubles the risk for depression. Furthermore, according one study, depression, in turn, increases the risk for hyperglycemia and complications of diabetes. Restoring mental health, both through medication and psychotherapy, not only improves quality of life but may help patients control their blood sugar levels.

Changes in Bone Quality

Diabetes changes bone quality and density, but the effects differ depending on type:

• Type 1 diabetes is associated with a slightly reduced bone density, putting patients at risk for osteoporosis and possibly fractures. The best medications for bone loss in patients with diabetes are the bisphosphonates, such as alendronate (Fosamax) and risedronate (Actonel). They not only help prevent bone loss but may even reduce daily insulin requirements in patients taking insulin. [See In-Depth Report #18: Osteoporosis.]
• Type 2 diabetes, on the other hand, is associated with an increased bone density but is also associated with fractures. In such cases, the bone quality itself may be impaired.

Older patients with either type of diabetes are at risk for falling, which compounds the risk for fracture.

Other Complications

Diabetes increases the risk for other conditions, including:

• Hearing loss
• Periodontal disease
• Carpal tunnel syndrome
• Nonalcoholic fatty liver disease, also called nonalcoholic steatohepatitis (NASH); a particular danger for people who are obese
• Colorectal cancer
• Uterine cancer

Resources

• www.diabetes.org -- American Diabetes Association
• www.niddk.nih.gov -- National Institute of Diabetes and Digestive and Kidney Diseases
• www.americanheart.org -- American Heart Association
• www.kidney.org -- National Kidney Foundation
• www.nei.nih.gov -- National Eye Institute
• www.medicalert.org -- Medic Alert
• www.eatright.org -- American Dietetic Association
• http://limaye.ecri.org -- Limaye Center

References

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Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, Flegal KM, Engelgau MM, et al. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health And Nutrition Examination Survey 1999-2002. Diabetes Care. 2006 Jun;29(6):1263-1268.

Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005 Jun 16;352(24):2477-2486.

Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005 Oct 8;366(9493):1279-1289.

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Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005 Oct 18;143(8):559-569.

Houston TK, Person SD, Pletcher MJ, Liu K, Iribarren C, Kiefe CI. Active and passive smoking and development of glucose intolerance among young adults in a prospective cohort: CARDIA study. BMJ. 2006 May 6;332(7549):1064-1069.

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Macintosh MC, Fleming KM, Bailey JA, Doyle P, Modder J, Acolet D, et al. Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study. BMJ. 2006 Jun 16; [Epub ahead of print]

Rosenstock J, Zinman B, Murphy LJ, Clement SC, Moore P, Bowering CK, et al. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2005 Oct 18;143(8):549-558.

Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care. 2006 Jun;29(6):1220-1226.

Taylor EN, Hu FB, Curhan GC. Antihypertensive medications and the risk of incident type 2 diabetes. Diabetes Care. 2006 May;29(5):1065-1070.

Thornley-Brown D, Wang X, Wright JT Jr, Randall OS, Miller ER, Lash JP, et al. Differing effects of antihypertensive drugs on the incidence of diabetes mellitus among patients with hypertensive kidney disease. Arch Intern Med. 2006 Apr 10;166(7):797-805.

Tirosh A, Shai I, Tekes-Manova D, Israeli E, Pereg D, Shochat T, et al. Normal fasting plasma glucose levels and type 2 diabetes in young men. N Engl J Med. 2005 Oct 6;353(14):1454-1462.

Tseng CH. Exogenous insulin use and hypertension in adult patients with type 2 diabetes mellitus. Arch Intern Med. 2006 Jun 12;166(11):1184-1189.

Whelton PK, Barzilay J, Cushman WC, Davis BR, Iiamathi E, Kostis JB, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005 Jun 27;165(12):1401-1409.

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