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In This Report

•	Highlights
•	Introduction
•	Causes
•	Risk Factors
•	Symptoms
•	Complications
•	Diagnosis and Screening Tes...
•	Dietary Goals and Exercise...
•	Treatment
•	Home Management of Diabetes...
•	Transplantation Procedures...
•	Resources
•	References

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•	Diabetes diet
•	Diabetes - type 2

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Diabetes - type 1

Highlights

Inhaled Insulin Puffs Out

When inhaled insulin (Exubera) was approved in 2006, it was thought to offer an attractive alternative to injected insulin. However, patients found the inhaler device inconvenient and unappealing, and sales have been poor. In 2008, a safety warning was added to Exubera’s prescribing label describing possible increased risks for lung cancer. The drug’s manufacturer plans to withdraw Exubera from the market, and other companies have halted development of their inhaled insulin products.

Investigational Drugs

Anti-CD3 monoclonal antibody drugs are continuing to move forward in clinical trials. Researchers hope that these experimental drugs may one day help preserve pancreatic function and delay the onset of type 1 diabetes. Anti-CD3 antibodies in late-stage clinical trials include otelixizumab and teplizumab.

Symptoms of Diabetes

Type 1 diabetes can occur at any age but usually first appears in childhood or adolescence. Type 1 diabetes accounts for 5 - 10% of all diabetes cases. Symptoms of both type 1 and type 2 diabetes include:

• Frequent urination
• Excessive thirst
• Extreme hunger
• Sudden weight loss
• Extreme fatigue
• Irritability
• Blurred vision

Warning Signs of Hypoglycemia

Hypoglycemia (low blood sugar) occurs when blood sugar (glucose) levels fall below normal. Patients with type 1 diabetes should be aware of these symptoms of hypoglycemia:

• Sweating
• Trembling
• Hunger
• Rapid heartbeat
• Confusion

It is important to quickly treat hypoglycemia and raise blood sugar levels by eating sugar, sucking on hard candy, or drinking fruit juice. Patients who are at risk for hypoglycemia should carry some sugar product with them in case an attack occurs. In rare and worst cases, hypoglycemia can lead to coma and death. Regular blood sugar monitoring throughout the day can help you avoid hypoglycemia. Patients are also encouraged to wear a medical alert ID bracelet or necklace that states they have diabetes and that they take insulin.

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 non-insulin-dependent diabetes mellitus (NIDDM) or maturity-onset diabetes.

Insulin

Both type 1 and type 2 diabetes share one central feature: elevated blood sugar (glucose) levels due to absolute or relative 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, digestion breaks carbohydrates down into sugar molecules (of which glucose is one) 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. (Glucose levels after a meal are called postprandial levels.)
• The rise in blood glucose levels signals important cells in the pancreas, called beta cells, to secrete insulin, which pours into the bloodstream. Within 20 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. (It should be noted that 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 - 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 stomach. In addition to secreting digestive enzymes, the pancreas secretes the hormones insulin and glucagon into the bloodstream. The release of insulin into the blood lowers the level of blood glucose (simple sugars from food) by enhancing glucose to enter the body cells, where it is metabolized. If blood glucose levels get too low, the pancreas secretes glucagon to stimulate the release of glucose from the liver.

Type 1 Diabetes

In type 1 diabetes, the disease process is more severe than with type 2 diabetes, 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.

Type 2 Diabetes

Type 2 diabetes is the most common form of diabetes, accounting for 90% of cases. About 20 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, and 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.

Maturity-Onset Diabetes in 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.

Gestational Diabetes. An estimated 5% of pregnant women develop a form of type 2 diabetes in their third trimester called gestational diabetes. Gestational diabetes is usually temporary. [For more information, see In-Depth Report #60: Diabetes - type 2.]

Diabetes Secondary to Other Conditions

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

Causes

Autoimmune Response

Type 1 diabetes is usually a progressive autoimmune disease, in which the beta cells that produce insulin are slowly destroyed by the body's own immune system. It is unknown what first starts this cascade of immune events, but evidence suggests that both a genetic predisposition and environmental factors, such as a viral infection, are involved.

Islets of Langerhans contain beta cells and are located within the pancreas. Beta cells produce insulin which is needed to metabolize glucose within the body.

Certain factors are thought to be important in this process:

• White blood cells called T lymphocytes produce immune factors called cytokines that attack and gradually destroy the beta cells of the pancreas. Important cytokines are interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma.
• Specific proteins are also critical in the process. They include glutamic acid decarboxylase (GAD), insulin, and islet cell antigens. These proteins serve as autoantigens. That is, they trigger the self-attack of the autoantibodies on the body's own beta cells.

Progression from the first stage, known as insulitis, to full-blown diabetes can take 7 years or longer. Unfortunately, by the time a person is aware that something is wrong and goes to the doctor with symptoms of type 1 diabetes, about 80 - 90% of the beta cells have been destroyed.

More than half of patients with insulitis do not develop diabetes. Researchers are greatly interested in discovering any factors that prevent the disease.

Genetic Abnormalities

Researchers have found at least 18 genetic locations, labeled IDDM1 - IDDM18, that are related to type 1 diabetes. The IDDM1 region contains the HLA genes that encode proteins called major histocompatibility complex. The genes in this region affect the immune response. New advances in genetic research are identifying other genetic components of type 1 diabetes. Other chromosomes and genes continue to be identified.

The odds of inheriting the disease, however, are only 10% if a first-degree relative has diabetes, and even in identical twins, one twin has only a 33% chance of having type 1 diabetes if the other has it. Children are more likely to inherit the disease from a father with type 1 diabetes than from a mother with the disorder.

Genetic factors cannot fully explain the development of diabetes. Over the past 30 years, a major increase in the incidence of type 1 diabetes has been reported in certain European countries, and the incidence has nearly tripled in the northeastern U.S. If genetic factors were the only cause of type 1 diabetes, such an increase in cases would take at least 400 years.

Viruses

Some researchers believe one or more viral infections may trigger the disease in genetically susceptible individuals. Researchers suggest the following scenario:

• An infection introduces a viral protein that resembles a beta-cell protein.
• T cells and antibodies are tricked by this resemblance into attacking the beta protein as well as the virus.

Among the viruses under scrutiny are enteric viruses, which attack the intestinal tract. Coxsackieviruses are a family of enteric viruses of particular interest. Epidemics of Coxsackie virus, as well as mumps and congenital rubella, have been associated with incidence of type 1 diabetes.

Risk Factors

An estimated 1 million people in the U.S. have type 1 diabetes, with about 30,000 new cases diagnosed each year. It is much less common than type 2 diabetes, however, consisting of only 5 - 10% of all cases of diabetes. Nevertheless, like type 2 diabetes, the incidence of type 1 diabetes among children and adolescents has been rising over the past few decades. Experts estimate that about 1 in every 400 - 600 children and adolescents has type 1 diabetes. While type 2 diabetes has been increasing among African-American and Hispanic adolescents, the highest rates of type 1 diabetes are found among Caucasian youth.

Risk Factors in Children

Type 1 diabetes can occur at any age but usually appears between infancy and the late 30s, most typically in childhood or adolescence. Boys and girls are equally vulnerable. Studies report the following may be risk factors for developing type 1 diabetes:

• Being ill in early infancy.
• Early foods. Some studies have reported that early exposure to cow's milk in infancy and not being breastfed increases the risk for type 1 diabetes. Early exposure to cereal -- not cow's milk -- has also been suggested to play a role in risk. Any risk from early dietary factors is still very low and likely to affect children who already have a genetically impaired immune response to dietary proteins. Breast milk contains factors that may help regulate the immune response and prevent diabetes in such children. National differences in risk also suggest that not all cow's milk is the same, and some proteins may confer higher risks than others. Overall, the role of compounds found in these foods remains controversial.
• Having a parent with type 1 diabetes.
• Having an older mother.
• Having a mother who had preeclampsia during pregnancy.
• Obesity in children has long been linked to a higher risk for type 2 diabetes. The common risk factor may be an increase in insulin secretion, which occurs with obesity. This theoretically could overstress the beta cells so that they become susceptible to damage by overactive immune factors (particularly cytokines), and eventually to destruction in children genetically vulnerable to type 1 diabetes.

Until recently, diabetes in children was almost always type 1 diabetes. Of major concern, however, are estimates that 8 - 45% of new diabetes cases in children are now type 2, most likely because of the increase in childhood obesity. [For more information, see In-Depth Report #60: Diabetes - type 2.]

Having Other Immune Abnormalities

The incidence of type 1 diabetes is higher than average among people with other autoimmune diseases, including Grave's disease, Hashimoto's thyroiditis (a form of hypothyroidism), Addison's disease, multiple sclerosis (MS), and pernicious anemia. Research has raised the possibility that all autoimmune diseases share a common genetic basis. A 2001 study found, for example, that the T cell immune factors in type 1 diabetes target the same self-antigens as in multiple sclerosis (MS). Both diseases have been associated with cow's milk protein. Many questions are unanswered, however. It is not known why the diseases develop in different locations to cause separate disorders or why some autoimmune events occur in everyone but not everyone develops an autoimmune disease.

Ethnicity

There is a very wide variation in incidence of type 1 among population groups. Type 1 diabetes appears to be most common in people of northern European descent and in specific Mediterranean groups (such as Sardinians). It is less common among Asians and African-Americans. Still, African-Americans with type 1 diabetes are 50% more likely to die from it than Caucasians, mostly due to lower-quality health care.

Symptoms

The process that destroys the insulin-producing beta cells can be long and insidious. At the point when insulin production bottoms out, however, type 1 diabetes usually appears suddenly and progresses quickly. Warning signs of type 1 diabetes include:

• Frequent urination (in children, a recurrence of bed-wetting after toilet training has been completed)
• Unusual thirst, especially for sweet, cold drinks
• Extreme hunger
• Sudden, sometimes dramatic, weight loss
• Weakness
• Extreme fatigue
• Blurred vision or other changes in eyesight
• Irritability
• Nausea and vomiting (acute symptoms)

Children with type 1 diabetes may also be restless, apathetic, and have trouble functioning at school. In severe cases, diabetic coma may be the first sign of type 1 diabetes.

Complications

Type 1 diabetes reduces the normal lifespan by about 5 - 8 years. However, survival rates are improving in all ethnic groups and both genders. Longer survival rates are probably due to improvements in monitoring and tighter control of blood glucose. There are two important approaches to preventing complications from type 1 diabetes:

• Intensive control of blood glucose and keeping glycosylated hemoglobin (HbA1c) levels below 7%. This approach is proving to 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. Blood glucose control helps the heart, but it is also very important that people with diabetes control blood pressure, cholesterol levels, and other factors associated with heart disease.

Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a life-threatening complication that develops when insulin stores are depleted. It is almost always caused by noncompliance with insulin treatments. Other contributing factors are lack of health insurance and intentionally reducing insulin doses in order to lose weight, which occurs with adolescent girls in an effort to keep weight down.

Diabetic ketoacidosis often develops 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 include:

• Nausea and vomiting
• Deep and rapid breathing may occur with frequent sighing
• Rapid heartbeat
• Cerebral edema, or brain swelling, is a rare but very dangerous complication that occurs in 1% of ketoacidosis cases and results in coma, brain damage, or death in many cases. Research suggests that the risk for this complication is significantly higher in children with severe ketoacidosis if they are also treated with bicarbonate to reduce acid levels.
• Other serious complications from DKA include aspiration pneumonia and adult respiratory distress syndrome.
• If the condition persists, coma and eventually death may occur, although over the past 20 years, death from DKA has decreased to about 2% of all cases.

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

Ketoacidosis is a serious condition of glucose build-up in the blood and urine. A simple urine test can determine if high ketone levels are present.

Hypoglycemia

Tight blood sugar (glucose) control increases the risk of low blood sugar (hypoglycemia). Hypoglycemia, also called insulin shock, occurs if blood glucose levels fall below normal. It is generally defined as a blood sugar below 70 mg/dL, although this level may not necessarily cause symptoms in all patients. Insufficient intake of food and excess exercise or alcohol intake may cause hypoglycemia. Usually the condition is manageable, but, occasionally, it can be severe or even life threatening, particularly if the patient fails to recognize the symptoms, especially while continuing to take insulin or other hypoglycemic drugs.

Risk Factors for Severe Hypoglycemia. Among young patients, the youngest children and boys of any age are at higher risk for hypoglycemia. Specific risk factors for severe hypoglycemia include:

• Patients attempting tight control of blood glucose and HbA1c levels
• Long-term diabetes
• Patients who do not comply with treatment (including those who are underinsured, have psychiatric disorders, or who are poorly educated about diabetes)
• Infections such as gastroenteritis or respiratory illnesses

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 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

Heart Disease and Stroke

Patients with type 1 diabetes are 10 times more at risk for heart disease than healthy patients. Heart attacks account for 60% of deaths in patients with diabetes, while strokes account for 25% of such deaths. Diabetes affects the heart in many ways:

• Both type 1 and 2 diabetes accelerate 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 (hypertension) usually develops if the kidneys become damaged. High blood pressure 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 from 15 - 53%.

Atherosclerosis is a disease of the arteries in which fatty material is deposited in the vessel wall, resulting in narrowing and eventual impairment of blood flow. Severely restricted blood flow in the arteries to the heart muscle leads to symptoms such as chest pain. Atherosclerosis shows no symptoms until a complication occurs.

Click the icon to see an image of the kidney.

Results from the Diabetes Control and Complications Trial (DCCT) prove that intensive blood sugar control reduces the long-term risk of heart disease complications by 50%. Intensive blood sugar control is even more important in reducing these risks than blood pressure- and cholesterol-lowering drugs. Researchers continued to follow these patients’ progress during the next 17 years. The benefits of tight blood glucose control persist over time and may halve the risk of heart attack, stroke, angina, or coronary artery disease.

Reducing 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). High systolic blood pressure during sleep often occurs before development of nephropathy. (Systolic pressure is the first and higher number in a blood pressure reading.) Home blood pressure monitoring may help identify patients with type 1 diabetes who are at risk for kidney damage.

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.

Adult 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.

Children should be treated for LDL cholesterol above 160 mg/dL, or above 130 mg/dL if they have other cardiovascular risk factors.

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.

Diabetic nephropathy, the leading cause of end-stage renal disease (ESRD), occurs in about 20 - 40% of patients with diabetes. Patients with ESRD have 13 times the risk of death compared to other patients with type 1 diabetes. 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. The prognosis of end-stage renal disease has greatly improved during the last 4 decades for patients with type 1 diabetes, and fewer people with type 1 diabetes are developing ESRD.

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 incontinence
• Erectile dysfunction
• Heart problems. 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.
• Rapid heart rates
• Lightheadedness when standing up (orthostatic hypotension)

Blood sugar control is an essential component in the treatment for neuropathy. Studies show that tight control of blood glucose levels delays the onset and slows progression of neuropathy. Heart disease risk factors may increase the likelihood of developing neuropathy. Lowering triglycerides, losing weight, reducing blood pressure, and quitting smoking may help prevent the onset of neuropathy.

Foot Ulcers and Amputations

About 15% of patients with diabetes experience serious foot problems. They are the leading cause of hospitalizations for these patients. The consequences of both poor circulation and peripheral neuropathy make this a common and serious problem for all patients with diabetes.

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. About 85% of amputations start with foot ulcers, which develop in about 12% of people with diabetes.

People with diabetes who are overweight, smokers, and have a long history of diabetes tend to be at most risk. 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.]

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.

Charcot Foot. Charcot foot or Charcot joint (medically referred to as neuropathic arthropathy) occurs in up to 2.5% of people with diabetes. Early changes appear similar to an infection, with the foot becoming swollen, red, and warm. Gradually, the 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 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. When the acute phase has passed, patients usually need lifelong protection of the foot using a brace initially and custom footwear.

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 - 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 In-Depth Report #25: Glaucoma.]

Description of Retinopathy. Retinopathy is a condition in which the retina 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.

All patients with diabetes should begin having a professional eye exam according to the following schedule:

• Children older than 10 years and with diabetes for at least 3 - 5 years
• Adolescents and adults with type 1 diabetes, within 5 years of diagnosis
• Adults with type 2 diabetes soon after diagnosis is made

After the first exam, most patients should have a yearly eye examination. Patients with no signs of retinal damage or low risk factors for retinopathy may only require screening every 2 - 3 years. Patients beginning a new or vigorous exercise program should have their eyes examined, as well as all patients planning pregnancy.

Click the icon to see an animation on diabetic retinopathy.

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.

Vaccination recommendations for patients with diabetes include:

• Annual influenza vaccination for all patients older than 6 months of age
• All patients should receive at least one vaccination against pneumococcal pneumonia, and any patient with cardiovascular disease, pulmonary disease, or kidney problems should receive a second vaccination in 5 years.

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, depression, in turn, increases the risk for hyperglycemia and complications of diabetes, according to one study. 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 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. [For more information, see In-Depth Report #18: Osteoporosis.]
• Type 2 diabetes, on the other hand, is associated with an increased bone density, but it 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 and other nerve entrapment syndromes
• Nonalcoholic fatty liver disease, also called nonalcoholic steatohepatitis (NASH); a particular danger for people who are obese
• Colorectal cancer
• Uterine cancer

Specific Complications in Women

Diabetes and Pregnancy. Both temporary diabetes that occurs during pregnancy (gestational diabetes) and pregnancy in a patient with existing diabetes can increase the risk for birth defects. Studies indicate that high blood sugar levels (hyperglycemia) may affect the developing fetus as soon as it is conceived.

Because glucose crosses the placenta, a woman with diabetes can pass high levels of blood glucose to the fetus. In response, the fetus secretes large amounts of insulin. This combination of high fetal blood levels of insulin and glucose can have significant effects:

• Excessive fetal weight gain, which can lead to complications during delivery
• Birth defects
• Breathing problems and delayed lung development
• Low blood sugar
• Higher future risk for obesity and diabetes

In addition to endangering the fetus, diabetes also presents risks to the pregnant woman, particularly preeclampsia, which is a potentially dangerous condition involving very high blood pressure during pregnancy. Pregnant women with diabetes are also at greater risk for retinopathy.

Effect on Estrogen. Diabetes appears to blunt some of the effects of estrogen, which may increase the risk for heart disease. Women with diabetes have a higher risk for early menopause, which, in one study, occurred at an average age of about 41 years.

Reproductive Cancers. Women with type 1 diabetes often have lumps in the breast that are benign but which make mammograms difficult to interpret. It is not clear whether these lumps are risk factors for breast cancer. One study indicated that women with diabetes have a higher risk for endometrial cancer and possibly for breast cancer.

Specific Problems for Adolescents with Type 1 Diabetes

Lack of Blood Glucose Control. Control of blood glucose levels is generally very poor in adolescents and young adults. Adolescents with diabetes are at higher risk than adults for ketoacidosis resulting from noncompliance. In a British study of young adults with type 1 diabetes, 15% were already hypertensive, and about half of these young people had signs of kidney damage. Young people who do not control glucose are also at high risk for permanent damage in small vessels, such as those in the eyes.

Eating Disorders. Up to a third of young women with type 1 diabetes have eating disorders and under-use insulin to lose weight. Anorexia and bulimia pose significant health risks in any young person, but they can be especially dangerous for people with diabetes.

Diagnosis and Screening Tests

Testing for Glucose Abnormalities

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

• FPG levels are considered normal up to 100 mg/dL (or 5.5 mmol/L).
• Levels of 100 - 125 mg/dL (5.5 - 7.0 mmol/L) are referred to as impaired fasting glucose, or pre-diabetes. These levels are considered 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 tests are 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 are tested in the morning.

Widespread screening of patients to identify those at higher risk for diabetes type 1 is not recommended.

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 normal up to 140 mg/dL.
• Levels of 140 - 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.

Patients who have the FPG and OGTT tests must not eat for at least 8 hours prior to the test.

The oral glucose tolerance test is used to diagnose diabetes. The first portion of the test involves drinking a special glucose solution. Blood is then taken several hours later to test for the level of glucose in the blood. Patients with diabetes will have higher than normal levels of glucose in their blood.

Test for Glycosylated Hemoglobin (Hemoglobin A1c). This test examines blood levels of glycosylated hemoglobin, also known as hemoglobin A1c (HbA1c). The test is not affected by recent food intake so it can be taken at any time.

• The results of a blood glucose test tell the patient and doctor how well the diabetes is controlled for only the day of the test.
• Once a blood sugar molecule sticks to a hemoglobin molecule, which are found in every red blood cell, it never lets go (a process called glycation). If a patient with diabetes has elevated blood glucose on many days, more blood glucose molecules will stick to the hemoglobin molecule. If that happens, the hemoglobin A1c level will be higher.
• Therefore, an elevated hemoglobin A1c level tells the doctor and the patient how well controlled the patients diabetes has been over the last 3 months or so.
• Measuring glycosylated hemoglobin is not recommended for making an initial diagnosis of diabetes, since a normal level does not rule out diabetes.

Elevated levels of glycosylated hemoglobin are strongly associated with most if not all of the complications of diabetes. Goal HbA1c levels for adults should be:

• Generally, around 7%.
• If an adult to is able to undergo very tight management of their diabetes without experiencing frequent or severe hypoglycemia, a HbA1c level as close to 6% as possible is desired,
• Levels of glycosylated hemoglobin as high as 11 - 12% indicate very poor glucose control

Goal HbA1c levels for children should be:

• Less than 7.5 - 8.5% for children under age 6 years
• Less than 8% for children age 6 - 12 years
• Less than 7.5% for children age 13 - 19 years

Schedule for HbA1c Monitoring:

• Every 6 months if diabetes is well controlled
• Every 3 months if not well controlled

Testing for Insulin Resistance. Investigators hope that some day a simple test for insulin resistance will be available to identify people at risk for diabetes. Some research suggests that measuring insulin and triglyceride levels during a fasting period may predict a person's sensitivity to insulin.

Autoantibody Tests

Type 1 diabetes is characterized by the presence of a variety of antibodies that attack the islet cells. These antibodies are referred to as autoantibodies because they attack the body's own cells -- not a foreign invader. Blood tests for these autoantibodies can help differentiate between type 1 and type 2 diabetes.

Screening Tests for Complications

Screening Tests for Heart Disease. All patients with diabetes should be tested for:

• Blood pressure. Your doctor should check your blood pressure at every visit. Blood pressure goals should be 130/80 mm Hg or lower.
• Lipid levels, including cholesterol. People with diabetes should aim for LDL levels below 100 mg/dL, HDL levels over 40 mg/dL, and triglyceride levels below 150 mg/dL. Testing should be performed yearly and perhaps every other year for patients with good lipid control and no evidence of heart disease.
• Cardiac exercise testing should be considered for adult patients with any symptoms or electrocardiogram findings, or before starting an exercise program.

Click the icon to see an image of an ECG.

Screening Tests for Kidney Damage. The earliest manifestation of kidney disease is microalbuminuria, in which tiny amounts (30 - 300 mg per day) of protein called albumin are found in the urine. Microalbuminuria is also a marker for other complications involving blood vessel abnormalities, including heart attack and stroke.

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 cleaning the blood.

Screening for Retinopathy. The American Diabetes Association recommends that patients with type 1 diabetes have an annual comprehensive eye exam, with dilation, to check for signs of retina disease (retinopathy). Patients at low risk may need exams only every 2 - 3 years.

Screening for Neuropathy. All patients should be screened for nerve damage (neuropathy), including a comprehensive foot exam. Patients who lose sensation in their feet should have a foot exam every 3 - 6 months to check for ulcers or infections.

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

Dietary Goals and Exercise

The treatment goals for a diabetes diet are:

• Achieve near-normal blood glucose levels. People with type 1 diabetes must coordinate calorie intake with medication or insulin administration, exercise, and other variables to control blood glucose levels. New forms of insulin now allow more flexibility in timing meals.
• Protect the heart and aim for healthy lipid (cholesterol and triglyceride) levels and control of blood pressure.
• Achieve reasonable weight. A reasonable weight is usually defined as a weight that is achievable and sustainable, rather than one that is culturally defined as desirable or ideal. Children, pregnant women, and people recovering from illness should maintain adequate calories for health.
• Manage or prevent complications of diabetes. People with diabetes, whether type 1 or 2, are at risk for a number of medical complications, including heart and kidney disease. Dietary requirements for diabetes must take these disorders into consideration.
• Promote overall health.

Overall Guidelines. There is no 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, and canola oils; avocados; and nuts) and omega-3 polyunsaturated (fish, flaxseed oil, and 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, and 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 more information, see In-Depth Report #42: Diabetes diet.]

Healthy Weight Control

Weight gain is a potential side effect of intense diabetic control with insulin. Being overweight can increase the risk for health problems. On the other hand, studies suggest that more than one-third of women with diabetes omit or underuse insulin in order to lose weight. Eating disorders have become a serious problem within the general population and are especially dangerous in patients with diabetes. Some evidence suggests that they contribute to about 20% of cases of recurrent ketoacidosis in young women. Ketoacidosis is a significant complication of insulin depletion and can be life threatening.

Exercise

Aerobic exercise has significant and particular benefits for people with type 1 diabetes. It increases sensitivity to insulin, lowers blood pressure, improves cholesterol levels, and decreases body fat. Because glucose levels swing dramatically during workouts, people with type 1 diabetes need to take certain precautions:

• Monitor glucose levels carefully before, during, and after workouts.
• Avoid exercise if glucose levels are above 300 mg/dL or under 100 mg/dL.
• To avoid hypoglycemia, patients should inject insulin in sites away from the muscles they use the most during exercise.
• Before exercising, avoid alcohol and if possible certain drugs, including beta-blockers, which increase the risk of hypoglycemia.
• Insulin-dependent athletes may need to decrease insulin doses or take in more carbohydrates, especially in the form of pre-exercise snacks. Skim milk is particularly helpful. They should also drink plenty of fluids.
• Good, protective footwear is essential to help avoid injuries and wounds to the feet.

Avoid resistance or high impact exercises. They can strain weakened blood vessels in the eyes of patients with retinopathy. High-impact exercise may also injure blood vessels in the feet. Because patients with diabetes may have silent heart disease, they should always check with their doctors before undertaking vigorous exercise.

Warning on Dietary Supplements

Various fraudulent products are often sold on the Internet as “cures” or treatments for diabetes. These dietary supplements have not been studied or approved. The US Food and Drug Administration (FDA) and Federal Trade Commission (FTC) warn patients with diabetes not to be duped by bogus and unproven remedies.

Treatment

Insulin is essential for strict control of blood glucose levels in type 1 diabetes. Tight blood glucose control is the best way to prevent major complications in type 1 diabetes, including those that affect the kidneys, eyes, nerve pathways, and blood vessels. Intensive insulin treatment in early diabetes may even help preserve any residual insulin secretion for at least 2 years.

There are, however, some significant problems with intensive insulin therapy:

• There is a higher risk for low blood sugar (hypoglycemia).
• Many patients experience significant weight gain from insulin administration, which may have adverse effects on blood pressure and cholesterol levels. It is important to manage heart disease risk factors that might develop as a result of insulin treatment.

A diet plan that compensates for insulin administration and supplies healthy foods is extremely important. [For more information, see In-Depth Report #42: Diabetes diet.] Pancreas transplantation eventually may be recommended for patients who cannot control glucose levels without frequent episodes of severe hypoglycemia.

Regimens for Intensive Insulin Treatment

The goal of intensive insulin therapy is to keep blood glucose levels as close to normal as possible.

Standard insulin therapy usually consists of one or two daily insulin injections, one daily blood sugar test, and visits to the health care team every 3 months. For strictly controlling blood glucose, however, intensive management is required. The regimen is complicated although newer insulin forms may make it easier.

There are two components to flexible insulin administration and a number of variations of insulin delivery for accomplishing them:

• Basal insulin administration. The basal component of the treatment attempts to provide a steady amount of background insulin throughout the day. Basal insulin levels maintain regular blood glucose needs. Insulin glargine now offers the most consistent insulin activity level, but other intermediate and long-acting forms may be beneficial when administered twice a day. Short-acting insulin delivered continuously using a pump is proving to a very good way to provide basal rates of insulin.
• Mealtime insulin administration. Meals require a boost (a bolus) of insulin to regulate the sudden rise in glucose levels after a meal.

In achieving insulin control the patient must also take other steps:

• The patient should perform four or more blood glucose tests during the day.
• Patients should coordinate insulin administration with calorie intake. In general, they should eat three meals each day at regular intervals. Snacks are often necessary.
• Insulin requirements vary depending on many non-nutritional situations during the day, including exercise and sleep. People are at enhanced risk for low blood sugar during exercise. Some patients experience a sudden rise in blood glucose levels in the morning -- the so-called "dawn phenomenon."
• The patient must also maintain a good diet plan and should visit the health care team of doctors, nurses, and dietitians once a month.

Because of the higher risk for hypoglycemia in children, experts recommend that intensive treatment be used very cautiously in children under 13 and not at all in very young children.

Types of Insulin

Insulin cannot be taken orally because the body's digestive juices destroy it. Injections of insulin under the skin ensure that it is absorbed slowly by the body for a long-lasting effect. The timing and frequency of insulin injections depend upon a number of factors:

• The duration of insulin action. Insulin is available in several forms, including: standard, intermediate, long-acting, and rapid-acting.
• Amount and type of food eaten. Ingestion of food makes the blood glucose level rise. Alcohol lowers levels.
• The person's level of physical activity. Exercise lowers glucose levels.

Fast-Acting Insulin. Insulin lispro (Humalog) and insulin aspart (Novo Rapid, Novolog) lower blood sugar very quickly, usually within 5 minutes after injection. Insulin peaks in about 4 hours and continues to work for about more 4 hours. This rapid action reduces the risk for hypoglycemic events after eating (postprandial hypoglycemia). Optimal timing for administering this insulin is about 15 minutes before a meal, but it can also be taken immediately after a meal (but within 30 minutes). Fast-acting insulins may be especially useful for meals with high carbohydrates.

Regular Insulin. Regular insulin begins to act 30 minutes after injection, reaches its peak at 2 - 4 hours, and lasts about 6 hours. Regular insulin may be administered before a meal and may be better for high-fat meals.

Intermediate Insulin. NPH (neutral protamine Hagedorn) insulin has been the standard intermediate form. It works within 2 - 4 hours, peaks 4 - 12 hours later, and lasts up to 18 hours. Lente (insulin zinc) is another intermediate insulin that peaks 4 - 12 hours and lasts up to 18 hours.

Long-Acting (Ultralente) Insulin. Long-acting insulins, such as insulin glargine (Lantus), are released slowly. Insulin glargine matches parts of natural insulin and maintains stable activity for more than 24 hours. Studies suggest that it poses less of a risk for hypoglycemia and weight gain than NPH. It has a higher incidence of pain at the injection site than NPH. Ultralente insulin peaks at 10 hours and lasts up to 20 hours but varies greatly in activity from day to day.

Combinations. Regimens generally include combinations of short and longer-acting insulins to help match the natural cycle. For example, one approach in patients who are intensively controlling their glucose levels uses 3 injections of insulin, which includes a mixture of regular insulin and NPH at dinner. Another approach uses 4 injections, including a separate short-acting form at dinner and NPH at bedtime, which may pose a lower risk for nighttime hypoglycemia than the 3-injection regimen.

Insulin Pens. Insulin pens, which contain cartridges of insulin, have been available for some time. Until recently, they were fairly complicated and difficult to use. Newer, prefilled pens (Humulin Pen, Humalog) are disposable and allow the patient to dial in the correct amount.

Inhaled Insulin. In 2006, the FDA approved the first non-injected form of insulin. Exubera is an inhaled form of insulin. Although Exubera was thought to provide an attractive alternative to injected insulin, many patients found the inhaler device to be cumbersome and awkward. In 2008, a warning was added to Exubera’s prescription label describing increased cases of lung cancer found among patients who used the product. Due to safety concerns and poor sales, the drug’s manufacturer announced plans to withdraw Exubera from the market. Other companies have halted development of their inhaled insulin products.

Insulin Pumps

Insulin Pumps. An insulin pump can improve blood glucose control and quality of life with fewer hypoglycemic episodes than multiple injections. The pumps correct for the “dawn phenomenon” (sudden rise of blood glucose in the morning) and allow quick reductions for specific situations, such as exercise. Many different brands are available.

The typical pump is about the size of a beeper and has a digital display. Some are worn externally and are programmed to deliver insulin through a catheter in the skin or the abdomen. They generally use rapid-acting insulin, the most predictable type. They work by administering a small amount of insulin continuously (the basal rate) and a higher dose (a bolus dose) when food is eaten.

Many adults, adolescents, and school children use insulin pumps. A 2006 study found that even very young children (ages 2 - 7 years) can successfully use insulin pumps and that the pumps provided better blood sugar control than twice-daily insulin injections.

The catheter at the end of the insulin pump is inserted through a needle into the abdominal fat of a person with diabetes. Dosage instructions are entered into the pump's small computer, and the appropriate amount of insulin is then injected into the body in a calculated, controlled manner.

Learning to use the pump can be complicated, although over time most patients find the devices are fairly easy to use. To achieve good control, patients and parents of children must undergo some training. The patient and doctor must determine the amount of insulin used -- it is not automatically calculated. This requires an initial learning period, including understanding insulin needs over the course of the day and in different situations and knowledge of carbohydrate counting. Frequent blood testing is very important, particularly during the training period.

Insulin pumps are more expensive than insulin shots and occasionally have some complications, such as blockage in the device or skin irritation at the infusion site. In spite of early reports of a higher risk for ketoacidosis with pumps, more recent studies have found no higher risk.

Supplementary Drugs for Hyperglycemia

Pramlintide (Symlin) is a new type of injectable drug that can help control postprandial hyperglycemia, the sudden increase in blood sugar after a meal. Pramlintide is injected before meals and can help lower blood sugar levels in the 3 hours after meals. Pramlintide is used in addition to insulin for patients who take insulin regularly but still need better blood sugar control. The FDA approved this drug in 2005 for adults with type 1 and type 2 diabetes. Pramlintide and insulin are the only two drugs approved for treatment of type 1 diabetes.

Pramlintide is a synthetic form of amylin, a hormone that is related to insulin. Side effects may include nausea, vomiting, abdominal pain, headache, fatigue, and dizziness. Patients with type 1 diabetes have an increased risk of severe low blood sugar (hypoglycemia) that may occur within 3 hours following a pramlintide injection. This drug should not be used if patients have trouble knowing when their blood sugar is low or have slow stomach emptying (gastroparesis).

Investigational Drugs

Anti-CD3 Antibodies. A new type of drug called an anti-CD3 monoclonal antibody is showing promise for helping patients newly diagnosed with type 1 diabetes. Results from a 2005 trial published in the New England Journal of Medicine indicated that 6-day treatment with the investigational anti-CD3 antibody otelixizumab helped stimulate the patients’ natural insulin production and decreased their need for insulin drug therapy. The beneficial effects lasted up to 18 months after treatment. Otelixizumab is currently in phase III clinical trials, and another anti-CD3 antibody, teplizumab, is in phase II/III trials. Researchers think that anti-CD3 antibody drugs affect the autoimmune response involved in type 1 diabetes and may help preserve the residual beta cell function of the pancreas.

Prevention and Treatment of Hypertension and Heart Disease

Medications for High Blood Pressure Control. 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 that all patients who have diabetes and high blood pressure should take an ACE inhibitor (or ARB) as part of their regimen for treating hypertension.

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).

Statins for Cholesterol Management. Statins are the best cholesterol-lowering drugs. They include atorvastatin (Lipitor), lovastatin (Mevacor and generics), pravastatin (Pravachol), simvastatin (Zocor and 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.

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 cholesterol is beneficial, statins are not as effective as other medications -- such as fibrates and niacin -- in addressing HDL and triglyceride imbalances. This is a common problem in type 2 diabetes. Combining a statin with one of 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 second choice after statins. 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 control lipids without causing serious blood glucose problems. [For more information, see In-Depth Report #23: Cholesterol.]

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. The recommended dose is 75 - 162 mg/day. Patients with diabetes for whom aspirin is recommended include those who have:

• Age over 40 years old
• History of heart problems
• Family history of heart disease
• High blood pressure or elevated cholesterol and
• Smokers

Prevention and Treatment of Retinopathy

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.) Tight control of blood pressure can also help protect against retinopathy. Aspirin therapy does not help prevent retinopathy.

Treatment of Retinopathy. Patients with severe diabetic retinopathy or macular edema (swelling of the retina) should see an eye specialist who is experienced in the management and treatment of diabetic retinopathy. Once damage to the eye develops, laser or photocoagulation eye surgery may be needed. Laser surgery can help reduce vision loss in high-risk patients.

Treatment of Foot Ulcers

About a third of foot ulcers will heal within 20 weeks with good wound care treatments. Some treatments are as follows:

• 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. It is generally reserved for patients with severe, full thickness diabetic foot ulcers that have not responded to other treatments, particularly when gangrene or an abscess is present.
• 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 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.

Treatment of 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, so patients at risk need to be monitored carefully.
• 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.
• Anti-seizure drugs used for peripheral neuropathy pain relief include gabapentin (Neurontin), pregabalin (Lyrica), carbamazepine (Tegretol), and valproate (Depakote). Pregabalin is classified as a controlled substance (like narcotics), which indicates a potential risk for abuse.

Treatments under investigation include acetyl-l-carnitine and intravenous alpha-lipoic acid. Although not well proven to be beneficial, patients may also try 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 also been reported to help 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. Patients need to watch their nutrition if the problem is severe.

Erectile dysfunction is also associated with neuropathy. Studies indicate that phosphodiesterase type 5 (PDE-5) drugs, such as sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), are safe and effective, at least in the short term, for patients with diabetes. Typical side effects are minimal but may include headache, flushing, and upper respiratory tract and flu-like symptoms. Patients who take nitrate medications for heart disease cannot use PDE-5 drugs.

Treatment of Kidney Problems

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. Research indicates that ACE inhibitors are the best class of blood pressure medications for delaying kidney disease and slowing disease progression in patients with type 1 diabetes. Angiotensin-receptor blockers (ARBs) are also very helpful.

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). However, patients with end-stage renal disease who are on dialysis generally need higher amounts of protein. [For more information, see In-Depth Report #42: Diabetes diet.]

Anemia. Anemia is a common complication of end-stage kidney disease. Patients on dialysis usually need injections of erythropoiesis-stimulating drugs to increase red blood cell counts and control anemia. In 2007, the FDA issued new warnings on darbepoetin alfa (Aranesp) and epoetin alfa (Epogen and Procrit). The warnings describe an increased risk for blood clots, stroke, and heart attack, and heart failure in patients with end-stage kidney disease when these drugs are given at higher than recommended doses.

The FDA recommends that patients with end-stage kidney disease who receive erythropoiesis-stimulating drugs should:

• Maintain hemoglobin levels between 10 - 12 g/dL
• Receive frequent blood tests to monitor hemoglobin levels
• Contact their doctors if they experience such symptoms as shortness of breath, pain, swelling in the legs, or increases in blood pressure

[For more information, see In-Depth Report #57: Anemia.]

Treatment of Gestational Diabetes

Some recommendations for preventing pregnancy complications include:

• Intensive blood sugar control during pregnancy may reduce the risk for problems in the infant.
• Monitoring blood glucose after meals may protect against preeclampsia more effectively than monitoring before meals.
• Aerobic exercise before and during pregnancy can lower glucose levels. (All pregnant women, particularly those with diabetes, should check with their doctors before embarking on a rigorous exercise regimen.)
• To prevent birth defects that affect the heart and nervous system, women with diabetes should take a higher dose of folic acid from the time of conception up to week 12 of pregnancy. They should also be checked for any heart problems.
• Women with diabetes should have an eye examination during pregnancy and up to a year afterward.

Although there was some concern that short-acting insulin lispro might increase the risk for birth defects, the most recent evidence suggests that it does not. In fact, some experts believe it achieves a better outcome and should be preferred to regular insulin in pregnant women. More research is needed.

Home Management of Diabetes

Glucose (Blood Sugar) Levels

Both low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia) are of concern for patients who take insulin. It is important, therefore, to carefully monitor blood glucose levels. In general, patients with type 1 diabetes need to take readings four or more times a day. Patients should aim for the following measurements:

• Pre-meal glucose levels of 90 - 130 mg/dL
• Bedtime levels of 110 - 150 mg/dL

Different goals may be required for specific individuals, including pregnant women, very old and very young people, and those with accompanying serious medical conditions.

Finger-Prick Test. A typical blood sugar test includes the following:

• A drop of blood is obtained by pricking the finger.
• The blood is then applied to a chemically treated strip.
• Monitors read and provide results.

Home monitors are about 10 - 15% less accurate than laboratory monitors, and many do not meet the standards of the American Diabetes Association. Most doctors believe, however, that they are accurate enough to indicate when blood sugar is too low.

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.

Some simple procedures may improve accuracy:

• Testing the meter once a month.
• Recalibrating it whenever a new packet of strips is used.
• Using fresh strips; outdated strips may not provide accurate results.
• Keeping the meter clean.
• Periodically comparing the meter results with the results from a laboratory.

Supplementary Monitoring Devices. Other devices are available for monitoring blood glucose. These devices are used in addition to traditional fingerstick test kits, and glucose meters but do not replace them:

• Continuous glucose monitoring systems (CGMS) use a needle-like sensor inserted under the skin of the abdomen to monitor glucose levels every 5 minutes. In 2007, the STS-7 System was approved. Using a disposable sensor, the STS-7 measures glucose levels for up to a week. An alarm will sound if glucose levels are too high or low. The older Minimed system measures glucose over a 72-hour period and has wireless communication between the monitor and an insulin pump.
• GlucoWatch is a battery-powered wristwatch-like device that measures glucose by sending tiny electric currents through the skin, a technique called reverse iontophoresis. It is painless and has a warning device when detecting high glucose levels. It takes 2 hours to warm up, and the sensor pads need to be changed every day. Glucowatch measures glucose levels three times per hour for up to 12 hours. About a quarter of the time, the results differ significantly from actual fingerstick tests, however.

Glycosylated Hemoglobin

Hemoglobin A1c (also called HbA1c , HA1c, or A1C) is measured periodically every 2 - 3 months to determine the average blood-sugar level over the lifespan of the red blood cell. Normal A1C levels should be below 7%. Home tests are also available for measuring A1c.

Urine Tests

Urine tests are useful for detecting the presence of ketones. These tests should always be performed during illness or stressful situations, when diabetes is likely to go out of control. The patient should also undergo yearly urine tests for microalbuminuria (small amounts of protein in the urine), a risk factor for future kidney disease.

Preventing Hypoglycemia

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

• Bedtime snacks are advisable if blood glucose levels are below 180 mg/dL (10 mmol/L). Protein snacks may be best.
• Some research has suggested that children (particularly thin children) are at higher risk for hypoglycemia because the injection goes into muscle tissue. Pinching the skin so that only fat (and not muscle) tissue is gathered or using shorter needles may help.
• Various insulin regimens are available that can reduce the risk. For example, taking a fast-acting insulin (insulin lispro) before the evening meal may be particularly helpful in preventing hypoglycemia at bedtime or during the night.
• 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 particularly critical to monitor blood glucose levels before driving, when hypoglycemia can be very hazardous.
• Patients who are at risk for hypoglycemia should always carry hard candy, juice, sugar packets, or commercially available glucose substitutes.

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, the patient should receive additional sugar by mouth and may need emergency medical treatment, possibly including an intravenous glucose solution.
• Family members and friends can learn to inject glucagon, a hormone, which, in contrast to insulin, raises blood glucose.

Click the icon to see an example of a glucagon kit.

Patients with type 1 diabetes should always wear a medical alert ID bracelet or necklace that states that they have diabetes and take insulin.

Foot Care

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.
• Apply moisturizers, but NOT between the toes.
• Gently use pumice to remove corns and calluses (patients should not use medicated pads or try to shave the corns or calluses themselves.)
• Trim toenials short and file the edges to avoid cutting adjacent toes.
• Well-fitting footwear is very important. People should be sure the shoe is wide enough. Patients should also avoid high heels, sandals, thongs, and going barefoot. Shoes with a rocker sole reduce pressure under the heel and front of the foot 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.
• Changes shoes 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.
• Consult a specialist in foot care for any problems.

Click the icon to see an image of foot inspection.

Transplantation Procedures

Islet-Cell Transplantation

Major advances in islet-cell transplantation are allowing more patients to come off insulin or reduce their use of it.

Major clinical trials are now using a specific islet-cell (also called beta-cell) transplantation procedure called the Edmonton protocol, which usually involves the following steps:

• As soon as there are sufficient numbers of islets available for transplantation, the patient is given intravenous antibiotics and oral vitamins E, B6, and A.
• A machine isolates islet cells taken from donor pancreases, generally from cadavers. Two or three organs are usually needed in order to supply enough islet cells to have any effect on insulin production. (This is a major limitation of the procedure.)
• Once the islets have been isolated, they are injected directly in a major vein in the patient's liver.
• The islets are carried to capillaries in the liver where they produce insulin.
• Specific drugs, such as tacrolimus, sirolimus, or rapamycin (Rapamume), are used to suppress the immune system. (Unlike immunosuppressant drugs used in other transplantation procedures, these drugs do not contain steroids, which destroy islet cells.) Immunosuppressants are needed for the rest of the patient's life so that the body does not reject these foreign islet cells.
• The procedure has to be performed two or more times over a period of 2 - 3 months. This generally requires multiple pancreas donors in order to achieve complete independence from insulin therapy. This is a major limitation to the procedure.

In 2006, the New England Journal of Medicine published the results of the first multicenter trial of the Edmonton protocol. The results indicated that this treatment may benefit some patients with severe type 1 diabetes. Of the 36 patients who underwent the transplant procedure, 44% no longer needed insulin injections a year after the final treatment. However, two-thirds of these insulin-independent patients needed to resume insulin injections within 2 years.

The Edmonton protocol achieved partial islet function in 28% of patients, which helped control hypoglycemic unawareness, a serious complication of diabetes. (In hypoglycemic unawareness, patients no longer recognize the symptoms of severe low blood sugar.) Even though these patients still needed insulin shots, they had better control of their diabetes. Researchers are continuing to work on refining the Edmonton protocol so that its benefits can be more sustainable and long lasting.

A major obstacle for the islet cell transplantation is the need for two or more donor pancreases to supply sufficient islet cells. Unfortunately, there are not enough pancreases available to make this procedure feasible for even 1% of patients. Researchers, then, are looking for alternative sources for islet cells. In one center, for example, researchers used pig islet cells as the donor source in children and did not administer immunosuppressant drugs. Half the children responded well to this approach. Another study reported that select patients may require only one donor.

Other research is focusing on umbilical cord cells, embryonic or adult stem cells, bone marrow transplantation, and other types of cellular therapies. These studies are still in very early stages, but experts predict that there will be major research advances in these fields in the coming years. A small, preliminary study published in 2007 in the Journal of the American MedicalAssociation looked at the effects of autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) in patients newly diagnosed with type 1 diabetes. AHST is an experimental treatment for type 1 diabetes. It involves treating a patient with high doses of drugs to suppress the immune system, then harvesting the patient’s own blood cells and re-infusing them back into the body. In the study, 14 out of 15 patients who underwent AHST were able to stop taking insulin shots.

Organ Transplantation

Whole pancreas transplants and double transplants of pancreases and kidneys are proving to have a good long-term success rate for some patients with type 1 diabetes. The operations help to prevent further kidney damage, and long-term studies indicate that they may even eventually reverse some existing damage. There is some evidence that heart disease and diabetic neuropathy improve after pancreas transplantation (although not retinopathy). However, this procedure has significant surgical and postsurgical complications in patients with diabetes. One 10-year study reported that survival rate at 10 years was 76%, and two-thirds of the patients had both pancreas and kidney function. Immunosuppressive drugs are needed lifelong with this procedure. Experts generally recommend transplants in cases of end-stage kidney failure or when diabetes poses more of a threat to the patient's life than the transplant itself.

Uncontrolled diabetes causes damage to many tissues of the body, including the kidneys. Kidney damage caused by diabetes most often involves thickening and hardening of the internal kidney structures. Strict blood glucose control may delay the progression of kidney disease in type 1 and type 2 diabetics.

Resources

• www.diabetes.org -- American Diabetes Association
• www.niddk.nih.gov -- National Institute of Diabetes and Digestive and Kidney Diseases
• www.jdrf.org -- Juvenile Diabetes Research Foundation
• www.nei.nih.gov -- National Eye Institute
• www.eatright.org -- American Dietetic Association
• www.kidney.org -- National Kidney Foundation
• www.diabetestrialnet.org -- Type 1 Diabetes International Clinical Trial Net
• www.medicalert.org -- Bracelets or neck chain emblems with personal medical information
• www.childrenwithdiabetes.com -- Children with diabetes online community

References

Alemzadeh R and Wyatt DT. Diabetes mellitus. In: Kliegman RM, ed. Nelson Textbook of Pediatrics. 18th edition. Saunders; 2007:chap 590.

American Diabetes Association. Standards of medical care in diabetes -- 2008. Diabetes Care. 2008 Jan;31 Suppl 1:S12-54.

American Diabetes Association (ADA). Standards of medical care in diabetes. VI. Prevention and management of diabetes complications. Diabetes Care. 2007 Jan;30(Suppl 1):S15-24.

Camilleri M. Clinical practice. Diabetic gastroparesis. N Engl J Med. 2007 Feb 22;356(8):820-9.

Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group, Jacobson AM, Musen G, Ryan CM, Silvers N, Cleary P, et al. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med. 2007 May 3;356(18):1842-52.

Farrar D, Tuffnell DJ, West J. Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD005542.

Fiorina P, Secchi A. Pancreatic islet cell transplant for treatment of diabetes. Endocrinol Metab Clin North Am. 2007 Dec;36(4):999-1013; ix.

Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006 Nov 16;355(20):2071-84.

Hakonarson H, Grant SFA, Bradfield JP, Marchand L, Kim CE, Glessner JT, et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature. 2007 Aug 2;448(7153):591-4. Epub 2007 Jul 15.

Hunt D. Foot ulcers and amputations in diabetes. Clin Evid. 2006 Jun;(15):576-84.

McMahon GT, Arky RA. Inhaled insulin for diabetes mellitus. N Engl J Med. 2007 Feb 1;356(5):497-502.

SEARCH for Diabetes in Youth Study Group , Liese AD, D'Agostino RB, Hamman RF, Kilgo PD, Lawrence JM, et al. The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006 Oct;118(4):1510-8.

Pieber TR, Treichel HC, Hompesch B, Philotheou A, Mordhorst L, Gall MA, et al. Comparison of insulin detemir and insulin glargine in subjects with Type 1 diabetes using intensive insulin therapy. Diabet Med. 2007 Jun;24(6):635-42. Epub 2007 Mar 22.

Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006 Sep 28;355(13):1318-30.

Skyler JS. Cellular therapy for type 1 diabetes: has the time come? JAMA. 2007 Apr 11;297(14):1599-600.

Vardi M, Nini A. Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus. Cochrane Database Syst Rev. 2007 Jan 24(1):CD002187.

Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, Pieroni F, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2007 Apr 11;297(14):1568-76.

Writing Group for the SEARCH for Diabetes in Youth Study Group , Dabelea D, Bell RA, D'Agostino RB, Imperatore G, Johansen JM, et al. Incidence of diabetes in youth in the United States. JAMA. 2007 Jun 27;297(24):2716-24.

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