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In This Report

•	Highlights
•	Introduction
•	Causes
•	Risk Factors
•	Symptoms
•	Life-Threatening Complicati...
•	Diagnosis
•	Dietary Goals and Exercise...
•	Treatment
•	Monitoring Tests
•	Long-Term Complications
•	Transplantation Procedures...
•	Prevention
•	Resources

Related Reports

•	Diabetes Diet
•	Diabetes: Type 2

Encyclopedia

•	Type 1 diabetes
•	Diabetes

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Diabetes: Type 1

Highlights

New Treatments

• Duloxetine (Cymbalta), a new designer antidepressant, has been approved for treatment of pain associated with diabetic peripheral neuropathy.
• Pregabalin (Lyrica) has been approved for neuropathic pain management.

Research Findings

Thiazolidinediones. Pioglitazone (Actos) works better than rosiglitazone (Avandia) when it comes to improving triglyceride and HDL lipid levels. All thiazolidinediones can cause liver damage; patients who take these drugs should have their liver enzymes checked regularly.

Acetyl-l-carnitine. The dietary supplement may relieve diabetic neuropathic pain, particularly if treatment is initiated when symptoms first begin.

Screening Tests

Fasting Plasma Glucose (FPG) Test

• FPG levels up to 100 mg/dl are considered normal.
• Levels between 100 and 126 mg/dl are referred to as impaired fasting glucose or pre-diabetes.
• Diabetes is diagnosed when FPG levels are 126 mg/dl or higher.

Oral Glucose Tolerance Test (OGTT)

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

Glucose Monitoring Tests: Recommended Levels

• Pre-prandial (before eating) plasma glucose levels between 90-130 mg/dl.
• Post-prandial (after eating) glucose levels less than 180 mg/dl.
• Hemoglobin A1C levels less than 7%.
• Blood glucose levels should be checked regularly (several times per day).

Heart Disease Tests: Recommended Goals for Diabetics

• Cholesterol goals: LDL below 100 mg/dl; HDL above 60 mg/dl; triglycerides below 150 mg/dl.
• Blood pressure goals: 130/80 mmHg or lower.

All patients with diabetes should be tested for hypertension and unhealthy cholesterol and lipid levels.

Other Screening Tests

• Kidney function. Microalbuminuria levels should be tested to monitor kidney function.
• Foot care. Neuropathy is a serious complication of diabetes and can pose a risk for foot ulcers. Patients should inspect their feet daily for changes in color, texture, or odor.
• Eye exams. Patients should receive annual eye exams to check for retinopathy.

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 normally works in the following way:

• During and immediately after a meal the process of 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 ten minutes after a meal insulin rises to its peak level.
• Insulin then 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 two to four 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, 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. An estimated 16 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 type 2 diabetics 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% to 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.

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's syndrome, Huntington's chorea, Wolfram's syndrome, leprechaunism, Rabson-Mendenhall syndrome, lipoatrophic diabetes, and others) and hormonal disorders (acromegaly, Cushing's 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 seven 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% to 90% of the beta cells have been destroyed.

It should be noted that more than half of those with insulitis does 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 that are related to type 1 diabetes. They appear to involve abnormal interactions among normal genes, mostly those known as I and II major histocompatibility genes, which affect the immune response.

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 an enteric virus of particular interest. (One study has suggested that respiratory infection in a child's first year, and not later, may be protective against diabetes, perhaps by priming the immune response so that it is better able to respond later on to other organisms.)

Risk Factors

Up to 1,000,000 people in the U.S. are estimated to have type 1 diabetes, with about 30,000 new cases diagnosed each year. It is much less common than type 2, however, consisting of only 7% to 10% of all cases of diabetes. Nevertheless, like type 2 diabetes, the incidence in type 1 has been rising over the past few decades in certain regions of the U.S. and some European countries, particularly in Finland and England.

Risk Factors in Children

Type 1 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 breast fed increased the risk for type 1 diabetes. Two studies in 2003 suggested that very early exposure to cereal--not cow's milk--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.
• Having an older mother.
• Having a mother with type 1 diabetes.
• Having a mother who had preeclampsia during pregnancy.
• Obesity in children has long been linked to a higher risk for type 2 diabetes. Two 2001 studies reported an association between high weight at birth and obesity during childhood as risk factors for type 1 diabetes as well. 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 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 between 8% and 45% of new diabetes cases in children are now type 2, most likely because of the increase in childhood obesity. [SeeWell-Connected Report #60 Diabetes Type 2.]

Having Other Immune Abnormalities

The incidence of type 1 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, in fact, 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). And 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 are, mostly due to lower-quality health care.

Symptoms

The process that destroys the insulin-producing beta cells can be a long and insidious one. 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.

Life-Threatening Complications

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 levels in order to lose weight. In one study, adolescent girls were at higher risk for ketoacidosis than other groups of children and young people.

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 include the following:

• Nausea and vomiting.
• Breathing may be abnormally deep and rapid with frequent sighing.
• The heartbeat may be rapid.
• 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 now suggests that the risk for this complication is significantly higher in children with severe ketoacidosis (indicated by low carbon dioxide levels and high nitrogen urea levels), and possibly if they are also treated with bicarbonate to reduce acid levels. More careful research is warranted.
• 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 employs rapid rehydration using a 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

Intensive insulin control increases the risk of hypoglycemia (also called insulin shock), which occurs if blood glucose levels fall below normal. Hypoglycemia may also be caused by insufficient intake of food, or excess exercise or alcohol. Usually the condition is manageable, but occasionally, it can be severe or even life threatening, particularly if the patient fails to recognize the symptoms.

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 are the following conditions:

• Intensively controlling blood glucose and HbA1c levels.
• Having long-term diabetes.
• Being less educated on the condition.
• Being underinsured.
• Also having psychiatric disorders.

Hypoglycemia unawareness. This is a condition in which people become insensitive to hypoglycemic symptoms, usually after experiencing severe episodes. It affects about 25% of those who use insulin. 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, such patients can often regain the ability to sense the symptoms. One 2001 study found that by temporarily letting up on glucose control and then tightening it again, diabetics could "reset" their awareness of hypoglycemic symptoms.

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

• Sweating.
• Trembling.
• Hunger.
• Rapid heartbeat.

Severely low blood glucose levels can precipitate neurologic symptoms:

• 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.

• Nocturnal hypoglycemia (which occurs during sleep) is a common problem for children, even those on nonintensive insulin therapy. (The risk for hypoglycemia is high in any case in children.) Bedtime snacks are advisable if blood glucose levels are below 180 mg/dL (10 mmol/L). Protein snacks may be best. (The use of the insulin pump may help prevent hypoglycemic episodes.)
• 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.
• For patients taking insulin, 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.
• 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.
• Diabetic patients on therapies that put them at risk for hypoglycemia should always carry hard candy, juice, sugar packets, or commercially available glucose substitutes designed for diabetic individuals.

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, possibly including the intravenous administration of a 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.

Experts have been concerned that the increased incidence of hypoglycemia accompanying strict blood glucose control could cause mental deterioration over time, but a six-year study has found no evidence of this in adolescents and adults. (The effect on young children, however, is not known.)

Diagnosis

Testing for Glucose Abnormalities

Fasting Plasma Glucose. The fasting plasma glucose (FPG) test is the standard test for diabetes. It is a simple blood test taken after eight 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 between 100 and 126 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 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.

Glucose Tolerance Test. The oral glucose tolerance test (OGTT) uses the following procedures:

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

The following results suggest different conditions:

• OGTT levels are normal up to 140 mg/dl
• Levels between 140 mg/dl and 200 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 tests require that the patient not eat for at least 8 hours prior to the test.

The oral glucose tolerance test is used to diagnose diabetes mellitus. 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 who have diabetes will have higher than normal levels of glucose in their blood.

Test for Glycated Hemoglobin. Another test examines blood levels glycated hemoglobin, also known as hemoglobin A1c (HbA1c). Measuring glycated hemoglobin is not currently used for an initial diagnosis, but it may be useful for determining the severity of 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 glycation.
• Glycation affects a number of proteins, and elevated levels of glycolated hemoglobin is 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% to 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. 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 called autoantibodies that attack the islet cells. These antibodies are referred to as autoantibodies, because they attack the body's own cells -- not a foreign invader. Fingerstick blood tests are now feasible that can test for these autoantibodies, which may be useful in differentiating between type 1 and type 2 diabetes.

Screening Tests for Complications

Screening for Heart Disease. All patients should be tested for hypertension and unhealthy cholesterol and lipid levels and given an electrocardiogram. In terms of cholesterol, diabetics should aim for LDL levels below 100 mg/dl, HDL levels over 60 mg/dl, and triglyceride levels below 150 mg/dl. Blood pressure goals should be 130/80 mmHg or lower. Other tests may be warranted in patients with signs of heart disease.

Click the icon to see an image of an ECG.

Screening for Kidney Damage and High Blood Pressure. The earliest manifestation of kidney damage is microalbuminuria, in which tiny amounts (30 to 299 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.

Of note, high blood pressure is strongly associated with diabetic nephropathy. In fact, patients with type 2 diabetes who show signs of microalbuminuria typically already have hypertension.

Type 1 diabetes patients with microalbuminuria, on the other hand, usually have normal blood pressure readings in the doctor's office. A 2002 study using home monitors, however, found that in type 1 patients, 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, then, may help identify type 1 patients at risk for kidney damage.

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

Dietary Goals and Exercise

The treatment goals for a diabetes diet are the following:

• To 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 are now allowing more flexibility in timing meals.
• To protect the heart and aim for healthy lipid (cholesterol and triglyceride) levels and control of blood pressure.
• To achieve reasonable weight. Overweight type 2 diabetics who are not taking medication should aim for a diet that controls both weight and glucose. A reasonable weight is usually defined as what is achievable and sustainable, rather than one that is culturally defined as desirable or ideal. Children, pregnant women, and people recovering from illness should be sure to maintain adequate calories for health.
• To 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.
• To promote overall health.

Overall Guidelines. There is no longer a single diabetes diet that will suit everyone. The overall approach is based on the U.S. Dietary Guidelines for healthy eating for all Americans, and includes the following:

• Overall, experts recommend that foods containing carbohydrate from whole grains, nuts, fruits, vegetables, and low-fat milk should be included in any healthy diet.
• Carbohydrates and monounsaturated fat should provide 60% to 70% of calories, but the mix should depend on calorie intake needed for weight loss or maintenance.
• Avoid saturated fats (found in animal products) and trans fatty acids (hard margarines, commercial products, fast foods). In selecting fats or oils, prefer monounsaturated fats (virgin olive oil, canola oil), although also include polyunsaturated oils as well (sunflower, rapeseed). Of note, a 2001 report suggested that trans fatty acids were a risk factor for type 2 diabetes while polyunsaturated were protective.
• Limit protein. Protein should provide 15% to 20% total calories (less in people with nephropathy.) In selecting proteins, eat in moderation and prefer fish or soy protein to poultry or meat. (Avoid, in any case, high-fat meats.)
• When choosing foods with sugar, choose fresh fruits, but do so in moderation.

[For detailed information, seeWell-Connected 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 diabetic women 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 diabetics. Some evidence suggests that they contribute to about 20% of cases of recurrent ketoacidosis in young women. Ketoacidosis is significant complication of insulin depletion and can be life threatening.

Exercise

Aerobic exercise is proving to have 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 diabetes need to take certain precautions:

• They should monitor glucose levels carefully before, during, and after workouts.
• Patients should probably avoid exercise if glucose levels are above 300 mg/dL or under 100 mg/dL.
• To avoid hypoglycemia, diabetics should inject insulin in sites away from the muscles they use the most during exercise.
• Before exercising, they should also 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 in the feet.

Resistance or high impact exercises should be avoided. 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 diabetics may have silent heart disease, they should always check with their physicians before undertaking vigorous exercise.

Treatment

Insulin is essential for strict control of blood glucose levels in type 1 diabetes, which is now established as the best way to prevent major complications in type 1 diabetes, including in the kidney, eyes, nerve pathways, and blood vessels. Although its effects on heart disease and stroke are less clear, evidence suggests intensive control will also have benefits for these major problems. Intensive insulin treatment in early diabetes may even help preserve any residual insulin secretion for at least two years.

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

• There is a higher risk for hypoglycemia, a possibly dangerous drop in blood glucose levels.
• 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 cardiovascular risk factors that might develop as a result of intensive treatment.

A diet plan that compensates for insulin administration and supplies healthy foods is extremely important. [For detailed information, see Well-Connected 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 therapy is to keep blood glucose levels as close to normal as possible. In one major study, even when levels were 40% higher than nondiabetic levels, benefits were still observed.

Standard insulin therapy is usually one or two insulin injections, one daily blood sugar test, and visits to the health care team every three months. For strictly controlling blood glucose, however, intensive management is required. The regimen is complicated although newer insulin forms are reporting ease of use with better control. Recent approaches for insulin administration attempt to mimic nature.

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 required.
• 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.

Insulin Forms

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-, 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.

Regular Insulin. Regular insulin (R) begins to act 30 minutes after injection, reaches its peak at two to four hours and lasts about six to eight hours or longer after that. Regular insulin may be administered before a meal and may be better for high-fat meals.

Intermediate-Acting Insulin. NPH (neutral protamine Hagedorn) insulin has been the standard intermediate-acting form. It works within one to two hours, peaks at four to 10 hours, and lasts up to 16 hours. Lente (insulin zinc) is another intermediate-acting insulin that peaks between four to 12 hours and up to 18 hours.

Long-Acting 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 are suggesting that it pose less of a risk for hypoglycemia and weight gain than NPH. It has a higher incidence of pain at the injection site than NPH. Detemir, another basal insulin form, is being investigated and might pose a lower risk for weight gain than others. Ultralente insulin peaks at 10 hours and lasts up to 20 hours but varies greatly in activity from day to day.

Fast-Acting Insulin. Insulin lispro (Humalog) and insulin aspart (Novo Rapid, Novolog) lower blood sugar very quickly and are short acting (lasting about four hours). This short action reduces the risk for hypoglycemic events after eating (postprandial hypoglycemia). Optimal timing for administering this insulin is about fifteen minutes before a meal, but it can be also taken immediately after a meal (but within 30 minutes). Fast-acting insulins may be especially useful for meals with high carbohydrates. In one study, lispro helped reduce the risk for nighttime hypoglycemia in children. Evidence suggests that short-acting insulin may improve quality of life compared to regular insulin. There is some concern that short-acting forms may cause birth defects if pregnant women take them. More research is needed to define the risk.

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 three injections of insulin, which includes a mixture of regular insulin and NPH at dinner. Another approach uses four-injections, including a separate short-acting form at dinner and NPH at bedtime, which may pose a lower risk for nighttime hypoglycemia than the three-injection regimen.

Alternative Methods for Delivering Insulin

Insulin Pumps. The use of the insulin pump is proving to control blood glucose control and improve quality of life with fewer hypoglycemic episodes than multiple injections. The pumps correct for the so-called dawn phenomenon and allow quick reductions for specific situations, such as exercise. Many brands are available (e.g., IR-1000, Cozmo, H-Tron Plus, D-Tron Plus, Minimed Paradigm, Dana Diabecare II.)

The typical pump is about the size of a pack of 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, which is 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.

At this time, adults and adolescents use the pumps, but they are proving to be helpful for children with diabetes, even very young children.

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 they are fairly easy to use. To achieve good control, patients and parents of children must undergo some training. The user and physician 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.

They 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 the pumps, more recent studies have found no higher risk.

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 Aerosol. Investigative oral insulin forms are receiving a lot of attention as a possible replacement for insulin shots. Some are inhaled (Eubera) or administered using a spray that is absorbed in the cheek lining (Oralin). Inhalants cannot completely replace injections altogether but may be useful before meals. They also might be useful for people with type 2 diabetes or in emergency situations when a rapid insulin boost is needed. The spray may have better effects on cholesterol levels than the inhaled form does. In fact, some studies report higher cholesterol levels with the inhaled insulin. The reasons for this are unclear.

Other Alternative Insulin Delivery Methods. Another promising avenue of investigation for delivering insulin is the use of ultrasound pulses.

Supplementary Agents Used to Prevent Postprandial Hyperglycemia

In addition to rapidly acting insulin, other agents are being investigated for control of postprandial hyperglycemia, the sudden increase in blood sugar after a meal, in patients with type 1 diabetes. Postprandial hyperglycemia is now believed to be a significant long-term threat to the body.

Pramlintide. Pramlintide (Symlin), known as an amylin analog, is derived from a natural hormone that acts in concert with the body's insulin in the pancreas to control hyperglycemia. It slows stomach emptying and delays absorption of nutrients in the intestine. It, therefore, prevents the surge in blood sugar that typically occurs after meals. It is proving to help control glucose after meals in combination with insulin, regardless of whether it is regular or fast-acting insulin or delivered with a pump. It does not appear to add any greater risk for weight gain or hypoglycemia. It is being considered for approval for both type 1 and type 2 insulin-dependent diabetes. No serious adverse effects have been reported to date. There is some concern that the delay in stomach emptying may pose problems for diabetics who are already experiencing this as a complication of neuropathy.

Monitoring Tests

Glucose (Blood Sugar) Levels

Both hypoglycemia and hyperglycemia are of concern for patients who are receiving insulin. It is important, therefore, to monitor blood glucose levels carefully. 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 between 90 and 130 mg/dL.
• Bedtime levels of between 110 and 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.
• Home monitors are generally used to provide results.

Home monitors are about 10% to 15% less accurate than laboratory monitors are and many do not meet the standards of the American Diabetes Association. Many experts believe, however, that most 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.

Less Invasive or Noninvasive Tests. A number of noninvasive or less painful tests are on the market or under investigation. The following are some examples:

• A battery-powered wristwatch-like device (GlucoWatch) 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 three hours to warm up and the sensor pads need to be changed every day. About a quarter of the time, it differs significantly from actual fingerstick tests, however, so it should be used to supplement, not replace, blood tests. Nevertheless, in one study it was very effective in improving glucose control in children and was well tolerated. The device in the study also included an alarm that allowed detection of nighttime hypoglycemia. Refinements in the technique should improve accuracy.
• The continuous glucose monitoring system (Minimed) uses a needle-like sensor inserted under the skin, which is attached to a beeper-like computer device worn by the patient. Glucose is measured every five minutes, and the results are stored in the device. After five days, the patient removes the sensor and the physician obtains data from the device, which is then used to identify trends and insulin needs. It is does not replace fingerstick tests.
• Some monitors, such as Sof-Tact and FreeStyle, have been designed to obtain blood from areas of the skin that are less sensitive. Both appear to be less painful than standard methods.
• Investigative pain-free monitors include laser devices (Altea MicroPor), microneedles, and infrared devices.

Glycated Hemoglobin

Hemoglobin A1c (HbA1c), or glycated hemoglobin, is measured periodically to determine the average blood-sugar level over the life span of the red blood cell, which is about eight to 10 weeks. In general, measurements suggest the following:

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

Home tests (DRx, Metrika A1c Now) are available for measuring HbA1c that may allow even better monitoring of glucose levels. Metrika A1c Now is now sold over the counter.

Urine Tests

Urine tests are useful for detecting the presence of ketones, which 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.

Eye Examinations

For patients beginning intensive insulin therapy, experts recommend an eye examination when starting treatments and every three months thereafter up to a year.

Long-Term Complications

Type 1 diabetes reduces the normal life span by an average of five to eight years. In general, however, survival rates are improving in all ethnic groups and both genders. Longer survival rates are probably due to improvements in monitoring and closer 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 7.0. This is proving to prevent complication 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. Evidence is merging that control of blood glucose also helps the heart, but its benefits most likely accrue over time. It is very important that people with diabetes control blood pressure, cholesterol levels, and other factors associated with heart disease.

Complications of Heart and Circulation

Heart attacks account for 60% and strokes for 25% of deaths in all diabetics. Diabetes effects 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 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. And some experts estimate that the mortality rates from neuropathy-related heart conditions ranges between 15% and 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.

Intensive 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 has been shown to be protective against heart attacks. In one 2000 study, low-dose aspirin was associated with a 30% lower risk for death from heart disease in adults with type 2 diabetes. Of note: people who are at risk for retinopathy should discuss the possible benefits of high-dose aspirin with their physician.

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). (Controlling systolic pressure may be especially important for reducing the risk for kidney complications.)

Anti-hypertensive agents that block angiotensin are the first option for may people with diabetes. Angiotensin is 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. Drugs that block them are ACE inhibitors and ARBs:

• Angiotensin-converting enzyme (ACE) inhibitors are the standard agents for people with diabetes and hypertension. They include captopril (Capoten), enalapril (Vasotec), quinapril (Accupril), benazepril (Lotensin), ramipril (Altace), perindopril (Aceon), and lisinopril (Prinivil, Zestril). These agents have remarkable benefits for people with diabetes, including reducing the risks of heart attack, stroke, and death. ACE inhibitors also delay the onset and progression of kidney disease. In many cases, however, combinations are required to achieve blood pressure goals. In such cases, low-dose diuretics or calcium-channel blockers are added as needed.
• Angiotensin-receptor blockers (ARBs), also known as angiotensin II receptor antagonists, are newer drugs that are similar to ACE inhibitors in effectiveness. They may have fewer side effects. Brands include losartan (Cozaar, Hyzaar), olmesartan (Benicar) candesartan (Atacand), telmisartan (Micardis), eprosartan (Teveten), irbesartan (Avapro), and valsartan (Diovan). In one study, ARBs appeared to reduce the risk of developing diabetes. Other studies have also reported protection against kidney disease even in people with normal blood pressure, making them particularly beneficial for people with diabetes.

Combinations of the two are under investigation, and studies suggest such combinations may be beneficial for people with diabetes and kidney disease.

Other anti-hypertensive agents may be important for specific groups. Diuretics appear to be more beneficial than ACE inhibitors for African Americans with diabetes. In one major study, these patients had lower rates of stroke and heart failure than those taking ACE inhibitors. Beta blockers, another group of anti-hypertensive agents, may have more benefits for patients with existing heart disease, although more research is needed to confirm this.

[For more information, seeWell-Connected Report #14 High Blood Pressure.]

Improving Cholesterol and Lipid Levels. Abnormal cholesterol and lipid levels are common in diabetes. High LDL cholesterol should always be lowered, but people with diabetes also often have additional harmful imbalances--low-HDL cholesterol and high triglycerides. Patients should aim for LDL levels below 100 mg/dl, HDL levels over 60 mg/dL and triglyceride levels below 150 mg/dL.

Statins are currently the best cholesterol-lowering agents for people with diabetes. They include pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), and atorvastatin (Lipitor). These agents are very effective for lowering LDL cholesterol levels. In addition, evidence suggests that statins reduces the risk for adverse heart events in people with even mild diabetes and in those with normal cholesterol levels. Furthermore, in one study, a statin was shown to reduce the risk by 30% of developing diabetes in people with high cholesterol. (Statins, however, do not appear to have any effect on blood vessel inflexibility in diabetes, which is an important risk factor for heart disease in these patients.) The primary safety concern with statins in people with diabetes 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 or niacin, in addressing HDL and triglyceride imbalances--a common problem in type 2 diabetes.

Combinations of statins with one these agents, then, may be important in people with diabetes. 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 fenofibrate (Tricor) and bezafibrate (Bezalip), are usually the first choice. Niacin has the most favorable effect on HDL and triglycerides of all the cholesterol drugs. However, about 30% of patients who take niacin experience elevated blood glucose levels. On the positive side, some studies have reported that diabetics who use niacin had little trouble with glucose control. In addition, niacin-statin therapy reduces the progression of heart disease. Some experts believe it now may be used as an alternative to or in combination with statins. Combinations with a new agent ezetimibe (Zetia) may also be beneficial. Ezetimibe inhibits the absorption of cholesterol in the intestines and is proving to be a very useful adjunct to statins for lowering LDL levels.

[For more information, seeWell-Connected Report #23 Cholesterol, Other Lipids, and Lipoproteins.]

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.

Treatment and Prevention of Nephropathy. Long-term studies are now reporting a 60% reduction in new cases of nephropathy with strict blood glucose control and a delay in progression of the disease. Targeting specific preventive measures may especially protect against kidney disease. They include maintaining glycolated hemoglobin levels at 7% or below, controlling blood pressure--particularly systolic pressure, and lowering not only LDL cholesterol but also triglycerides.

The antihypertensive drugs ACE inhibitors are proving to protect against progression of kidney disease even in people with normal blood pressure. They are now the agents of choice for both preventing and managing nephropathy in type 1 diabetes. Newer agents called angiotensin-II-receptor blockers (ARBs), such as losartan (Cozaar) and irbesartan (Avapro), are also helpful for both conditions.

Sulodexide is an agent based on a natural substance called a glycosaminoglycan, which helps reduce blood clotting. Studies are suggesting that it may help prevent nephropathy with few side effects. (It also may be helpful for foot ulcers.)

If the kidneys fail, the patient will need to go on dialysis. Symptoms of kidney failure may include swelling in the feet and ankles, itching, fatigue, and pale skin color.

Neuropathy

Diabetes reduces or distorts nerve function causing a condition called neuropathy. It particularly affects sensation. It is a common complication that affects nearly half of both type 1 and type 2 diabetics after 25 years. Neuropathy usually starts in the fingers and toes and moves up to the arms and legs (called a stocking-glove distribution). Symptoms include the following:

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

The most serious consequences of neuropathy affect the legs and feet and pose a risk for ulcers and, in very severe cases, amputation. In some cases, neuropathy may mask angina, the warning chest pain for heart disease and heart attack. Diabetic patients should be aware of other warning signs of a heart attack, including sudden fatigue, sweating, shortness of breath, nausea, and vomiting.

Neuropathy Pain and its Treatment. Studies show that tight control of blood glucose levels also delays the onset and slows progression of neuropathy, although there is some concern that the increased incidence of hypoglycemia with intensive insulin control may actually cause nerve damage.

A number of agents are used for neuropathy depending on its effects. Some used for neuropathy pain include the following:

• Topical medications, particularly capsaicin (the active ingredient in hot peppers), are commonly used for local neuropathy pain. One study reported that a spray containing isosorbide dinitrate, which helps open blood vessels, was helpful in reducing burning and pain in about half of patients.
• Alpha lipoic acid dramatically improved neuropathy in one study when administered intravenously to a group of patients with diabetes. Animal studies suggest that this potent antioxidant may have nerve-protective properties. Alpha lipoic acid is available over-the-counter. However, this substance is not regulated in the US and, as with all natural remedies, the safety and effectiveness of over-the-counter supplements cannot be guaranteed.
• Acetyl-l-carnitine is another supplement that may help relieve pain, particularly if treatment is initiated when symptoms first appear. It is currently used more commonly in Europe than in the United States, but results from clinical trials have been positive.
• 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 have adverse effects on heart rhythm, which make them problematic for many patients, particularly elderly ones.
• Duloxetine (Cymbalta) is a serotonin and norepinephrine reuptake inhibitor, a newer type of antidepressant, that was approved in 2004 for treatment of pain associated with diabetic peripheral neuropathy.
• Pregabalin (Lyrica) was aprroved in December 2004 for neuropathic pain management. Pregabalin will be classified as a controlled substance (like narcotics) which indicates a potential risk for abuse.
• Anti-seizure drugs, such as gabapentin (Neurontin) or valproate, may prove to an effective alternative for treating painful neuropathy.
• Transcutaneous electrostimulation involves administering mild electrical pulses to painful areas. Some evidence suggests this procedure may help reduce pain, particularly in combination with a tricyclic.
• Tramadol (Ultram), a painkiller that is similar to opioids, achieved moderate pain reduction in one study and may have fewer side effects than anti-seizure drugs or tricyclics. It carries a slight risk for addiction. Nausea, headache, and constipation are common.

Other Complications of Neuropathy. Neuropathy also affects other functions and treatments are needed to reduce their effects as well. 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.

Impotence in men 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 diabetics experience serious foot problems. They are the leading cause of hospitalizations for these patients.

Diabetes is responsible for more than half of all the lower limb amputations performed in the U.S. Each year there are about 88,000 non-injury amputations and between 50% and 75% of them are due to diabetes. Worse, the number is increasing as the prevalence in diabetes type 2 rises. 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. 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.

According to a 2003 government survey, 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 had had the disease for more than 20 years and were insulin-dependent were at the highest risk. Related conditions that put people at risk include peripheral neuropathy, peripheral arterial disease, foot deformities, and a history of ulcers.

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 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 could significantly reduce the risk of ulcers and amputation. Some tips for preventing problems include the following:

• 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 diabetic patients wear shoes that are too narrow. Patients should also avoid high heels, sandals, thongs, and going barefoot. Shoes with a rocker sole (e.g., LucRo) reduce pressure under the heel and front of the foot by 35% to 65% and may be particularly helpful. Custom-molded boots (e.g., Conformer Diabetic Boot) 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 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.

Click the icon to see an image of foot inspection.

Treating Foot Ulcers in Diabetes. About one-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 (e.g. irrigation) means.
• Hydrogels (Nu-Gel, Intrasite Gel, Scherisorb, Clearsite, Duoderm, Geliperm) are helpful in healing ulcers and are noninvasive and soothing.
• Felted foam appears to be helpful in healing ulcers on the sole of the foot.

Investigative Agents for Treating Foot Ulcers. A number of recent investigative agents and procedures for treating foot ulcers include the following:

• Cultures of human skin cells or human skin equivalent (HSE) (e.g., Dermagraft, Apligraf, or Regranex) stimulate new cell growth and help heal skin ulcers. Studies are showing that HSE promotes healing and the risk for rejection of such grafts is low. Adverse effects include infections at other sites.
• Administering hyperbaric oxygen (oxygen given at high pressure) is showing promise in promoting healing. In one study, for example, patients who had had ulcers that had not responded to treatment for over three months received daily treatments that lasted 90 minutes for two 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.
• Sulodexide is an agent based on a natural substance called a glycosaminoglycan, which helps reduce blood clotting. Studies are suggesting that it may be helpful for treating foot ulcers but improving blood flow.
• Granulocyte-colony stimulating factor, or G-CSF (filgrastim, Neupogen, Amgen) has accelerated healing and significantly reduced the need for surgery in some studies. A 2003 study, however, indicated that offered no additional advantages compared with antibiotics and bed rest.
• Low-molecular weight heparin, which is a blood thinner, is being investigated for treating foot ulcers.
• Monochromatic near-infrared photo energy (MIRE) uses light therapy to improve sensation in the feet of patients with peripheral neuropathy.

Devices to Heal Ulcers and Protect the Foot. Researchers are also using or investigating various devices to heal or prevent ulcers. The following are some examples:

• 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 is useful for ulcer healing and for Charcot foot. Although it is very effective in healing ulcers, recurrence is common.
• Noncontact normothermic wound therapy (Warm-UP) uses a unit that applies infrared radiant heat for an hour three times a day. In one study, 70% of the wounds treated were healed compared to 40% that received standard gauze treatments. More research is needed to determine if this approach has any advantages over other measures.
• Felted foam uses a multi-layered foam pad over the bottom of the foot with an opening over the ulcer. Small studies have suggested that it is effective in healing ulcers in this area.

Retinopathy and Eye Complications

Diabetes accounts for 12,000 to 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, seeWell-Connected Report #26 Cataractsor 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, however. 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, possibly causing severe visual loss or blindness. The sensation of seeing flashing lights may indicate retinal detachment.

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 six years after diagnosis. Any patient on insulin or who has had diabetes for more than 20 years should have a yearly eye examination. Patients with no signs of retinal damage or risk factors for retinopathy may only require screening every three years.

Click the icon to see an animation on diabetic retinopathy.

Prevention of Retinopathy. Fortunately, severe and even moderate vision loss is largely preventable with intensive control of blood glucose levels. (Note: intense glucose control can cause early worsening of retinopathy, although this is nearly always counterbalanced by long-term benefits.) Measures for reducing risks to the heart (e.g., ACE inhibitors for lower blood pressure and drugs that improve cholesterol) may also have protective 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 physicians.

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.

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 slow 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% to 15% during flu epidemics and they are six times more likely to be hospitalized with complications from flu than nondiabetics who have flu. Everyone with diabetes should have influenza vaccinations annually 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 also helps 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 fracture. The best medications for bone loss in patients with diabetes may be 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 Well-Connected 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 are at risk for falling, which compounds the risk for fracture.

Other Complications

Other complications of diabetes include the following:

• Diabetics have a slightly higher prevalence of hearing loss than nondiabetics.
• Up to half of people with diabetes are at risk for nonalcoholic fatty liver disease, also called nonalcoholic steatohepatitis (NASH). It is a particular danger in people who are obese.
• Women with type 2 diabetes face a higher risk for uterine cancer, although only if they are obese. Both women and men with diabetes appear to have a higher risk for colon and rectal cancers.
• Much evidence exists on the link between type 1 and type 2 diabetes and periodontal disease. People with these diseases have 15 times the risk of the nondiabetic population.

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 hyperglycemia may effect 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:

• It leads to excessive fetal growth.
• It may also contribute to delayed maturation of the lungs or to the death of the fetus.
• It increases the risk for birth defects. (In one study the risk for some kind of malformations in the infant was 4.8% in women who were diabetic before their pregnancies. It was only 1.5% in nondiabetic women and 1.2% in women who developed gestational diabetes during pregnancy.)

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. Pregnant women with diabetes are also at greater risk for retinopathy.

Some suggestions for preventing complications include the following:

• 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 physicians before embarking on a rigorous exercise regimen.)
• Women with diabetes should have an eye examination during pregnancy and up to a year afterward.

Of note: 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.

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 in 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.

Self-Destructive Behaviors. One study found that young people with diabetes have a higher than average rate of suicidal fantasies. Although the actual rate of suicide was no higher than that of their nondiabetic peers, such thoughts are strongly associated with self-destructive behavior.

Of particular note, up to one-third of young women with type 1 diabetes have eating disorders and underuse insulin to lose weight. Anorexia and bulimia pose significant health dangers in any young person--but they can be especially severe in people with diabetes.

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 taken 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 agents, such as tacrolimus, sirolimus, or rapamycin (Rapamume), are used to suppress the immune system. (Unlike immunosuppressant drugs used in other transplantation procedures, these agents used 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 two to three months. This generally requires multiple pancreas donors in order to achieve complete independence from insulin therapy. This is a major limitation to the procedure.

The need for two or more donor pancreases to supply sufficient islet cells is particularly troublesome, since 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 agents. Half the children responded well to this approach. Another study reports that selected patients may require only one donor. Other research is focusing on using stem cells and cells from embryos to produce insulin, but any advances in these areas are years away.

Organ Transplantation

Whole pancreas transplants and double transplants of pancreases and kidneys are proving to have a good long-term success rate for selected type 1 patients. The operations help to prevent further kidney damage, and long-term studies are finding that they may even eventually reverse some existing damage. There is some evidence that heart disease and diabetic neuropathy improves after pancreas transplantation (although not retinopathy). One 10-year study reported that survival rate at 10 years was 76.3%, and two-thirds of the patients had both pancreas and kidney function. Immunosuppressive drugs are also needed life-long with this procedure. Experts are now recommending transplants in cases of end-stage kidney failure or when diabetes poses more of a threat to the patient's life than does 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.

Prevention

Fingerstick blood tests are now available that can test for autoantibodies that identify children who are at high risk for developing type 1 diabetes. At this time, however, there is no way to prevent type 1 diabetes and all preventive therapies are investigative. Until there are ways to prevent the condition, however, such screening tests are expensive and provide little value.

Although insulin is the mainstay of type 1 diabetes treatment, research is ongoing to develop other approaches that might, in time, even be curative. The basis for nearly all experimental measures for prevention and treatment of type 1 diabetes is stabilization of beta cells. Preventive measures are sometimes defined as primary and secondary:

• Primary prevention attempts to preserve all beta cells before the disease process starts.
• Secondary prevention hopes to deter further beta cell destruction once it has started and before symptoms arise.

The following are some investigative approaches.

• One approach uses the body's own immune system to impede or prevent beta-cell destruction. Genetically designed antibodies called monoclonal antibodies (MAbs) are being developed that target factors believed to trigger the disease process. In a small 2002 study, for example, the use of an anti-CD3 MAb helped maintain residual insulin or even improve insulin production in nine out of 12 patients over the course of a year. More studies are underway.
• Another target is insulin-like growth factor-I (IFG-I), which regulates islet beta cell and protects against type 1 diabetes. The substance itself is unstable, however. Researchers are looking for similar compounds that may be a more reliable source for drug development. One such agent, IGF-I/IGFBP-3 complex, is showing promise.

A unique anti-inflammatory compound, lisofylline, inhibited immune factors that attacked beta cells in mouse studies. Human trials are probably years away.

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.islet.org -- The Islet Foundation
• www.medicalert.org -- Bracelets or neck chain emblems with critical personal medical information
• www.insulinfree.org -- Insulin-Free World
• www.childrenwithdiabetes.com -- Information on children with diabetes
• www.insulin-pumpers.org -- Support site for people on insulin pumps

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