ComplicationsofDiabetesMellitus

Foreword

Preface

Psychosocial Problems
Prevention
Detection
Treatment
References

Acute Glycemic Complications
Diabetic Ketoacidosis; Background
Prevention
Guidelines for Sick Days
Record for Sick Days
Detection
Treatment
Hyperglycemic Hyperosmolar Nonketotic Coma
Prevention
Detection
Treatment
Hypoglycemia
Prevention
Detection
Treatment
Teaching Patients to Avoid Acute Glycemic Complications
References

Adverse Outcomes of Pregnancy
Pregestational and Gestational Diabetes; Background
Caring for the Patient With Pregestational Diabetes
Treatment
Caring for the Patient With Gestational Diabetes
Treatment
References

Disease
Prevention
Detection
Treatment
References

Eye Disease
Prevention of Diabetic Retinopathy
Detection and Monitoring of Diabetic Retinopathy
Treatment and Referral
References

Kidney Disease
Prevention
Detection
Treatment
References

Cardiovascular Disease
Prevention
Detection
Treatment
References

Neuropathy
Prevention
Detection
Differential Diagnosis
Treatment
References

Foot Problems
Prevention
Detection and Monitoring
Treatment
References

Appendix A, Office Guide

Acknowledgments

POINT OF CONTACT FOR THIS DOCUMENT:

Tables
Clinical Manifestations Of Eye Diseases
Example of An Office Guide

Figures
Natural History Of Diabetic Nephropathy In Persons With Insulin

Foreword

The scope of the present revised edition has been broadened to cover nine complications of diabetes, and the recommendations for the previous five. We anticipate continued widespread use of this guide in assisting practitioners in the care of their patients with diabetes. The recommendations are clear, practical, and based upon scientific evidence, and they can be generally implemented in an office practice. We believe that they are conceptually consistent with the American Medical Association’s new emphasis on practice parameters.

Although this publication is meant to provide freestanding and practical assistance in an office practice, the most appropriate use is in continuing education programs and workshops. In these settings, the practical application of the recommendations can be discussed and barriers to their application in individual practices overcome.

We congratulate the Centers for Disease Control in its efforts to update this guide and wish it the same success as the previous edition.

Charles M. Clark, Jr., M.D.
Indiana University School of Medicine
Indianapolis, Indiana

Preface

An office guide is included as an appendix. The office guide is a brief synopsis of the recommendations contained in the body of the text and is designed so that it may be photocopied and placed in the patient’s medical record.

A companion publication entitled Take Charge of Your Diabetes: A Guide for Patients is available. It is written in nontechnical language and emphasizes the same preventive measures and treatments. The sequence of the chapters corresponds with the sequence in this document.

William H. Herman, M.D.
University of Michigan Medical Center
Ann Arbor, Michigan

Psychosocial Problems

Description. Like other chronic illnesses, diabetes mellitus poses a wide range of problems for patients and their family members. These problems include pain, hospitalization, changes in lifestyle and vocation, physical disabilities, and threatened survival. Direct psychological consequences can arise from any one of these factors, making it harder for patients to treat their diabetes and live productive, enjoyable lives.

Populations at risk —

Diabetes itself does not cause changes in personality or psychiatric illness, but particular subgroups of the diabetic population appear to be at risk for developing psychosocial problems. Young people with insulin- dependent diabetes mellitus (IDDM) may have a higher prevalence of eating disorders, such as anorexia nervosa and bulimia, and adults with longstanding diabetes and major medical complications have a higher prevalence of symptoms of depression and anxiety. Elderly persons who have non-insulin-dependent diabetes mellitus (NIDDM) and other symptomatic medical conditions may also have a higher risk of developing psychological problems.

Patients with IDDM diagnosed before age 5 and older patients with NIDDM may have associated alterations in cognitive or intellectual functioning. The pathophysiology of these cognitive changes is not well understood. In the young patients, these cognitive changes may be linked to recurring episodes of severe hypoglycemia. In the older patients, both microvascular and artherosclerotic disease are possible factors.

Barriers to self-care.

Research has indicated that psychological and social factors can profoundly influence a patient’s success at adhering to a prescribed regimen of self- care. Patients may fail to care for themselves if they have certain attitudes or beliefs, including the following:

• Anticipating an early cure.
• Believing that their self-care regimen is too difficult.
• Believing that treatment is unlikely to improve or control their health problems.

Several other psychosocial factors can influence how well patients care for themselves:

• Stressful events in the patient’s life.
• Development of a new complication.
• The availability and quality of social support for the patient.
• Psychiatric problems unrelated to the patient’s diabetes.
• The health care provider’s approach to medical care.

This therapeutic alliance will take shape over time, through discussions identifying the patient’s expectations of, and feelings about, treatment. Although the patient should not be forced to set particular goals, the practitioner may be able to broaden or refine existing objectives to include improving the patient’s adjustment to having diabetes.

Over time, this alliance may lead to better glycemic control by helping the patient address such self-care barriers as low motivation, preconceived judgments about treatment, and fears about diabetes.

Some psychosocial barriers stem from personal, family, and cultural beliefs that may conflict with suggested treatment. A patient may resist following a prescribed diet, for instance, because of certain cultural beliefs about weight. Such beliefs should be given their due respect; patients respond best to advice that does not seem to prejudge their beliefs.

Certain medical conditions can be reliable indicators of Psychosocial barriers. Recurrent hypoglycemia, frequent episodes of diabetic ketoacidosis, and very high glycosylated hemoglobin levels should each be recognized as a possible sign of personal or family problems. Although brittle, or unstable, diabetes can sometimes have a metabolic basis, interrupted or erratic self-care is by far a more common cause–and psychosocial problems may underlie this cause.

To help uncover problem areas, the practitioner may want to conduct discussions along the following lines:

• Ask patients to describe how they feel about the following issues of self-care:
  • The importance of glycemic control.
  • The feasibility of adhering to a prescribed diet.
  • The importance of self-monitoring of blood glucose.
  • The patient’s susceptibility to developing complications.
  • The efficacy of treating complications.
  • The reasonableness of the practitioner’s recommendations and expectations.
  • Ask patients to describe any stressful events or situations, such as changes in job, school, place of residence, and immediate family (for example, death or divorce). Ask whether any other events could be creating barriers to a self-care program.
  • Determine whether patients have adequate social and family support. Specifically, ask patients to whom they can turn for help in caring for themselves.
  • Ask about problems concerning mood, anxiety, and sense of well-being.
  • Ask young women who might be at risk for eating disorders whether they have skipped insulin doses, dieted excessively, eaten in binges, or vomited.
  • Ask specific questions about topics that patients may hesitate to talk about, such as sexual problems.
  • Determine how effectively patients use available information about diabetes. Ask whether they find it difficult to retain or add to such knowledge.

The practitioner may then be able to counsel patients and provide useful solutions.

The practitioner will need to identify, for possible referral, mental health professionals who are knowledgeable about diabetes and who can serve as collaborators in treating the patient. If these individuals are not familiar with diabetes, they can be given materials (such as this guide) that provide basic information.

Refer the following persons:

• Parents of children or adolescents in whom diabetes has recently been diagnosed. A single psychosocial evaluation of the family unit may be important to the overall educational process of raising a child who has diabetes.
• Patients who in one year have had two or more episodes of severe hypoglycemia or diabetic ketoacidosis without obvious causes.
• Patients whom you–the health care professional–find frustrating. The mental health professional may prove a valuable consultant for treating these patients.

Remember that diabetes is a chronic illness. Even if treatment activities fail to bring change within a short time, remaining involved with the patient and the patient’s family and providing an accepting atmosphere may lead to increased motivation for change.

Encourage patients and their families to attend group sessions. Medical and psychosocial information can be given at these sessions, which can also provide a forum for discussion of personal concerns. These sessions can be led by health care professionals, including physicians, nurses, and dietitians, and may meet several times a year. Local diabetes organizations may sponsor or know of such groups.

Patient Education Principles:

• Inform patients about the typical personal concerns that come with diabetes, about the problems faced in accepting the disease and adapting to it, and about the impact diabetes has on emotional and social functioning.
• Involve families in treatment and education sessions.
• Encourage parents to help their young children and adolescents who are having problems controlling their diabetes.
• Encourage parents to give adolescents increasing responsibility for their diabetes–but not to force them to take these steps.
• Encourage families to provide help for their older relatives, who may find insulin difficult or frightening to use or who may have trouble changing lifelong dietary habits.
• Encourage families to ensure that school nurses and teachers are educated about the needs of children with diabetes and that nursing homes provide proper treatment to elderly patients with diabetes.

Feste C. The Physician Within. Minneapolis: Diabetes Center, 1987.

Jacobson AM, Hauser ST. Behavioral and psychological aspects of diabetes. In: Ellenberg M, Rifkin H, eds. Diabetes Mellitus: Theory and Practice. 3rd ed. Vol. 2. New Hyde Park, New York: Medical Examination, 1983.

Acute Glycemic Complications

In diabetes mellitus, severe hyperglycemia may result from absolute or relative insulin deficiency. In some patients, the condition may culminate in diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma. Profound hypoglycemia may result from a relative excess of insulin. Symptoms associated with acute hyperglycemia generally develop more slowly (over hours or days) than do symptoms associated with an acute fall in the level of blood glucose (over minutes).

Occurrence. The annual incidence of DKA ranges from three to eight episodes per 1,000 persons with diabetes. It is much more common among persons with insulin-dependent diabetes mellitus (IDDM) than among those with non-insulin-dependent diabetes mellitus (NIDDM).

DKA may be the initial manifestation of previously unrecognized IDDM. More often, DKA develops in persons known to have diabetes. Patients with IDDM who fail to take insulin or who do not receive extra insulin during flulike illness, pneumonia, or myocardial infarction may develop DKA. Patients with NIDDM who experience severe stress may secrete more contra-insulin hormones; these further compromise limited insulin secretion, which may in turn lead to DKA.

Morbidity and mortality. Before insulin was available, patients with diabetes often died of DKA; now, the mortality rate associated with DKA is less than 5%. However, persons who develop DKA experience pain and suffering, lose time from school or work, have increased hospitalization rates, and have high medical costs. Serious medical sequelae include cerebral edema (in young people), aspiration pneumonia, and adult respiratory distress syndrome.

Three general circumstances may allow DKA to develop:

• Low index of suspicion.
• Inappropriate cessation of insulin therapy.
• Mismanagement of intercurrent illness, often due to inadequate education.

Index of suspicion. Many people may not know the signs and symptoms of diabetes. At times, even when a person seeks medical help, a health care provider may fail to recognize the warning signs of hyperglycemia–particularly when the patient is very young (an infant), is very old (such as an octogenarian), or has unusual symptoms (such as mental deterioration without nausea or vomiting).

Therefore, to prevent DKA or to minimize its extent, the health care provider must have a high index of suspicion for DKA. In emergency rooms, clinics, and physicians’ offices, routine use of a glucose/ketone urine dipstick may allow for early identification of decompensating diabetes.

Inappropriate cessation of insulin therapy. Under circumstances such as those described below, insulin therapy may be inappropriately discontinued.

• Adolescents with diabetes may not adhere to a prescribed program, and their parents may not provide appropriate supervision.
• Patients with major emotional or psychosocial problems may fail to adhere to their usual medical program.

Intercurrent illness. Both patients and health care providers may incorrectly assume that when no food or fluid is consumed, no insulin should be taken. However, when ill or stressed, the patient with diabetes should promptly test the glucose level in blood and/or urine and test the urine for ketones. The patient should follow a sick-day protocol and consult with the health care provider. Both patients and providers must understand the proper management of diabetes during intercurrent illness. (See "Guidelines for Sick Days".)

Analysis and referral. For the patient who has experienced DKA, the health care provider should do the following:

• Determine why DKA occurred.
• Assess the patient’s self-care practices.
• Modify individual guidelines (as appropriate).
• Implement preventive measures to prevent subsequent episodes.

When recurrent episodes of DKA occur, the practitioner should determine the medical and psychosocial components of the episodes. Patients with difficult-to-manage IDDM should be referred to a diabetologist. Patients with underlying psychosocial problems should be referred to a mental health professional.

The guidelines and record for sick days on the following page are adapted from Take Charge of Your Diabetes: A Guide for Patients. Review these guidelines and discuss them with patients before illness occurs. Explain how to keep a record, and stress the importance of self-monitoring.

Health care provider’s name:

Health care provider’s telephone number:

1. If you feel too sick to eat normally, call your health care provider right away. Describe in detail how you feel. 2. Keep taking insulin when you feel sick. Don’t stop taking insulin even if you can’t eat. Your health care provider may change your insulin dose or may tell you to drink liquids that have sugar in them.
3. Weigh yourself every day and write down your weight. 4. Take your temperature every morning and evening. Write down the readings. (For small children or for someone who is breathing through the mouth, use a rectal thermometer.) If your temperature is above normal (99 F), drink extra liquids.
5. If you weigh 80 pounds or more, try to drink at least 12 eight- ounce glasses of liquid per day. Write down how much you drink. If you throw up, call your health care provider right away. You may need to go to the hospital or have special medical treatment. 6. Every 4 hours or before every meal, measure the glucose level in your blood. Write down the results. If the level is less than 60 mg/dL or consistently higher than 240 mg/dL, call your health care provider. Every 4 hours or each time you pass urine, test your urine for ketones and write down the results.
7. If you start to have trouble breathing, call your health care provider (or have someone do it for you) or go to a nearby emergency room. 8. Every 4 to 6 hours, write down whether you feel awake or sleepy. If you feel very sleepy or can’t concentrate, have someone call your health care provider right away.
9. If your health care provider asks you to, call every day to describe your daily record (see "Record for Sick Days" below). Your health care provider may adjust your daily insulin dosage.

How often Question Answer Every day How much do you weigh today? _____ pounds Every evening How much did you drink today? _____ glasses Every morning What is your temperature? AM ______ and every evening PM ______ Every 4 hours How much medication Time Dose or before did you take? ______ ______ every meal ______ ______ ______ ______ ______ ______ ______ ______ ______ ______ Every 4 hours What is the level of Time Level or before glucose in your blood? ______ ______ every meal ______ ______ ______ ______ ______ ______ ______ ______ ______ ______ Every 4 hours What is the level of Time Level or each time ketones in your urine? ______ ______ you pass urine ______ ______ ______ ______ ______ ______ ______ ______ ______ ______ Every 4 to How are you Time Condition 6 hours breathing? ______ ______ ______ ______ ______ ______ ______ ______ ______ ______ ______ ______

If you feel unusually sleepy or can’t concentrate, have someone call your health care provider or take you to an emergency room.

• Altered mental status.
• Fatigue.
• Weight loss.
• Blurred vision.
• Thirst.
• Excessive urination.
• Enuresis.
• Abdominal pain.
• Nausea or vomiting.

Monitoring. All patients with IDDM should be taught to prevent DKA. Encourage patients to monitor their blood glucose level and advise them to monitor the urine for ketones when the blood glucose level is 240 mg/dL or more and/or acute illness develops.

Insist that patients contact you promptly when the blood glucose level remains at 240 mg/dL or more, ketonuria develops, or acute illness persists.

Periodically assess how proficient patients are with self- monitoring and reassess their understanding of self-care during acute illness. (See "Guidelines for Sick Days".)

If DKA is mild and the patient is quickly responding to therapy, replacement of fluids, electrolytes, and insulin may occur in the emergency room. If DKA is more severe, hospitalize the patient at once to ensure adequate treatment and monitoring of the clinical state until recovery ensues. An intensive care unit is the preferred site for the treatment of severe DKA.

Health care providers whose experience with DKA is episodic and infrequent should not hesitate to arrange for the patient’s prompt referral to a specialist experienced in the care of patients with DKA. A detailed summary of the treatment of DKA is available in the American Diabetes Association’s Physician’s Guide to Insulin- Dependent (Type 1) Diabetes.

Note: See "Patient Education Principles".

Definition. Hyperglycemic hyperosmolar nonketotic coma (HHNKC) is characterized by severe hyperglycemia (glucose level typically greater than 600 to 800 mg/dL), dehydration, and altered mental status — in the absence of ketosis. In HHNKC, hyperglycemia causes glycosuria. Osmotic diuresis results in volume contraction and a reduction in both the glomerular filtration rate and glucose excretion. Worsening hyperglycemia causes further extracellular hypertonicity and intracellular dehydration.

Central nervous system dysfunction in persons with HHNKC is probably due to hyperosmolarity. The absence of ketosis has not been entirely explained but may be due to the secretion of insulin in amounts sufficient to suppress ketogenesis.

Occurrence. HHNKC occurs most often among persons over 60 years of age. Most persons with HHNKC have a history of NIDDM, but in a sizable minority, NIDDM is undiagnosed or untreated. When persons who are chronically ill, debilitated, or institutionalized have mild renal insufficiency and lack normal thirst mechanisms or access to water, they are at risk of developing HHNKC. Acute illnesses (stroke, myocardial infarction, or pneumonia), drugs (diuretics or glucocorticoids), surgery, and, occasionally, large glucose loads (through enteral or parenteral nutrition or peritoneal dialysis) may precipitate HHNKC.

Severity. The mortality rate for HHNKC has been reported to be as high as 50%, primarily because of the age of the population most at risk and the acute precipitating causes.

• Has a history of NIDDM.
• Has an altered level of consciousness.
• Takes diuretics or glucocorticoids.
• Lacks free access to drinking water.
• Has a poor support system at home or lives in a nursing home.
• Is receiving enteral or parenteral nutrition.

Early diagnosis of diabetes or early identification of worsening hyperglycemia will permit appropriate therapy that will prevent the development of HHNKC.

When therapy is successful, the patient may be significantly sensitive to further insulin. Ultimately, the patient may achieve metabolic control through diet and/or oral agents.

Note: See "Patient Education Principles".

Occurrence. Any person with diabetes who takes an oral hypoglycemic agent or insulin may experience low blood glucose. Severe hypoglycemia occurs more often in patients who are following an intensified insulin therapy protocol (with the target glucose level near the normal range), whose diet and activity vary widely, who have a long duration of diabetes, and/or who have autonomic neuropathy. Patients with a history of severe hypoglycemia are at increased risk for future episodes. Often the cause is multifactorial. A delay or decrease in food intake, vigorous physical activity, and alcohol consumption all may contribute.

By emphasizing the relation between hypoglycemia and delayed or decreased food intake or increased physical activity, you may help patients anticipate and avoid the condition. If patients regularly and correctly monitor their blood glucose level, impending hypoglycemia may be avoided. Patients who know how to treat hypoglycemia can reduce its impact and severity.

To minimize the risk of hypoglycemia, cooperation is required between the patient, family members, other persons close to the patient (including friends, teachers, and colleagues), and health care providers. Stress the importance of such persons knowing the signs and symptoms of hypoglycemia and how to treat it.

Severe hypoglycemia occurs when the patient ignores, inappropriately treats, lacks, or does not recognize the early warning signs or when glucose counterregulation fails to return the blood glucose level to normal.

Person Action _________________________________________________________________________ Patient Eat 10 to 15 grams of rapidly absorbable carbohydrate (3 to 5 pieces of hard candy, 2 to 3 packets of sugar, or 4 ounces of fruit juice) to abort the episode. Repeat in 15 minutes, as necessary. Friend or If the patient is unable to treat himself or herself, family administer oral carbohydrate. If the patient is unable to member swallow, administer glucagon subcutaneously or intramuscularly. For children younger than 3 years of age, give 0.5 mg glucagon; for children 3 years of age and older and for adults, give 1.0 mg. Practitioner If the patient shows signs and symptoms of severe hypoglycemia, administer glucagon or inject 25 grams of sterile 50% glucose intravenously. Analyze the cause of the episode. Often, a modest reduction in the insulin dosage should be advised. Reeducate the patient about preventing hypoglycemia by discussing the timing of meals and physical activity, the use of alcohol, and the frequency of self-monitoring of blood glucose. Those patients who develop hypoglycemia while taking oral hypoglycemic agents should be closely monitored for at least 48 to 72 hours to prevent a possible recurrence.

Patient Education Principles:
For patients with diabetic ketoacidosis–

• Be sure your patients with diabetes know the following:
  • If they are at risk for DKA.
  • When they are most susceptible to DKA.
  • What they can do to prevent DKA.
  • When they should contact you.

For patients with hyperglycemic hyperosmolar nonketotic coma–

• Remind persons responsible for the elderly, the infirm, or the chronically ill to look for the signs and symptoms of diabetes when their patients do not thrive. Recommend that a blood glucose screening test be performed at the bedside.

For patients with hypoglycemia–

• Ensure that patients who use oral hypoglycemic agents or insulin understand the signs and symptoms, causes, and treatment of hypoglycemia.
• Instruct patients who use oral hypoglycemic agents or insulin to wear a bracelet or necklace that identifies them as having diabetes and to carry sugar or some other source of simple carbohydrate that can be used to promptly treat hypoglycemia.
• Advise persons with diabetes to tell close friends, teachers, or colleagues about their diabetes, how to recognize hypoglycemia, and what to do if an emergency occurs.
• Ensure that patients particularly prone to hypoglycemia who are treated with insulin have glucagon available and that family members and friends know how to administer it.
• Instruct patients with diminished awareness of the signs and symptoms of hypoglycemia to monitor their blood glucose levels at frequent intervals so that unexpected episodes can be recognized early and more severe hypoglycemia forestalled.
• Consider changing the level of diabetes control in the following patients:
  • Those who do not or cannot recognize the early warning signs of hypoglycemia.
  • Those who do not understand the educational details of avoiding or treating hypoglycemia.
  • Those whose lifestyle makes them vulnerable to life-threatening episodes of hypoglycemia.

Butts DE. Fluid and electrolyte disorders associated with diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic coma. Nursing Clinics of North America. 1987;22:827-836.

Carroll P, Matz R. Uncontrolled diabetes in adults. Diabetes Care. 1983;6:579-585.

Casparie AF, Elzing LD. Severe hypoglycemia in diabetic patients. Diabetes Care. 1985;8:141-145.

Consensus statement of self-monitoring of blood glucose. Diabetes Care. 1987;10:95-99.

The DCCT Research Group. Diabetes Control and Complications Trial (DCCT): results of feasibility study. Diabetes Care. 1987;10:1-19.

Foster DW, McGarry JD. The metabolic derangements and treatment of diabetic ketoacidosis. New England Journal of Medicine. 1983;309:159-169.

Keller U. Diabetic ketoacidosis: current views on pathogenesis and treatment. Diabetologia. 1986;29:71-77.

Kitabchi AE, Matteri R, Murphy MB. Optimal insulin delivery in diabetic ketoacidosis and hyperglycemic, hyperosmolar nonketotic coma. Diabetes Care. 1982;5(suppl 1):78-87.

Physician’s Guide to Insulin-Dependent (Type I) Diabetes: Diagnosis and Treatment. Alexandria, Virginia: American Diabetes Association, 1988.

Physician’s Guide to Non-Insulin-Dependent (Type II) Diabetes: Diagnosis and Treatment. 2nd ed. Alexandria, Virginia: American Diabetes Association, 1988.

Sperling MA. Diabetic ketoacidosis. Pediatric Clinics of North America. 1984;31:591-610.

Adverse Outcomes of Pregnancy

When a woman who is known to have diabetes becomes pregnant, she is said to have pregestational diabetes. When a woman develops diabetes during pregnancy or is first recognized as having this condition during pregnancy, she is said to have gestational diabetes. Each year, approximately 10,000 infants are born to women with pregestational diabetes, and 60,000 to 90,000 infants are born to women with gestational diabetes.

The factor most important to the outcome of pregnancy is how well the mother’s glucose level is controlled before and during pregnancy. When women with diabetes receive optimal care, the perinatal mortality rate for their offspring approaches the corresponding rate for the general population. However, when pregnant women with diabetes do not receive expert treatment, the perinatal mortality rate for their offspring more than doubles.

Human placental lactogen reaches its peak late in pregnancy; during the third trimester, insulin requirements rise. Gestational diabetes most often appears during this period of maximum insulin resistance, and ketoacidosis may be seen — particularly in patients with insulin-dependent diabetes mellitus who do not increase their insulin dose appropriately.

Effect on the fetus. Because glucose crosses the placenta by facilitated diffusion, maternal hyperglycemia produces fetal hyperglycemia. Fetal hyperinsulinemia occurs in response to this abnormal metabolic environment. Hyperinsulinemia, combined with hyperglycemia, leads to excessive fetal growth. It may also contribute to intrauterine fetal death, delayed fetal pulmonary maturation, and neonatal hypoglycemia.

The incidence of major congenital malformations is increased approximately fourfold among infants of women with pregestational diabetes. Approximately 9% of pregnancies complicated by pregestational diabetes result in the birth of infants with central nervous system, cardiac, renal, skeletal, and other malformations. Major malformations may occur in 20% to 25% of infants born to women with very poor glycemic control during organogenesis, as evidenced by markedly elevated glycosylated hemoglobin levels during the first trimester.

Other factors that may increase the risk for fetal anomalies include early age at onset of maternal diabetes and microvascular disease in the mother. The earlier the age at onset of pregestational diabetes, the worse the prognosis is for successful pregnancy.

Effect on the mother. Pregnancy may be associated with exacerbation of diabetic eye disease, especially in women with unrecognized or untreated proliferative diabetic retinopathy. Diabetic women with nephropathy and hypertension are at greater risk for preeclampsia and fetal growth retardation than are women without nephropathy. Death has been reported among pregnant women with diabetes and coronary artery disease.

The outcome of pregnancy complicated by pregestational diabetes is improved when care begins before conception. Each visit with a woman of childbearing age who has diabetes should be considered a preconceptional visit. Discuss family planning and ask the patient her thoughts about a future pregnancy.

Results of a glycosylated hemoglobin test provide overall assessment of glycemic control. Pregnancy should be deferred until excellent glycemic control is achieved, as indicated by a normal or near normal glycosylated hemoglobin level. Counsel patients about nutrition and teach them how to monitor their blood glucose levels and how to adjust their insulin treatment.

For patients who are planning to become pregnant, establish baseline data that can be used to assess maternal and perinatal risk, including the following:

• History of diabetic ketoacidosis and severe hypoglycemia.
• Blood pressure measurement.
• Eye examination.
• Quantitative assessment of renal function and urinary protein or albumin excretion.
• Electrocardiogram (if indicated).

Patients whose pregnancy is complicated by diabetes often experience significant emotional and financial stresses. Assess the patient’s emotional or psychosocial support and financial resources through discussion with the patient, her partner, and her family.

Emphasize the dangers of smoking and of consuming alcohol when pregnant.

• An obstetrician or a specialist in maternal-fetal medicine.
• An internist or diabetologist.
• A pediatrician or neonatologist.
• A diabetes educator.
• A dietitian.
• A social worker.

Every effort should be made to refer patients to medical centers that can provide comprehensive support. If such referral is not possible, members of the health care team should frequently consult with each other by telephone.

Glucose level. Excellent control of maternal diabetes is a critical objective both before and during pregnancy. During normal pregnancy, mean maternal plasma glucose levels rarely exceed 120 mg/dL and range from fasting levels of 60 mg/dL to 2-hour postprandial levels of 120 mg/Dl. Use these values as the therapeutic objective for patients whose pregnancies are complicated by pregestational diabetes.

Diet. During the latter half of pregnancy, the patient with pregestational diabetes needs to eat approximately 35 kilocalories per kilogram of her ideal prepregnancy body weight each day, or approximately 2200 to 2400 calories per day. A weight gain of 24 to 28 pounds is recommended for most patients; however, for obese patients with noninsulin-dependent diabetes mellitus, the preferred daily dietary intake is 25 kilocalories per kilogram of ideal prepregnancy body weight, or approximately 1600 to 1800 calories per day.

The calories should be derived as follows: approximately 50% from complex carbohydrates, 30% from fats, and 20% from proteins. Patients will require three meals and up to three snacks each day. A bedtime snack is particularly important to decrease the risk of nocturnal hypoglycemia.

Monitoring. Patients with insulin-treated diabetes should monitor their blood glucose levels at least four times a day — either before or 2 hours after each meal and at bedtime. Before breakfast, patients should test for ketones in their urine. Ask patients to record results in a log book and to note any changes in diet and exercise and any problems with hypoglycemia.

Measure the glycosylated hemoglobin level at least once each trimester to assess overall glycemic control.

Insulin therapy. Patients treated with oral hypoglycemic agents should be switched to insulin before they become pregnant. Human insulin should generally be used. Patients with insulin-treated diabetes require an individualized insulin regimen based on their exercise plan and blood glucose levels.

Most patients will require at least two injections a day of a mixture of intermediate-acting (NPH or lente) and short-acting (regular) insulin. Selected patients may be treated with multiple daily injections (that is, regular insulin before each meal and an injection of intermediate- or long-acting ultralente| insulin at bedtime). For some patients, continuous subcutaneous insulin infusion is an option, but it appears to offer no significant advantage over multiple daily injections. Patients who prefer the flexibility offered by the pump may be started on such therapy, and those who have used a pump before pregnancy may continue to do so.

Fetal assessment. Maintain a program of fetal assessment throughout pregnancy. Measure the maternal serum alpha-fetoprotein level at 16 weeks of gestation to screen for neural tube defects and other fetal anomalies. Perform a detailed ultrasonographic examination at 16 to 18 weeks of gestation. If indicated, assess the fetal cardiac structure by echocardiography at 20 weeks of gestation. When performed by experienced professionals, such tests allow detection of most major fetal malformations. If an anomaly is found, skilled counseling must be provided for the patient.

During the third trimester, assessment of fetal growth and well- being becomes most important. Fetal growth may be evaluated by serial ultrasonographic examination every 4 to 6 weeks. Fetal well-being may be determined by a variety of techniques, including the following:

• Maternal monitoring of fetal activity.
• Antepartum heart rate testing by using the nonstress or contraction stress test.
• Biophysical profile that includes an ultrasonographic evaluation of fetal activity, fetal breathing movements, fetal tone, and amniotic fluid volume.

Although these tests may be initiated at 28 weeks of gestation, they are most often begun at 32 weeks and performed once or twice a week until delivery.

Delivery. If the patient maintains excellent glucose control, if her blood pressure is normal, and if antepartum fetal testing shows no evidence of fetal compromise, delivery may occur at term. If delivery is planned before term, assess fetal pulmonary maturation by measuring the ratio of amniotic fluid lecithin to sphingomyelin (L/S) and the level of acidic phospholipid phosphatidyglycerol. If ultrasound suggests excessive fetal size, delivery by cesarean section may be elected.

Delivery must take place where expert maternal and neonatal care are available. Breast-feeding should be encouraged.

Postpartum care. In the immediate postpartum period, reassess the patient’s meal plan and adjust her treatment program. Maternal insulin requirements fall significantly, usually to- or even below- prepregnancy levels.

During the patient’s postpartum follow-up visit, encourage her to diet, if necessary, to achieve her ideal body weight. Contraception should be discussed. Low-dose oral contraceptives or a progestin-only pill may be offered to patients who have no evidence of hypertension or vascular disease. For patients with hypertension or vascular disease, a barrier method of contraception, such as a diaphragm, is preferred. If the patient has completed her family or if she has serious vascular disease, sterilization should be discussed.

Screening. All pregnant women should be screened for gestational diabetes. If only those patients with recognized historical or clinical risk factors are screened, a significant number of cases of gestational diabetes will be missed.

Timing. Screen for gestational diabetes at approximately 24 to 28 weeks of gestation. Screening may be indicated before 24 weeks if the patient has a history of any of the following:

• Polydipsia or polyuria.
• Recurrent vaginal and/or urinary tract infections.
• Glycosuria of 1+ or greater on two or more occasions or 2+ or greater on one occasion.
• Hydramnios.
• Having given birth to an infant who was large for gestational age.
• Gestational diabetes.

Method for screening. Patients need not be fasting when the screening test is performed. Use a 50-gram oral glucose load and measure the patient’s glucose level after one hour. If the venous plasma glucose is 140 mg/dL or higher, schedule a 100-gram oral glucose tolerance test (see next paragraph).

Method for diagnosis. In pregnancy, the oral glucose tolerance test should be performed as follows:

• Perform the test in the morning, after at least 3 days of unrestricted diet (more than 150 grams of carbohydrate per day) and unrestricted physical activity and after an overnight fast of at least 8 hours but not more than 14 hours.
• Ask the patient to remain seated. If she smokes, ask her not to do so during the test.
• Administer a 100-gram oral glucose load.
• Measure venous plasma glucose when the patient is fasting and at 1, 2, and 3 hours after administering the glucose load.
• Diagnose gestational diabetes when two or more of the following concentrations are met or exceeded.

___________________________________________________________________________ Time of Glucose Test Concentration ___________________________________________________________________________ Fasting 105 mg/dL After glucose 1 hour 190 mg/dL 2 hours 165 mg/dL 3 hours 145 mg/dL ___________________________________________________________________________

• If the initial glucose tolerance test is normal but the patient is thought to be at high risk for gestational diabetes, or if one concentration is met or exceeded, consider repeating the glucose tolerance test at 32 weeks of gestation.

Although blood glucose measurements using glucose-oxidase-impregnated test strips are useful for monitoring treatment, they are not sufficiently precise for diagnostic purposes. Glycosuria and glycosylated hemoglobin tests are also not sensitive enough to be used to diagnose gestational diabetes.

Diet. Dietary therapy is the mainstay of treatment for patients with gestational diabetes. The daily dietary plan should contain approximately 2000 to 2400 calories distributed among three meals and a bedtime snack.

Monitoring. Ideally, the efficacy of the diet is assessed by daily self-monitoring of blood glucose. Weekly measurements of fasting and postprandial glucose levels are also an acceptable method of monitoring.

Pharmacologic therapy. If the fasting plasma glucose level exceeds 105 mg/dL and/or the 2-hour postprandial value exceeds 120 mg/dL, treatment with human insulin should be initiated. Patients who require insulin should be instructed in glucose self-monitoring.

Oral hypoglycemic agents should not be used during pregnancy.

Fetal assessment. Patients with insulin-treated gestational diabetes require a program of fetal surveillance identical to that recommended for patients with pregestational diabetes (see the earlier discussion). Begin fetal surveillance by 34 weeks of gestation for patients with non-insulin-treated gestational diabetes who develop preeclampsia or have a history of intrauterine death. Begin fetal surveillance at 40 weeks of gestation for patients with uncomplicated non-insulin-treated gestational diabetes who have not delivered.

Postpartum care. All patients with gestational diabetes should undergo a 75-gram oral glucose tolerance test at 6 to 8 weeks postpartum to determine whether abnormal carbohydrate metabolism has persisted.

The glucose tolerance test should be performed as follows:

• Perform the test in the morning, after at least 3 days of unrestricted diet (more than 150 grams of carbohydrate per day) and unrestricted physical activity and after an overnight fast of between 8 and 14 hours.
• Ask the patient to remain seated. If she smokes, ask her not to do so during the test.
• Administer a 75-gram oral glucose load.
• Measure the venous plasma glucose when the patient is fasting and 30, 60, 90, and 120 minutes after administering the glucose load.
• Diagnose abnormal glucose tolerance according to the following criteria:

__________________________________________________________________________ Glucose Concentration __________________________________________________________________________ Normal Impaired Time of Glucose Glucose Diabetes Test Tolerance Tolerance Mellitus ___________________________________________________________________________ Fasting <115 mg/dL <140 mg/dL >140 mg/dL and and or After glucose <200 mg/dL 1 value >200 1 value>200 (30, 60, and mg/dl mg/dL mg/dL 90 minutes) and and and 120 minutes <140 mg/dL >140 mg/dL >200 mg/dL but <200 mg/dL --------------------------------------------------------------------------

Encourage patients to achieve their ideal body weight to decrease their likelihood of developing non-insulin-dependent diabetes mellitus. Patients with a history of gestational diabetes should be annually evaluated for onset of diabetes.

For contraception, patients may use low-dose oral contraceptive pills, progestin-only pills, or barrier methods.

Patient Education Principles:
For patients with pregestational diabetes

• Emphasize the importance of prepregnancy care.
• Work with the patient, her partner, her family, and other health care providers to improve the patient’s nutrition, exercise program, and glucose control.
• Recommend that conception be delayed until the patient’s blood glucose control is excellent and the glycosylated hemoglobin level is normal or near normal.
• Explain the risks of birth defects and adverse perinatal outcomes and the need for fetal surveillance.
• Recommend that the patient’s vascular condition be thoroughly evaluated before she becomes pregnant. Explain that pregnancy may exacerbate advanced diabetic retinopathy but generally does not permanently worsen diabetic nephropathy.
• Explain that, overall, pregnancy does not shorten the life expectancy of a woman with diabetes but does increase her risk for hypoglycemia and ketoacidosis and for associated mortality.
• Inform patients with coronary atherosclerosis that their risks for morbidity or mortality may be greater during pregnancy.
• Discuss the emotional and financial demands of pregnancy with the patient, her partner, and her family.
• Inform patients about lifestyle elements–such as drinking alcoholic beverages and smoking–that increase the risk for a poor outcome of pregnancy. Emphasize that patients will need to modify such behaviors before becoming pregnant.

For patients with gestational diabetes —

• Work with the patient, her partner, her family, and other health care providers to improve the patient’s nutrition, exercise program, and glucose control.
• Explain the risks of adverse perinatal outcomes and the need for fetal surveillance.
• Inform patients that they are at increased risk both for developing gestational diabetes during future pregnancies and for developing overt diabetes later in life.
• Encourage physical activity and postpartum weight loss to decrease the likelihood of developing diabetes later in life.
• Recommend an evaluation at 6 to 8 weeks postpartum, and annually thereafter, for detecting the development of diabetes.

For patients with a history of gestational diabetes–

• Recommend screening for overt diabetes before subsequent pregnancies.
• Recommend early screening for the onset of carbohydrate intolerance during subsequent pregnancies.

Freinkel N, Gabbe SG, Hadden DR, et al. Summary and recommendations of the Second International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes. 1985 ;34(suppl 2):123-126.

Fuhrmann K, Reiher H, Semmler K, Fischer F, Fischer M, Glockner E. Prevention of congenital malformations in infants of insulin- dependent diabetic mothers. Diabetes Care. 1983;6:219-223.

Gabbe SG. Management of diabetes mellitus in pregnancy. American Journal of Obstetrics and Gynecology. 1985;153:824-828.

Greene MF, Hare JW, Cloherty JP, et al. First-trimester hemoglobin A(1) and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology. 1989;39:225-231.

Landon MB, Gabbe SG. Glucose monitoring and insulin administration in the pregnant diabetic patient. Clinical Obstetrics and Gynecology. 1985;28:496-506.

Mills JL, Knopp RH, Simpson JL. et al. Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis. New England Journal of Medicine. 1988;318:671-676.

Mills JL, Simpson JL, Driscoll SG, et al. Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. New England Journal of Medicine. 1988;319:1617-1623.

Schwartz R. The infant of the diabetic mother. In: Davidson JK, ed. Clinical Diabetes Mellitus. New York: Thieme. 1986.

Steel JM. Prepregnancy counseling and contraception in the insulin- dependent diabetic patient. Clinical Obstetrics and Gynecology. 1985;28:553-566.

Disease

Definition. The term periodontal disease describes a group of localized infections that affect the tissue surrounding and supporting the teeth.

The two most common forms of periodontal disease are gingivitis and periodontitis. Gingivitis, an early and reversible condition, is an inflammation of the soft tissues surrounding the teeth. Persons with gingivitis have tender, edematous, red gums that may bleed upon gentle pressure, such as from toothbrushing.

Periodontitis is a progressive inflammatory condition that destroys periodontal ligament fibers and alveolar bone and can eventually cause tooth loss. Although gingivitis usually precedes periodontitis, not all gingivitis progresses to periodontitis.

For all persons, the keys to preventing periodontal disease are good oral hygiene and regular dental care. A third element crucial to persons with diabetes is good glycemic control; poorly controlled diabetes can invite or promote periodontal disease.

Occurrence. disease is widely prevalent. Forty to 50% of U.S. adults report gingival bleeding, and over 80% of adults have objective evidence of previous periodontal disease. The prevalence and severity of periodontal disease increase markedly with age. Eight percent of adults younger than age 65 and 34% of adults 65 and older have evidence of advanced periodontal destruction.

Among children and adolescents with poorly controlled insulin- dependent diabetes mellitus and among adults with poorly controlled non-insulin-dependent diabetes mellitus, the prevalence of periodontal disease is considerably greater than it is among their nondiabetic peers. The severity of periodontal disease is also usually greater among persons with diabetes.

Pathophysiology. disease is initiated by the toxic

metabolic products of bacteria in dental plaque. Other associated factors include smoking, vitamin C deficiency, dental restorations, and prostheses.

disease appears to be aggravated by increased levels of blood glucose and by other conditions associated with poor glycemic control. Altered microbial flora, impaired immunity, vascular changes, and abnormal collagen metabolism may contribute to the development and severity of periodontal disease among persons with diabetes.

• Inform patients of their increased risk of developing periodontal disease.
• Inform patients of the association between poor glycemic control and periodontal disease.
• Explain that severe periodontal disease and other oral infections may adversely affect glycemic control.
• Motivate patients to care for their teeth and gums.
• Explain how dental plaque contributes to periodontal disease.
• Inform patients that they can partly remove plaque by brushing and flossing their teeth at least twice a day.
• Explain that teeth lost to periodontal disease may be difficult to replace. Dentures often fit poorly over gums damaged by periodontitis; the resulting discomfort may limit a patient’s dietary choices and may thus impede diabetes management.

To ensure that patients receive the regular professional dental care critical to preventing periodontal disease, the health care provider should do the following:

• Instruct patients to see a dentist at least every 6 months. Patients with periodontal disease will need to schedule more frequent appointments.
• Provide a list of recommended dentists or local dental clinics if the patient does not have a dentist.
• Urge patients to inform their dentist that they have diabetes. If possible, ask for the dentist’s name and telephone number; you may need to alert this person to the special problems of treating a person with diabetes.

Efficient brushing and flossing removes the more superficial supragingival dental plaque. Subgingival plaque, as well as calculus (hard deposits of plaque, also called tartar), will require professional removal. For some patients, the dentist may prescribe antiplaque rinses, such as chlorhexidene.

To evaluate personal oral hygiene, the dentist or dental hygienist should ask patients to demonstrate how they remove plaque. Patients can then be shown, if necessary, how to more effectively care for their teeth.

The health care provider should inspect the patient’s mouth for the following signs of dental disease:

• Puffy, red gums.
• A buildup of plaque.
• Obviously decayed teeth.
• The characteristic bad breath of periodontitis.

Patients showing these possible indicators of periodontal disease should be referred to a dentist.

Severe periodontal disease can be present without obvious inflammation. A complete dental examination, including periodontal probing of gum pockets, is necessary to determine the presence and severity of periodontal infection.

The health care provider should work with the dentist in planning treatment and scheduling dental appointments. The health care provider should also be consulted before the patient is pretreated with an antibiotic or is hospitalized.

Patient Education Principles:

• Help patients maintain good control of their blood glucose levels.
• Instruct patients to do the following to remove plaque:
• Brush their teeth with a soft toothbrush and a fluoridated toothpaste at least twice a day, especially before going to sleep.
• Rinse their toothbrush thoroughly after each brushing, store it vertically (with the bristles at the top), and replace it at least every 3 months. (Toothbrushes can harbor bacteria.)
• Use dental floss, bridge cleaners, water sprayers, or other cleaning aids recommended by their dentist.
• Emphasize the importance of seeking regular preventive dental care at least every 6 months (or according to the dentist’s recommended schedule).
• Encourage patients to ask their dentist for further instructions or advice on caring for their teeth.
• Instruct patients to see a dentist if they have bad breath, an unpleasant taste in the mouth, bleeding gums, sore gums or teeth, red or swollen gums, difficulty chewing, or loose teeth.
• Urge patients to inform their dentist that they have diabetes and to remind their dentist of this when they make appointments. Patients should also give their dentist their health care provider’s name and telephone number.
• Stress the importance of scheduling dental appointments that do not interfere with the patient’s insulin and meal schedule. The best time for an appointment may be a few hours after breakfast. Tell patients not to skip a meal or insulin before an appointment.

Manouchehr-Pour M, Bissada NF. disease in juvenile and adult diabetic patients: a review of the literature. Journal of the American Dental Association. 1983;107:766-770.

Murrah VA. Diabetes mellitus and associated oral manifestations: a review. Journal of Oral Pathology. 1985;14:271-281.

National Institute of Dental Research. Detection and Prevention of Disease in Diabetes. Bethesda, Maryland: US Department of Health and Human Services, Public Health Service, 1986. Publication NIH 86-1148.

Williams RC. Periodontal disease. New England Journal of Medicine. 1990;322:373-382.

Eye Disease

Diabetes mellitus is a major cause of blindness in the United States and is the leading cause of new blindness in working-aged Americans. Diabetic retinopathy alone accounts for at least 12% of new cases of blindness each year in the United States. People with diabetes are 25 times more at risk for blindness than the general population. The estimated annual incidence of new cases of proliferative diabetic retinopathy and diabetic macular edema are 65,000 and 75,000, respectively. Approximately 700,000 Americans have proliferative diabetic retinopathy –the most sight- threatening form of retinopathy — and 500,000 have diabetic macular edema. Over a lifetime, 70% of people with insulin- dependent diabetes mellitus (IDDM) will develop proliferative diabetic retinopathy, and 40% will develop macular edema. Both complications, if untreated, frequently lead to serious visual loss and disability.

Diabetic retinopathy is often asymptomatic in its most treatable stages. Unfortunately, only about half of persons with diabetes receive adequate eye care. Early detection of diabetic retinopathy is critical.

The results of National Eye Institute-supported multicenter clinical trials of laser surgery and vitrectomy surgery have demonstrated that the risk of blindness from diabetes can be reduced.

• Timely laser surgery can reduce the risk of visual loss from high-risk proliferative diabetic retinopathy by approximately 60%.
• Timely laser surgery can reduce the risk of moderate visual loss from clinically significant diabetic macular edema by 50%.
• Vitrectomy can restore useful vision in some diabetic patients whose retinopathy is too advanced for laser surgery.

Diabetic retinopathy and macular edema. The process by which diabetes results in retinopathy and macular edema is not fully understood. It is known that diabetes causes the retinal capillaries to become functionally less competent. Five clinical pathological processes can be recognized in diabetic retinopathy:

• Formation of microaneurysms (outpouchings of the capillary walls).
• Increased vascular permeability of retinal capillaries.
• Closure of retinal capillaries and arterioles.
• Proliferation of new vessels and fibrous tissues.
• Contraction of fibrous tissue and hemorrhage and/or retinal detachment due to traction.

Nonproliferative and proliferative diabetic retinopathy and macular edema have several clinical manifestations (Table 1). Diabetic macular edema can be associated with any stage of diabetic retinopathy.

Cataracts. Cataracts are 1.6 times more common in people with diabetes than in those without diabetes. Furthermore, cataracts occur at a younger age and progress more rapidly in people with diabetes. Young people with IDDM occasionally develop snowflake or metabolic cataracts. These may lessen or resolve with improved glycemic control. Fortunately, cataract extraction with or without lens implantation is 90% to 95% successful in restoring useful vision, but the surgery is not without potential complications that are more frequent in patients with diabetes.

Open-angle glaucoma. Open-angle glaucoma is 1.4 times more common in the diabetic population. The prevalence of glaucoma increases with the patient’s age and with the length of time the patient has had diabetes. Medical therapy for open-angle glaucoma is generally effective. Argon laser trabeculoplasty may normalize intraocular pressure in over 80% of patients in whom medical therapy has proven ineffective.

Neovascular glaucoma. Neovascular glaucoma is a more severe type of glaucoma that most commonly occurs among patients with severe proliferative diabetic retinopathy and retinal detachments. It occasionally follows vitrectomy or cataract surgery. Early recognition and emergency panretinal laser surgery may prevent full development of this devastating type of glaucoma. Diagnosis and evaluation require slit-lamp examination of the iris and gonioscopic evaluation of the filtration angle.

Because coexisting medical problems — including hypertension and renal disease — may affect the development and progression of diabetic retinopathy, blood pressure should be routinely measured. If hypertension exists even at borderline levels, it should be monitored and treated as needed. Aspirin treatment (650 mg per day) neither alters the progression of diabetic retinopathy nor increases the risk of vitreous hemorrhage. Therefore, diabetic retinopathy is not a contraindication for the medical use of aspirin.

Because diabetic retinopathy and diabetic macular edema cannot be prevented, routine early evaluation, timely laser surgery, and careful follow-up are critical.

The following examination schedule is designed to ensure the early detection and monitoring of diabetic eye disease:

• All patients with IDDM of more than five years duration and all patients with non-insulin-dependent diabetes mellitus should have yearly eye examinations including a history of visual symptoms, measurement of visual acuity, measurement of intraocular pressure, and dilation of the pupils with thorough vitreous and retinal examination including stereoscopic examination of the macula.
• Retinopathy may progress more rapidly during puberty. Children in this developmental stage should have yearly eye examinations, regardless of how long they have had diabetes.
• Any woman who is planning pregnancy should be examined before pregnancy by a practitioner experienced in the diagnosis and classification of diabetic retinopathy. Any woman with known diabetes who becomes pregnant should be examined for retinopathy early in the first trimester. Retinopathy may progress very rapidly during pregnancy; close cooperation among the health care team is critical.

The practitioner may elect to perform the examination, but because proper stereoscopic examination requires dilation of the pupils and specialized techniques, such as binocular indirect ophthalmoscopy, referral to ophthalmologists or optometrists appropriately trained and skilled in the diagnosis and classification of diabetic eye disease is preferred.

After the initial eye examination, persons with diabetes should receive complete examinations once a year, unless more frequent examinations are indicated by the presence of abnormalities.

The patient should be under the care of a retinal specialist or ophthalmologist experienced in the treatment of diabetic retinopathy when any of the following conditions are identified (see Table 1 for definitions):

• Proliferative retinopathy.
• Macular edema.
• Preproliferative retinopathy (severe or very severe nonproliferative retinopathy).
• Nonproliferative retinopathy in children during puberty or women during pregnancy.

People with any degree of retinal disease–including those who have lost vision from retinopathy–should continue to receive regular eye care. Vitrectomy surgery may restore usable vision for some individuals who have lost sight from vitreous hemorrhage or fibrous tissue proliferation with traction detachment. Postsurgical treatment requires proper refraction, low vision evaluation, optical aids, and other techniques and devices to enable the person to use even severely limited vision. Referral to optometrists or ophthalmologists specializing in low vision may be appropriate. Support groups for the visually challenged and organizations providing vocational rehabilitation are available in most areas. All practitioners should be familiar with appropriate rehabilitative referral sources for their patients with visual impairment.

Certain patients with vitreous hemorrhage or recent traction retinal detachment may be candidates for vitrectomy. Laser surgery and vitrectomy surgery should be performed by a retinal specialist or other ophthalmologist experienced in laser surgery and the management of diabetic eye disease.

Patients with functionally decreased visual acuity should be referred for low vision evaluation and appropriate visual, vocational, and psychosocial rehabilitation.

Patient Education Principles:

• Inform patients that sight-threatening eye disease is a common complication of diabetes and may be present even with good vision. Remind them to report all ocular symptoms, since essentially any symptoms may be diabetic in origin. Blurred vision while reading may indicate macular edema. The presence of floaters may indicate hemorrhage, and flashing lights may indicate retinal detachment. Inform patients that early detection and appropriate treatment of diabetic eye disease greatly reduces the risk of visual loss.
• Inform patients about the possible relationship between glycemic control and the subsequent development of ocular complications.
• Tell patients about the association between hypertension and diabetic retinopathy. Stress the importance of the diagnosis and continuing treatment of hypertension. Urge patients to work closely with their health care team.
• Help patients understand the natural course and treatment of diabetic retinopathy and the importance of yearly eye examinations.
• Tell patients with diabetic retinopathy about the availability and benefits of early and timely laser photocoagulation therapy in reducing the risk of visual loss.
• Inform patients about their higher risks of cataract formation, open- angle glaucoma, and neovascular glaucoma.
• Tell all patients with any visual impairment (including blindness) about the availability of visual, vocational, and psychosocial rehabilitation programs.

Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: clinical application of Diabetic Retinopathy Study (DRS) findings, DRS report no. 8. Ophthalmology. 1981;88:583-600.

Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report no. 1. Archives of Ophthalmology. 1985;103:1796-1806.

Klein BEK, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care. 1990:13:34-40.

Klein R. The epidemiology of diabetic retinopathy: findings from the Wisconsin Epidemiologic Study of Diabetic Retinopathy. International Ophthalmology Clinics. 1987;27:230-238.

Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Archives of Ophthalmology. 1984:102:520-526.

Klein R, Klein BEK, Moss SE. et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Archives of Ophthalmology. 1984;102:527-532.

Klein R, Moss SE, Klein BEK. et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XI. The incidence of macular edema. Ophthalmology. 1989;96:1501-1510.

Preferred Practice Pattern–Diabetic Retinopathy. San Francisco: American Academy of Ophthalmology, 1989.

Kidney Disease

Description. Diabetic nephropathy represents a distinct clinical syndrome characterized by albuminuria, hypertension, and progressive renal insufficiency. Diabetic nephropathy can lead to end-stage renal disease (ESRD), a serious condition in which a patient’s survival depends on either dialysis or kidney transplantation.

Occurrence. Among persons who have had insulin-dependent diabetes mellitus (IDDM) for 20 years, the incidence of ESRD approaches 40%. Among whites, the incidence of ESRD is lower among those with non- insulin-dependent diabetes mellitus (NIDDM) than among those with IDDM. Because NIDDM is much more common than IDDM, the number of whites with NIDDM who develop renal failure each year is about the same as for those with IDDM. In certain populations–including blacks, Hispanics, and Native Americans–persons with NIDDM have a higher incidence of ESRD.

About a third of new cases of ESRD in the United States are attributed to diabetes. These persons account for about a third of the $2.8 billion per year that is spent for the care of patients with ESRD.

Pathophysiology–IDDM. The natural history of renal involvement in persons with IDDM has been well characterized. See (Figure 1). When diabetes is first diagnosed, the histological appearance of the kidney is normal. Within three years, however, the typical changes of diabetic glomerulosclerosis appear: thickening of the glomerular basement membrane and mesangial expansion.

Renal blood flow and the glomerular filtration rate (GFR) are characteristically elevated, correlating with an increase in kidney size and weight. Mild albuminuria may be present if glycemia is not well regulated. Because of renal hyperfiltration, serum creatinine and urea nitrogen concentrations are usually slightly reduced.

After 10 to 15 years, the first laboratory evidence of renal damage may appear with the presence of persistent microalbuminuria (30 to 300 mg per 24 hours). In IDDM, the prevalence of hypertension increases markedly in patients with microalbuminuria, and hypertension clearly contributes to the progression of renal disease.

Clinical diabetic nephropathy is said to be present when a patient who has had diabetes for more than five years and has evidence of diabetic retinopathy develops clinically apparent albuminuria (>300 mg per 24 hours) and has no evidence of any other cause of kidney disease. When these criteria are fulfilled, a clinical diagnosis of diabetic nephropathy can generally be made without performing a renal biopsy.

About four years after the onset of clinical diabetic nephropathy, the serum creatinine level rises to 2 mg/dL or greater. Within an additional three years, about one-half of patients will have developed ESRD.

Pathophysiology–NIDDM. The natural history of renal

involvement in persons with NIDDM is not well established. Although microalbuminuria has been shown to be associated with the development of clinical diabetic nephropathy, the precise level of microalbuminuria that reliably predicts this condition has yet to be determined. Some individuals with low levels of albuminuria do not develop renal failure. In these persons, albuminuria may be due to the presence of other complicating renal diseases, such as obstructive uropathy, hypertension, or arteriolosclerosis, or may reflect an age-related increase in urinary albumin excretion.

In patients with albuminuria, blood pressure regulation is of critical importance in slowing the progression to renal failure. Other strategies that may slow the progression of renal disease include limiting the patient’s protein intake, maintaining good glycemic control, promptly treating urinary tract infections, and avoiding potentially nephrotoxic drugs and radiographic dyes.

Each year, obtain a sensitive quantitative measure of urinary albumin or protein excretion. In general, the protein excretion rate is about one third greater than that for albumin. Thus, a protein excretion rate of approximately 400 mg per 24 hours would correspond to an albumin excretion rate of 300 mg per 24 hours.

Measure renal function (serum creatinine and/or creatinine clearance) each year.

Before establishing a diagnosis of diabetic nephropathy, exclude other possible causes of renal disease–particularly, obstructive uropathy and infection. If diabetic retinopathy is not present, suspect a nondiabetic cause of renal disease.

Hypertension is a common development with the onset of diabetic nephropathy or shortly thereafter. If the patient’s initial blood pressure is higher than 140/90 mm Hg, at least three additional readings should be obtained over the next month.

• Aggressively monitor and treat high blood pressure (>140/90 mm Hg) or significant increments in blood pressure (20/10 mm Hg or greater on careful follow-up) in patients with renal disease.
• Encourage all nonpregnant adults with diabetes, especially those with renal involvement, to limit their daily protein intake to 0.8 g/kg of body weight, as recommended by the American Diabetes Association.
• Strive to achieve good glycemic control, without undue side effects from hypoglycemia, in all diabetic patients, especially those with microalbuminuria.
• Recommend consultation with a diabetologist and/or a nephrologist if patients have microalbuminuria (30 to 300 mg per 24 hours), clinically overt albuminuria (>300 mg per 24 hours), nephrotic syndrome, elevated serum creatinine (>2 mg/dL), or diminished GFR (<50 mL per minute).
• Instruct patients with microalbuminuria or diabetic nephropathy to receive yearly eye examinations.
• Assess cardiovascular risk factors–particularly hypercholesterolemia and cigarette smoking–and provide appropriate treatment, especially for patients with NIDDM.
• Seek and treat other causes of renal disease, particularly obstructive uropathy and infection. Promptly treat any urinary tract infections. Repeat a urine culture after treatment to ensure resolution.

Patients who have developed ESRD will require kidney transplantation, hemodialysis, or peritoneal dialysis to prolong their lives. Because diabetic complications — especially retinopathy and neuropathy — progress more rapidly with the onset of renal failure, dialysis is usually instituted earlier (when the concentration of serum creatinine reaches about 6 mg/dL) for people with diabetes than for those without diabetes. Kidney transplantation is preferable to dialysis when a living relative of the patient is available as a donor; the patient’s chances of survival are otherwise about equal among these three courses of treatment. The ultimate choice will require the input of the patient, the patient’s family, the primary health care provider, and a nephrologist.

Patient Education Principles:

• Inform patients about the potential renal complications of diabetes.
• Inform patients about the association between hypertension and accelerated renal disease. Discuss the need for regular blood pressure measurements and encourage patients to measure their own blood pressure at home. Stress the importance of treating hypertension.
• Explain the potential role that excessive protein in the diet may play in the pathogenesis and progression of diabetic nephropathy.
• Explain the possible relationship between poor glycemic control and the development of diabetic renal disease.
• Emphasize the importance of achieving and maintaining ideal body weight and of undertaking a regular physical exercise program as strategies for preventing hypertension and improving glycemic control.
• Review with patients the symptoms of urinary tract infection. Instruct patients to contact their health care provider if such symptoms occur.
• Review with patients which drugs are potentially nephrotoxic. Explain the danger of radiographic dye studies.
• Review the natural history of clinical diabetic nephropathy with patients who have this condition. Discuss the therapeutic options dialysis versus transplantation–for ESRD.

Consensus statement. Proceedings from the International Symposium on Preventing the Kidney Disease of Diabetes Mellitus: public health perspectives. American Journal of Kidney Diseases. 1989;13:2-6.

DeFronzo RA. Diabetes and the kidney: an update. In: Olefsky JM, Sherwin RS, eds. Diabetes Mellitus: Management and Complications. New York: Churchill Livingstone, 1985.

Kaplan NM, Rosenstock J, Raskin P. A differing view of treatment of hypertension in patients with diabetes mellitus. Archives of Internal Medicine. 1987;147:1160-1162.

Mogensen CE, Schmitz A, Christensen CK. Comparative renal pathophysiology relevant to IDDM and NIDDM patients. Diabetes/Metabolism Reviews. 1988;4:453-483.

Viberti GC, Walker JD. Diabetic nephropathy: etiology and prevention. Diabetes/ Metabolism Reviews. 1988;4:147-162.

The Working Group on Hypertension in Diabetes. Statement on hypertension in diabetes mellitus. Archives of Internal Medicine. 1987; 147: 830-842.

Cardiovascular Disease

Occurrence. Cardiovascular disease is the leading cause of morbidity and mortality among persons with diabetes. In the United States in 1986, approximately 80,000 deaths from cardiovascular disease were associated with diabetes.

The annual risk for death from cardiovascular disease is two to three times greater for persons with diabetes than for persons without diabetes. For persons with diabetes, the risk for cerebrovascular disease and for coronary artery disease is two to three times greater, and the risk for peripheral vascular disease is five times greater. Among persons without diabetes, women have a lower rate of cardiovascular disease than men do; among persons with diabetes, women are not preferentially spared.

Risk factors. In persons with diabetes, smoking is a powerful risk factor for cardiovascular disease, and the prevalence of smoking appears to be higher in young people (less than 21 years old) with diabetes than in young people without diabetes.

Hypertension, also a strong risk factor for cardiovascular disease, occurs two to three times more often in persons with diabetes than in persons without diabetes. The risk for cardiovascular disease increases linearly with increases in blood pressure.

Abnormalities in the concentration of lipids and lipoproteins in plasma have been reported to occur in almost 30% of persons with diabetes. The risk for cardiovascular disease is directly proportional to the concentration of low-density lipoprotein (LDL) cholesterol and inversely proportional to the concentration of high-density lipoprotein (HDL) cholesterol. Although hypertriglyceridemia is common among persons with non-insulin- dependent diabetes mellitus, whether the triglyceride level independently predicts cardiovascular disease is uncertain.

The precise relationship between hyperglycemia and atherosclerosis is also unknown. Among persons with diabetes, several concomitant conditions may affect the etiology of atherosclerosis: obesity, inactivity, hyperinsulinemia, abnormalities in platelet function, and defects in blood coagulation and flow.

Among persons with diabetes, part of the increased likelihood of cardiovascular disease appears to be a consequence of the increased frequency of risk factors. Yet diabetes itself is an independent risk factor for cardiovascular disease.

Smoking. Smoking cessation may be the most important modification in behavior that can be made to reduce the risk for cardiovascular disease. Stress to patients the importance of not smoking. Encourage those who smoke to quit, and remind those who do not smoke not to start.

Blood pressure. Blood pressure should be closely monitored in patients with diabetes. When blood pressure is increased over 140/90 mm Hg, nonpharmacologic therapy should be instituted. Medication may need to be initiated early, depending on the blood pressure level. When selecting drugs for treating hypertension, consider their potential adverse effects on other risk factors for cardiovascular disease.

Plasma lipids. The incidence of atherosclerotic heart disease and the morbidity associated with this condition can be decreased in nondiabetic populations by reducing the plasma cholesterol level. When the total cholesterol is more than 200 mg/dL and the LDL cholesterol is more than 130 mg/dL, nonpharmacologic therapy should be instituted.

Plasma glucose. The relationship between plasma glucose and the development of cardiovascular disease is less clear. However, poor glycemic control is often associated with hyperlipidemia. Improved glycemic control has been shown to lower the concentration of cholesterol and triglycerides in plasma and to raise the concentration of HDL cholesterol in persons with diabetes who are either hyperlipidemic or normolipidemic.

Weight, exercise, and aspirin therapy. Additional recommendations for preventing cardiovascular disease in diabetic patients include weight loss (for obese persons) and an increased level of physical activity. For patients who have had cardiovascular events, aspirin therapy may help to prevent mortality or additional morbidity from cardiovascular disease.

At every office visit (at least four times a year)

• Measure the patient’s blood pressure with a cuff appropriate for the patient’s size.
• Ask patients whether they have had symptoms of the following conditions:

___________________________________________________________________________ Condition Symptoms such as ___________________________________________________________________________ Cerebral vascular disease Transient blindness, dysarthria, or unilateral weakness. Coronary artery disease Chest pain or pressure, dyspnea, and congestive heart orthopnea, paroxysmal nocturnal failure dyspnea, or edema.(Painless myocardial infarction is common among diabetic patients, and they may have angina or myocardial infarction with atypical symptoms.) Peripheral vascular disease Intermittent claudication or foot ulcers that do not heal. ---------------------------------------------------------------------------

At least once a year

• Ask patients about their use of tobacco.
• Auscultate for bruits over all large arteries and palpate all peripheral pulses.

Once a year

• Measure triglycerides (TG), total cholesterol (TC), and HDL cholesterol levels in the fasting state, and calculate the level of LDL cholesterol. For TG under 400 mg/dL,
  LDL = TC – HDL – (TG \ 5)
  For children, consider measuring lipids every two years.
• Obtain a baseline electrocardiogram in all patients with diabetes and repeat the procedure yearly for those with clinically apparent cardiovascular disease.

Hypertension. If the patient’s blood pressure exceeds 140/90 mm Hg at two visits, begin nonpharmacologic therapy, including a low- sodium, alcohol-restricted diet designed for weight reduction. Regular exercise has also been shown to have a beneficial effect on blood pressure. Blood pressure should be maintained below 140/90 mm Hg. For individual patients, consider earlier pharmacologic intervention when indicated by clinical conditions (for example, diastolic blood pressure greater than 110 mm HG) and the presence of other risk factors (such as albuminuria).

After three months of nonpharmacologic therapy, if the diastolic blood pressure remains above 90 mm Hg, begin pharmacologic treatment. Select drugs that do not worsen other risk factors for cardiovascular disease (including lipids) and that do not induce or worsen autonomic neuropathic complications of diabetes (including hypoglycemia unawareness, orthostatic hypotension, or impotence).

Hyperlipidemia. When the calculated LDL cholesterol level is greater than 130 mg/dL, consider the following guidelines for glycemic control, diet, and exercise.

Glycemic control. Glycemic control should be improved through diet, use of sulfonylureas, or insulin therapy. Weigh the benefits of improved glycemic control against the potential risk for hypoglycemia.

Dietary therapy. Dietary therapy should be instituted to reduce the weight of obese patients and to try to lower the LDL cholesterol level to below 130 mg/dL. Consider the following restrictions on diet:

• Calorie restriction for weight reduction if obesity is present.
• Total fat less than 30% of total calories.
• Saturated fats less than 10% of total calories. Complex carbohydrates and fiber (especially soluble fiber) can be substituted for the usual intake of saturated fats. Preliminary studies suggest that some diabetic patients with hypertriglyceridemia may benefit by restricting carbohydrate intake to 40% to 45% of total calories. In those patients, monounsaturated fats may be used to maintain caloric balance.
• Cholesterol less than 300 mg per day.

Exercise. Weigh the potential benefits of exercise against the risks and recommend an exercise program, if appropriate. Regular aerobic exercise has been shown to be a useful adjunct to weight loss and to have a beneficial effect on lipids, especially levels of triglycerides and HDL cholesterol. Exercise may also cause a modest drop in the LDL cholesterol level. Before patients begin an exercise program, determine whether they have hypoglycemia unawareness, postural hypotension, proliferative retinopathy, painless myocardial ischemia, or insensitive feet. An exercise stress test is recommended for all diabetic patients over 40 years old who are considering an exercise program.

Reevaluation. After six months of therapy, if a patient’s LDL cholesterol level is above 160 mg/Dl, consider drug therapy. Drugs used to treat patients with hypercholesterolemia include bile acid sequestrants (cholestyramine or colestipol), HMGCoA reductase inhibitors (lovastatin), fibric acid derivatives (gemfibrozil or clofibrate), nicotinic acid, and probucol. Drugs used to treat patients with hypertriglyceridemia include fibric acid derivatives (gemfibrozil or clofibrate) and nicotinic acid.

Existing cardiovascular disease. Clinically apparent cardiovascular disease poses considerable diagnostic and therapeutic challenges to the practitioner. Consider consulting with specialists (such as cardiologists, neurologists, and vascular surgeons) early in the course of such disease. The guidelines below address some of the cardiovascular diseases common among persons with diabetes.

Cerebral vascular disease. Patients with signs or symptoms of cerebral vascular disease should be referred for specialized diagnostic tests, including noninvasive Doppler flow studies and, if necessary, carotid arteriography. Caution should be used with dye studies in patients with preexisting renal disease and/or dehydration. Patients with symptomatic cerebral vascular disease may be treated with aspirin and anticoagulants. If symptoms persist despite pharmacological treatment and if correctable vascular lesions are present, surgery may be considered.

Coronary artery disease. Heart disease due to coronary atherosclerosis is the most common cause of morbidity and mortality in patients with diabetes. Patients with signs or symptoms of coronary artery disease should receive a complete evaluation, including exercise testing and, if

necessary, coronary arteriography. Contrast-dye studies should be used with caution because of the possible coexistence of diabetic nephropathy. Nitrates, calcium channel blockers, and beta blockers may be prescribed for patients with angina. Consider coronary angioplasty or bypass surgery for patients with appropriate coronary lesions or intractable angina. Unless contraindicated, aspirin should be given after acute myocardial infarction. Because of their ability to prevent reinfarction in nondiabetic subjects, beta blockers may be used in patients with diabetes after myocardial infarction–with attention to possible hypoglycemia and/or hyperlipidemia.

Peripheral vascular disease. Generally, no effective medical treatment is available for patients with peripheral vascular disease, although some patients may benefit from pentoxifylline. Patients who have incapacitating symptoms of peripheral vascular disease (such as rest pain) or who have foot lesions that are poorly healing require careful evaluation. To detect surgically correctable peripheral vascular disease, first use clinical examination of the pulses and then consider noninvasive means (Doppler flow study). Contrast-dye studies should be used with caution because of the possible coexistence of diabetic nephropathy. Refer patients for surgery, as appropriate.

Patient Education Principles:

• Inform patients with diabetes that their risk of developing cardiovascular disease is higher than that of persons without diabetes.
• Inform patients of the absolute necessity of not smoking.
• Emphasize to patients the importance of following dietary principles appropriate for their conditions (such as hypertension or hyperlipidemia).
• Inform patients that hypertension and hyperlipidemia must be treated vigorously.
• Tell patients to immediately report symptoms of cardiovascular disease (for example, transient ischemic attack, chest pain, and claudication) so that investigation and treatment can begin promptly.

Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham Study. Journal of the American Medical Association. 1979;241:2035-2038.

Kaplan NM, Rosenstock J, Raskin P. A differing view of treatment of hypertension in patients with diabetes mellitus. Archives of Internal Medicine. 1987;147:1160-1162.

Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering. Journal of the American Medical Association. 1984;251:365-374.

National Diabetes Data Group. Diabetes in America. Bethesda, Maryland: US Department of Health and Human Services, 1985. Publication NIH 85-1468.

1984 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Archives of Internal Medicine. 1984;144: 1045-1057.

Steering Committee of the Physicians’ Health Study Research Group. Preliminary report: findings from the aspirin component of the ongoing physicians’ health study. New England Journal of Medicine. 1988;318:262-264.

Working Group on Diabetes in Hypertension. Statement on hypertension in diabetes mellitus. Archives of Internal Medicine. 1987;147:830-842.

Neuropathy

Persons with diabetes who develop neuropathy may have no symptoms or may experience pain, sensory loss, weakness, and autonomic dysfunction. Neuropathy may result in significant morbidity and may contribute to other major complications, such as lower extremity amputation.

There are three major types of diabetic neuropathy:

• Distal symmetrical polyneuropathy.
• Focal neuropathy.
• Autonomic neuropathy.

Distal symmetrical polyneuropathy. This most common of the diabetic neuropathies is characterized by insidious onset, symmetrical distribution, and progressive course. Although its cause is unclear, distal symmetrical polyneuropathy is believed to result from abnormal neural metabolism, generalized neural ischemia, or both. The onset and course of illness cannot be predicted for an individual patient, but increasing age, male sex, increasing height, longer duration of diabetes, poorer glucose control, hypertension, alcohol consumption, and smoking may be independent risk factors.

Estimates of the prevalence of distal symmetrical polyneuropathy differ greatly, but approximately 12% of patients have this condition when diabetes is diagnosed, and nearly 60% have it after 25 years.

Three overlapping clinical syndromes have been described:

• Acute painful neuropathy, an uncommon but extremely unpleasant complication of diabetes, often occurs without evidence of other significant neurologic impairment. It may occur early or late in the course of diabetes and may be associated with the institution of insulin treatment or with abrupt or considerable weight loss. Patients develop dysesthesia and paresthesia in the lower extremities. The severe, burning pain is often associated with cutaneous hyperesthesia and is worse at night. Objective evidence of neuropathy may be minimal. Symptoms generally resolve slowly, within months of achieving good glycemic control. Relapses are rare.
• Small fiber neuropathy may occur after only a few years of diabetes. Patients have varying degrees of pain and sensory loss; they usually feel a burning pain and may develop dysesthesia. Prominent features of small fiber neuropathy are distal loss of temperature sensation and of pinprick or pressure sensation. Vibratory sensation, position sense, muscle strength, and ankle reflexes are generally unimpaired. Neuropathic ulcers occasionally occur at sites of trauma.
• Large fiber neuropathy generally occurs in the setting of small fiber neuropathy. Patients have impaired distal vibration sensation and impaired distal position sense. Ankle reflexes are reduced or lost. In more severe instances, patients develop sensory ataxia and have a positive Romberg’s test. Large fiber neuropathy is most strongly associated with the development of neuropathic foot ulcers and neuropathic arthropathy affecting the interphalangeal, metatarsophalangeal, and ankle joints.

Focal neuropathy. Focal neuropathy is an uncommon condition believed to occur after the acute occlusion of a blood vessel produces ischemia in a nerve or group of nerves. The characteristics of focal diabetic neuropathy are sudden onset, an asymmetrical nature, and a self-limited course. Near total recovery generally occurs within two weeks to 18 months. Examples of focal diabetic neuropathies are cranial neuropathies, truncal neuropathies, mononeuropathies, radiculopathies, and plexopathies. Both sensory and motor components may be present.

Autonomic neuropathy. This troubling complication of diabetes encompasses multiple disturbances affecting the following systems: sudomotor (possible symptoms include heat exhaustion), pupillary (poor night vision), adrenomedullary (hypoglycemia unawareness), cardiovascular (orthostatic hypotension and painless myocardial ischemia), gastrointestinal (gastroparesis, constipation, diarrhea, and fecal incontinence), and

urogenital (bladder dysfunction and sexual dysfunction).

The following complications can occur with autonomic neuropathy:

___________________________________________________________________________ Condition Description ___________________________________________________________________________ Orthostatic Suspect this condition when a patient reports hypotension having postural faintness, weakness, visual impairment, or syncope. In patients whose intravascular volume is not depleted, autonomic neuropathy may be diagnosed if the systolic blood pressure falls more than 30 Hg or if the diastolic blood pressure falls more than 10 mm Hg when the patient changes from a lying to a standing position. Gastroparesis May be associated with symptoms of anorexia, early satiety, bloating, abdominal pain, nausea, and vomiting. Signs may include weight loss and erratic glycemic control. Constipation A common manifestation that may be difficult to treat. Diabetic diarrhea May last from a few hours to several weeks. May be severe and watery, is generally worse at night, and is often preceded by abdominal cramps. During remissions, the patient may report constipation. Fecal incontinence Associated with a reduced threshold of conscious rectal sensation, low basal internal sphincter pressure, and reduced voluntary control of the external anal sphincter. Diabetic bladder Associated with defective perception of dysfunction bladder filling and decreased reflex bladder emptying. Patients may strain to initiate a stream, may be unable to completely void, may dribble when urinating, and may have recurrent urinary tract infections. Sexual dysfunction Men may experience impotence. Women may experience decreased vaginal lubrication and dyspareunia. ---------------------------------------------------------------------------

Practitioners should urge patients to avoid other risk factors associated with the development of peripheral polyneuropathy. These include consumption of alcohol, poor nutrition, exposure to chemical toxins, use of certain drugs, and physical injury to the nerves (such as entrapment and compression).

• Peripheral pain, paresthesia, or numbness.
• Weakness.
• Hypoglycemia awareness.
• Orthostatic lightheadedness.
• Gastrointestinal symptoms, such as bloating, nausea, vomiting, constipation, diarrhea, and loss of bowel control.
• Urogenital symptoms, such as loss of bladder control and sexual dysfunction.

Distal temperature sensation. Touch a cool piece of metal (such as a tuning fork) to the patient’s foot; ask the patient to describe the object’s temperature. Another method is to alternately touch the patient’s foot with a test tube containing cool water and another containing warm water; ask the patient to distinguish between these objects.

Distal pinprick or pressure sensation. Have the patient close his or her eyes. Hold a pin lightly between your thumb and forefinger and touch it to the patient’s foot. Ask the patient to say when a sensation is felt and whether the sensation is sharp or dull. Clarify a doubtful response by alternately touching the patient with the point and the head of the pin. As an alterative, pressure sensation can be assessed with a monofilament.

Distal vibratory sensation. Tap a 128 hz tuning fork and place the end of the handle on a bony surface of the patient, such as the distal first metatarsal head or the malleoli of the ankles. Ask the patient to say when the vibration ceases.

Position sense. Have the patient close his or her eyes. Grasp between your thumb and index finger the lateral and medial sides of the patient’s toe. Ask the patient to describe the toe’s position as you alternately flex and extend it.

Distal symmetrical polyneuropathy. The differential diagnosis includes the following:

• Medications
• Exposure to toxins, including ethanol, organic solvents, and heavy metals.
• Uremia.
• Hypothyroidism.
• Pernicious anemia.
• Intoxication from vitamin B6.
• Syphilis.
• Gammopathy or myeloma.
• Malignancy.
• Collagen vascular disease.
• Porphyria.
• Hereditary neuropathy.

Focal neuropathy. The differential diagnosis includes the following:

___________________________________________________________________________ Type Differential Diagnosis ___________________________________________________________________________ Cranial neuropathy Increased intracranial pressure, aneurysm, tumor. Truncal neuropathy Cardiopulmonary disease, degenerative joint disease, disc disease, tumor, Paget's disease. Mononeuropathy Trauma, hemorrhage, tumor. multiplex ___________________________________________________________________________ Autonomic neuropathy. The differential diagnosis includes the following: ___________________________________________________________________________ Manifestation Differential Diagnosis ___________________________________________________________________________ Hypoglycemia Medications, lack of knowledge about unawareness hypoglycemia Orthostatic hypotension Medications, hypovolemia, panhypopituitarism, pheochromocytoma, Shy-Drager syndrome. Gastroparesis Medications, ketoacidosis, gastric or intestinal obstruction. Constipation Medications, dehydration, intestinal obstruction. Diarrhea Medications, dietary sorbitol or lactose, enteric pathogens, bacterial overgrowth, primary intestinal diseases, pancreatic exocrine insufficiency. Impotence Medications, hormonal abnormalities, vascular disease, psychogenic disease. ___________________________________________________________________________

Inform patients with distal sensory or motor abnormalities about foot care. Tell patients who have lost sensation in their feet to wear special protective footwear and to avoid activities (such as jogging) that can traumatize the feet (see "Foot Problems").

If painful neuropathy persists or worsens, consider referring the patient to a diabetologist.

Focal neuropathy. After other causes are excluded (see previous section under differential diagnosis), management is palliative. Spontaneous resolution generally occurs within a period of months but may persist over years.

Autonomic neuropathy. Various treatments are available for autonomic neuropathy. If signs or symptoms of autonomic neuropathy are present, consider referring the patient to a diabetologist.

Hypoglycemia unawareness. If necessary, alter patients’ targeted goals for glycemic control. Encourage patients to monitor their blood glucose regularly. Instruct patients to carry with them a source of simple sugar and to wear a necklace or bracelet that identifies them as having diabetes. Patients should also have glucagon available; their family and friends need to know how and when to use it.

Orthostatic hypotension. Patients may benefit from improved glycemic control (to reduce glycosuria), from volume and salt repletion, and from mechanical support with waist-high elastic stockings. Vasoconstrictors may be indicated.

Gastroparesis. Patients may benefit from correction of metabolic abnormalities (including hyperglycemia, ketosis, and hypokalemia), from dietary modification (eating small, liquid, low-fiber, low-fat meals), and from a prokinetic agent such as metoclopramide.

Constipation. Patients may benefit from correction of glycosuria, adequate hydration, a high-fiber diet, and psyllium.

Diarrhea. Patients may benefit from a bowel program that includes ingesting dietary fiber and making regular efforts to move the bowels. Another possible treatment is a short-term trial of an antidiarrheal agent (such as loperamide or diphenoxylate hydrochloride and atropine sulfate) or a broad-spectrum antibiotic with anaerobic coverage (such as tetracycline or metronidazole hydrochloride). Metoclopramide may occasionally be beneficial.

Fecal incontinence. Patients may be candidates for biofeedback training.

Diabetic bladder dysfunction. Patients may benefit from treatment to improve bladder emptying and to reduce the risk of urinary tract infection.

Impotence. Patients may benefit from noninvasive devices to assist erection, from a semirigid or inflatable penile prosthesis, or from papaverine injections.

Patient Education Principles:

• Inform patients about the possible relationship between poor glycemic control and the subsequent development of diabetic neuropathy.
• Explain possible risk factors (such as consumption of alcohol and exposure to chemical toxins) and concomitant neural insults that may hasten the development or progression of diabetic neuropathy.
• Stress that because sensory or motor neuropathy may be asymptomatic, routine evaluation is necessary even for patients who have no symptoms of neuropathy.
• Explain that diabetic neuropathy can contribute to the development of other complications, including loss of limb.
• Inform patients who have lost sensation in their feet about the importance of caring for their feet, wearing proper shoes, and getting appropriate exercise.
• Discuss the signs and symptoms of autonomic neuropathy.
• Explain the benefits of treatment to patients with autonomic neuropathy.

Cyrus J, Broadstone VL, Pfeifer MA, Greene DA. Diabetic peripheral neuropathy, part II: autonomic neuropathies. The Diabetes Educator. 1987; 13:111-114.

Dyck P J, Thomas PK, Asbury AK, Winegrad AI, Porte D Jr, eds. Diabetic Neuropathy. Philadelphia: W.B. Saunders, 1987.

Pfeifer MA, Greene DA. Diabetic Neuropathy. Kalamazoo, Michigan: The Upjohn Company, 1985. (Current Concepts booklet).

Physician’s Guide to Insulin-Dependent (Type 1) Diabetes: Diagnosis and Treatment. Alexandria, Virginia: American Diabetes Association, 1988.

Foot Problems

Persons with diabetes are at significant risk for lower extremity amputations; such procedures are 15 times more common among persons with diabetes than among those without diabetes. Yet if patients whose feet are particularly at risk are aggressively sought out and treated, up to 50% of amputations can be prevented.

Pathophysiology. Peripheral neuropathy, peripheral vascular disease, and infection all may contribute to amputation in patients with diabetes. Peripheral neuropathy may contribute to loss of sensation in the feet and to the development of foot deformities. In insensitive feet, deformities can cause pressure points that are vulnerable to ulceration. Inadequate blood supply and infection can then lead to osteomyelitis and gangrene.

Many persons with diabetes who undergo a lower extremity amputation have an amputation of the contralateral leg within a few years. This occurs not only because of peripheral neuropathy and peripheral vascular disease but also because the remaining foot bears increased pressure and frequently develops ulceration and infection.

The in-hospital mortality rate for diabetic patients who receive an amputation is higher than the rate for nondiabetic patients. In general, morbidity and mortality are high among diabetic patients who have amputations. All diabetic patients who undergo amputation require close supervision for other medical problems, particularly coronary artery disease.

Occurrence. Persons with diabetes account for approximately 50,000 (or 50%) of all nontraumatic amputations performed in the United States each year. The risk is greater for patients over 40 years old who have had diabetes for more than 10 years.

Cost. Although there is some variation, the average hospital stay for an amputation is approximately 25 days, and the average in- hospital cost is $25,000.

• Identification of feet at risk.
• Prevention of foot ulcers.
• Treatment of foot ulcers.
• Prevention of recurrence of foot ulcers.

Identification of feet at risk. The diabetic patient with distal symmetrical polyneuropathy and peripheral vascular disease has feet at risk for problems. At each visit, the health care provider should inquire for symptoms of peripheral neuropathy, including pain, burning, tingling, and numbness. Patients with insensitive feet may not be aware of ulcerations or lesions. Therefore, the shoes and stockings must be removed at every visit–at least four times a year–and the feet inspected for dryness, calluses, corns, and ulcers. The health care provider should also inspect between the toes and inspect for deformities. At least once a year, the health care provider should assess the patient’s ability to sense temperature, pinprick or pressure, touch, and vibration and should test muscle strength and deep tendon reflexes (see chapter 8, "Neuropathy").

At every visit, the health care provider should also ask the patient about symptoms of intermittent claudication. In persons with diabetes and neuropathy, severe ischemia may exist without symptoms. At least once a year, the health care provider should palpate the following pulses: dorsalis pedis, posterior tibial, popliteal, and femoral.

Prevention of foot ulcers. Diabetic patients with feet at risk must learn foot hygiene and how to protect their feet. Changes in activity may be needed. Patients with foot deformities almost always require specially molded, extra-depth shoes. Deformed feet will not fit into ordinary shoes, although the patient, because of loss of sensation, may think they fit. The wearing of ordinary shoes on deformed feet may result in abrasions, ulcerations, and infection, which can lead to gangrene and amputation. If the patient’s circulation is good, prophylactic correction of foot deformities should be considered.

Peripheral polyneuropathy may have a number of etiologies, such as drugs, alcohol, chemical toxins, and uremia. These must always be considered in the differential diagnosis of neuropathy in the patient with diabetes.

Factors that contribute to peripheral vascular disease should be avoided or treated. Smoking, the most significant risk factor for peripheral vascular disease, is associated with atherosclerosis, and even one cigarette can cause vasoconstriction that lasts for an hour or longer. Other risk factors for peripheral vascular disease should be treated, including hypertension, hypercholesterolemia, and perhaps hyperglycemia.

Rest pain and night pain are major indications for vascular surgery. Other indications are ulcers that will not heal, infections resistant to treatment, and incipient gangrene. In recent years, there has been an increase in the success of vascular surgical procedures. There are, however, risks to persons with diabetes who undergo vascular surgery, including the risk of angiography (see "Kidney Disease"). Conservative measures should thus always be considered before vascular surgery. Pentoxifylline may improve the circulation in patients with peripheral vascular disease; aspirin and dipyridamole have not been

conclusively shown to be effective. Oral vasodilators are ineffective in improving blood flow, and sympathectomy is not helpful in these patients.

Treatment of foot ulcers. Carefully evaluate and vigorously debride foot ulcers to establish the depth of the ulcer. Use X-ray studies to help exclude the possibility of imbedded foreign objects or osteomyelitis. If osteomyelitis is suspected, use follow-up radiographs and appropriate scans to help establish the diagnosis. Where there is significant infection, use parenteral antibiotics. Since anaerobes frequently occur in the foot ulcers of diabetic patients, take both aerobic and anaerobic bacterial cultures to help select antibiotics.

Ulcers that occur in areas other than the usual plantar area, that cannot be explained by previous trauma or ill-fitting shoes, or that do not respond to aggressive treatment should be biopsied.

Ensure that patients do not put weight on the affected foot. Patients who do not feel pain will likely continue to walk; the resulting pressure on the foot will prevent healing. Total bed rest or the use of crutches may be required. Total-contact casts have been shown to help patients with foot ulcers ambulate while ulcers heal; the casts redistribute pressure so that the area of the ulcer bears much less weight than it would otherwise.

Good glycemic control also may help the patient’s foot to heal. Topical use of hyperbaric oxygen, however, is not effective.

Prevention of recurrence of foot ulcers. Without special post- ulcer care, recurrence of the ulcer is almost certain. Such care may entail a change in job, a change in walking habits, and most importantly, special shoes. Extra-depth shoes with molded plastic insoles help redistribute weight and may prevent recurrent ulcers. In one study, ulcers recurred in only about 20% of patients who wore these special shoes, whereas ulcers recurred in 80% of patients who resumed wearing ordinary shoes.

If ulcers recur despite protective shoes, the most likely cause is a bony deformity. If the patient’s circulation is good, orthopedic procedures to repair such deformities may help prevent recurrence of the ulcer.

The health care provider should ensure that these patients are instructed in proper foot care (see "For Patients With Diabetes: How to Care for Your Feet," on pages 83-84). A member of the health care team should instruct patients to do the following:

• Wash their feet daily.
• Inspect their feet daily.
• Use foot creams or lubricating oil.
• Cut their toenails correctly.
• Never cut calluses or corns.
• Avoid self-medication and extremes of temperature.
• Never walk barefooted.
• Wear appropriate shoes.
• Inspect the inside of the shoes daily.
• Seek medical care for all skin lesions.

If these patient instructions cannot be given during regular office visits, the health care provider should arrange to collaborate with another qualified specialist.

Deformities. If the foot is deformed, the patient will likely need consultation and should benefit from having specially molded shoes. Surgical correction should be considered for bunions, claw toes, or hammer toes–if the patient’s circulation is good.

Neuropathic ulcers. When a neuropathic ulcer is present, consultation may be necessary, and the patient may need to be hospitalized where resources for proper treatment are available. Whenever a patient is hospitalized for any reason or is put at bed rest, heel protection should be used; the heels must be checked daily for evidence of pressure injury.

Additional considerations. Caring for the feet of persons with diabetes is complex. The expertise of professionals from many disciplines is often required. Health care providers may not be able to manage all aspects of foot care by themselves and may need to consult with other professionals:

• A diabetes nurse educator can teach about foot care.
• A pedorthist can provide special shoes for the patient with foot deformities.
• A podiatrist can help with the design and selection of special shoes and shoe inlays and can teach the patient how to manage calluses, corns, toenails, and minor foot deformities.
• A neurologist can help with the differential diagnosis of complicated peripheral neuropathies.
• A vascular surgeon can help improve peripheral blood flow in cases of peripheral vascular disease.
• An expert in infectious diseases can advise on the treatment of infected foot ulcers (with or without osteomyelitis).
• An orthopedist may be needed to treat major foot deformities or perform amputation.
• A social worker and a rehabilitation expert can help with the various socioeconomic problems, including loss of job, that may result from foot problems and particularly from amputation.

For Patients With Diabetes: How to Care for Your Feet

Wash your feet daily. Dry them carefully, especially between the toes. Don’t soak your feet (unless instructed to do so by your health care provider). If your feet are dry, apply a very thin coat of lubricant (oil or cream) to them after bathing and drying them. Don’t put oil or cream between your toes.

Inspect your feet daily. Use an unbreakable mirror to help see the bottom of your feet. If your vision is impaired, ask someone to check your feet for you. Check for scratches, cuts, or blisters. Always check between your toes.

Cut your toenails by following the contour of the nail. Smooth the corners with an emery board. Don’t trim into the corners of your toenails or cut ingrown toenails. If redness appears around your toenails, see your health care provider immediately.

Don’t cut corns or calluses. Don’t use corn plasters or chemicals for removing corns or calluses. Don’t use strong antiseptic solutions or adhesive tape on your feet.

Avoid extreme temperatures. Test water with your hand or elbow before bathing. Don’t walk on hot surfaces, such as sand at the beach or cement around swimming pools. In winter, wear wool socks and protective foot gear, such as fleece-lined boots. Don’t apply hot water bottles or heating pads to your feet. If your feet are cold at night, wear socks.

Don’t walk barefooted–even indoors. Don’t wear sandals with thongs between your toes. Don’t wear shoes without stockings or socks. Inspect the inside of your shoes every day for foreign objects, nail points, torn linings, and rough areas. Shoes should be comfortable at the time of purchase. Don’t buy shoes that are too tight and depend on them to stretch out. Break in new shoes before wearing them regularly. Ask your health care provider or podiatrist about the types of shoes most appropriate for you.

Don’t wear restrictive clothing (such as leg garters). Avoid crossing your legs; doing so can cause pressure on the nerves and blood vessels in the legs.

Don’t smoke.

Don’t drink alcohol excessively.

See your health care provider regularly and be sure your feet are examined at least four times a year.

Tell your health care provider or podiatrist at once if you develop a blister or sore on your foot. Be sure to tell your podiatrist that you have diabetes.

Patient Education Principles:

• Instruct patients on the importance of regular foot care.
• Inform patients about the relationship between neuropathy, peripheral vascular disease, and foot ulcers.
• Urge patients to avoid risk factors associated with worsening of neuropathy.
• Urge patients not to smoke–particularly if they have peripheral vascular disease.
• Inform patients about special shoes for preventing or treating foot problems.
• Refer patients to a certified pedorthist if they have foot deformities or otherwise need special shoes.
• Inform patients about the availability of podiatric services; encourage patients to use these services.

Boulton AJM, Bowker JH, Gadia M, et al. Use of plaster casts in the management of diabetic neuropathic foot ulcers. Diabetes Care. 1986;9:149-152.

Edmonds ME, Blundell MP, Morris ME. Thomas EM, Cotton LT, Watkins PJ. Improved survival of the diabetic foot: the role of a specialised foot clinic. Quarterly Journal of Medicine. 1986;60:763-771.

Levin ME, O’ NeaI LW, eds. The Diabetic Foot. 4th ed. St. Louis: CV Mosby, 1988.

Appendix A, Office Guide

(Table 2) Example of an office guide.

Acknowledgments

The following persons prepared chapters of this publication: Jerry Cavallerano, Ralph DeFronzo, Steven Gabbe, Alan Jacobson, Marvin Levin, Michael Pfeifer, Philip Raskin, Susan Szpunar, and Fred Whitehouse.

The following persons served as primary reviewers of the draft chapters: Harry Bennert, Stephen Corbin, Donald Coustan, Daniel Cox, Allen Drash, Catherine Feste, Douglas Greene, William Herman, Ronald Klein, Robert Luke, David Nathan, Pasquale Palumbo, Roger Pecoraro, Anthony Rizzo, Peter Savage, and F. William Wagner, Jr.

The following organizations have lent their support in the development of this publication: the American Association of Diabetes Educators, the American Diabetes Association, the American Dietetic Association, the Juvenile Diabetes Foundation, the National Diabetes Advisory Board, and the Technical Advisory Committee of the Division of Diabetes Translation.

The following persons have also assisted in the preparation of this publication: Robert Anderson, David Ballard, Elizabeth Barrett-Connor, Diane Bild, Alton Brown, Frank DeStefano, Joycelyn EIders, Mary Anne Farrell, Catherine Feste, Florence Fiori, Earl Ford. Richard Hamman, Maureen Harris, Carlos Hernandez, Saunders Hupp, Sharon Johnson, William Jubiz, Richard Kahn, Barbara Klein, Raymond Kuehne, Daniel Lorber, Maria Ludi, James Marks, Robert Moran, Ben Muneta, Jeffrey Newman. John O’Brian, James Pichert, Gayle Reiber, Alice Ring, William Robinson, Dawn Satterfield, Richard Scheffler, Maria Segarra, Stephen Sepe, Mohamed Shakir, Karl Sussman, Frank Vinicor, John Waller, Jr., Scott Wetterhall, Julie Will, and Deborah Wingard.

The editor acknowledges with gratitude Charles M. Clark, Jr., Dorothy Gohdes, and Fran Wood for contributing critical reviews of the entire manuscript and Kelly Fearer for her secretarial assistance.

Division of Diabetes Translation, Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, Georgia

POINT OF CONTACT FOR THIS DOCUMENT:

Table 1. Clinical Manifestations of Eye Diseases =============================================================================== _ Nonproliferative Diabetic Retinopathy Nonproliferative Diabetic Retinopathy - Retinal microaneurysms. - Occasional blot hemorrhages. - Hard exudates. - One or two soft exudates. Preproliferative Diabetic Retinopathy - Presence of venous beading. - Significant areas of large retinal blot hemorrhages. - Multiple cotton wool spots (nerve fiber infarcts). - Multiple intraretinal microvascular abnormalities. Prolliferative Diabetic Retinopathy - New vessels on the disc (NVD). - New vessels elsewhere on the retina (NVE). - Preretinal or vitreous hemorrhage. - Fibrous tissue proliferation. High-Risk Proliferative Diabetic Retinopathy - NVD with or without preretinal or vitreous hemorrhage. - NVE with preretinal or vitreous hemorrhage. Dibetic Macular Edema - Any thickening of retina <2 disc diameters from center of macula. - Any hard exudate <2 disc diameters from center of macula with associated thickening of the retina. - Any nonperfused retina inside the temporal vessel arcades. - Any combination of the above. ===============================================================================

Table 2. Example of an Office Guide =============================================================================== Office Guide Patient's Name:_______________________________________________ Address:______________________________________________________ Phone: home ( )_______________________ work ( )_______________________ Date of birth: _______/_______/________ mo day year Year of diagnosis:_______________________ Type od diabetes: IDDM___ NIDDM___ Other________________________ Diet: calories______________________ meals and snacks (circle) breakfast snack lunch snack dinner snack snack Exercise: type__________ frequency_______________/week duration______minutes time of day____________________ Monitoring: blood glucose_____ urine glucose_____ urine ketones_____ frequency_______________________________________/day Oral hypoglycemia agent:________________________________________________ Insulin:________________________________________________________________ Other medications:______________________________________________________ ===============================================================================

原文链接：https://wonder.cdc.gov/wonder/prevguid/p0000063/p0000063.asp