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Definition

A disorder of the metabolism characterized by chronic hyperglycemia due to either an absolute insulin deficiency or a reduction in its biologic effectiveness, or both. Classified as insulin dependent diabetes mellitus (IDDM) and non insulin dependent diabetes mellitus (NIDDM).

History

Symptoms

100M: Polyuria, polydipsia, and polyphagia. Weight loss and fatigue are common.

NIDDM: Frequently asymptomatic; blurred vision, pruritus, recurrent skin and vaginal infections, paresthesias, and obesity are common.

General

IDDM: Patient may report wide fluctuations in blood glucose levels. Only 10 to 20 percent of diabetics are of this type.

NIOOM: Accounts for 80 to 90 percent of cases of diabetes mellitus.

Age

IDDMM: Usually develops in childhood or adolescence but may begin at any age.

NIDDM: Generally affects those over the age of 40.

Onset

IDDM: Usually acute in younger patients, but may be gradual in adults.

NIDDM: Gradual, months to years.

Duration: Slow and progressive.

Intensity: Usually mild, but may be incapacitating at any stage of illness.

Aggravating Factors: Dietary indiscretion, physical illness, trauma, noncompliance with insulin or medical regimen.

Alleviating Factors

IDDM: Tight control of hyperglycemia with proper insulin regimen and dietary compliance.

NIDDM: Weight loss, exercise, and medical compliance.

Associated Factors

IDDM: Frequently also have hypertension and lipid abnormalities.

NIDDM: Hypertension, hyperlipidemia, and atherosclerosis are often associated.

Physical Examination

General: Obesity (usually localization of fat deposits on the upper segments of the body) and mild hypertension are common in NIDDM. Postural hypotension indicates a depleted plasma volume in IDDM.

Cardiovascular: May find decreased or absent peripheral pulses, particularly in the lower extremities.

HEENT: Funduscopic examination should be performed to look for cataracts, hemorrhages, microaneurysms, exudates, and cotton-wool spots.

Neurologic: Evaluate sensation using all modalities including touch, temperature, proprioception, and vibratory sense; all are decreased in patients with peripheral neuropathy.

Skin: Eruptive xanthomas on flexor surfaces of limbs and buttocks are not uncommon. Erythematosus, violaceous, plaques on the anterior surfaces of the lower legs due to necrobiosis lipoidica diabeticorum are rare. It is not uncommon to see brownish, atrophic lesions in the pretibial regions. Candidal infections can produce edema, erythema, and papular rash in intertriginous regions of the breasts, axilla, and between the fingers.

Pathophyisology

IDDM: Patients with IDDM are genetically predisposed (95 percent of patients possess human leukocyte antigen-DR3 or DR4, or both) to autoimmune destruction of pancreatic beta cells. This response is triggered by antibodies to the islet cells or to the patient’s own endogenous insulin. These patients usually present with severe hyperglycemia or even ketoacidosis. Eighty to ninety percent of the insulin secreting beta cells must be destroyed before hyperglycemia develops Circulating insulin is virtually absent within a year of onset of diabetes as a result of the absence of endogenous secretion, despite the presence of insulinogenic stimuli. Plasma glucagon level is elevated.

NIDDM: Patients with NIDDM tend to have basal insulin secretion that is increased or normal. The majority of these patients have an element of tissue insensitivity to insulin irrespective of their weight. Insulin resistance is usually present which is aggravated by .the aging process and abdominal visceral obesity with a postreceptor defect and decreased insulin binding to plasma membrane receptors. This commonly leads to a state of hyperinsulinemia.

Diagnostic Studies

Laboratory

Urinalysis: Glucosuria and ketonuria are frequently seen.

Fasting blood sugar: Of 140 mg/dl or higher on more than one occasion establishes the diagnosis.

Oral glucose tolerance test (OGTT): Diagnosis is established by a blood glucose level greater than 200 mg/dl 2 hours after a 75 g glucose-load and greater than 200 mg/dl at 30 or 60 minutes after a 75 g glucose-load.

Glycosylated hemoglobin (hemoglobin Aid: Measures the state of glycemia over the preceding 8 to 12 weeks.

Serum insulin level: May be elevated in some NIDDM patients.

Blood urea nitrogen/Creatinine levels: Are frequently elevated in diabetic nephropathy.

lipid profile: Frequently see elevated triglycerides and decreased high-density lipoprotein cholesterol in NIDDM patients.

Radiology: Not applicable.

Other

Electrocardiography (ECG): Frequently normal but may show evidence of ischemia (T-wave inversion, S-T segment elevation) in patients with microvascular disease.

Differential Diagnosis

Traumatic: Not applicable.

Infectious

Urinary tract infection: Polyuria may be present. Usually differentiated by the prescence of pyuria, bacteriuria or a positive urine culture. Urinary tract infections frequently lead to an exacerbation of diabetes mellitus.

Metabolic

Diabetes insipidus: Patients present with polyuria. No evidence of hyperglycemia or glucosuria.

Cushing syndrome: Abnormal dexamethasone suppression test or an increased 24 hour urinary free cortisol (> 100 ug/24 h); CT scan may reveal adrenal neoplasm.

Pheochromocytoma: Elevated plasma catecholamines, 24 hour urine metanephrine or vanillylmandelic acid; CT scan may reveal neoplasms of the adrenal medulla.

Hypothyroidism/hyperthyroidism: Abnormal thyroid function studies.

Cirrhosis: Elevated liver function studies, history of hepatitis or alcohol abuse.

Neoplastic

Glucagonoma of pancreatic alpha cells: Positive-CT scan of pancreas. Vascular Anemia: Decreased hemoglobin and hematocrit. May have nutritional deficiency.

Congenital: Not applicable.

Acquired Depression: History of anhedonia, sleep disturbance, disturbed appetite, decreased libido.

Pancreatitis: Elevated serum amylase and lipase. May have history of alcohol abuse or cholelithiasis.

Medication-induced hyperglycemia: Glucocorticoids, sympathomimetic drugs, nicotinic acid, thiazide diuretics, phenytoin, and pentamidine.

Treatment

The two major goals of management are normalization of blood glucose levels and prevention of microvascular and macrovascular complications. These goals are achieved by the following measures:

1. Patient education: A team approach (physician, physician assitant, nurse educator, dietician) to treatment is crucial. Patient and family need to understand the treatment plan with 100 percent certainty.

2. Diet: The goals of management are different in IDDM and NIDDM patients.

a. IDDM: An American Diabetic Association (ADA) diet stresses the major goal of calorie restriction as a means of achieving or maintaining ideal weight. This includes a restriction of fat intake to less than 35 percent of total calories and a cholesterol reduction of less than 300 mg daily. Carbohydrates can be ingested liberally (as much as 60 percent of total calories) as long as refined and simple carbohydrates are avoided as snacks. Percentage of total calories from protein should be 15 to 20 percent. Saccharin and aspartame are noncaloric sweeteners, while sorbitol and fructose are caloric sweeteners, none of which alter the glycemic control.

b. NIDDM: The mainstay of therapy for the obese patient is weight reduction by calorie restriction and low-fat intake.

3. Exercise: Moderate intensity aerobic exercise 3 to 4 times/week for 30 to 45 minutes may have numerous beneficial effects. Insulin is more rapidly absorbed when injected into a limb that is exercised and can result in hypoglycemia.

4. Oral hypoglycemic agents (sulfonylureas): Used when above measures fail to normalize blood glucose level. Sulfonylureas work best when administered before a meal because they increase the postprandial insulin output from the pancreas. These agents are contraindicated in patients with a sulfa allergy. Second generation agents (glyburide, glipizide) are safer than older agents because of their ability to be excreted in the bile in patients with renal disease.

a. First generation sulfonylureas: Tolbutamide (Orinase): 500 mg to 1.5 g dose given every day or twice a day; Tolazamide (Tolinase): 100 mg to I g in dose given every day or twice a day; Chlorpropamide (Diabinase): 250 to 750 mg given orally every day.

b. Second-generation sulfonylureas: Glyburide (DiaBeta, Micro­nase): 1.25 to 20 mg dose given every day or twice a day; Glipizide (Glucotrol): 2.5 to 40 mg dose given every day or twice a day. Maximum doses should be split in doses twice a day. Since the major side effect is hypoglycemia, patients should be started on the lowest effective dose with the dosage increased every I to 2 weeks until the maximum dosage is reached.

5. Insulin: Indicated for all patients with IDDM and for NIDDM patients in whom glucose is inadequately controlled by diet, exercise, and oral hypoglycemic agents (fasting blood glucose >140 mg/dl).

a. Species sources: Currently available animal insulin preparations include beef, pork, or a combination of the two. Human insulin is now available in synthetic preparations and is the favored choice due to less antigenicity compared to beef or pork insulins.

b. Human insulin (Humulin) is recommended for diabetic patients first starting on insulin to avoid inducing insulin antibodies.

c. Patients receiving insulin should monitor their own blood glucose before breakfast, lunch, dinner, and at bedtime (urine glucose measurements have decreased specificity). The results of these levels form the basis for adjusting the insulin dosage. Insulin sites should be rotated on a daily basis. The most efficient sites are the anterior abdominal wall, anterior thighs, and posterior arms. It is crucial to clean injection site and to avoid areas of inflammation, scarring, and lipoatrophy.

d. The dosage requirement for subcutaneous insulin is decided on an individual basis. In general, adults require less insulin (0.6 to 0.8 U/kg/d) than adolescents (l to 1.5 U/kg/d). Insulin dosages are most commonly divided into two injections (one injection 20 to 30 minutes before breakfast and dinner). Usually these injections include a combination of regular plus NPH (neutral protamine Hagedorn for semilente plus lente]) insulin. Regular insulin wili prevent large fluctuations in the blood glucose concentration that results from absorption of carbohydrates from the morning and evening meals. The morning NPH insulin dosage will be active for the noon meal. The evening dose of NPH will act throughout the night to maintain suppression of glucose production by the liver .

As a general rule, two-thirds of the total daily insulin dose (TDD) is given in the AM and one-third in the evening. This is frequently subdivided into two-thirds intermediate-acting insulin and one-third short-acting insulin in the AM. Dinner dosing is divided into one-sixth being short-acting insulin and one-sixth being intermediate-acting insulin. For example, if TDD is 48 U, 32 U is given before breakfast (21 U NPH/11 U regular) and 16 U given before dinner (8 U NPH/8 U regular). Other common schedules for insulin administration:

• NPH and regular insulin in AM with regular insulin before dinner and NPH insulin at bedtime.
• Regular insulin at each meal with semilente at bedtime. Management of early morning hypoglycemia:.
• Somogyi effect occurs in patients with IDDM who develop nocturnal hypoglycemia (diagnosis is established by having the patient check blood glucose level at 4:00 AM) which stimulates counterregulatory hormones that produce high blood glucose levels by 7:00 AM.
• Dawn phenomenon can occur in both IDDM and NIDDM patients. This refers to a morning (4:00 to 8:00 AM) rise in plasma glucose concentration that occurs in response to a surge of growth hormone. Diagnosis is established by normal blood glucose level at 3:00 to 4:00 AM and hyperglycemia at 8:00 AM.
• Waning of circulating insulin levels is the most common cause of AM hyperglycemia.

Complications Of Diabetes Mellitus

Acute complications of diabetes mellitus are as follows:

1. Diabetic ketoacidosis: Results from severe insulin deficiency and is manifested by severe dehydration and alterations in mental status. Common etiologies for diabetic ketoacidosis are infection, inflammation, poor compliance with medications, surgery, stress, and trauma. Clinical manifestations include polyuria, polydipsia, hyperventilation (Kussmaul respirations), tachycardia, and dehydration. Patients often have the characteristic fruity odor of ketones on their breath. Nausea, vomiting, and abdominal pain are common. Laboratory findings in diabetic ketoacidosis include hyperglycemia, ketosis, and an anion gap metabolic acidosis. Patients are treated as follows:

a. Insulin: The intravenous route is preferred. A bolus dose of 10 to 15 U of regular insulin followed by continuous infusion of 5 to 10 U/h. Monitor serum glucose hourly for the first 2 hours then every 2 to 4 hours. When the serum glucose level approaches 250 to 300 mg/dl, decrease the insulin dosage to 2 to 3 U/h and continue this dose until adequate fluid replacement has been achieved and metabolic acidosis has been resolved. The patient can then be restarted on their normal daily insulin regimen.

b. Fluid replacement: The usual fluid deficit is 0.1 L/kg. Fluid replacement should begin promptly, even before laboratory results have been received. Normal saline is used unless the patient is elderly or has a history of congestive heart failure (CHF), in which 0.45 NaCI is substituted. 1 L/h for the first 2 to 3 hours, 250 to 500 ml/h for the next 12 hours. Continue at 200 to 300 ml/h until the serum glucose concentration drops below 250 mg/dl; change intravenous fluid to D5.45 NaCI to protect against excessive osmotic shifts of fluids into the cerebral tissues.

c. Potassium replacement: Total body potassium is depleted as acidosis shifts potassium from intracellular to extracellular spaces. The osmotic diuresis pulls potassium into urinary stream.

d. Metabolic acidosis: If serum HC03 is 6 mEq/L or less or the pH is 7.10 or less (or both) bicarbonate should be given in a sufficient amount to raise the bicarbonate concentration to 10 to 12 mEq/L.

e. Monitoring of therapy: Heart rate, blood pressure, respiratory rate, and mental status should be recorded every 30 to 60 minutes. Serum potassium and bicarbonate, as well as the anion gap and an ECG should be monitored every 1 to 2 hours.

Blood glucose should be monitored hourly by fingersticks. A decrease in the anion gap or increase in plasma bicarbonate indicates that ketogenesis has been inhibited.

f. Complications of diabetic ketoacidosis include cerebral edema, cardiac dysrhythmias, shock, myocardial infarction, and acute pancreatitis.

2. Hyperosmolar nonketotic coma: State of extreme hyperglycemia, severe dehydration, serum hyperosmolarity, absence of severe ketoacidosis, and altered mental status. This condition is precipitated by a stressful event such as infection, surgery, poor medical compliance, cerebrovascular accident, and myocardial infarction.

a. The patient is usually an elderly patient who is dehydrated from lack of fluid intake or impaired thirst drive. Clinical manifestations include seizures, mental obtundation, polyuria, nausea, vomiting, physical evidence of dehydration (dry mucous membranes, poor skin turgor), neurologic deficits, and orthostatic hypotension.

b. Laboratory findings include severe hyperglycemia (usually >600 mg/dl), hyperosmolality (serum osmolality >340 mg/ dl), metabolic acidosis is not usually present.

c. Treatment: The guidelines for therapy are essentially the same as for diabetic ketoacidosis with the exception of bicarbonate therapy.

3. Hypoglycemia: There are various causes of hypoglycemia in the diabetic patient. Commonly, a hypoglycemic event occurs after a skipped meal, unusual physical exertion, and errors in insulin administration (such as giving inappropriate amounts of insulin); overdose of an oral agent may also produce hypoglycemia. Less common causes include hypothyroidism, hypopituitarism, or Addison’s disease. Medications that can exacerbate hypoglycemia include salicylates and beta blockers.

a. Of particular importance is that not all patients with severe hypoglycemia will have autonomic symptoms (palpitations, diaphoresis), particularly those with autonomic dysfunction. Instead, they may only experience neuroglycopenic symptoms (light-headedness, impaired memory, and syncope).

b. Treatment for severe hypoglycemia is a 1 ampule (50 ml) of D50W given intravenously. This can be followed by a second ampule or continuous intravenous glucose (usually D5W), depending on the response. Patients who are susceptible to attacks may benefit by carrying a 1 mg ampule of glucagon for a quick subcutaneous or intramuscular injection followed by oral glucose administration. The mainstay of therapy is still prevention and education.

Pediatric Considerations

Diabetes mellitus is the most common childhood endocrine disorder. The predominant form affecting children is IDDM (type I, previously referred to as juvenile-onset diabetes). Other forms of diabetes in childhood are uncommon and usually associated with obesity, pancreatic disease (e.g., cystic fibrosis), or a few rare syndromes.

Most children with diabetes are now diagnosed early, with the classic symptoms of polyuria and polydipsia. Weight loss of several weeks duration due to dehydration and calorie loss from glucosuria may exist. Other common complaints include enuresis in a previously toilet-trained child, fatigue, weakness, and listlessness. Rarely does one see a child present with a full-blown picture of severe diabetic ketoacidosis as was once commonly seen.

Hyperglycemia must be documented to exclude glucosuria secondary to a renal tubular defect. An oral glucose tolerance test is rarely necessary in children. A random blood glucose level greater than 300mgldL (16.6 mm01/1) or a fasting blood glucose greater than 200 mg/dL (11 mm01/1) is diagnostic. Other studies may include the following: urinalysis, complete blood count and differential, ketones, pH, glycosylated hemoglobin, electrolytes, blood urea nitrogen and creatinine.

For a newly diagnosed nonketoacidotic diabetic, hospitalization is usually not necessary as long as family members receive adequate education and the child is carefully monitored when insulin treatment is begun. All caretakers must learn about diabetes, how to give injections, and how to perform home blood glucose monitoring. Patients and their families must learn to recognize and quickly treat the acute and subacute complications. In addition to education, diabetic treatment should include insulin, diet management, exercise, stress reduction, and blood glucose and urine ketone monitoring. Medic-Alert tags should be encouraged. Synthetic human insulin is recommended for newly diagnosed children.

A newly diagnosed diabetic without ketonuria may start with 0.25 U/kg/d by subcutaneous injection. If ketonuria was or is present, the child usually does not produce much insulin and will require 0.5 U/kg/d. Established diabetics usually require 1.0 U/kg/d and during adolescence the dose usually increases to 1.25 to 1.50 U/kgld. A twice daily injection of a combination of regular insulin plus an intermediate-acting (NPH or Lente) insulin is recommended to approximate the physiologic insulin release in a non diabetic state.

Approximately two-thirds of the total dose is usually given before breakfast and the other one-third before dinner. Careful adjustment of the total daily insulin dose must reflect response patterns documented by blood glucose testing over several days. Adolescents should be responsible for much of their own management with support from parents. Children younger than 10 or 11 should generally not be responsible for administering their own insulin shots. Approximately two-thirds of newly diagnosed diabetic children will exhibit some recovery of beta cell function during the initial phase of treatment.

This “honeymoon” phase results in a significant decrease in their requirements for exogenous insulin in order to remain normoglycemic. This phase may last weeks to months, but eventually the autoimmune disease results in the complete destruction of beta cell function and total dependence on exogenous insulin. Dietary management of diabetic children includes a consistent balanced diet with age appropriate calorie intake and consistent meal schedule. Children require approximately 1000 calories plus 100/year of age daily. Fat intake should be restricted to approximately 30 percent of total calories. Carbohydrates should account for 55 to 60 percent and the remainder should be derived from protein. The diet should contain complex carbohydrates and the use of refined sugar and simple carbohydrates should be minimized.

Cholesterol and intake of saturated fats should be reduced. It is important to insulin control that the daily eating pattern (both meals and snacks) remains consistent in time and intake. Younger children usually have three meals and three snacks a day. Breakfast and lunch should each account for approximately two-tenths of total daily calorie intake, dinner three-tenths, and snacks (mid­morning, mid-afternoon, bedtime) each one-tenth. Older children often omit the mid-morning snack and these calories may be added to breakfast or lunch.

Referral to a nutritionist is an important component of diabetes management. Understanding the principles of balanced nutrition and food exchanges is important to family and patient compliance with dietary requirements and restrictions.

Regular aerobic exercise should be encouraged to foster a sense of well-being, promote peer relationships, maintain proper weight and blood pressure, and improve glucoregulation and lipid metabolism. The benefits of exercise outweigh the risks of hypoglycemia during and following exercise. An additional carbohydrate exchange for every 30 minutes of exercise consumed 30 minutes before exercise may prevent hypoglycemic reactions.

Hypoglycemia (insulin reaction) is the most commonly encountered complication of diabetes. It occurs suddenly with the common symptoms being shakiness, sweating, restlessness, and behavioral changes. If left untreated, central nervous system glucopenia may result in confusion, loss of consciousness, and seizure. Concentrated simple sugar such as candy or a nondietetic soft drink should be given. Glucagon, 0.5 mg for a child or 1.0 mg for an adolescent, should be given if the patient is unresponsible or unable to swallow.

Urine ketones should be checked with any illness or any time a blood glucose level is above 240 mg/dL. If moderate or large ketonuria is present, a healthcare provider should be consulted and a dose of regular insulin equivalent to 10 to 20 percent of the total daily dose should be administered subcutaneously every three hours until the urine ketones are small or negative. Juices and other fluids should be encouraged. If Kussmaul respirations, fruity or acetone odor to the breath, or other signs of ketoacidosis develop, the patient should be evaluated in a medical facility immediately.

Routine follow up of the diabetic patient is essential. An interim history should be obtained and should focus on the child and family’s adjustment to the disease. Questions regarding school performance and peer relationships should be explored. Glucose monitoring results should be reviewed as well as insulin doses and injection techniques and sites. A diet history can provide an accurate nutritional assessment of both intake and timing. More specific questions should explore sleeping patterns, nocturia, reactions and a review of systems focusing on any illness that might potentially interfere with diabetic control. Growth charts must be accurately maintained with height and weight assessed at each visit. Blood pressure, peripheral pulses, fundoscopic examinations, and neurologic assessment should be carefully evaluated during the physical examination. A glycosylated hemoglobin performed every 3 months will provide an objective measure of glucose control over the preceding 2 to 3 month period. Yearly laboratory studies should include urinalysis, blood urea nitrogen, creatinine, cholesterol, triglycerides, thyroid antibodies, and thyroid stimulating hormone. A 24-hour urine collection for protein and creatinine clearance should be done in the case of proteinuria. An annual referral to ophthalmology is recommended.

Obstetrical Considerations

There are two categories of diabetes mellitus that can occur in the pregnant patient; chronic diabetes mellitus and gestational diabetes. There is a 9 to 12 percent occurrence of gestational diabetes and less than 1 percent incidence of IDDM.

A mother with diabetes is at increased risk of developing pregnancy induced hypertension, chronic hypertension, hydramnios, pyelonephritis, and antepartum and postpartum infections. Infants are also at risk for congenital defects, macrosomia, prematurity, and respiratory distress syndrome. During the neonatal period there is the possibility of the infant manifesting hypoglycemia, hypocalcemia, hyperbilirubinemia, polycythemia, and/or renal vein thrombosis. The overall neonatal mortality rate is 1 to 5 percent. One of the key factors in reducing the risk of poor fetal and maternal outcome is maintaining tight control of glucose levels. The course of the pregnancy can be further optimized if the diabetic condition is fine-tuned prior to conception.

All obstetric patients should be screened for glucose intolerance. Borderline or latent diabetic conditions may become clinically apparent when the patient becomes pregnant due to an alteration in glucose tolerance brought on by pregnancy. The American College of Obstetricians and Gynecologists (ACOG) classification system is very useful in managing the pregnant diabetic patient. Insulin therapy needs to be instituted if the fasting blood sugar is greater than 105 mg/dl. or the 2 hour postprandial level is greater than 120 mg/dl. The patient should be monitored closely via the fasting blood sugar and 2 hour’ postprandial, and intermittent hemoglobin Alc throughout the pregnancy. Ultrasonic surveillance should be done at regular intervals during the first two trimesters and every 2 to 4 weeks during the third trimester to screen for the development of fetal macrosomia. At 15 to 19 weeks of gestation, maternal serum alphafetoprotein should be done to screen for neural tube defects. Maternal weight gain is recommended at 25 to 35 pounds. Episodes of ketoacidosis should be avoided altogether because of its effect on lowering the intellectual function of the fetus. The patient should also have a comprehensive ophthalmologic test every trimester due to the increased incidence of diabetic retinopathy during pregnancy.

The newly diagnosed diabetic patient should also receive a baseline ECG and 24 hour urine protein and creatinine clearance. Time of delivery must be precisely chosen to avoid the possibility of respiratory distress versus profound glucose alterations in the fetus. The patient must be maintained in a euglycemic state during labor and delivery.

Oral hypoglycemic agents, the sulfonylureas, are contraindicated in pregnancy.

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