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21 Diabetes Mellitus and Related Disorders

Cho điểm
Diabetes Mellitus and Related Disorders
Ernesto Bernal-Mizrachi
Carlos Bernal-Mizrachi
Diabetes Mellitus
General principles
Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

DM is present in 7% of the U.S. population but it is estimated that 6.2 million are undiagnosed. DM type 2 is the most common cause of death in United Sates.
This metabolic disorder is accompanied by hypertension and hypercholesterolemia in half of the adult diabetic patients, increasing the risk for the development of diabetic-induced complications.1
Classification of Diabetes and Related Disorders
DM is classified into four clinical classes2:

Type 1 diabetes accounts for <10% of all cases of DM and results from a cellular-mediated autoimmune destruction of the β cells of the pancreas.

The rate of destruction is rapid in some individuals (mainly infants and children) and slow in others (mainly adults, known as late-onset autoimmune diabetes [LADA]).
This form of diabetes is characterized by severe insulin deficiency. Exogenous insulin is required to control blood glucose, prevent diabetic ketoacidosis (DKA), and preserve life.
A transient period of insulin independence (“honeymoon phase”) or reduced insulin requirement may occur early in the course of type 1 DM.

Type 2 diabetes accounts for >90% of all cases of DM. Type 2 DM is initially characterized by insulin resistance followed by failure of β cells to compensate for the increased insulin requirements.

It is usually a disease of adults; however, type 2 DM is being increasingly diagnosed in younger age groups.
Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. Frequency varies in different ethnic groups.
It is estimated that in up to 50% of affected people the disease is undiagnosed.
Insulin secretion is usually sufficient to prevent ketosis under basal conditions, but DKA can develop during severe stress.
Other specific types of DM include those that result from genetic defects in insulin secretion or action, exocrine pancreatic disease, pancreatectomy, endocrinopathies (e.g., Cushing syndrome, acromegaly), drugs, and other syndromes.

Gestational DM complicates approximately 4% of all pregnancies and usually resolves after delivery, although affected women remain at an increased risk for development of type 2 DM later in life.

All patients with gestational diabetes should undergo a 75-g oral glucose tolerance test at 6÷8 weeks postpartum to determine whether abnormal carbohydrate metabolism has persisted.
Weight loss is encouraged to decrease the likelihood of developing diabetes mellitus after delivery.
Patients with a history of gestational diabetes should be annually evaluated for onset of diabetes.
The diagnosis of DM can be established using any of the following criteria:

Plasma glucose of 126 mg/dL or greater after an overnight fast. This should be confirmed with a repeat test.

Symptoms of diabetes and a random plasma glucose of 200 mg/dL or greater

Oral glucose tolerance test that shows a plasma glucose of 200 mg/dL or greater at 2 hours after a 75-g glucose load

Diagnosis of prediabetes. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) refer to intermediate states between normal glucose tolerance and DM type 2. IFG and IGT are risk factors for type 2 diabetes and micro- and macrovascular complications.

IGT is defined by a 2-hour oral glucose tolerance test plasma glucose from 140 mg/dL to 199 mg/dL.

IFG is defined by fasting plasma glucose of 100 mg/dL to 125 mg/dL.

Lifestyle modification is recommended for persons with IGT or IFG, but the rationale for drug therapy has not been established.
Principles of Management of DM
The therapeutic goals are alleviation of symptoms, achievement of metabolic control, and prevention of acute and long-term complications of diabetes.

Glycemic control is set at the same goal for type 1 and type 2 diabetes: average preprandial capillary blood glucose values of 90÷130 mg/dL, postprandial capillary blood glucose values <180 mg/dL, and HbA1c of <7% or as close to normal as possible while avoiding significant hypoglycemia.2
This degree of glycemic control has been associated with the lowest risk for long-term complications in patients with type 13 as well as type 2 DM.4
An individualized, comprehensive diabetes care plan is necessary to accomplish these goals.
Assessment of glycemic control consists of the following:
Self-monitoring of capillary blood glucose (SMBG) is an important tool in preventing hypoglycemia and adjusting medications to reach glucose goals. It is recommended for all patients but especially for patients treated with insulin. SMBG should be carried out three or more times a day for patients using multiple insulin injections.

HbA1c provides an integrated measure of blood glucose profile over the preceding 2÷3 months; it should be obtained approximately every 3 months or at least twice a year in well-controlled patients. Any suspicion of a discordant HbA1c level should be followed up by assessment of the self-monitoring blood glucose technique, hemoglobin level, and hemoglobin electrophoresis. Normal HbA1c levels in population studies are 4%÷6% using the Diabetes Control and Complications Trial (DCCT) assay.

Ketonuria grossly reflects ketonemia. All DM patients should monitor urine ketones using Ketostix or Acetest tablets during febrile illness or persistent elevated glucose (>300 mg/dL) or if signs of impending DKA (e.g., nausea, vomiting, abdominal pain) develop.

Patient education is integral to successful management of diabetes. Diabetes education should be reinforced at every opportunity, particularly during hospitalization for diabetes-related complications.

Dietary modification. Dietary modification provides a balanced diet to achieve adequate nutrition and maintains an ideal body weight.

Caloric restriction to at least 1,000÷1,200 kcal/d for women and 1,200÷1,600 kcal/d for men is recommended for overweight individuals.
Total caloric intake can be distributed as follows: 45%÷65% of total caloric intake as carbohydrates, 10%÷30% as protein, and <30% as total fat (<7% saturated fat) with <300 mg/d of cholesterol.
In patients with low-density lipoprotein (LDL) cholesterol >100 mg/dL, restrain the total fat to 25% of total calories, saturated fat to <7%, and <200 mg of cholesterol per day.
Patients with diabetic nephropathy are usually restricted to a protein intake of 0.8 g/kg/d. With deterioration in renal function, further restriction in protein intake (0.6 g/kg) can be considered in selected patients.
Monitoring the total grams of carbohydrate by using carbohydrate counting is key in the adjustment of the insulin therapy and achievement of the glycemic control. Carbohydrate allowance should be individualized based on glycemic control, plasma lipids, and weight goals.
Exercise improves insulin sensitivity, reduces fasting and postprandial blood glucose, and offers numerous metabolic, cardiovascular, and psychological benefits in diabetic patients.

Medications for diabetes are more effective when instituted as part of a comprehensive management approach that includes diet and exercise.

Diabetes Mellitus in Hospitalized Patients
Indications for hospitalization in diabetic patients
DKA is characterized by a plasma glucose of >250 mg/dL in association with an arterial pH <7.30 or serum bicarbonate level of <15 mEq/L and moderate ketonuria or ketonemia.

Hyperosmolar nonketotic state includes marked hyperglycemia (≥400 mg/dL) and elevated serum osmolality (>315 mOsm/kg), often accompanied by impaired mental status.

Hypoglycemia is an indication if induced by a sulfonylurea drug or resulting in coma, seizures, or altered mentation.

Newly diagnosed type 1 DM and newly recognized gestational DM can be an indication for hospitalization, even in the absence of ketoacidosis (see Type 1 Diabetes and Diabetic Ketoacidosis).

Patients with newly diagnosed type 2 DM who meet the criteria for hospitalization often have severe hyperglycemia and may require insulin therapy for initial stabilization, even in the absence of ketoacidosis or hyperosmolar syndrome (see Type 2 Diabetes and Nonketotic Hyperosmolar Syndrome).

Management of diabetes in hospitalized patients
Hyperglycemia is a common finding in hospitalized patients. The prevalence of diabetes in hospitalized adults is conservatively estimated at 12%÷25%. Patients presenting to hospitals may have unrecognized diabetes or hospital-related hyperglycemia.
HbA1c can help to identify diabetes in hospitalized patients.
Accumulating evidence suggests that tight glycemic control improves mortality and morbidity in patients after coronary artery bypass graft (CABG), stroke, and cardiac surgery.
Intensive glucose control in surgical intensive care unit (ICU) patients significantly decreases in-hospital sepsis, acute renal failure requiring dialysis or hemofiltration, rate of transfusion, and polyneuropathy, and patients were less likely to require prolonged mechanical ventilation.
However, in medical ICU patients, intensive insulin therapy significantly reduced morbidity but not the overall mortality. Mortality was only significantly decreased in medical ICU patients with intensive insulin therapy who stayed for ≥3 days, and hypoglycemia was identified as an independent risk factor for death in medical ICU patients.
Therefore, caution should be applied to the widespread implementation of tight glycemic control in the ICU setting or medicine wards. Future studies are needed and the protocols should be individualized to the specific hospital environment.5,6,7
Glucose targets in hospitalized patients
Glucose levels should be kept close to 110 mg/dL in the intensive care unit. In the noncritical care units, preprandial glucose should be kept as close to 90÷130 mg/dL and maximal glucose <180 mg/dL.8
Patients hospitalized for reasons other than diabetes who are eating normally should continue the outpatient diabetes treatment, unless specifically contraindicated.

The common practice of sliding scale administration of regular insulin alone, q6h, based on bedside capillary blood glucose levels, seldom gives satisfactory results; regimens that include intermediate-acting insulin along with short-acting insulin give superior glycemic control.
Insulin doses should be given in relation to meals and should be adjusted according to glucose levels.9 Blood glucose should be monitored at least two to four times a day, especially in patients treated with insulin.
Adjustments in the next-day SC insulin dose are indicated if correction doses of insulin are frequently required. Extreme values (>300 mg/dL or <60 mg/dL) from bedside capillary blood glucose meters should be confirmed using laboratory measurements.
If persistent hyperglycemia is observed in febrile or sick patients, plasma ketones or urine ketone reaction by dipstick (Ketostix) or Acetest tablets should be determined and IV insulin should be considered to achieve glucose targets.
HbA1c should be measured if no recent result is available.
Oral medications for diabetes should be reviewed with regard to potential toxicities.

Sulfonylureas predispose to developing hypoglycemia in hospitalized patients not consuming their routine diet. Caution but not contraindication is recom-mended.

Metformin should be withheld 1 day before any diagnostic evaluation that involves the use of iodinated radiocontrast dyes. It can be restarted 48 hours after radiocontrast exposure and documentation of normal renal function. Metformin therapy should also be discontinued in the presence of sepsis, congestive heart failure (CHF), renal dysfunction, or other conditions that predispose to lactic acidosis.

Thiazolidinediones should not be administered to patients with hepatic dysfunction as indicated by elevated serum transaminases or CHF.

Glucosidase inhibitors should be continued unless the patient has gastrointestinal illness.

Patients hospitalized for reasons other than diabetes who are required to fast should discontinue oral antidiabetic medications.

In patients requiring insulin, IV insulin infusion is recommended (see Diabetes Mellitus in Surgical Patients, Chapter 1, Patient Care in Internal Medicine). Alternative treatment for diabetics during these conditions is to administer one-half to two-thirds of the patient's long or intermediate insulin dose along with short-acting insulin by sliding scale.
An IV infusion of 5% dextrose in water (D5W) or dextrose in saline at 75 to 125 mL/hr should be provided to maintain plasma glucose between 90 and 180 mg/dL. Additional SC doses of short-acting insulin (1÷4 units) are indicated when blood glucose levels are >200 mg/dL.
It is recommended that transition from insulin drip to SC insulin be done before a meal, preferably before breakfast. Insulin drip should be discontinued 30 minutes to 1 hour after patients received SC regular insulin and intermediate-acting insulin;
however, if Lispro or Aspart insulin is used, insulin drip should be discontinued after SC insulin has been administered.
For patients receiving glargine for basal insulin regimen, half of the basal insulin dose can be given as NPH at breakfast in addition to the usual short-acting insulin, and the total dose of glargine resumed at night.
Diabetic patients with emergency surgery
Exclude DKA and neuropathy complications mimicking surgical emergencies.
Assess glycemic, acid-base, electrolyte (potassium, magnesium, and phosphate), and fluid status.
Restore circulating volume, control acidosis, and correct potassium abnormalities if surgery can be delayed.
Intravenous insulin, glucose, and potassium infusion should be administered to achieve target blood glucoses (see “Glucose targets in hospitalized patients”). Hourly glucose measurements are mandatory to adjust insulin and glucose infusions. Potassium should be monitored at least every 2 hours and replaced aggressively as required.

Enteral nutrition.10 Short-acting insulin by sliding scale should be used initially until the patient is tolerating tube feedings. When infusion rates are >30 mL/hr, start NPH or lente at half of the patient's morning preadmission dose, and then adjust the dose daily to keep glucose levels between 100 and 200 mg/dL.

Total parenteral nutrition (TPN). Individuals with type II diabetes who require TPN are likely to require large amounts of insulin. See Chapter 2, Nutrition Support, for insulin management of patients on TPN.

Type 1 Diabetes and Diabetic Ketoacidosis
General Prinicples
A comprehensive approach is necessary for successful management of type 1 DM. A team approach that includes the expertise of diabetes educators, dietitians, and other members of the diabetes care team offers the best chances of success.
Treatment of type 1 DM requires lifelong insulin replacement.

Insulin preparations. After SC injection, there is individual variability in the duration and peak activity of insulin preparations and day-to-day variability in the same subject (Table 21-1).

Rapid-acting insulins include regular insulin, lispro, insulin aspart, and glulisine. Regular insulin can be administered intravenously, intramuscularly, or subcutaneously. An IV bolus of regular insulin exerts maximum effect in 10÷30 minutes and is quickly dissipated.

Intermediate-acting insulins include NPH (isophane) and lente (zinc). These insulins are released slowly from SC sites and reach peak activity after 6÷12 hours, followed by gradual decline.

Long-acting insulins are absorbed more slowly than the intermediate-acting preparations. Long-acting insulins provide a steady “basal”
supply of circulating insulin when administered once or twice a day. Glargine and detemir are “peaklessâ€
bioengineered human insulin analogs with an extended duration of activity. These insulins are generally administered once daily as a subcutaneous injection at bedtime, in a regimen that includes premeal regular insulin or insulin lispro. In type 1 DM patients, two injections are sometimes required for 24-hour coverage.

Concentration. Most insulins now contain 100 units/mL (U-100). A U-500 preparation is available for the rare patient with severe insulin resistance.

Mixed insulin therapy. Rapid-acting insulins (regular, lispro, and aspart) can be mixed with intermediate-acting (NPH and lente) or long-acting (ultralente)

insulins in the same syringe for convenience. The rapid-acting insulin should be drawn first, cross contamination should be avoided, and the mixed insulin should be injected immediately. Commercial premixed insulin preparations do not allow dose adjustment of individual components but are convenient for patients who are unable or unwilling to do the mixing themselves.
TABLE 21-1 Approximate Kinetics of Human Insulin Preparations After Subcutaneous Injection
SC insulin delivery. The anterior abdominal wall, thighs, buttocks, and arms are the preferred sites for SC insulin injection. Absorption is fastest from the abdomen, followed by the arm, buttocks, and thigh, probably as a result of differences in blood flow. Injection sites should be rotated within the regions rather than randomly across separate regions, to minimize erratic absorption. Exercise or massage over the injection site may accelerate insulin absorption.

Inhaled insulin was recently approved. It should be administered within 10 minutes before meals. Patients have to be trained in the appropriate procedure for inhalation of insulin. The insulin is available in 1-mg and 3-mg blister packs (1 mg is equivalent to approximately 2.5÷3.0 units of subcutaneously injected insulin). Typically, patients should use one or two inhalations for any given dose. Insulin has a rapid onset of action, faster than regular insulin with a duration of action between that of insulin lispro and regular insulin. Hypoglycemia, cough, and bitter taste were reported. This insulin preparation is not currently recommended in smokers or in patients with pulmonary disorders including asthma due to unclear alteration of insulin absorption.

Initial insulin dosage for optimal glycemic control is approximately 0.5÷1.0 units/ kg/d for the average nonobese patient. A conservative total daily dose is given initially; the dose is then adjusted, using blood glucose values.

A regimen of multiple daily insulin injections is preferred to obtain optimal control.
This regimen provides approximately 40%÷50% of the total daily dose of insulin as basal insulin supply, using one or two injections of long-acting or intermediate-acting insulin.
The remainder is given as three doses of rapid-acting insulin divided across the main meals, empirically or in proportion to the carbohydrate content. Typically 1 unit of insulin per 10÷15 g of carbohydrate consumed is typical.
The conventional insulin regimen uses a mixture of short- and intermediate-acting insulins administered before breakfast and before the evening meal.

Approximately two-thirds of the total daily dose is injected in the morning and one-third in the evening.
Approximately two-thirds of each injection comprises intermediate-acting insulin and one-third is rapid-acting insulin (“rule of thirds”).

These proportions should be modified for patients with unusual work schedules or eating patterns.
The units of individual insulin components of each injection are then adjusted using values from preprandial and bedtime blood glucose monitoring.
Continuous SC insulin infusion is a tool for intensive diabetes control in selected patients.

It provides 50% of total daily insulin as basal insulin and the remainder as multiple preprandial boluses of insulin, using a programmable insulin pump.
As with the multiple daily insulin injections regimen, the premeal insulin doses are adjusted to the carbohydrate content of each meal.
Sliding scale administration of regular insulin alone to hospitalized patients, based on bedside capillary blood glucose levels, rarely achieves satisfactory glycemic control; regimens that include intermediate-acting insulin give superior results.9

Monitoring. Blood glucose should be monitored at least four times a day (preprandially and at bedtime) in hospitalized patients with type 1 DM. The HbA1c should be obtained if no recent result is available. Urine should be tested for ketones whenever hyperglycemia (>300 mg/dL) persists.

Epidemiology and Pathophysiology
DKA, a potentially fatal complication, occurs in up to 5% of patients with type 1 DM annually; it is seen less frequently with type 2 DM. It is a manifestation of severe insulin deficiency, often in association with stress and activation of counterregulatory hormones (e.g., catecholamines, glucagon).

Precipitating factors for DKA include inadvertent or deliberate interruption of insulin therapy, sepsis, trauma, myocardial infarction, and pregnancy. DKA may be the first presentation of type 1 and, rarely, type 2 DM.

A high index of suspicion is warranted, because clinical presentation may be nonspecific.
Clinical Features
Clinical features include polyuria, polydipsia, weight loss, nausea, vomiting, and vaguely localized abdominal pain.

Tachycardia; decrease of capillary filling; rapid, deep, and labored breathing (Kussmaul respiration); and fruity breath odor are common physical findings.
Prominent gastrointestinal (GI) symptoms may give rise to suspicion for intra-abdominal pathology.
Dehydration is invariable and respiratory distress, shock, and coma can occur.
Laboratory Evaluation
Labs will show an anion gap metabolic acidosis and positive serum ketones.
Plasma glucose usually is elevated, but the degree of hyperglycemia may be moderate (≤300 mg/dL) in 10%÷15% of patients in DKA. Pregnancy and alcohol ingestion are associated with “euglycemic DKA.”

The urine ketone reaction correlates poorly with ketonemia but is usually positive in DKA.
Hyponatremia, hyperkalemia, azotemia, and hyperosmolality are other findings.
Serum amylase and transaminases may be elevated.
A focused search for a precipitating infection is always prudent.
An electrocardiogram (ECG) should be performed to evaluate electrolyte abnormalities and for unsuspected myocardial ischemia.
Management and Treatment
Management of DKA should preferably be conducted in an ICU. If treatment is conducted in a non-ICU setting, close monitoring by a physician is mandatory until ketoacidosis resolves and the patient's condition is stabilized. The therapeutic priorities are fluid replacement, adequate insulin administration, and potassium repletion. Administration of bicarbonate, phosphate, magnesium, or other therapies may be advantageous in selected patients but is not a first-line consideration.

IV access and supportive measures should be instituted without delay.

Fluid deficits of several liters are common in DKA patients and can be estimated by subtracting the current weight from a recently known dry weight. The average degree of dehydration for most patients is approximately 7%÷9% of body weight. Hypotension indicates a loss of >10% of body fluids.11

Initially, restoration of circulating volume using isotonic (0.9%) saline should be accomplished. The first liter should be infused rapidly (if cardiac function is normal) and should be followed by additional fluids at a rate of 1 L/hr until the volume deficit is corrected. Hypotonic saline (0.45%) can be used in patients with severe hypernatremia (>155 mEq/L).

The next goal is to replenish total body water deficits; this can be accomplished using a 0.45% saline infusion at 150÷500 mL/hr if the corrected serum sodium is normal or elevated; 0.9% NaCl at a similar rate is appropriate if corrected serum sodium is low. Rate of the fluid replacement depends on the degree of dehydration and cardiac and renal status. Do not exceed a change in osmolality >3 mOsm/kg/hr. The success of the fluid replacement is judged by improvement in blood pressure, measurement of fluid balance, and clinical examination.
Maintenance fluid replacement is continued until the fluid intake/output records indicate an overall positive balance similar to the estimated fluid deficit. Complete fluid replacement in a typical DKA patient may require 12÷24 hours to accomplish.

Insulin therapy. Sufficient insulin must be administered to turn off ketogenesis and correct hyperglycemia.

An IV bolus of regular insulin, 10÷15 units (0.15 unit/kg), can be administered. This should be followed by a continuous infusion of regular insulin at an initial rate of 5÷10 units/hr (or 0.1 unit/kg/hr). A solution of regular insulin, 100 units in 500 mL 0.9% saline, infused at a rate of 50 mL/hr delivers 10 units/hr of insulin.

A decrease in blood glucose of 50÷75 mg/dL/hr is an appropriate response; lesser decrements suggest insulin resistance, inadequate volume repletion, or a problem with insulin delivery. If insulin resistance is suspected, the hourly dose of regular insulin should be increased progressively by 50%÷100% until an appropriate glycemic response is observed.

Excessively rapid correction of hyperglycemia at rates >100 mg/dL/hr should be avoided to reduce the risk of osmotic encephalopathy.

Maintenance insulin infusion rates of 1÷2 units/hr are appropriate when serum bicarbonate rises to 15 mEq/L or higher and the anion gap has closed. Once oral intake resumes, insulin can be administered SC and the parenteral route can be discontinued. It is prudent to give the first SC injection of insulin approximately 30 minutes before stopping the IV route.

Dextrose (5%) in saline should be infused once plasma glucose decreases to 250 mg/dL and the insulin infusion rate should be decreased to 0.05 units/kg/hr to prevent dangerous hypoglycemia.

Potassium deficit should always be assumed or anticipated, regardless of plasma levels on admission. Insulin therapy results in a rapid shift of potassium into the intracellular compartment.

The goal is to maintain plasma potassium in the normal range and thereby prevent the potentially fatal cardiac effects of hypokalemia. Potassium status should be documented from the outset; this includes ECG to rule out rare life-threatening hyperkalemia.
Potassium should be added routinely to the IV fluids at a rate of 10÷20 mEq/hr except in patients with hyperkalemia (>6.0 mmol/L and/or ECG evidence), renal failure, or oliguria confirmed by bladder catheterization.
Patients who present with hypokalemia should receive higher doses of potassium, 40 mEq/hr or greater, depending on severity.
Potassium chloride is an appropriate initial choice, but this can later be changed to potassium phosphate to reduce chloride load.
Monitoring of therapy
Blood glucose should be monitored hourly, serum electrolytes every 1÷2 hours, and arterial blood gases as often as necessary.
Serum sodium tends to rise as hyperglycemia is corrected; failure to observe this trend suggests that the patient is being overhydrated with free water.
Serial serum ketone assays are not necessary, because ketonemia lags behind clinical recovery; closure of the anion gap is a more reliable index of metabolic recovery.
Use of a flowchart is an efficient method of tracking clinical data (e.g., weight, fluid balance, mental status) and laboratory results during the management of DKA.
Continuous ECG monitoring may be required for proper management of potassium in patients with oliguria or renal failure.
Bicarbonate therapy is not routinely necessary and may be deleterious in certain situations.

However, bicarbonate therapy may be appropriate and should be considered for DKA patients who develop (a) shock or coma, (b) severe acidosis (pH 6.9÷7.1), (c) severe depletion of buffering reserve (plasma bicarbonate <5 mEq/L), (d) acidosis-induced cardiac or respiratory dysfunction, or (e) severe hyperkalemia.
Sodium bicarbonate, 50÷100 mEq in 1 L of 0.45% saline infused over 30÷60 minutes, can be given in these situations. Bicarbonate treatment should be guided by arterial pH measurement and continued until the indications are no longer present.
Care should be taken to avoid hypokalemia; an additional dose of potassium, 10 mEq, should be included with each infusion of bicarbonate unless hyperkalemia is present.
Phosphate and magnesium stores are subnormal in DKA patients, and plasma levels (particularly phosphate) decline further during insulin therapy. The clinical significance of these changes is unclear, and routine replacement of phosphate or magnesium is not necessary.

In hypophosphatemic patients with compromised oral intake, the use of potassium phosphate in maintenance IV fluids can be considered (see Chapter 3, Fluid and Electrolyte Management).
Magnesium therapy is indicated in patients with ventricular arrhythmia and can be administered as magnesium sulfate (50%) in doses of 2.5÷5.0 mL (10÷20 mEq magnesium) IV.
IV antimicrobial therapy should be started promptly for documented bacterial, fungal, and other treatable infections. Empiric broad-spectrum antibiotics can be started in septic patients, pending results of blood cultures (see Chapter 14, Human Immuno-deficiency Virus Infection and Acquired Immunodeficiency Syndrome).

Complications of DKA include life-threatening conditions that must be recognized and treated promptly.

Lactic acidosis may result from prolonged dehydration, shock, infection, and tissue hypoxia in DKA patients. Lactic acidosis should be suspected in patients with refractory metabolic acidosis and a persistent anion gap despite optimal therapy for DKA. Adequate volume replacement, control of sepsis, and judicious use of bicarbonate constitute the approach to management.

Arterial thrombosis manifesting as stroke, myocardial infarction, or an ischemic limb occurs with increased frequency in DKA. However, routine anticoagulation is not indicated except as part of the specific therapy for a thrombotic event.

Cerebral edema, a dire complication of DKA, is observed more frequently in children than adults.

Symptoms of increased intracranial pressure (e.g., headache, altered mental status, papilledema) or a sudden deterioration in mental status after initial improvement in a patient with DKA should raise suspicion for cerebral edema.
Overhydration with free water and excessively rapid correction of hyperglycemia are known risk factors.
A fall in serum sodium or failure to rise during therapy of DKA is a clue to imminent or established overhydration with free water. Neuroimaging with a computed tomography (CT) scan can establish the diagnosis. Prompt recognition and treatment with IV mannitol is essential and may prevent neurologic sequelae in patients who survive cerebral edema.
Rebound ketoacidosis can occur due to premature cessation of insulin therapy.

Prevention of DKA. Every episode of DKA suggests a breakdown in clinical communication. Diabetes education should therefore be reinforced at every opportunity, with special emphasis on (a) self-management skills during prodromal sick days; (b) the body's need for more, rather than less, insulin during such illnesses; (c) testing of urine for ketones; and (d) procedures for obtaining timely and preventive medical advice.

Type 2 Diabetes and Nonketotic Hyperosmolar Syndrome
General principles
Type 2 DM results from defective compensatory β-cell growth and secretory responses to insulin resistance.
The loss of pancreatic β cells is progressive and insulin secretion is usually sufficient to prevent ketosis under basal conditions. However, type 2 DM patients can develop DKA when exposed to severe stress.
The mechanisms underlying the β-cell loss in type 2 DM are unknown, but genetic and environmental factors are major components.
Recommended glycemic goals for patients with type 2 DM are the same as in type 1 DM.
The achievement of these goals requires individualized therapy and a comprehensive approach that incorporates lifestyle and pharmacologic interventions. Several considerations should be taken into account before choosing oral agents (Table 21-2) in patients with type 2 DM:
Oral therapy should be initiated early in patients that failed glycemic control after a short-term trial of diet and exercise.
Monotherapy with maximum doses of insulin secretagogues, metformin, or thiazol-idinediones yields comparable glucose-lowering effects.
The glucose-lowering effects of insulin secretagogues are observed within days, but approximately 20% of patients do not respond to these agents. In contrast, the maximum effects of metformin or thiazolidinediones may not be observed for several weeks.
A second or third agent including insulin should be added if no response is achieved with monotherapy.
Glycemic control with monotherapy is less likely to occur in patients with very high glucose readings (>240 mg/dL) at the time of diagnosis.12 Combination therapy or insulin should be considered as first line for these patients.

TABLE 21-2 Characteristics of Oral Antidiabetic Agents
Because residual pancreatic β-cell function is required for the glucose-lowering effects of sulfonylureas, repaglinide, metformin, and thiazolidinediones, many patients with advanced type 2 DM do not respond satisfactorily to these agents and insulin therapy is recommended early for such patients.
Moreover, the toxicity profile of some oral agents may preclude their use in patients with pre-existing illnesses.
Insulin secretagogues
Sulfonylureas increase insulin secretion by binding to specific receptors in β cells. All sulfonylureas are equally effective in controlling hyperglycemia at equivalent doses.

These agents should be taken 30÷60 minutes before food and should never be administered to fasting patients.
Chlorpropamide and glyburide are metabolized to an active metabolite with significant renal excretion and should be avoided in the setting of impaired renal function and used with caution in elderly patients.
Therapy should be initiated with the lowest effective dose and increased gradually over several days or weeks to the optimal dose.
Good responders to sulfonylurea include newly diagnosed type 2 diabetics with mild to moderate fasting hyperglycemia.
Hypoglycemia is more common with long-acting sulfonylureas.
Weight gain is also a notable adverse effect.
Repaglinide is a meglitinide analog that augments food-stimulated insulin secretion with a similar glucose-lowering effect as sulfonylureas. Unlike sulfonylureas, however, the meglitinides have a very short onset of action and a short half-life.

Repaglinide can be used as a single agent or in combination with metformin in patients with type 2 DM.
The dose range is 0.5÷4.0 mg PO with two to four meals daily; the drug should be taken within 30 minutes before meals and skipped if no meal is planned.
Adverse effects include hypoglycemia and weight gain.
Nateglinide, a D-phenylalanine derivative chemically distinct from other insulin se-cretagogues, acts directly on the pancreatic β cells to stimulate early insulin secre-tion.13

It is taken 10 minutes before breakfast, lunch, and dinner and leads to significant insulin secretion within 15 minutes with a return to baseline in 3÷4 hours, effectively controlling postprandial hyperglycemia. The maximum effective dosage is 120 mg.
There is a potential for drug interactions between nateglinide and medications affected by the cytochrome P-450 system.
The drug is well tolerated and the risk of hypoglycemia appears minimal.
Metformin, the only biguanide in current clinical use, inhibits hepatic glucose output and stimulates glucose uptake by peripheral tissues. It is the preferred agent for patients in whom weight gain is not desirable.

Metformin should be taken with food and beginning with a single 500-mg or 850-mg tablet, the dose is increased slowly every 1÷2 weeks until optimal glycemic effect is achieved or 2,000 mg/d is reached.
GI symptoms occur in 20%÷30% of patients but are seldom serious and can be minimized by slow dosage titration.
Lactic acidosis, the most serious adverse effect, has an incidence of approximately 3 per 100,000 patient-years and a significant mortality rate. Risk factors for lactic acidosis include renal dysfunction, hypovolemia, tissue hypoxia, infection, alcoholism, and cardiopulmonary disease.
A serum creatinine level >1.5 mg/dL in men (>1.4 mg/dL in women) or a glomerular filtration rate of <70 mL/min are contraindications to metformin use.
Metformin should be discontinued at the time of the radiographic contrast procedure and not restarted for 48 hours.
Other situations in which metformin therapy should be avoided include cardiogenic or septic shock, congestive heart failure requiring pharmacologic therapy, severe liver disease, pulmonary insufficiency with hypoxemia, and severe tissue hypoperfusion.14
α-Glucosidase inhibitors block polysaccharide and disaccharide breakdown and decrease postprandial hyperglycemia when administered with food. Two members of this class, acarbose and miglitol, exert maximal effects at a dosage of approximately 150 mg/d.

Each drug should be initiated at low doses (25 mg PO daily÷tid, with food) and increased slowly in weekly steps of 25 mg to minimize GI intolerance.
Monotherapy with these agents seldom gives satisfactory results, but their addition to other drugs can improve glycemic control.
Dose-related adverse effects are diarrhea, bloating, abdominal cramping, and flatulence.
Acarbose has been associated with elevation in liver enzymes, and therefore periodic monitoring of transaminases is recommended.
Hypoglycemia in patients who are receiving regimens that include α-glucosidase inhibitors should be treated with glucose, not sucrose.
Thiazolidinediones (TZDs) increase insulin sensitivity in muscle, adipose tissue, and liver. Therefore, patients with considerable endogenous insulin secretion respond better to these agents.

The risk of drug-induced hepatotoxicity with this class mandates close monitoring of liver function, particularly during the initial 12 months of drug exposure. Edema and cytopenia, from increased plasma volume, also occur with these agents.
TZDs can precipitate congestive heart failure in patients who have cardiovascular disease and are in borderline compensation; therefore, therapy with these agents is not recommended in patients with significant heart disease (New York Heart Association class 3 and 4 cardiac status). Before starting TZDs, the physician should determine previous existence of cardiac disease, concomitant use of medications associated with fluid retention, edema, and shortness of breath. The risk of congestive heart failure is increased in patients with previous history of heart failure, coronary artery disease (CAD), hypertension, long-standing diabetes, left ventricular hypertrophy, pre-existing edema, edema after TZD therapy, insulin therapy, advanced age, renal failure, and aortic and mitral valve disease.15
Resumption of ovulation may occur in some premenopausal women with anovulatory cycles after TZD therapy. Therefore, contraceptive practice should be reviewed to prevent unintended pregnancy. The two TZDs currently available, rosiglitazone and pioglitazone, appear to have similar efficacy on glycemia.
Rosiglitazone can be used alone as an adjunct to diet and exercise or in combination with metformin or a sulfonylurea.

The usual starting dosage is 4 mg PO daily (or 2 mg PO bid) taken with or without food. This can be advanced to 8 mg PO daily (or 4 mg PO bid) after 12 weeks if glycemic response is inadequate.
Although data from clinical trials suggest a low propensity for hepatotoxicity, regular monitoring of hepatic transaminases is required in patients treated with rosiglitazone.
Potential drug interaction with phenobarbital, rifampin, amiodarone, and fluconazole can occur.
Pioglitazone can also be used as a single agent (as an adjunct to diet and exercise) or in combination with sulfonylurea, metformin, or insulin.

The initial dosage is 15 mg or 30 mg PO daily, taken with or without food; this can be increased after several weeks to 45 mg PO daily for optimal effect.
Regular monitoring of hepatic transaminases is required during pioglitazone therapy.
Pioglitazone alters the levels of medications metabolized by cytochrome P-450 isoform CYP 3A4 (carbamazepine, cyclosporine, felodipine, and some oral contraceptives, among others).
Insulin therapy in type 2 DM is indicated in:

Patients in whom oral agents failed to sustain glycemic control
Nonketotic hyperosmolar crisis
Newly diagnosed patients with severe hyperglycemia
Pregnancy and other situations in which oral agents are contraindicated
The success of insulin therapy depends on the use of sufficient doses of insulin (0.6 to >1.0 units/kg of body weight per day) to achieve normoglycemia, rather than any specific pattern of insulin administration.

Once-daily injections of intermediate-acting or long-acting insulin at bedtime or before breakfast and daily or twice-daily combinations of intermediate- and short-acting insulins have all been used with good results.
Insulin glargine at bedtime and rapid-acting insulin at mealtimes is a good regimen to simulate physiologic insulin secretion.
Large doses of insulin (>100 units/d) usually are required for optimal glycemic control. Weight gain in this population can be considerable.
The risk of insulin-induced hypoglycemia, the most dangerous side effect, is low in this population, but its frequency increases as patients approach normal HbA1c levels or when deterioration of kidney function occurs.
Glucagonlike peptide 1 (GLP-1) agonists. GLP-1 is an intestinal peptide that is secreted in response to food and regulates postprandial glycemia. It also protects and induces proliferation of β cells, making it an attractive alternative new therapy for diabetes.

Exenatide, a GLP-1 receptor agonist, has been shown to decrease postprandial hyperglycemia, reduce glucagon secretion, and induce weight loss.
It has been approved as adjunctive therapy to sulfonylureas and/or metformin in patients who have not achieved control with these oral agents.16,17 Data on long-term therapy with this agent are not available yet.
Therapy should be initiated with 5 mcg twice daily and could be increased to 10 mcg after 1 month of therapy. The most common side effect is nausea.
Combination therapy. About 60% of patients on monotherapy may have worsening of metabolic control during the first 5 years of therapy, and concurrent use of two or more medications with different mechanisms of action may be necessary (United Kingdom Prospective Diabetes Study [UKPDS]).

Dose increase and addition of agents should be performed in a short period of time until glucose control is achieved.
Combination therapy using a secretagogue and an insulin sensitizer should be considered as first line in patients with HbA1c levels ≥9. Widely used regimens include a sulfonylurea plus metformin (most common), or a TZD plus a sulfonyl- urea.
Triple combination therapy has not been studied extensively and is considered somewhat controversial.
The combination of a TZD plus insulin is less accepted because of a higher incidence of congestive heart failure exacerbations.
Several combinations are already available (metformin-glibenclamide, rosiglitazone and metformin, and glipizide and metformin HCl).
Nonketotic Hyperosmolar Syndrome
General Principles
Nonketotic hyperosmolar syndrome (NKHS) is one of the most serious life-threatening complications of type 2 DM.

Hyperosmolar hyperglycemic state occurs primarily in patients with type 2 DM, although that diagnosis may not have been known previously.
In 30%÷40% of cases, NKHS is the initial presentation of a patient's diabetes.18
NKHS is significantly less common than DKA with an incidence of <1 case per 1,000 person-years.
Ketoacidosis is absent because insulin levels may effectively prevent lipolysis and subsequent ketogenesis yet are inadequate to facilitate peripheral glucose uptake and to prevent hepatic residual gluconeogenesis and glucose output.
Precipitating factors include stress, infection, stroke, noncompliance with medications, dietary indiscretion, and alcohol and cocaine abuse. Impaired glucose excretion is a contributory factor in patients with renal insufficiency or prerenal azotemia.
Clinical Findings
In contrast to DKA, the onset of NKHS is usually insidious. Several days of deteriorating glycemic control are followed by increasing lethargy. Clinical evidence of severe dehydration is the rule. Some alterations in consciousness and focal neurologic deficits may be found at presentation or may develop during therapy. Therefore, repeated neurologic assessment is recommended.
Laboratory Findings
Clinical findings include (a) hyperglycemia, often >600 mg/dL; (b) plasma osmolality >320 mOsm/L; (c) absence of ketonemia; and (d) pH >7.3 and serum bicarbonate >20 mEq/L. Prerenal azotemia and lactic acidosis can develop. Although some patients
will have detectable urine ketones, most patients do not have a metabolic acidosis. Lactic acidosis may develop from an underlying infection or other cause.
Differential Diagnosis
The differential diagnosis of NKHS includes any cause of altered level of consciousness, including hypoglycemia, hyponatremia, severe dehydration, uremia, hyperammonemia, drug overdose, and sepsis. Seizures and acute strokelike syndromes are common presentations.
The goals of therapy are:
Restoration of hemodynamic stability and intravascular volume by fluid replacement
Correction of electrolyte abnormalities
Gradual correction of hyperglycemia and hyperosmolarity with fluid replacement and insulin therapy
Detection and treatment of underlying disease states and precipitating causes. However, such efforts should not delay fluid replacement and insulin therapy.
Initial treatment can make a difference in the frequency of complications and outcome. Therapy must be individualized based on the degree of dehydration and underlying cause (sepsis, renal and cardiac function). Rapid vein access and urinary catheterization are essential.

Restoring hemodynamic stability is the first aim. Restoration of intravascular volume should be followed by correction of total body water deficit. Compared to DKA, patients with NKHS may require as much as 10÷12 L positive fluid balance over 24÷36 hours to restore total deficits.

Electrolyte management
Although the potassium level may be initially normal or even high, all patients with NKHS are potassium depleted. Rehydration and insulin therapy usually result in hypokalemia, and this should be corrected.
If the initial potassium levels are low, replacement should begin immediately after urine output is ensured. Lactic acidosis requiring bicarbonate therapy may develop as a complication of NKHS or metformin therapy.
Insulin therapy. Insulin plays a secondary role in the initial management of NKHS, and fluid therapy always should precede insulin administration.

In patients with marked hyperglycemia (>600 mg/dL), regular insulin, 5÷10 units IV, should be given immediately, followed by continuous infusion of 0.1÷0.15 units/kg/hr. Lower doses of a regular insulin bolus can be used for less severe hyperglycemia.
Once plasma glucose decreases to 250÷300 mg/dL, insulin infusion can be decreased to 1÷2 units/hr and 5% dextrose should be added to the intravenous fluids. After full rehydration and clinical recovery, regular insulin can be given SC and patients can thereafter resume their usual diabetes therapy.
Monitoring of therapy. Use of a flowchart is helpful for tracking clinical data and laboratory results.

Initially, blood glucose should be monitored every 30÷60 minutes and serum electrolytes every 1÷2 hours; frequency of monitoring can be decreased during recovery.
Neurologic status must be reassessed frequently; persistent lethargy or altered mentation indicates inadequate therapy. On the other hand, relapse after initial improvement in mental status suggests too-rapid correction of serum osmolarity.
Underlying illness. Detection and treatment of any underlying predisposing illness is critical in the treatment of NKHS. Antibiotics should be administered early, after appropriate cultures, in patients in whom infection is known or suspected as a precipitant to a hyperosmolar hyperglycemic state (HHS). A high index of suspicion should be maintained for underlying pancreatitis, GI bleeding, renal failure, and thromboembolic events, especially acute myocardial infarction.

Complications of NKHS include thromboembolic events (cerebral and myocardial infarction, mesenteric thrombosis, pulmonary embolism, and disseminated intravascular coagulation), cerebral edema, adult respiratory distress syndrome, and rhabdomyolysis.

Chronic Complications of Diabetes Mellitus
Prevention of long-term complications is one of the main goals of diabetes management. Appropriate treatment of established complications may delay their progression and improve quality of life.
Microvascular complications include diabetic retinopathy, nephropathy, and neuropathy. These complications are directly related to hyperglycemia and can be prevented by maintaining tight glycemic control.

Diabetic retinopathy
General Principles
Diabetic retinopathy (DR) is diagnosed in 80% and 90% of type 1 diabetics after 10 and 15 years of diagnosis, respectively. DR is far less frequent in type 2 diabetics.19
DR is classified in background retinopathy with or without maculopathy (microan-eurysms, retinal infarcts) and proliferative retinopathy.
Other ocular abnormalities associated with diabetes include cataract formation, dyskinetic pupils, glaucoma, optic neuropathy, extraocular muscle paresis, floaters, and fluctuating visual acuity. The latter is related to changes in blood glucose.

The presence of floaters may be indicative of preretinal or vitreous hemorrhage; immediate referral for ophthalmologic evaluation is warranted.
Annual examination by an ophthalmologist is recommended at the time of diagnosis of all type 2 DM patients and at the beginning at puberty or 3÷5 years after diagnosis for patients with type 1 DM. Dilated eye examination should be repeated annually by an experienced physician or ophthalmologist. Early detection is critical as therapy is more effective at these stages. In general, any diabetic with visual symptoms or abnormalities should be referred for ophthalmologic evaluation.
Background retinopathy usually is not associated with loss of vision. However, the development of macular edema or proliferative retinopathy (particularly new vessels near the optic disk) requires elective laser photocoagulation therapy to preserve vision. Vitrectomy is indicated for patients with vitreous hemorrhage or retinal detachment.
Diabetic nephropathy
General Principles
Approximately 25%÷45% of patients with type 1 DM develop clinically evident diabetic nephropathy during their lifetime, and this is the leading cause of end-stage renal disease (ESRD).19 The risk of nephropathy seems to be equivalent in the two types of diabetes.20
Microalbuminuria precedes overt proteinuria (>300 mg albumin/d) by several years in type 1 and type 2 DM. The mean duration from diagnosis of type 1 diabetes to development of overt proteinuria is 17 years, and the time from the occurrence of proteinuria to ESRD averages 5 years. In type 2 DM, microalbuminuria can be present at the time of diagnosis.

Screening for microalbuminuria is mandatory because patients with nephropathy are often asymptomatic and because a number of effective intervention strategies can slow disease progression. Annual screening should be performed in type 1 patients who have had diabetes for >5 years and all type 2 diabetic patients starting at diagnosis.

Measurement of the microalbumin-to-creatinine ratio (normal, <30 mg albumin/g creatinine) in a random urine sample is recommended for screening. At least two to three measurements within a 6-month period should be performed to establish the diagnosis.21
Prevention and Treatment
Intensive control of diabetes and hypertension is an effective intervention for incipient or established diabetic nephropathy.

In type 1 and type 2 patients with or without hypertension and microalbuminuria, angiotensin-converting enzyme (ACE) inhibitors delay the progression of nephropathy.
In type 2 patients with hypertension, creatinine >1.5 mg/dL, and macroalbuminuria, angiotensin II receptor blockers (ARBs) delay progression of nephropathy.
Nondihydropyridine calcium channel blockers, beta-blockers, or diuretics can be used in patients unable to tolerate ACE inhibitors or ARBs.22
Dietary protein restriction may be beneficial in some patients.
Diabetic neuropathy
General Principles
It is the most common neuropathy in developed countries and accounts for more hospitalizations than all the other diabetic complications combined. Sensorimotor diabetic peripheral polyneuropathy is a major risk factor for foot trauma, ulceration, and Charcot arthropathy, and is responsible for 50%÷75% of nontraumatic amputations.23
Diabetic neuropathy can be classified in (a) subclinical neuropathy, determined by abnormalities in electrodiagnostic and quantitative sensory testing; (b) diffuse clinical neuropathy with distal symmetric sensorimotor and autonomic syndromes; and (c) focal syndromes.
Sensation in the lower extremities should be documented at least annually, using either a light-touch monofilament or a tuning fork (frequency of 128 Hz).
Clinical Syndromes
Painful peripheral neuropathy responds variably to treatment with tricyclic antidepressants (e.g., amitriptyline, 10÷150 mg PO at bedtime), topical capsaicin (0.075% cream), or anticonvulsants (e.g., carbamazepine, 100÷400 mg PO bid or gabapentin 1,800÷3,600 mg/d). Patients should be warned about adverse effects, including sedation and anticholinergic symptoms (tricyclics), burning sensation (capsaicin), and blood dyscrasias (carbamazepine).

Orthostatic hypotension is a manifestation of autonomic neuropathy, but common etiologies (e.g., dehydration, anemia, medications) should be excluded. Treatment is symptomatic: postural maneuvers, use of compressive garments (e.g., Jobst stockings), and intravascular expansion using sodium chloride, 1÷4 g PO qid, and fludrocortisone, 0.1÷0.3 mg PO daily. Hypokalemia, supine hypertension, and CHF are some adverse effects of fludrocortisone.

Intractable nausea and vomiting in diabetes are manifestations of impaired GI motility from autonomic neuropathy. Surveillance for DKA is warranted in insulin-treated patients with nausea and vomiting, because interruption of insulin therapy is widespread among such patients. Other causes of nausea and vomiting should be excluded.

Management of diabetic gastroenteropathy can be challenging. Frequent, small meals (six to eight per day) of soft consistency that are low in fat and fiber provide relief for some patients. Parenteral nutrition may become necessary in some individuals. Improvement in glycemic control also is beneficial, because hyperglycemia delays gastric emptying.

Pharmacologic therapy includes the prokinetic agent metoclopramide, 10÷20 mg PO (or as a suppository) before meals and at bedtime, and erythromycin, 125÷500 mg PO qid. Extrapyramidal side effects (tremor and tardive dyskinesia) from the antidopaminergic actions of metoclopramide may limit therapy.

Cyclical vomiting that is unrelated to a GI motility disorder or other clear etiology may also occur in diabetic patients and appears to respond to amitriptyline, 25÷50 mg PO at bedtime.

Diabetic cystopathy, or bladder dysfunction, results from impaired autonomic control of detrusor muscle and sphincteric function. Manifestations include urgency, dribbling, incomplete emptying, overflow incontinence, and urinary retention. Recurrent urinary tract infections are common in patients with residual urine. Treatment with bethanecol, 10 mg tid, or intermittent self-catheterization may be required to relieve retention.

Diabetic diarrhea should only be diagnosed after exclusion of other causes of diarrhea. The pathogenesis of diabetic diarrhea is unclear, so treatment is empiric. Repeated courses of broad-spectrum antibiotics (e.g., azithromycin, tetracycline, cephalosporins) may be beneficial; loperamide or octreotide, 50÷75 mcg SC bid, can be effective in patients with intractable diarrhea.

Macrovascular complications of DM
Coronary heart disease (CHD), stroke, and peripheral vascular disease are responsible for 80% of deaths of diabetics.24
Risk factors for macrovascular disease include insulin resistance, hyperglycemia, microalbuminuria, hypertension, hyperlipidemia, cigarette smoking, and obesity.
Aggressive risk factor reduction lowers the risk of both micro- and macrovascular complications in patients with diabetes.
Glycemic control should be optimized to hemoglobin A1c <7 and as close to normal as possible.
Hypertension should be controlled to a target blood pressure of <130/80 mm Hg (or < 125/75 mm Hg in patients with proteinuria).
Hyperlipidemia should be treated appropriately, with a target low-density lipoprotein cholesterol level of <100 mg/dL, or < 70 mg/dL in patients with known CHD. High-density lipoprotein (HDL) cholesterol levels of >50 mg/dL, and triglyceride levels of <150 mg/dL should be achieved.
Cigarette smoking should be actively discouraged, and weight loss should be promoted in obese patients.
Aspirin, 81÷325 mg/d, is of proven benefit in secondary prevention of myocardial infarction or stroke in diabetic patients.
Coronary artery disease24 occurs at a younger age and may have atypical clinical presentations in patients with diabetes.

Myocardial infarction carries a worse prognosis, and angioplasty gives less satisfactory results in diabetic patients.
Cardiovascular risk factors should be assessed at least annually and treated aggressively (see Goals, above). ECG should be obtained yearly, and there should be a low threshold for ordering stress tests.
Screening with cardiac stress test should be performed in patients with a history of peripheral or carotid occlusive disease; sedentary lifestyle; age >35 years who plans to begin a vigorous exercise program; or patients with two or more of the following CHD risk factors: dyslipidemia, hypertension, smoking, a positive family history of premature coronary disease, and the presence of micro- or macroalbuminuria.25
Management of diabetes after acute myocardial infarction
Hyperglycemia (glucose >110 mg/dL), with or without a prior history of diabetes, is an independent predictor of in-hospital mortality and congestive heart failure in patients admitted for acute myocardial infarction.26 However, the results of the studies that investigated tight glucose control with insulin in the setting of acute myocardial infarction in type 2 diabetics are inconclusive.27,28,29 Nevertheless, given the consistent epidemiologic association, it is reasonable to expect that glucose-lowering effects in acute conditions could lead to clinical benefit.
Peripheral Vascular Disease
General Principles
Diabetes and smoking are the strongest risk factors for peripheral vascular disease (PVD). In diabetics, the risk of PVD is increased by age, duration of diabetes, and presence of peripheral neuropathy. PVD is a marker for systemic vascular disease involving coronary, cerebral, and renal vessels. Diabetic patients with PVD have increased risk for subsequent MI or stroke regardless of the PVD symptoms.
Clinical Presentation
Symptoms of PVD include intermittent claudication, rest pain, tissue loss, and gangrene, but most of the patients are asymptomatic due to concomitant neuropathy.
Physical examination findings including diminished pulses, dependent rubor, pallor on elevation, absence of hair growth, dystrophic toenails, and cool, dry, fissured skin are signs of vascular insufficiency.
The ankle-to-brachial index (ABI) defined as the ratio of the systolic blood pressure in the ankle divided by the systolic blood pressure at the arm is the best initial diagnostic test. An ABI <0.9 by handheld 5- to 10-MHz Doppler probe has a 95% sensitivity for detecting angiogram-positive PVD.30
Screening ABI should be performed in (a) diabetics older than 50 years of age, (b) diabetics younger than 50 years of age who have other PVD risk factors (e.g., smoking, hypertension, hyperlipidemia, or duration of diabetes 10 years),31 and (c) patients with symptoms of PVD.
Risk factors should be controlled, with similar goals described for coronary artery disease (see Macrovascular Complications of Diabetes).
Antiplatelets agents such clopidogrel (75 mg/d) have additional benefits when compared to aspirin in diabetics with PVD.31
Therapy for intermittent claudication could also benefit by exercise rehabilitation and cilostazol (100 mg bid). This medication is contraindicated in patients with CHF.
Miscellaneous Complications
Miscellaneous complications such as erectile dysfunction and diabetic foot ulcers have multiple etiologies.

Erectile Dysfunction
General Principles
It is estimated that 40%÷60% of men with diabetes have erectile dysfunction (ED), and the prevalence varies depending on the duration of diabetes. In addition to increasing age, ED is associated with smoking, poor glycemic control, low HDL, neuropathy, and retinopathy.
ED in diabetics is multifactorial. It can result from nerve damage, impaired blood flow (vascular insufficiency), adverse drug effects, endocrinopathy, psychological factors, or a combination of these etiologies.
If endocrinologic evaluation is negative and other treatable causes have been excluded, most diabetics respond to phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil). Typical doses include sildenafil 50÷100 mg or vardenafil 10 mg 1 hour prior to sexual activity, and tadalafil 10 mg/d prior to sexual activity. Glycemic control should be intensified and could be a helpful adjuvant therapy, and specialist referral should be considered if the problem persists. Cardiovascular status should be considered before starting these agents. Sildenafil should not be used concurrently with nitrates to prevent severe and potentially fatal hypotensive reactions.
Diabetic Foot Ulcers
General Principles
The prevalence of foot ulcers is 4%÷10% and the lifetime incidence is as high as 25%.32
Causative factors include neuropathy, excessive plantar pressure, and repetitive trauma. Vascular insufficiency, poor healing, and polymicrobial infection are major contributors to ulcer formation.
Screening to identify patients at risk for ulcers includes detection of loss of protective sensation by monofilament (see Peripheral Neuropathy) and peripheral vascular disease.

Poorly managed foot ulcers may result in limb loss from amputation. Patient education should emphasize prevention: daily foot examination, application of moisturizing lotion, use of proper footwear, and caution with self-pedicure.
The exposed feet should be inspected and palpated at every patient encounter; significant findings, such as calluses, hammertoes or other deformities, and soft tissue lesions, should be evaluated.
Diabetic foot infections should be treated aggressively. Proper management includes a multidisciplinary approach that includes orthopedic surgeons, specialized nursing care, and close monitoring. Revascularization should be considered as an integral part of the management of food ulcers. The presence of deep infection with abscess, cellulitis, gangrene, or osteomyelitis is an indication for hospitalization and prompt surgical drainage. Acute treatment of foot infections is dependent on severity, as outlined below.
Mild to moderate cellulitis. Rest, elevation of the affected foot, and relief of pressure are essential components of treatment and should be initiated at first presentation. In localized cellulitis and new ulcers, Staphylococcus aureus and streptococci are the most frequent pathogens. Therapy with oral dicloxacillin, first-generation cephalosporin, amoxicillin/clavulanate, or clindamycin is recommended.

Moderate to severe cellulitis. This type of involvement requires intravenous therapy and admission to the hospital. Consultation for debridement and aerobic and anaerobic cultures are necessary when necrotic tissue is present. Intravenous oxacillin/nafcillin, a first-generation IV cephalosporin, ampicillin/sulbactam, clindamycin, and vancomycin are options for therapy. Antibiotic coverage should subsequently be tailored according to the clinical response of the patient, culture results, and sensitivity testing.

Moderate to severe cellulitis with ischemia or significant local necrosis. It is important to determine the presence of bone involvement and peripheral vascular disease since failure to diagnose osteomyelitis and ischemia often results in failure of wound healing.

Bone involvement is present if bone is seen at the base of the ulcer or is easily detected by gentle probing with a blunt sterile probe. Radiographs are not very sensitive for diagnosis and leukocyte scanning or magnetic resonance imaging offers better specificity.
Presence of peripheral vascular disease is suspected by absence of pedal pulses or decreased capillary filling.
Intravenous antibiotics, bedrest, surgical debridement, culture obtained from the base of the ulcer, and bone culture help direct antibiotic therapy.
Ampicillin/sulbactam and ticarcillin/clavulanate are first-line agents; piperacillin/ tazobactam, clindamycin plus ciprofloxacin, ceftazidime, cefepime, cefotaxime, or ceftriaxone plus metronidazole are good alternatives for initial therapy.
In the presence of osteomyelitis, 20÷12 weeks of intravenous antibiotic therapy is recommended. Ulcers with localized or generalized gangrene require surgical amputation.
Clinical Presentation
Hypoglycemia is a clinical syndrome in which low serum (or plasma) glucose levels lead to symptoms of sympathoadrenal activation (sweating, anxiety, tremor, nausea, palpitations, and tachycardia) from increased secretion of counterregulatory hormones (e.g., epinephrine).
Neuroglycopenia occurs as the glucose levels decrease further (fatigue, dizziness, headache, visual disturbances, drowsiness, difficulty speaking, inability to concentrate, abnormal behavior, confusion, and ultimately loss of consciousness or seizures).
Hypoglycemia is uncommon in patients not treated for diabetes. Iatrogenic factors usually account for hypoglycemia in the setting of diabetes, whereas hypoglycemia in the nondiabetic population could be classified as fasting or postprandial.
Iatrogenic hypoglycemia complicates therapy with insulin or sulfonylureas and is a limiting factor to achieve glycemic control during intensive therapy in patients with DM.

Risk factors for iatrogenic hypoglycemia include skipped or insufficient meals, unaccustomed physical exertion, misguided therapy, alcohol ingestion, and drug overdose.
Recurrent episodes of hypoglycemia impair recognition of hypoglycemic symptoms, thereby increasing the risk for severe hypoglycemia (hypoglycemia un-awareness).
Hypoglycemia unawareness results from defective glucose counterregulation with blunting of autonomic symptoms and counterregulatory hormone secretion during hypoglycemia. Seizures or coma may develop in such patients without the usual warning symptoms of hypoglycemia.
Isolated episodes of mild hypoglycemia may not require specific intervention. Recurrent episodes require a review of lifestyle factors; adjustments may be indicated in the content, timing, and distribution of meals, as well as medication dosage and timing. Severe hypoglycemia is an indication for supervised treatment.
Readily absorbable carbohydrates (e.g., glucose and sugar-containing beverages) can be administered orally to conscious patients for rapid effect. Alternatively, milk, candy bars, fruit, cheese, and crackers may be adequate in some patients with mild hypoglycemia. Hypoglycemia associated with acarbose or miglitol therapy should preferentially be treated with glucose. Glucose tablets and carbohydrate supplies should be readily available to patients with DM at all times.

IV dextrose is indicated for severe hypoglycemia, in patients with altered consciousness, and during restriction of oral intake. An initial bolus, 20÷50 mL of 50% dextrose, should be given immediately, followed by infusion of D5W (or D10W) to maintain blood glucose above 100 mg/dL. Prolonged IV dextrose infusion and close observation is warranted in sulfonylurea overdose, in the elderly, and in patients with defective counterregulation.

Glucagon, 1 mg IM (or SC), is an effective initial therapy for severe hypoglycemia in patients unable to receive oral intake or in whom an IV access cannot be secured immediately. Vomiting is a frequent side effect, and therefore care should be taken to prevent the risk of aspiration. A glucagon kit should be available to patients with a history of severe hypoglycemia; family members and roommates should be instructed in its proper use.

Education regarding etiologies of hypoglycemia, preventive measures, and appropriate adjustments to medication, diet, and exercise regimens are essential tasks to be addressed during hospitalization for severe hypoglycemia.

Hypoglycemia unawareness can develop in patients who are undergoing intensive diabetes therapy. These patients should be encouraged to monitor their blood glucose frequently and take timely measures to correct low values (<60 mg/dL). In patients with very tightly controlled diabetes, slight relaxation in glycemic control and scrupulous avoidance of hypoglycemia can restore the lost warning symptoms.

Hypoglycemia unrelated to diabetes therapy is an infrequent problem in general medical practice.

Plasma or capillary blood glucose should be obtained, whenever feasible, to confirm hypoglycemia.
Any patient with a serum glucose concentration <60 mg/dL should be suspected of having a hypoglycemic disorder, and further evaluation is required if the value is <50 mg/dL.
Absence of symptoms with these levels of glucose suggests the possibility of artifactual hypoglycemia. These levels are usually accompanied by symptoms of hypoglycemia. Detailed evaluation is usually required in a healthy-appearing patient, whereas hypoglycemia may be readily recognized as part of the underlying illness in a sick patient.33 Major categories include fasting and postprandial hypoglycemia.
Fasting hypoglycemia can be caused by inappropriate insulin secretion (e.g., insulinoma), alcohol abuse, severe hepatic or renal insufficiency, hypopituitarism, glucocorticoid deficiency, or surreptitious injection of insulin or ingestion of a sulfonylurea.

These patients present with neuroglycopenic symptoms but episodic autonomic symptoms may be present. Occasionally patients with recurrent seizures, dementia, and bizarre behavior are referred for neuropsychiatric evaluation, which may delay timely diagnosis of hypoglycemia.
Definitive diagnosis of fasting hypoglycemia requires hourly blood glucose monitoring during a supervised fast lasting up to 72 hours and measurement of plasma insulin, C-peptide, and sulfonylurea metabolites if hypoglycemia (<50 mg/dL) is documented. Patients who develop hypoglycemia and have measurable plasma insulin and C-peptide levels without sulfonylurea metabolites require further evaluation for an insulinoma.

Postprandial hypoglycemia often is suspected, but seldom proven, in patients with vague symptoms that occur 1 or more hours after meals.

Alimentary hypoglycemia should be considered in patients with a history of partial gastrectomy or intestinal resection in whom recurrent symptoms develop 1÷2 hours after eating. The mechanism is thought to be related to too-rapid glucose absorption, resulting in a robust insulin response. These symptoms should be distinguished from dumping syndrome, which is not associated with hypoglycemia and occurs in the first hour after food intake. Thus, frequent small meals with reduced carbohydrate content may ameliorate symptoms.

Functional hypoglycemia. Symptoms that are possibly suggestive of hypoglycemia, which may or may not be confirmed by plasma glucose measurement, occur in some patients who have not undergone GI surgery. This condition is referred to as “functional hypoglycemia.”
The symptoms tend to develop 3÷5 hours after meals. Current evaluation and management of functional hypoglycemia are imprecise; some patients show evidence of IGT and may respond to dietary therapy.

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