Cause or Category	Examples
Genetic defects of beta-cell function	Maturity-onset diabetes of the young (MODY)
Genetic defects in insulin action	Lipoatrophic diabetes
Diseases of exocrine pancreas	Pancreatitis, cystic fibrosis
Endocrinopathies	Acromegaly, Cushing’s syndrome, hyperthyroidism
Drug or chemical induced	Nicotinic acid, thiazides
Infections	Congenital rubella, cytomegalovirus
Uncommon forms of immune-mediated diabetes	Antibody against insulin receptor
Other genetic syndromes occasionally associated with diabetes	Down, Klinefelter’s, Turner’s

From Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003;26(suppl 1):4-20.

Genetics

The exact nature of how diabetes or at least the risk of diabetes is transmitted is still not well understood. It is known that those with HLA DR3 and DR4 (human lymphocytic antigens that are cell surface markers) have a fourfold increased risk of developing type 1 diabetes. If a person has both antigens, the risk increases to 12 times normal. There is a very strong familial transmission, with concordance of type 2 in 90% of identical twins older than 40, compared with 50% in type 1 diabetes. Certain genetic types (e.g., MODY) may have different responses to medications than other types.

Complications

Mortality in diabetic adults with heart disease is two to four times higher than in nondiabetic persons, and strokes occur two to four times more often in diabetic patients. Approximately three quarters of diabetic adults have high blood pressure. Diabetic retinopathy is now the leading cause of blindness in adults, and DM is also the leading cause of end-stage renal disease (44% of all cases). About two thirds of diabetic patients have some form of neural damage (e.g., peripheral neuropathy, gastroparesis, carpal tunnel syndrome, erectile dysfunction). Younger diabetic adults are twice as likely to have periodontal disease, and all those with poorly controlled diabetes are three times more likely to have gum disease. GDM poorly controlled in the first trimester can cause major birth defects (5%-10% of pregnancies) and spontaneous abortions (15%-20%).

The total direct costs (costs of medical care and services) and indirect costs (disability, work loss, premature mortality) of diabetes in 2007 were an estimated $174 billion ($116 billion for direct, $58 billion for indirect).

Prevention

When diabetes is controlled, the risk of complications decreases. For example, for every 1% decrease in HbA_1c, there is a corresponding 40% decrease in the risk of microvascular complications. Similarly, for every 10–mm Hg drop in blood pressure, there is a 12% reduced risk of cardiovascular and microvascular complications; controlling LDL cholesterol reduces risks of large-vessel disease even further (20%-50%). Appropriate eye and foot programs (e.g., laser therapy, podiatry monitoring) can reduce the risk of loss of vision or amputation by 50% or more.

Pathophysiology

Common Mechanisms

The pathogenic mechanisms resulting in DM are generally divided into (1) primary defects in beta-cell function, causing variable insulin deficiency (type 1diabetes), and (2) defects in the peripheral action of insulin associated with a slowly evolving loss of the beta cells’ ability to compensate (type 2 diabetes). The failure of beta cells in type 1 is most likely caused by autoimmunity, comparable to other disorders affecting endocrine gland function (e.g., Hashimoto’s thyroiditis, Addison’s disease). Anti–islet cell antibodies are markers of the ongoing process resulting in type 1 diabetes. Beta-cell failure of type 2 diabetes is thought to result from primary genetic defects or acquired dysfunction, as in mitochondrial metabolism that reduces the oxidation of glucose and fatty acids needed for insulin synthesis and secretion. Such defects in mitochondrial function may also account for the peripheral insulin resistance in skeletal muscle, liver, and adipose tissue at the onset of type 2 diabetes. The insulin secretory function of beta cells and muscle energy metabolism can be significantly improved by any intervention that reduces hyperglycemia and hyperfatty acidemia. These observations are the basis of reversible glucotoxicity and lipotoxicity. Thus any diabetic patient with type 1 or 2 diabetes may have similar mechanisms of both insulin deficiency and insulin resistance.

The clinical characteristics of type 1 and 2 diabetes are shown in Table 34-2. However, diabetic classification and nomenclature have required frequent revisions over the years as the pathogenesis of DM is better understood and changes in culture and human behavior continue to alter its clinical expression. The finding of hyperglycemia on routine examinations of apparently healthy individuals has resulted in a new DM subclass that does not lend itself to easy classification. The finding of anti–islet cell antibodies designates this group as latent autoimmune diabetes of adults (LADA). This group mostly consists of young adults who have a prolonged subclinical development of DM. The diabetes may remain indolent or more rapidly deteriorate into classic insulin-dependent type 1 diabetes, or it may continue to evolve into insulin resistance and dependency coincident with weight gain. In this case, LADA patients are clinically indistinguishable from type 2 patients but have continuing risk of deteriorating to insulin dependency. Thus a patient recognized to have DM may have diverse etiopathogenic mechanisms causing insulin dependency and resistance resulting in hyperglycemia.

Table 34-2 Characteristics of Types 1 and 2 Diabetes Mellitus

Sign	Type 1	Type 2
Age of onset	Usually childhood and adolescence	About 40 years, increasing with age; adolescence with childhood obesity
Family history, concordance in twins	Uncommon; 50% before age 40	Common, 95% afterage 40
Diagnostic markers	Anti-GAD, undetectable C peptide	C peptide variable: high with insulin resistance; low values improve with glycemic control.
Other associated disorders	Primary hypothyroidism, celiac disease, other autoimmune endocrine disorders	Metabolic syndrome
Glycemic control, ketosis	Marked brittleness, ketosis prone with hyperglycemia	Stable hyperglycemia without ketosis
Treatment requirement	Absolute need for insulin; coincident genetic insulin resistance that might respond to oral drugs	Therapeutic lifestyle changes with and without oral agents; insulin is required when other measures fail.

GAD, Glutamic acid decarboxylase.

Adolescents with significant obesity who develop type 2 diabetes are younger at presentation than usual, so age of onset of type 2 now overlaps with type 1 diabetes. Because their obesity is often intractable, their marked state of insulin resistance at DM onset eventually becomes a state of insulin deficiency. When DM patients develop marked hyperglycemia and dyslipidemia, the resulting glucotoxicity and lipotoxicity cause systemic cellular dehydration along with triglyceride accumulation in skeletal muscle. These acquired defects further accentuate defects in beta-cell insulin secretion and muscle insulin sensitivity. Pathogenic mechanisms may differ (Fig. 34-1), but the resulting glucotoxicity and lipotoxicity so impair insulin secretion and effectiveness that diabetes from any mechanism may lead to similar metabolic crises: diabetic ketoacidosis with or without hyperosmolality.

Figure 34-1 How normal or genetically impaired beta cells can be affected by inflammation and overnutrition, resulting in absolute or relative loss of insulin secretory reserve and the activation of the common mechanism leading to diabetic crisis. 1° IR, Primary insulin resistance; 2° IR, secondary insulin resistance; DKA, diabetic ketoacidosis; FFA, free fatty acids; TRG, triglycerides.

Mechanisms Underlying Other Specific Types of Diabetes

A diverse array of genetic defects or acquired clinical disorders can impair beta-cell function or insulin sensitivity, resulting in hyperglycemia and the diagnosis of diabetes mellitus (see Table 34-1). These patients generally appear to have type 2 diabetes at presentation and manifest varying degrees of diabetic severity during the course of their primary disorder.

Presentation

Key Points

• Fasting glucose values of at least 200 mg/dL usually indicate significant beta-cell failure comparable to type 1 diabetes. Beta-cell loss in type 2 may still be reversible, however, even after long periods, if gluco/lipotoxicity is successfully treated.

• Hyperglycemia (even at prediabetes levels), dyslipidemia, and hypertension associated with increased abdominal girth are the cardinal signs of metabolic syndrome.

• Somatic symptoms and signs of type 2 diabetes usually take years to develop; the prolonged “latent” phase depends on the severity of hyperglycemia.

Type 1 Diabetes

The symptoms of type 1 diabetes may be indolent or precipitous, depending on the rate of decrease in insulin secretion. Indolent asymptomatic diabetes can decompensate as a result of a coincident illness. The resulting hyperglycemia causes polydipsia and polyuria from the osmotic effects of glycosuria. Weight loss, blurred vision, and fatigue occur as energy metabolism is disordered. Most patients become aware of a problem at this point, and the diagnosis is easily recognized if the patient seeks help.

If the insulin deficiency is allowed to become profound, the disorder in FFA metabolism results in ketonuria, which accentuates the osmotic diuresis. The stress of illness can increase counterregulatory hormones (epinephrine, cortisol, growth hormone) that antagonize the effects of already-reduced insulin. The result is increasing hyperglycemia and further osmotic diuresis. Progressive hyperglycemia causes intravascular and intracellular dehydration, which reduces beta-cell function and insulin delivery to the periphery. Gastric dysfunction can occur under these conditions, further compromising fluid intake. The result is a “glucotoxic” state in which dehydration compromises the kidney’s ability to excrete ketones, whose production is accelerated by insulin’s failure to regulate FFA oxidation. Acidemia as a result of marked ketonemia causes hyperventilation and subsequent dyspnea. The increasing hyperglycemic state with dehydration causes brain hyperosmolality, producing lethargy, stupor, and if uninterrupted with insulin therapy, coma. This sequence is the description of the descent into diabetic ketoacidosis.

Diabetes mellitus may be discovered incidentally in an asymptomatic child or adult when hyperglycemia is noted on a comprehensive metabolic profile or glycosuria on routine urinalysis. Presuming that a lean child, adolescent, or adult has an autoimmune process leading to type 1 diabetes would be strongly supported by the finding of anti–islet cell antibodies. Asymptomatic patients with mild hyperglycemia thought to have an autoimmune pathogenesis require glucose monitoring to determine when therapeutic intervention is needed. Although these patients are likely to respond early to a variety of oral agents like any type 2 patient, no interventions have been effective thus far in slowing their progression to clinically overt type 1 requiring insulin. Prudent lifestyle measures, including exercise, dietary discretion, glucose monitoring, and oral therapies designed to reduce insulin secretion, may be efficacious over a surprisingly long period in deferring insulin therapy.

Type 2 Diabetes

The typical indolent course of type 2 diabetes can be further extended by a therapeutic lifestyle. However, this does not mean it is any less serious than type 1 as a state of accelerated vascular aging. Unfortunately, treating middle-aged and older patients with long-term type 2 diabetes with aggressive pharmacologic methods to correct hyperglycemia has failed to improve cardiovascular outcomes (ACCORD, 2008; VADT, 2009). Improved glycemic control in type 2 diabetes, as in type 1, has been shown to preclude progression of small-vessel disease and nerve function disorder to diabetic retinopathy, nephropathy, and neuropathy (UKPDS, 1998a).

Dyslipidemia, Hypertension, and Atherosclerosis

The unexpectedly negative outcomes of diabetic studies targeting hyperglycemia as a cardinal risk factor for progression of atherosclerosis emphasize the need to correct dyslipidemia and hypertension typical of the type 2 diabetic state. Dyslipidemia occurs chiefly when beta cells are unable to maintain the high insulin levels required to inhibit lipolysis from adipose cells. The resulting free fatty acidemia associated with high insulin levels causes the liver to repackage these energy substrates into more triglyceride-rich lipoproteins.

Hyperinsulinemia has also been associated with hypertension, changes in vascular responsiveness (endothelial dysfunction), and appearance of inflammatory proteins, especially C-reactive protein. The precise causal factor in these relationships and relative importance of these changes are not well understood.

Overt Type 2 Diabetes

Remarkably, only 20% to 25% of individuals with hyperinsulinemia and insulin resistance progress to overt type 2 diabetes. This progression begins when FSG becomes 100 mg/dL or greater, the threshold for the diagnosis of prediabetes. Type 2 diabetes may be diagnosed at this phase if a casual postprandial glucose of 200 mg/dL or higher is detected.

Most patients diagnosed with type 2 diabetes may not note the typical hyperglycemic symptoms described for type 1 diabetes. The difference may be that type 2 diabetes evolves over years below the symptomatic threshold because sufficient insulin is present to prevent the marked lipolysis and ketonemia more typical of type 1 diabetes, with its obligatory water and electrolyte losses. Most patients with type 2 diabetes are discovered incidentally, such as during routine risk factor assessment for cardiovascular disease or other work-up for various symptoms, including peripheral sensorimotor neuropathy, Bell’s palsy, erectile dysfunction, visual changes, and gastrointestinal complaints, which may lead to finding an elevated FSG and the diagnosis of type 2 diabetes.

Management

Behavioral Therapy

Key Point

• Self-management is the essence of behavioral therapy for DM, consisting of daily glucose monitoring, diet, exercise, and insulin adjustment.

The diagnosis of diabetes mellitus requires lifestyle adjustments and enduring major inconveniences and sacrifices to deal successfully with the disorder. Behavioral adjustments reduce the difficulty of controlling type 1 diabetes, but their impact in a type 2 patient can be so powerful as to alter the course of the disorder. All patients receive rational treatment regimens, but those who consciously monitor their diet and glucose variations learn how to make daily adjustments to achieve near-normalization of glucose values. Positive daily outcomes usually stimulate a continuing self-managing effort. Thus the goal of diabetic treatment is to promote this “winning attitude” toward the disorder.

KEY TREATMENT

Risk management: A therapeutic lifestyle based on achieving weight control and maintaining physical fitness can delay the onset of diabetes mellitus in persons in the high-risk groups (ADA, 2009; Knowler et al., 2002; Tuomeilehto et al., 2001) (SOR: A).

Global risk management: All patients should be advised not to smoke. Patients with blood pressure greater than 130/80 mm Hg should receive pharmacologic therapy in addition to lifestyle therapy. Even in patients without overt cardiovascular disease, the primary goal is LDL level less than 100 mg/dL (ADA, 2009; Haffner, 1998; Haire-Joshu et al., 1999; Hanson et al., 1998; UKPDS, 1998b; Vaccaro et al., 2004) (SOR: A).

Glucose Monitoring

Monitoring behavior is itself therapeutic because it warns of the risk of hypoglycemia or a shift to a hyperglycemic state caused by dietary indiscretion or a smoldering stress. Glucometers are now available that require less than 1 μL of blood (taken up by capillary action). A sample may be taken from a fingertip, earlobe, forearm, or thigh, with the result available in 5 to 15 seconds. Arm or thigh values are derived from interstitial glucose concentration and may be approximately 15 minutes “out of phase” with blood values if the patient is not in a fasting steady state. Average monitored values over 14 to 30 days correlate with HbA_1c values. Monitored glucose data are also the basis of formulating therapeutic targets. For a young girl with diabetes, the fasting target may be 150 mg/dL to avoid early-morning hypoglycemia. As she matures, the target becomes the current American Diabetes Association (ADA) goal of less than 120 mg/dL fasting and before meals. In elderly diabetic patients, glycemic targets again can be liberalized to preclude hypoglycemic risks.

Although costs of monitoring must be considered, frequent glucose monitoring usually indicates the patient is well motivated and is attempting to make the necessary adjustments that will improve their mean glucose value and impact favorably on the HbA_1c. In an informed patient with stable type 2 diabetes, there is less evidence that daily is any more effective than weekly testing.

KEY TREATMENT

Insulin treatment of type 1 and monotherapy or combination therapy of type 2 diabetic patients, when guided by self–glucose monitoring, can accomplish tight glycemic control to HbA_1c less than 7%, which reduces the occurrence and progression of the microangiopathic complications of DM (ADA, 2009; DCCT, 1993; UKPDS, 1998a) (SOR: A).

Nutrition and Diet

Key Points

• Intentional weight loss can help reverse hyperglycemia, dyslipidemia, hypertension, and other risk factors in patients with type 2 diabetic pathoetiologies.

• Caloric restriction without an accompanying exercise program is much less likely to succeed, although increased eating in compensation for exercise is a potential pitfall.

Dietary consistency will also ease the difficulties of living with diabetes. As with a regular exercise program, a stable diet will simplify insulin treatment schedules in type 1 patients but will not produce the marked effects observed in type 2 patients. Therefore, dietary manipulation should be directed toward ensuring content regularity rather than weight loss in type 1 patients.

Dietary Principles and Weight Loss

In terms of medical nutrition therapy, there is no longer a specific diabetic diet; all recommendations are individualized as part of a comprehensive plan that includes exercise and appropriate medical therapies. A meal plan that includes a variety of usual foods is recommended as long as the plan is healthy, with conscious control of carbohydrate intake. Weight loss will improve blood pressure control and, along with decreasing fat intake and increasing physical activity, will reduce fasting lipid levels.

It is not necessary to attempt weight loss before instituting medical therapy, especially since weight loss alone may not provide any glycemic control in highly insulin-deficient patients. However, a multifaceted approach with education, reduced energy, and fat-calorie intake, increased regular physical activity, and other lifestyle changes can produce long-term weight loss and glycemic improvement. Less need for calories in elderly patients leads to obvious dietary changes. Of note, patients should not avoid breads and other starches; in fact, complex carbohydrates are an important part of the modern approach to diabetes.

Dietary Details

The current dietary principles recommended by ADA are the same as those of the American Heart Association (AHA). The caloric content should be that which will permit a patient with type 2 diabetes to attain a body mass index (BMI) of 25 kg/m². With gender, height, weight, and age known, the basal daily caloric requirement and the desired weight can be obtained from standard online calculators. A simpler method, for patients with routine and not intensely physical activities, is to estimate the daily caloric expenditure by multiplying the ideal weight in kilograms by 30 calories/kg. Weight loss can be safely achieved if the patient is taught how to reduce caloric intake by 100 calories per day for each 10 pounds of desired weight loss over 1 year. National Institutes of Health guidelines advocate that weight changes be methodically accomplished over long periods. This will preclude acute energy shifts that could cause gallstones, gout, and depression and have 95% likelihood of recidivism. The guidelines suggest a weight loss goal of 7%, usually rounded to 10%, per year until the patient attains ideal BMI. For example, for a patient with type 2 diabetes weighing 200 pounds, the advice should be to lose 20 pounds in 1 year by reducing dietary caloric intake by 200 calories per day and/or increasing energy expenditure by that amount.

If a new and reduced weight set point is achieved in the central nervous system, longitudinal studies have shown a reduction in the progression of prediabetes, which confirms widespread clinical experience that the weight loss has a reversal effect on type 2 diabetes.

Dietary Recommendations

The 2008 ADA guidelines considered the risk and advisable intake of carbohydrates, fats, proteins, and other food ingredients. Monitoring carbohydrate by counting, exchanges, or experience-based estimation remains a key strategy in achieving glycemic control. Saturated fat should be less than 7% of calories, and there should be minimal trans fat. Total cholesterol should be less than 200 mg daily. Higher fiber intake may improve glycemic control; thus fiber intake should be at least 14 g/1000 calories daily. Sugar, alcohols, and nonnutritive sweeteners are safe when consumed within daily levels established by the Food and Drug Administration (FDA). Usual dietary protein of 15% to 20% of calories is appropriate in diabetes in the absence of significant renal insufficiency. Reduction of protein intake to 0.8 to 1.0 g/kg/day in diabetic individuals with early stages of chronic kidney disease, and to less than 0.8 g/kg/day in later stages, may improve renal function. High-protein diets (>20% of calories) are not recommended for weight loss because the long-term effects on renal function are unknown. A reduced sodium intake of 2300 mg/day, with a diet high in fruits, vegetables, and low-fat dairy products, is prudent. For patients with diabetes and symptomatic heart failure, dietary sodium intake of less than 2000 mg/day may reduce symptoms.

Alcohol

The general consensus is that alcohol in moderation is appropriate for diabetic patients, if only for its protective cardiac effects. “Moderate drinking” means a glass of red wine daily, depending on body mass. Also, for accurate carbohydrate counting, the patient must include the amount in alcohol.

Exercise

Key Points

• Exercise is the single best broad-spectrum therapeutic activity to offset the age-related decline of lean body mass and the consequent loss of insulin sensitivity.

• Exercise does not always promote glucose utilization.

• Clinical prudence requires that cardiac risk be evaluated before a patient engages in a rigorous exercise regimen.

• A prudent guideline is to instruct a nonactive patient to stay within a pulse rate 60% of maximum heart rate for age, before progressing to 75% to 85%.

In addition to dietary guidelines, the U.S. Department of Agriculture (USDA, 2005) also recommends daily exercise activities for weight loss and health maintenance. The difference in these objectives is related to the duration and the intensity of exercise. The advocacy of exercise, as with dieting and food choices, has become an American industry. Exercise is an essential intervention in the diabetic lifestyle. Studies show that exercise activities even without weight loss result in consistently beneficial and safe outcomes. In type 2 diabetic patients with HbA_1c of less than 9%, exercise can lower this indicator by 1%. A similar effect in type 1 diabetes has not been demonstrated, despite improved insulin sensitivity. However, both type 1 and 2 patients show improved serum lipid profile and increased fibrinolytic proteins after exercise. Based on its effects in improving athletic performance, exercise in a diabetic patient encourages good cardiac function with increased circulation to muscles and the periphery.

Risks

Hypoglycemia

As with other effective antidiabetic treatments, exercise has risks, especially in patients who maintain good glycemic control. These risks can be reduced, however, by applying increased care in exercising and its timing. Patients who engage in rigorous activities such as team sports can experience a dramatic hypoglycemic reaction either at the time of the activity or later that night. This risk can be prevented by anticipating and monitoring glucose during exercise. The hypoglycemia is a result of energy expended as oxidized glucose and fatty acids and the latent effects of exercise, which improve muscle blood flow and insulin sensitivity for hours, further facilitating glucose uptake. All these phenomena accelerate plasma glucose clearance, which may require decreasing antidiabetic therapies, especially insulin dosages, to prevent a late, insidious decline in glucose. Understanding all the effects of a particular exercise allows adjustments in treatment and nutrient supplementation.

Hyperglycemia

Rigorous exercise undertaken when insulin levels are insufficient and glycemic control is unsatisfactory will stimulate a stress reaction in which epinephrine activates glycogenolysis. If insulin is insufficient to signal muscle utilization of this hepatic outpouring of glucose, marked hyperglycemia results. Ketosis may also occur as lipolysis, stimulated by the sympathetic nervous system, is unregulated. To avoid this diametrically opposed reaction, rigorous exercises should be initiated only when the blood sugar is known to be under control. The more intense the activity, the more monitoring and nutritional supplementation are necessary. However, overeating in response to exercise is not appropriate.

Complications Associated with Heart and Microvasculature

There are also organ-specific risks of exercise in diabetes. Many cardiac patients are found to be unaware of their type 2 diabetes; almost all long-term patients with diabetes have cardiac dysfunction, often “silent ischemia.”

Retinopathy and Neuropathy

Rigorous exercise that elevates blood pressure can exacerbate exudative and proliferative retinopathy. These findings may limit exercise to low-intensity activities such as walking, which is safe and effective, even in patients with reduced cardiac function.

Walking

Walking improves peripheral perfusion and diverts blood volume to the lower extremities, where muscles have greater capacitance. Blood pressure and cardiac afterload are reduced. Regular walking can even overcome intermittent claudication by stimulating collateralization. With sufficient effort and duration, and even if done in short but repeated patterns as part of the activities of daily living, walking can facilitate weight loss. Postprandial walking may be more effective than preprandial walking (Colberg et al., 2009).

Walking can become hazardous, however, when the foot is affected by marked sensorimotor peripheral neuropathy. Exercise involving the feet requires that the patient is aware of risks and understands how to avoid them. Dry, thin skin lacking the cooling and lubricating effects of sweating is very susceptible to blistering when walking causes rubbing of the foot within the shoe. Prior foot injuries resulting from neuropathic trauma or the microfractures of diabetic osteonecrosis often cause foot deformities and uneven distribution of weight over the surface of the foot. The hyposensitive skin beneath bony deformities is at risk for ulceration. Prophylactic treatment requires orthotic devices, daily foot lubrication, and footwear that is soft with room to expand. Rather than contraindicating exercise of the foot and lower leg, advanced diabetic foot problems benefit from the increased perfusion accompanying non-weight-bearing exercise. Safe, effective exercise activities helpful in this situation use devices that “lock” the feet into the pedals of a stationary bicycle or an elliptical cycler.

Exercise Prescription

The type, duration, and intensity of exercise as therapy for diabetes is often decided by patient preference and common sense based on the patient’s age and abilities and the previous considerations. As noted with walking, modest but periodic low-intensity efforts such as stationary cycling, arm conditioning with light weights, and dancing for 30 to 45 minutes with brief rest period, as often as daily, but at least three times per week, will achieve measurable improvement in HbA_1c and lipid levels, indicative of the overall physiologic benefit.

For patients under age 40, the maximum heart rate (HR) is calculated simply by subtracting the patient’s age from 220; for a 35-year-old patient, maximum HR would be 220 − 35, or 185 beats/min. Within a 30-minute exercise regimen, after a 5-minute warm-up, there should be 20 minutes of exercise in the pulse range of 111 to 124 beats/min (60%-67% of 185), followed by another 5 minutes of a cool-down phase. With more conditioning, the patient should aim to exercise in the range of 75% to 85% (139-157 beats/min). For patients over 40, the formula for maximum HR is 208 − (0.7 × age); for a 45-year-old patient, 208 – (0.7 × 45) = 208 − 32 = 176 beats/min, with the calculated HR guideposts of 106 (60%), 118 (67%), 132 (75%), and 150 (85%) beats/min.

Pharmacologic Therapies

Key Points

• The ongoing UKPDS combines oral agents and insulin to confirm that better glycemic control lessens microangiopathic complications in type 2 diabetes, independent of the agents used.

• Lowering blood glucose at any time will augment the action of oral medications, which are intended to take over control once the hyperglycemia is overcome.

Glycemic Targets

Since the publication of the Diabetes Control and Complication Trial (DCCT) in 1993, which demonstrated that improved glycemic control meant less neuropathy, retinopathy, and nephropathy in patients with type 1 diabetes, development of antidiabetic agents has accelerated. These include the α-glucosidase inhibitors, metformin, meglitinides, thiazolidinediones (also called glitazones), designer insulins, synthetic analogs of pancreatic peptides called amylin, and incretins, as well as antagonists of incretin degradation called dipeptidyl peptidase inhibitors. How intensely these agents should be used to limit the macrovascular complications of diabetes (coronary heart disease, peripheral vascular disease, stroke) requires continuing study.

Although the efficacy of attaining HbA_1c values in the low 7% range resulted in reduced microangiopathic complications, the DCCT and U.K. Prospective Diabetic Study (UKPDS) did not provide conclusive evidence of protection from macrovascular complications. In contrast, UKPDS demonstrated the efficacy of antihypertensive therapy given primarily as a beta blocker or angiotensin-converting enzyme (ACE) inhibitor in slowing the progression of proteinuria and reducing cerebrovascular and cardiac events. Other clinical trials of the statins showed that diabetic patients experience better cardiovascular outcomes with relatively brief treatment. Controlling other major cardiovascular risk factors in DM has a more readily apparent effect on improving diabetic macrovascular outcomes than correction of hyperglycemia.

Considering these data, professional societies recommend that glycemic targets be applied with clinical judgment based on the patient’s age and life expectancy, which would relate to the patient’s risk of developing microangiopathic complications. Thus an HbA_1c target of about 6.5% is appropriate for a young diabetic patient with type 1 but inappropriate for 75-year-old woman with type 2 and cardiovascular disease. Hemoglobin A_1c values of less than 8% in type 2 patients are readily attainable and would likely slow the progression of retinopathy, neuropathy, and subtle renal loss while preventing an acute metabolic decompensation associated with rapid onset of infection. Glycemic targets of 7% or less are ideal if attained without the risk of hypoglycemia unawareness.

Table 34-3 lists the classes of antidiabetic drugs, mode and duration of action, effectiveness, and side effects. The introduction of the newer agents now allows the clinician to consider drugs that address a specific etiopathogenic mechanism. If the patient is thought to have a type 1 presentation, insulin at the onset is the logical and safest treatment, as discussed later. Oral medications, at least in the short term, should be advised for type 2 diabetic presentations. Behavioral therapies can produce dramatic improvement even at higher HbA_1c values, but a FSG over 200 mg/dL indicates marked insulin insufficiency, and some form of drug therapy (including insulin) is necessary to reduce such values expeditiously. Instituting drug therapy should not deemphasize behavioral therapies; as noted, once the inertia of gluco/lipotoxicity is overcome with drugs, effective behavioral therapies could control DM indefinitely.

Table 34-3 Classification of Noninsulin Antidiabetic Agents