Sample Chapter

December 2007

Section 9 Metabolism

Type 2 diabetes mellitus is similar to type 1 and other forms of diabetes in that it is defined by high levels of plasma glucose and is associated with many long-term complications caused or enhanced by hyperglycemia and related metabolic abnormalities. It differs from other types of diabetes in its very high prevalence, gradual onset and progression, complex underlying physiologic defects, and significance as a major public health problem. Current estimates are that of the approximately 21 million persons with diabetes in the United States, up to 90% have type 2 diabetes. About a third of those, or 7 million persons, are not yet diagnosed and therefore are not being treated. Moreover, both the incidence and prevalence of type 2 diabetes are increasing.

Although type 2 diabetes is strongly determined by inheritable factors, it is likely polygenic, and the specific genetic mechanisms remain poorly understood. The underlying defects include abnormalities of the insulin-producing beta cells of the pancreatic islets; diminished sensitivity of muscle, adipose tissue, and liver to the effects of insulin; and alterations of normal mechanisms controlling carbohydrate and lipid metabolism after ingestion of nutrients. These abnormalities, especially loss of normal sensitivity to insulin, are affected by various behavioral and environmental factors—notably, decreased physical activity and increased calorie intake leading to obesity.

In addition to high levels of glucose in plasma, type 2 diabetes is characterized by high levels of free fatty acids and abnormal lipoprotein patterns, as well as by changes of various hormonal and neural regulatory mechanisms affecting all tissues of the body. The consequences of these abnormalities include impairment or loss of vision, renal insufficiency, various forms of neuropathy and cognitive impairment, and greatly increased risks of heart disease, stroke, and peripheral vascular disease. Although the short-term effects of hyperglycemia and other metabolic abnormalities of type 2 diabetes are often minimal and even tolerable, the cumulative burden of disability and early mortality is very significant. Early diagnosis and effective treatment of hyperglycemia, associated cardiovascular risk factors, and the various complications of diabetes are essential to relieve these long-term burdens.

Diabetes

Diabetes is defined by the glycemic threshold at which retinopathy begins to occur, as documented in population-based studies.¹ Levels of fasting plasma glucose (FPG), plasma glucose 2 hours after ingestion of 75 g of glucose, and hemoglobin A_1c (HbA_1c) predict retinopathy equally well. The American Diabetes Association (ADA) glycemic criteria for type 2 diabetes mellitus are FPG values of 126 mg/dl (7 mmol/L) or higher, or 2-hour glucose challenge test results of 200 mg/dl (11.1 mmol/L) or higher [see Table 1]. HbA_1c levels above 6% correlate similarly with the appearance of retinopathy; however, because the assay has not been standardized worldwide, results can be confounded by hematologic variants or the presence of hematologic disorders. In addition, HbA_1c measurement is more expensive than glucose measurement. For these reasons, this test has not been endorsed for diagnosis. Nevertheless, HbA_1c can be measured during acute illness to assess the patient's glycemic history; values over 7% are routinely associated with glucose values in the diabetic range. Also, because of its convenience as a measure of chronic hyperglycemia, HbA_1c is used as an indicator of medical risk in research studies and to measure the success of glycemic therapies in clinical practice.

Prediabetes

Less pronounced hyperglycemia, intermediate between normal glucose levels and diabetes, is called prediabetes and is divided into two categories: impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) [see Table 1].¹ Normal glucose levels are defined as less than 100 mg/dl (5.5 mmol/L) after fasting overnight, and less than 140 mg/dl (7.8 mmol/L) 2 hours after ingestion of 75 g of glucose. IFG is defined by overnight plasma glucose values of 100 to 125 mg/dl (5.6 to 6.9 mmol/L), and IGT by 2-hour glucose challenge test values of 140 to 199 mg/dl (7.8 to 11.1 mmol/L). Both conditions are associated with a high future risk of diabetes, but they may not result from the same dominant pathogenetic mechanism, and they coexist in only about one third of persons with prediabetes. Persons with IFG or, especially, IGT are also at increased risk for cardiovascular disease, at least partly because of associated risk factors such as obesity, central adiposity, hypertension, and abnormal lipoprotein patterns. In addition, epidemiologic analyses suggest that even modest elevations of glucose (or associated lipid or hormonal changes) may have harmful effects on vascular tissue. Whether normalization of glycemia can reduce cardiovascular risks in this setting is still unknown, however.² Both IFG and IGT are common and are usually not recognized.

Figure 1. Age-related Prevalence of Diabetes

Surveys in the United States show a progressive increase of the prevalence of diabetes, most of which is type 2 diabetes.³ In 1990, 4.9% of persons 18 years of age or older in the United States reported having diagnosed diabetes. By 2001, this proportion had increased to 7.9%. The frequency of known diabetes by self-report in 2001 was somewhat higher in women than men (8.9% versus 6.8%), and it was higher in African Americans (11.2%) and Hispanics (9.0%) than in whites (7.2%). These figures must be lower than the actual prevalence of diabetes, because earlier studies have shown that up to a third of persons with diabetes do not know they have the disease.⁴ The same 2001 figures show a strong association of known diabetes with increasing age: the prevalence climbs from 2.1% in persons 18 to 29 years of age to 15.5% in persons 70 and older [see Figure 1]. Obesity is also strongly associated with diabetes, with a prevalence of 14.9% in persons with class II obesity (defined as a body mass index [BMI] of 35.0 to 39.9 kg/m2) and 25.6% in persons with class III obesity (BMI ³ 40), compared with 4.1% in persons of normal weight.

From data of this kind, supplemented by information on demographic trends, the future prevalence of diabetes in the United States population has been projected.⁵ The mathematical model predicts that a male born in the year 2000 has a 33% chance of developing diabetes in his lifetime; if he does develop diabetes, his lifespan is likely to be 9 years shorter than that of a person without diabetes. A female is predicted to have a 39% lifetime risk and to lose 12 years of life if she develops the disease.

Much of the increase in diabetes rates is related to the increased prevalence of obesity in the United States and elsewhere in the world.⁶ This so-called epidemic of obesity is presumed to stem from lower levels of physical activity and a shift from traditional eating patterns toward diets of high fat content and high caloric density⁷ [see 3:X Obesity].

Family history is also an important risk factor. An extraordinary example is found among the Pima Indians on the Gila River reservation in Arizona, where 50% of the adult population has type 2 diabetes mellitus. A strong hereditary influence is also demonstrated in monozygotic twins, in which diabetes, if present in one of the twins, nearly always develops in the other twin as well. Offspring and siblings of diabetic patients are at high risk for the disease.

No HLA markers have been identified for type 2 diabetes mellitus, in contrast to type 1 diabetes mellitus [see 9:I Type 1 Diabetes Mellitus]. The common forms of type 2 diabetes mellitus seem to represent a complex multigenic disorder.⁸ Examination of known pathophysiologic mechanisms suggests many logical candidate genes. Study of a variety of genes associated with the cellular actions of insulin has thus far failed to provide clear answers.⁹ Genes that could cause obesity or that could impair growth or survival of beta cells are under active investigation. One promising candidate gene is a variant of transcription factor 7-like-2 (TCF7L2) that may contribute to regulation of proglucagon gene expression in gut endocrine cells. This variant has been proposed to account for 21% of the risk of type 2 diabetes in Icelandic, Danish, and United States populations.¹⁰

The metabolic syndrome (also known as syndrome X, insulin resistance syndrome, Reaven syndrome, and the cardiometabolic syndrome) is defined by the clustering of multiple cardiovascular risk factors.¹¹ Among these are elevated BMI; increased abdominal girth or waist-hip ratio; hypertension; high serum triglyceride levels; low serum high-density lipoprotein (HDL) concentrations; microalbuminuria; and IFG, IGT, or type 2 diabetes [see 3:X Obesity].

The choice of diagnostic criteria for the metabolic syndrome has been controversial. Other questions raised are whether there is a single characteristic (such as a specific form of insulin resistance) unifying the various risk factors, and how the concept can be clinically useful. Because the majority of persons with IFG, IGT, and type 2 diabetes have some of these additional risk factors, and because many persons without glycemic abnormalities but with these other risk factors eventually develop diabetes, these issues are relevant to the management of diabetes.

The INTERHEART study provides guidance on the relationship between the metabolic syndrome, diabetes, and cardiovascular disease.¹² This study evaluated over 15,000 myocardial infarction (MI) patients in 52 countries, and a similar number of persons without MI. Four lifestyle-related risk factors (smoking, eating fruits and vegetables, exercise, and drinking alcohol) and five other cardiovascular risk predictors (diabetes, hypertension, abdominal obesity, apoprotein B/apoprotein A ratio, and a psychosocial index) were measured. Diabetes itself conferred a 4.3-fold increased risk of MI in women and 2.7-fold increase in men and accounted for about 15% of the overall (adjusted) risk of MI in the population. In comparison, abdominal obesity increased risk 2.2-fold and accounted for almost 35% of overall risk, and hypertension increased risk 2.5-fold and accounted for somewhat less than 30% of overall risk. However, over 90% of the total risk in the population was accounted for by the combined effects of the nine easily measured and potentially modifiable risk factors. These findings confirm that identifying other cardiovascular risk factors in patients with diabetes or prediabetes is essential. They also support the view that treating individual risk factors separately may be sufficient, without invoking additional unique risks linked to an overarching syndrome. Moreover, there is at present no single intervention that can reverse or blunt all aspects of the metabolic syndrome and that has been proven to reduce the associated risk of cardiovascular disease.

The alterations of metabolism in patients with type 2 diabetes partially overlap with those alterations of metabolism seen in patients with type 1 diabetes. Absolute or relative deficiency of insulin is common to both disorders, as is a severe disturbance of the patterns of glucose and lipid levels in plasma. However, the fluctuations of plasma glucose are less extreme in type 2 diabetes than in type 1 diabetes, and the exaggerated catabolic state of severe insulin deficiency often seen in type 1 is uncommon in type 2. Rather than being lean and likely to lose weight during periods of hyperglycemia, patients with type 2 diabetes are characteristically overweight or obese and often are gaining weight when diagnosed. The pathophysiologic abnormalities of type 2 diabetes are best understood when divided into three components: relative insulin deficiency, diminished sensitivity of tissues to the effects of insulin, and abnormal metabolic responses to eating.

Insulin Deficiency

Figure 2. Insulin Response in Type 2 Diabetes

Although the microscopic appearance of insulin-producing beta cells of the pancreatic islets may be relatively normal early in the course of type 2 diabetes, insulin secretion is always abnormal.¹³ The most characteristic abnormality is a reduction of the rapid (acute-phase) secretion that normally occurs after the beta cell is stimulated by the rapid intravenous injection of glucose. Diminished early secretion of insulin is also seen after oral ingestion of glucose. The insulin response to a graded infusion of glucose, producing progressively higher basal glucose levels, is diminished as well¹⁴ [see Figure 2]. Under normal conditions, the secretion of insulin in response to an acute stimulus is enhanced by an elevation of basal glucose levels, an effect known as glucose potentiation, but this is diminished in patients with type 2 diabetes. Normal rhythmic oscillations of insulin secretion and pulses of insulin secretion in response to endogenous pulses of plasma glucose are also altered, reflecting a fundamental abnormality of beta cell regulatory mechanisms. Because of these abnormalities, the beta cells fail to secrete insulin in the finely tuned manner that normally keeps glucose concentrations between 70 and 130 mg/dl.

After 10 or more years of type 2 diabetes, insulin secretion is markedly reduced. Beta cells are visibly fewer in number and also contain accumulations of amyloid protein derived from condensation of molecules of another beta cell peptide hormone, amylin.¹⁵ Whether islet amyloid injures beta cells or is a marker of other destructive processes is not clear. The mechanisms responsible for the reduced survival of beta cells—for example, enhanced programmed cell death (apoptosis)—and the impaired differentiation of islet precursor cells into new beta cells is currently under study.¹⁶

Insulin Resistance

Figure 3. Glucose Uptake by Tissues in Type 2 Diabetes

The gold standard for testing the insulin sensitivity of tissues is with a euglycemic glucose insulin clamp. Insulin is infused at a constant rate; the rate of glucose infusion necessary to maintain plasma glucose at a constant basal level is considered a measure of peripheral insulin sensitivity. Because muscle and adipose tissue are the main sites of disposal of glucose given intravenously, this method mainly defines the ability of these tissues to remove glucose from plasma. The mass of muscle tissue, the perfusion of this tissue, and the responsiveness of individual cells to insulin all contribute to this measure of insulin sensitivity. In type 2 diabetes, this measure is routinely diminished, and the patient is said to be insulin resistant^17,18 [see Figure 3].

Another important site of insulin action is the liver, which is the main source of glucose production during fasting. Although hepatic sensitivity to insulin is more difficult to measure, it too is routinely diminished in patients with type 2 diabetes.¹⁸

The cellular mechanisms underlying insulin resistance in muscle, adipose tissue, and liver are complex and incompletely understood. They include changes of insulin signaling pathways [see 9:I Type 1 Diabetes Mellitus]; increases in the amounts of intracellular fat; elevated levels of circulating free fatty acids (FFA) and other adipose tissue products; and effects of increased glucagon, cortisol, epinephrine, and norepinephrine. The relationships between excessive intra-abdominal adipose tissue and diminished insulin sensitivity of muscle and liver are under intensive study. Among the mediators are high circulating concentrations of FFA, tumor necrosis factor-a, and the adipokine resistin, which reduce insulin sensitivity; and reduced concentrations of the adipose cell hormone adiponectin, which normally increases the insulin sensitivity of tissues.¹⁹ In a person without diabetes, as weight and adiposity increase, beta cells compensate for the resulting decline in insulin sensitivity by increasing insulin output. This poorly understood adaptive response is increasingly ineffective in patients with type 2 diabetes, leading to increasing hyperglycemia.²⁰

Metabolic Responses to Eating

Most of the glucose cleared from the peripheral circulation during fasting is taken up at a constant rate by the CNS and other tissues that do not require insulin for glucose uptake. Thus, the rate of hepatic glucose production determines fasting glucose concentrations. The main factors regulating hepatic glucose production are the portal insulin and glucagon concentrations and the sensitivity of the liver to insulin. Regulation of postprandial plasma glucose and other metabolic pathways involves additional mechanisms.^21,22 Rapid, large increases in insulin secretion result in the suppression of hepatic glucose production (by reducing both gluconeogenesis and glycogenolysis); the level of insulin in peripheral plasma becomes high enough to increase the uptake of glucose by muscle and adipose tissue. The ingestion of food leads to the secretion of other hormones that affect glucose regulation. Amylin is secreted by the beta cell with insulin. Amylin's actions include slowing of gastric emptying, suppression of glucagon secretion, and an increase in the sense of satiety, limiting food intake. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the intestinal mucosa after eating. Both GLP-1 and GIP potentiate prandial insulin secretion and slow gastric emptying; GLP-1, like amylin, suppresses glucagon secretion and increases satiety. These changes limit food intake, prolong the time during which nutrients are absorbed, reduce glucose production, promote the uptake of glucose by the liver, and enhance peripheral uptake of the portion of ingested carbohydrate that passes through the liver. Thus, little postprandial hyperglycemia occurs. Uptake of ingested fat by adipose tissue is enhanced by insulin stimulation of ipoprotein lipase, limiting postprandial hypertriglyceridemia.

Figure 4. Glucose Tolerance Testing in Healthy vs. Diabetic Persons

Many of these mechanisms are impaired in type 2 diabetes²³ [see Figure 4]. Secretion of both insulin and amylin after meals is delayed and reduced. Plasma levels of GLP-1 are decreased, and the potentiation of insulin secretion by GIP is impaired. Glucagon secretion is not well suppressed and may instead increase after meals. Hepatic glucose production is not adequately suppressed, and the removal of excess glucose from the peripheral circulation is impaired. Fasting and postprandial hypertriglyceridemia may appear. The abnormalities of amylin and GLP-1 may also contribute to difficulty with weight control.

Glucose Toxicity

Inadequate regulation of plasma glucose and associated metabolic pathways can lead to a vicious cycle in which hyperglycemia and high levels of FFAs reduce both insulin secretion and insulin action.²⁴ This process has been termed glucose toxicity (or glucolipotoxicity). Onset of glucose toxicity may occur after a period of stable or gradually progressing hyperglycemia; more rapid deterioration may be caused either by the addition of a new factor (e.g., a viral illness or glucocorticoid treatment) or attainment of a critical level of hyperglycemia. The diagnosis of diabetes is often made at this time. Initiation of successful treatment with any modality can break the cycle of glucose toxicity; this leads to an improvement in insulin secretion and a reversal in insulin resistance to a greater degree than the direct effects of the treatment alone. After vigorous initial treatment, much simpler and less intensive efforts may maintain glycemic control.

Glycemic Profiles

Figure 5. Glucose and Insulin Patterns in Type 2 Diabetes

The net effect of the underlying abnormalities on typical 24-hour glucose and insulin patterns in untreated patients with type 2 diabetes is shown [see Figure 5].²⁵ The FPG level is elevated, with further incremental increases in the postprandial glucose level occurring during the day. The fasting plasma insulin level is not greatly altered from the level seen in weight-matched persons without diabetes, but postprandial increments in insulin are moderately delayed and reduced in magnitude. This relationship between glucose and insulin reflects a reduction in insulin response to rising FPG levels; the FPG level is continuously elevated and just enough insulin is secreted to prevent further increase. In effect, in a person with untreated type 2 diabetes, the glucose regulatory system is reset so as to maintain a higher FPG level. This higher level can be quite stable, in the absence of treatment, for long periods.

A notable feature of the glycemic profile is that when control is relatively poor, most of the excess glycemic exposure of tissues results from basal hyperglycemia (i.e., elevated fasting and preprandial glucose levels) rather than postprandial hyperglycemia.²⁶ Because current treatments are principally effective in decreasing FPG levels, patients whose hyperglycemia is well controlled with medications frequently have lower FPG levels but less improvement in elevations in postprandial glucose levels.

Figure 6. Retinopathy in Type 2 Diabetes

Because there is a strong genetic predisposition for type 2 diabetes that becomes clinically manifest in the presence of environmental factors, hyperglycemia typically appears intermittently or gradually over a period of years. When a woman with genetic vulnerability becomes pregnant, gestational diabetes [see 9:IV Gestational Diabetes] may occur as an early transitory manifestation of type 2 diabetes; the diabetes goes into remission after delivery but returns years later as permanent type 2 diabetes. Acute illness or therapy with glucocorticoids may also precipitate hyperglycemia and lead to the diagnosis. However, it is also common for asymptomatic, gradually progressive hyperglycemia to occur in the absence of any medical condition other than obesity, and thus escape detection for years. An analysis of two populations, one in the United States and one in Australia, has shown that retinopathy, an easily identified (but, in its early stages, silent) complication of hyperglycemia, is often present when type 2 diabetes is diagnosed and then increases in prevalence linearly [see Figure 6].²⁷ Projection of the prevalence slope backward, to a period preceding the diagnosis, showed that hyperglycemia was likely to have been present in these populations for at least 4 to 7 years before diagnosis.²⁷ Similarly, in the United Kingdom Prospective Diabetes Study (UKPDS), many patients with newly diagnosed type 2 diabetes were found to have retinopathy visible on retinal examination (21%), an abnormal electrocardiogram (18%), absent pedal pulses (13%), or an abnormal vibration threshold in the feet (7%).²⁸

In patients with multiple risk factors for developing type 2 diabetes, an effort to prevent the emergence of overt disease is highly desirable. Randomized clinical trials have shown that the risk of progression from IGT to diabetes can be reduced by lifestyle changes or pharmacologic interventions. The Diabetes Prevention Program (DPP),²⁹ the Finnish Diabetes Prevention Study,³⁰ and the Da Qing IGT and Diabetes Study³¹ showed that intensive diet and exercise therapy reduced the progression from IGT to diabetes over 3 to 6 years by 42% to 58%. The weight loss achieved and the amount of exercise performed were modest—5.6 kg (7% of body weight) and 150 minutes of brisk walking a week in the DPP.

The DPP also included a placebo-controlled metformin treatment arm. In this arm, taking 850 mg of metformin twice daily was associated with a 31% reduction of progression to diabetes. Most of this effect persisted after a 1-week washout from metformin. Lifestyle intervention was particularly effective in older persons, whereas metformin was about as effective for middle-aged or younger persons. In the STOP-NIDDM trial, 100 mg of acarbose three times daily, compared with placebo, reduced progression to diabetes by 25%.³² In a group of Hispanic women with previous gestational diabetes, daily treatment with 400 mg of troglitazone (a thiazolidinedione no longer commercially available), compared with placebo, reduced the development of diabetes.³³ This benefit was still present after an 8-month drug washout.

The largest diabetes prevention trial to date, the international DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial, followed 5,269 patients with prediabetes over a median of 3 years.³⁴ In this trial, progression to type 2 diabetes occurred in 10.6% of patients who received 8 mg of rosiglitazone daily, compared with 25% of placebo recipients—a risk reduction of 62%. Heart failure was reported in 0.5% of study subjects taking rosiglitazone, compared with 0.1% of placebo recipients.

Despite these results, preventive drug therapy needs further testing. Lifestyle intervention, however, is strongly encouraged in all persons at risk for type 2 diabetes.³⁵ Although the efficacy, safety, and consistency of lifestyle interventions are impressive, long-term follow-up is needed to determine how long patients can maintain this therapy and how durable the benefits from either lifestyle changes or drugs will be. Equally important is whether cardiovascular events will eventually be reduced. A secondary analysis from the STOP-NIDDM trial suggests a reduction in MI and total cardiovascular disease events.³⁶

Screening for diabetes by measurement of FPG is recommended for persons without symptoms who are older than 45 years of age, especially if they are overweight (BMI of 25 or greater). Screening should be repeated at 3-year intervals. Earlier or more frequent screening should be considered for patients who have had gestational diabetes; who belong to a high-risk ethnic population (e.g., African, Hispanic, Native American, or Asian); who have a family history of diabetes; or who have hypertension, hypertriglyceridemia, or other risk factors for diabetes or cardiovascular disease.³⁷ It is also reasonable to screen for diabetes in patients who present with a first cardiovascular event.

Although patients with type 2 diabetes mellitus may present with symptoms as florid as those of type 1 diabetes mellitus (but usually not with spontaneous ketonuria), most patients with type 2 disease have relatively mild polyuria and polydipsia; many cases are diagnosed only by office screening or other health checks. The diagnosis is established by a randomly sampled (not fasting) plasma glucose value above 200 mg/dl, accompanied by symptoms suggesting hyperglycemia, or an FPG value above 126 mg/dl, with or without symptoms. In either case, a confirmatory second test is required.¹ Oral glucose tolerance testing (OGTT) is more sensitive but is not recommended for routine use because it is less convenient and reproducible and more costly. Moreover, the treatment recommended for most overweight or obese patients would be the same regardless of OGTT results: a combined regimen of nutritional therapy, exercise, and weight loss.

Goals of Therapy

In general, the goals of treatment of type 2 diabetes are the same as for type 1. For a typical patient, these include an HbA_1c level of less than 7%, fasting and preprandial glucose levels between 90 and 130 mg/dl, and peak postprandial glucose values below 180 mg/dl.³⁸ It is generally advisable to lower FPG into the target range first, as this is the floor above which all other blood glucose tests of the day will rise. Less stringent glycemic targets should be selected for older patients and patients with severe or complex associated medical conditions, or social or behavioral barriers to self-care. All patients with diagnosed diabetes should learn about the disorder itself, its natural history and complications, and the range of therapies available. All should learn about self-measurement of blood glucose (SMBG) and obtain the necessary equipment.

The major risk factors for cardiovascular disease—hypertension, dyslipidemia, and smoking—should be assessed and treated if present. Basic instruction on medical nutrition therapy should be provided, and the patient should try to reduce weight or at least prevent further weight gain.

Nutrition and Physical Activity

Better eating and exercise behavior can markedly reduce the progression from prediabetes to diabetes [see Prevention, above]. Once type 2 diabetes has developed, achieving glycemic targets with lifestyle modification is more challenging. All patients in the UKPDS study entered an intensive 3-month dietary program as initial therapy.³⁹ Only 16% of those enrolled achieved excellent glycemic control, defined as an FPG of 108 mg/dl or less, with dietary treatment alone. At the end of 1 year, only about 9% of the starting group maintained this level of control. This experience confirms what is obvious in clinical practice: even motivated patients, with support from medical providers, have difficulty controlling overt diabetes with nutritional efforts and exercise alone.

Nevertheless, much evidence confirms that patients who are able to follow excellent dietary regimens obtain profound benefit, and most patients will obtain some benefit from their efforts.^36,40 With the help of a dietitian, patients should be provided with individualized, culturally appropriate instructions to reduce intake by at least 250 to 500 calories a day. Such a decrease generally leads to an overall weight loss of 0.5 to 1 lb a week. Alternatively, the patient can be instructed to reduce daily caloric intake to below the basal metabolic rate, which can be estimated at 10 calories per pound (20 cal/kg) of ideal body weight. This will decrease energy intake to less than energy expenditure. Consensus guidelines recommend that the diet consist of less than 30% total fat, less than 10% saturated fat, less than 10% polyunsaturated fat, 10% to 15% monounsaturated fat, 10% to 20% protein, and 50% to 55% carbohydrate.⁴¹ Table sugar and other concentrated forms of carbohydrates are allowable in small portions at any one time (e.g., 5 g or 1 tsp of table sugar). Adding high-fiber foods can also lower plasma glucose modestly.⁴² Learning to count the contemplated grams of carbohydrate before each meal helps some patients limit postprandial glucose increases. Periodic reinforcement of nutritional recommendations by the dietitian and physician is essential.

Weight losses of 5% to 10% (10 to 20 lb) produce significant decreases in FPG and HbA_1c over 1 to 3 months.⁴⁰ In the UKPDS, mean HbA_1c fell from 9% to 7% during the 3-month dietary run-in period.³⁹ However, the group randomized to receive nutritional treatment alone showed significant weight gain and gradual worsening of glycemic control in the first 2 years. For patients such as these, several drugs may be considered to assist with weight control. These include orlistat,⁴³ a gastrointestinal lipase inhibitor that causes malabsorption of fat calories; sibutramine,⁴⁴ an inhibitor of dopamine, norepinephrine, and serotonin reuptake; and rimonabant,⁴⁵ an agent that blocks endocanabinnoid receptors. Even after the addition of a weight-loss drug, nutritional efforts remain essential. Surgical procedures altering gastric volume or intestinal pathways^46,47 can effectively control both weight and type 2 diabetes and are gaining acceptance for very obese patients (BMI > 35) who are unresponsive to other therapy [see 3:X Obesity]. These procedures may work in part by altering the concentrations of gastrointestinal hormones that regulate appetite or satiety.

Additional benefits accrue from gradually increased exercise aimed at achieving at least 60% of maximal heart rate (220 minus age), such as walking 45 minutes at a brisk pace (approximately 3 to 5 miles an hour) three to five times a week.⁴⁸ Exercise decreases insulin resistance and glycemia, contributes modestly to weight loss, reduces the risk of future cardiovascular disease, improves prognosis should an MI occur, and enhances the patient's sense of well-being and physical fitness. Conversely, physical inactivity predicts mortality in men with type 2 diabetes mellitus.⁴⁹ In the presence of known coronary artery disease (CAD), the exercise should be prescribed with input from the patient's cardiologist. If the patient has had type 2 diabetes mellitus for 5 to 10 years or longer or already has peripheral vascular or cerebral vascular disease, autonomic neuropathy, microalbuminuria, dyslipidemia, or a history of smoking, an ECG is essential and an ECG exercise tolerance test is prudent before starting a formal exercise program.

Antihyperglycemic Drugs

A wide array of pharmacologic agents is available for treatment of type 2 diabetes [see Tables 2, 3, and 4]. The effects of various drugs on HbA_1c are fairly similar, ranging from about 0.5% to 2.0% (absolute) reduction from the starting value [see Table 3] (except for insulin, which can achieve greater reductions). With all agents, the reduction of HbA_1c is generally greater when starting from a higher baseline level, but most patients whose initial HbA_1c is above 9% will not be able to reach the 7% target with a single oral agent. Because each class has a different mode of action, their effects are generally additive, and it is possible to combine agents from different classes for optimal results.

Sulfonylureas

Sulfonylureas (SUs) are the oldest oral antihyperglycemic drugs and continue to have an important place in treatment. Their primary mechanism of action is to close adenosine triphosphate-sensitive potassium (K_ATP) channels in the membrane of beta cells (and other cells). In the beta cell, this causes an influx of calcium and stimulation of exocytosis of insulin granules. SUs are most effective in patients who have had diabetes for less than 10 years and can still secrete considerable amounts of insulin. Although initial doses of SUs directly stimulate secretion of insulin, long-term treatment mainly potentiates the effects of glucose (and other stimuli such as amino acids) on insulin secretion, allowing adequate insulin levels at lower glucose levels. The result is a predominant reduction of FPG, typically 50 to 70 mg/dl, with very little effect on postprandial increments.⁵⁰ Fasting plasma insulin levels remain about the same, and postmeal increments of insulin are modestly greater than before starting treatment. These changes of glucose lead to a reduction of HbA_1c by 1% to 2%.⁵¹

For most patients, SU treatment is initiated with the lowest recommended dose, and the dose is increased every 1 to 2 weeks until target blood glucose levels are attained or a practical maximal dose is reached. Modern SUs (e.g., extended-release glipizide, glimepiride) are usually taken in a single daily dose but occasionally are more effective when taken twice daily. Symptomatic patients with an FPG greater than 250 mg/dl may begin with half the maximal recommended dose; the rapid glycemic improvement usually seen is one of the advantages of SUs for such patients.

Hypoglycemia, in particular, and weight gain are adverse effects of SUs. Hypoglycemia is especially frequent and severe in elderly patients who live alone and lack involved family or friends.^52,53 Concern about an increased rate of cardiovascular mortality associated with SUs has persisted since publication of results from the University Group Diabetes Program in 1970.⁵⁴ This study showed an excess of cardiovascular and total mortality associated with tolbutamide. Reassuringly, the UKPDS did not show any trend toward increased cardiovascular events or mortality with SUs.⁵⁵ Tolbutamide is no longer widely used, but glyburide (called glibenclamide in Europe), which remains in common use, has been shown to interfere with ischemic preconditioning, a cardioprotective mechanism related to K_ATP channels in myocardial cells.⁵⁶ Whether this effect indeed causes increased cardiovascular risk has not been fully proven or disproven, and probably never will be because the introduction of newer SUs has rendered the issue moot. Glimepiride, glipizide, and gliclazide appear to lack glyburide's unwanted effect on the myocardium and should be preferred for this reason. These SUs also are less dependent on normal renal function for clearance and cause less hypoglycemia.⁵⁷ SUs are contraindicated in patients with hepatic insufficiency and are dangerous when combined with heavy use of alcohol. Patients with hypoglycemia caused by SUs, particularly those with long half-lives, need close monitoring until they demonstrate the ability to maintain normal plasma glucose levels without carbohydrate supplementation.

Other Beta Cell Stimulants

Repaglinide and nateglinide are newer beta cell stimulants that differ in structure and timing of action from SUs.⁵⁸ Like SUs, they bind to K_ATP channels in beta cells,⁵⁹ but they are more rapidly absorbed and cleared. Nateglinide has an especially rapid and transitory effect, peaking at about an hour and lasting about 4 hours. This pattern leads to greater reduction of postprandial increments of glucose but less effect on FPG than is seen with SUs. As monotherapy, repaglinide and nateglinide are most logically used early in type 2 diabetes, when FPG is not greatly elevated. Because of their short half-lives they are less likely than SUs to cause prolonged hypoglycemia.⁵⁸ To avoid hypoglycemia, these agents should be taken only with meals, ideally 10 to 15 minutes before the patient starts to eat. Like SUs, they can cause weight gain.

a-Glucosidase Inhibitors

The a-glucosidase inhibitors (AGIs) available in the United States are acarbose and miglitol. These agents are poorly absorbed but act within the gut to inhibit the digestion of complex carbohydrates, leading to a delay of glucose absorption. Glycemic increments after meals are typically reduced by 30 to 50 mg/dl, and FPG is reduced by 15 to 20 mg/dl; HbA_1c generally falls 0.5% to 0.8%.⁶⁰ These agents have no statistically significant effect on lipid levels or body weight.⁶¹ AGIs are mostly useful as monotherapy for patients whose principal problem is postprandial hyperglycemia. They must be taken at the start of a meal. Flatulence, abdominal cramping, and diarrhea are frequent side effects, resulting from undigested carbohydrate reaching bacteria in the lower bowel. These symptoms often limit patient acceptance of treatment with AGIs. Treatment should start with 25 mg, and doses should be increased very gradually to enhance tolerance. Except for rare elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, AGIs are nontoxic. Although hypoglycemia does not occur with monotherapy, it can result when an AGI is added to an SU, nateglinide or repaglinide, or insulin. Should hypoglycemia occur, patients must be warned to treat it only with pure glucose (e.g., glucose tablets) because absorption of starches and sucrose is delayed by the therapeutic actions of AGIs.

Metformin

Metformin is the only member of the biguanide drug class used in the United States.⁶² Metformin decreases hepatic glucose production, mostly through inhibiting gluconeogenesis.^63,64 Because it requires the presence of insulin to be effective and because plasma insulin levels decrease during its use, metformin may be considered an hepatic insulin sensitizer. Metformin can reduce FPG by 50 to 70 mg/dl; it has less effect on postprandial increments, resulting in reduction of HbA_1c by 1% to 2%.⁶⁵ Weight is unchanged or may decline.⁶²

Hypoglycemia almost never occurs with metformin monotherapy. Metformin also decreases plasma triglyceride and low-density lipoprotein (LDL) cholesterol levels, and it sometimes increases HDL cholesterol levels. In addition, plasma plasminogen activator inhibitor-1 (PAI-1) activity declines.⁶⁶ These effects on cardiovascular risk factors may explain one of the most interesting observations in the UKPDS. Compared with conventional diet treatment, metformin monotherapy substantially decreased the incidence of MI, diabetes-related death, and all-cause mortality in obese patients.⁶⁷ Although metformin monotherapy has similar glycemic effects in both normal-weight and obese patients with type 2 diabetes mellitus, obese patients especially benefit because of the absence of weight gain.

The most common side effects of metformin therapy are diarrhea (which can be severe), nausea, and abdominal cramps. To reduce the likelihood of these symptoms, the starting dosage should not exceed 500 mg twice a day, and the drug should be used only with special caution by patients with inflammatory gastrointestinal disease. The maximum effective dosage is 2,000 mg/day.⁶⁸ The most feared adverse effect associated with metformin is lactic acidosis.⁶⁹ Whether this association is caused by metformin (as was clearly the case with phenformin, an older biguanide) or is coincidentally occurring in individuals at risk for lactic acidosis for other reasons has never been firmly determined. Given this uncertainty, metformin, which is entirely dependent on renal clearance, should not be used by patients with renal insufficiency or in patients at risk for developing it. The following are contraindications to the use of metformin: serum creatinine level greater than 1.4 mg/dl in women and greater than 1.5 mg/dl in men; intravenous administration of radiographic iodinated contrast media; acute MI; heart failure; and any ischemic condition. Nausea, vomiting, tachypnea, and change in mental status call for measurements of serum electrolytes and lactate to rule out lactic acidosis.

Thiazolidinediones

Thiazolidinediones (TZDs), a newer class of oral drugs, include pioglitazone and rosiglitazone.⁷⁰ TZDs act by binding to the peroxisome proliferator-activated receptor gamma (PPARg), thereby regulating the expression of multiple genes.⁷¹ They improve insulin sensitivity in muscle and adipose tissue, and they improve hepatic insulin sensitivity and reduce hepatic glucose production as well.⁷¹ Some of these effects stem from suppression of FFA release and enhancement of adiponectin secretion from adipose tissue. Randomized trials indicate that early in the course of type 2 diabetes, a TZD can stabilize or improve glycemic control at least as well as other agents, without causing hypoglycemia.^72–74 Like metformin, TZDs require the presence of insulin, and thus they may be ineffective in slender, insulin-deficient patients. Although their glycemic effects are greater in obese patients, some obese persons respond less well than others. Typically, TZDs decrease FPG by 40 to 60 mg/dl, with a moderate additional reduction of postprandial increments.⁷⁰ HbA_1c decreases by about 1% to 1.5%. Plasma insulin levels also decrease. In patients with marked elevations of FPG, it is appropriate to begin TZDs at a midrange dose (e.g., 4 mg rosiglitazone or 30 mg pioglitazone). Otherwise, the lowest dose is appropriate. Because the clinical effects develop slowly (over 4 to 12 weeks), the dosage should not be increased at intervals shorter than 12 weeks. TZDs often cause weight gain, consisting partly of adipose tissue and partly of extracellular fluid, sometimes of 40 lb or more.⁷⁵ The accumulation of fluid presents as peripheral edema, which can be troublesome in itself, and less often as congestive heart failure. For that reason, TZDs should not be used by patients with previous congestive failure or known impairment of myocardial function. The hemoglobin level and hematocrit may decline, perhaps in part from hemodilution. The adipose tissue gain is largely subcutaneous rather than visceral.

The first TZD to be marketed, troglitazone, was withdrawn from use because of its association with rare severe hepatic toxicity, in some cases leading to liver transplantation or death. In clinical studies, neither rosiglitazone nor pioglitazone caused AST and ALT elevations in excess of those caused by placebo, and subsequent evaluations have not confirmed an excess of hepatic failure. However, liver function studies must be performed before and during TZD treatment; the Food and Drug Administration warns that rosiglitazone and pioglitazone should not be prescribed if the ALT level is greater than 2.5 times the upper limit of normal, and the drugs should be stopped if such levels are reached on periodic follow-up testing.

Recent reports suggest additional risks with the use of TZDs. Both rosiglitazone and pioglitazone may increase the risk of fractures in women, especially fractures of the extremities.⁷⁶ In addition, a meta-analysis of data from 42 studies suggested that rosiglitazone increases the risk of myocardial infarction⁷⁷; this study prompted further review by the FDA. On the basis of other published and unpublished data that provide contradictory evidence about the risk of ischemic cardiovascular events in patients taking rosiglitazone, the FDA recommended that rosiglitazone continue to be marketed⁷⁸; however, the agency further recommended that information be added to the labeling of rosiglitazone to indicate a potential risk of ischemic cardiovascular events associated with this drug.⁷⁸ The FDA's review of the safety of rosiglitazone use is ongoing.

The question whether the ischemic risks of rosiglitazone that were reported in the meta-analysis represent a class effect of thiazolidinediones must be considered. Unlike rosiglitazone, pioglitazone has been studied in a prospective, randomized trial of cardiovascular outcomes (the PROACTIVE study).⁷⁹ The primary end point, a broad composite that included coronary and peripheral vascular events, showed a trend toward benefit from pioglitazone. Some evidence indicates that pioglitazone causes fewer myocardial infarctions than does rosiglitazone; however, current evidence is inconclusive. In the PROACTIVE trial, hospital admissions for congestive heart failure were significantly increased with pioglitazone, even in this population from which known congestive heart failure was excluded.⁷⁹

In August 2007, the FDA determined that a label change was needed for the entire class of TZD antidiabetic drugs; the black-box warning—the FDA's strongest form of warning—emphasizes that TZDs may cause or worsen heart failure in some patients.⁸⁰ The strengthened warning advises physicians to observe patients carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema occurring after the start of drug therapy. Patients with these symptoms who then develop heart failure should receive appropriate management of heart failure, and the use of the TZD should be reconsidered. TZDs are contraindicated in patients with serious or severe heart failure who have marked limits on their activity and who are comfortable only at rest. The American Heart Association and the ADA recommend assessing for risk factors for heart failure before starting TZD therapy in diabetic patients; using these agents cautiously (i.e., starting at low doses and titrating upward slowly and carefully while monitoring for symptoms) in patients who have risk factors for heart failure or who have asymptomatic or mildly symptomatic heart failure; and avoiding the use of TZDs in patients with New York Heart Association class III or IV heart failure.⁸¹ The net long-term cardiovascular risks versus benefits of TZDs require further study.

Insulin

About 40% of patients with known type 2 diabetes in the United States use insulin. Some of them actually have late-onset type 1 diabetes and need insulin very soon after diagnosis. Insulin should be considered as initial therapy for patients of any age who have a sudden onset of diabetes, hyperglycemia over 300 mg/dl, significant recent weight loss, and increased urine volume accompanied by thirst. Some of these patients will be found to have type 1 diabetes and will require insulin permanently. Those with type 2 diabetes may recover a degree of insulin secretion and sensitivity through reversal of glucose toxicity, in which case control with oral agents alone may be possible after a tapering of insulin dosage.⁸²

In the more common situation, the progression of type 2 diabetes is gradual and insulin becomes necessary only after years of successful treatment with diet, exercise, and oral therapies. Use of insulin in this setting differs from insulin therapy for type 1 diabetes in several ways. First, beta cell function is markedly reduced but not absent, so insulin therapy is a supplement rather than a complete replacement, at least when first started. As a result, type 2 patients can take insulin with less exact dosing and timing than is possible in type 1 diabetes. Second, the dosage needed may be much higher than in type 1 diabetes, as a result of insulin resistance. Daily requirements of up to 1 U/kg are common, and some very obese patients may need 400 U a day or more. Third, concern about potential adverse effects of insulin has provoked much discussion and in some cases reluctance to use insulin for type 2 diabetes. Epidemiologic studies in persons without diabetes or with prediabetes show a correlation between plasma insulin levels and cardiovascular risk,⁸³ leading to concern that treatment with insulin might further increase this risk by further increasing insulin levels and causing weight gain as well. Fortunately, administering metformin along with insulin greatly reduces the tendency to gain weight.⁸⁴ Moreover, treatment with insulin in the UKPDS did not increase cardiovascular events.⁸⁵ Long-term follow-up of type 1 patients from the Diabetes Control and Complications Trial (DCCT) has provided further reassurance, showing about 50% reduction of cardiovascular events in patients who had received intensive insulin treatment, compared with less intensive insulin treatment.⁸⁵ In addition, insulin treatment can improve physiologic markers of cardiovascular risk, and insulin has anti-inflammatory properties.⁸⁶ Finally, although insulin can cause serious hypoglycemia, the frequency and severity of events is much lower in type 2 than in type 1 diabetes. Although hypoglycemia should always be kept to a minimum, it rarely prevents patients with type 2 diabetes from maintaining good glycemic control through the skilful use of insulin. Ongoing trials should clarify both the risks and benefits of insulin therapy for type 2 diabetes, but the balance of current evidence suggests that fears about potential hazards of insulin in patients with type 2 diabetes have been excessive.

All the formulations of insulin used for type 1 diabetes may be used for type 2 diabetes [see Table 4] and [see 9:I Type 1 Diabetes Mellitus]. In addition, premixed insulins can be used effectively by some patients with type 2 diabetes, whereas they are rarely indicated in type 1 diabetes. Mixtures commonly available consist of 70% neutral protamine Hagedorn (NPH) and 30% regular human insulin, 70% protamine aspart and 30% unmodified aspart, or 75% protamine lispro and 25% unmodified lispro.

Gastrointestinal Hormone Agents

Two injectable agents that mimic the agonist effects of GI peptide hormones have become available for treating diabetes.⁸⁷ Pramlintide, which is an analogue of the hormone amylin, is indicated for use in patients who have not achieved optimal glycemic control despite taking both basal and preprandial injections of insulin and whose HbA_1c level is below 9.0%. It adds to postprandial control by slowing gastric emptying and suppressing glucagon levels, and it frequently leads to reductions in food intake and weight. HbA_1c is typically reduced by about 0.5%. Insulin can easily cause postprandial hypoglycemia when pramlintide is added, so the dose of preprandial insulin should be reduced by half when pramlintide is started. Because pramlintide can cause nausea and vomiting, especially at the initiation of treatment, it should be started at low dosage (e.g., 30 to 60 µg) with slow titration to full dosage, usually 120 µg with each meal. Careful patient education is necessary because pramlintide doses, which are expressed in micrograms, must be converted to insulin unit equivalents for injection with a U-100 insulin syringe.

Exendin is a naturally occurring peptide that is derived from the saliva of the Gila monster. Its effects are very similar to those of GLP-1. Synthetically produced exendin-4, called exenatide, is approved for use in patients taking a sulfonylurea, metformin, or both. It is given by injection twice daily. Like pramlintide, it slows gastric emptying, suppresses glucagon, and favors weight loss, but, unlike pramlintide, exenatide potentiates insulin secretion. A 1% reduction of HbA_1c is typically seen. To minimize nausea and vomiting, exenatide should be started at 5 µg twice daily and increased to 10 µg after a month. Hypoglycemia can occur if an SU is used concurrently. Another GLP-1 receptor agonist, liraglutide, is in clinical trials.

Animal studies show that exenatide (and probably other agents that mimic or potentiate the effect of GLP-1) may improve the survival or regeneration of beta cells, and it is hoped a similar effect will occur in humans. Should this prove true, the clinical value of these agents would greatly increase. GLP-1 and other peptide hormones have very short half-lives because they are rapidly inactivated by the plasma enzyme dipeptidyl peptidase IV (DPP-IV). Orally administered agents that block DPP-IV have been developed. The DPP-IV inhibitors vildagliptin and sitagliptin are less effective than exenatide or pramlintide in limiting postprandial hyperglycemia; they do not cause weight loss, but they do reduce HbA_1c levels about as effectively as exenatide, and they may also protect beta cells. Sitagliptin was approved by the FDA in October 2006 for use as monotherapy and as combination therapy with metformin or a thiazolidinedione. Vildagliptin is being tested in clinical trials. The long-term roles of all the agents related to GI hormones will depend on the results of ongoing studies.

Principles of Pharmacotherapy

Because type 2 diabetes is a chronic, progressive disorder, it requires a long-term strategy.^88,89 Several basic principles have emerged. Standard, evidence-based methods of treatment should be used whenever possible. However, because of the heterogeneity of this disorder and the variability of daily living patterns, some patients require individualized methods that are not fully validated by specific studies. A definite target for glycemic control should always be established, and treatment should be systematically intensified to attain this target. The usual evidence-based target is an HbA_1c level of 7%. Because multiple physiologic defects underlie type 2 diabetes, several agents with different mechanisms of action (combination therapy) will be needed in most cases. Combination therapy should begin with the simplest regimen and lead to more complex combinations.

Oral Monotherapy

It is something of a misnomer to describe therapy consisting of a single oral agent as monotherapy, because nutritional treatment and exercise should always be employed when an oral agent is started. For this reason, treatment with a single drug may be regarded as the simplest form of combination therapy.

Because the evidence of benefit from therapy with metformin and the SUs is most complete and because these drugs have been used the longest, they are the standard initial oral treatments. Metformin leads to weight loss rather than gain; in addition, when used as a single-agent therapy, it does not cause hypoglycemia. In general, patients with initial HbA_1c levels below 9% are best started on metformin, especially if they are obese. The ADA and the European Association for the Study of Diabetes recommend metformin treatment, along with lifestyle interventions, as the first step in the treatment of type 2 diabetes.⁸⁸

SUs are equally effective as metformin, however, and have advantages in some settings. SUs act more rapidly than metformin and can be taken once daily. In general, patients with HbA_1c above 9% should start with an SU.

Patients whose FPG level is barely elevated but who have especially prominent postprandial hyperglycemia may be candidates for an AGI or nateglinide as the initial agent. Should future studies verify either a unique cardiovascular benefit or a beta cell protective effect of TZDs, an agent from this class may be considered for initial therapy. At present, however, evidence does not support this as a routine practice.

Oral Combination Therapy

Improved understanding of the pathogenesis of hyperglycemia in type 2 diabetes mellitus and longer experience with oral therapies have greatly increased interest in and the popularity of combinations of oral drugs.^89,90 In patients with severe hyperglycemia, none of the current drugs reliably reduces HbA_1c to 7% when used alone, probably because they act primarily by correcting single abnormalities. Moreover, all forms of monotherapy (including insulin used conventionally, but possibly not TZDs) become less effective after a number of years.

The need to advance from monotherapy to combination therapy was best shown by the UKPDS experience.^55,91 Combinations attack two or more different causes of hyperglycemia simultaneously—for example, metformin can reduce insulin resistance in the liver while an SU increases basal insulin secretion.⁶⁵

Moreover, when monotherapy fails after initial success, switching to a drug from a different drug class has not been effective (except for insulin). By contrast, addition of either metformin⁶⁵ or a TZD⁹² to an SU did lower HbA_1c significantly. The combinations of metformin with repaglinide,⁹³ metformin with a TZD,⁶⁴ and repaglinide with a TZD94 have also been more effective than any of these agents given alone. AGIs complement the different actions of each of the other drugs, including insulin.⁹⁵ All other oral drugs are effective when added to SUs, except probably repaglinide or nateglinide, for which data are still lacking. Metformin and a TZD also work in triple combination with an SU, repaglinide, or nateglinide. Combinations of oral drugs may at least postpone having to initiate insulin therapy.

Pharmaceutical companies have responded to these considerations by marketing combination pills containing two agents in a fixed-dose combination. The proposal that these formulations might improve adherence is plausible but has not been rigorously tested. It is also possible that the multiplicity of formulations, dosages, and names might increase the risk of medication errors, and that the inability to titrate dosages separately might lead to either excessive side effects or inadequate titration. Objective comparisons of separately given or combined antihyperglycemic agents are mostly lacking.

Insulin Treatment

Addition of insulin to oral agents The simplest way to introduce insulin to the regimen in patients who have been using oral antihyperglycemic agents is to add a single injection of longer-acting (basal) insulin while continuing the other agents at the same dosages.⁸⁹ The transition is easily understood by patients, permits starting with a low dose, and requires only a single daily fasting (prebreakfast) glucose test to guide adjustment of the dose. Both hypoglycemia and worsening hyperglycemia are very uncommon with this tactic, in contrast to what may occur when oral agents are stopped and a more complex insulin regimen is started abruptly. The usual insulin preparations for this purpose are NPH, glargine, and, more recently, detemir. NPH is started at bedtime, and detemir is started in the evening or at bedtime. Both NPH and detemir have to be taken twice daily for optimal results in some patients. Glargine is taken at bedtime, in the morning, or before dinner and only rarely needs to be taken twice daily. Common starting doses are 10 units or 0.1 to 0.15 units/kg. Titration of insulin doses should be done systematically, on the basis of the patient's SMBG values before breakfast. One approach is to increase by 2 units once or twice a week until the FPG level is less than 120 mg/dl.⁹⁶ Another strategy, used in the Treat-to-Target Trial,⁹⁷ is to increase the dose weekly, in increments of 6 to 8 units, until the FPG declines to 140 mg/dl or less; this typically takes 4 to 6 weeks. The insulin dose is then increased in increments of 2 to 4 units. With this approach, target FPG levels are typically achieved within 12 weeks.

When the FPG level is adequately controlled on the oral drug regimen but postprandial glucose is not, an alternative approach is to add a dose of regular or rapid-acting insulin before each meal. If regular insulin is used, the dose should be taken at least 30 minutes before eating. If a rapid-action insulin analogue is used, it can be taken just before the meal or just afterward. Titration schedules for this approach are less well tested than for basal insulin, and whether to use glucose measurements for both efficacy and safety before the next meal (or at bedtime), as opposed to 1 to 2 hours after the meal to guide changes, has also not been studied adequately. This lack of clear algorithms, together with the need for frequent dosing and glucose testing, has limited the use of this approach. The introduction of an inhalable insulin formulation may make the approach more appealing.⁹⁸

Adding premixed insulin in two daily doses is also an option. In such cases, it is usual to begin by administering equal doses (e.g., 5 to 10 units) before breakfast and dinner, with SMBG performed before breakfast and before dinner and doses systematically titrated on the basis of those results. This method is widely used, and can be effective, but studies show that midday hypoglycemia and significant weight gain may occur with it.⁹⁹

Whether to continue oral therapies after insulin therapy proves successful has been debated. In general, continuation of one or more oral agents improves the success of insulin treatment in patients with type 2 diabetes, though it adds complexity and cost. Oral therapy with any type of agent may improve the glycemic control achieved, but metformin has the additional benefit of limiting weight gain. The combination of a TZD with insulin increases the concern regarding congestive heart failure. When multiple injections of insulin are needed because of a decline in endogenous insulin secretion, SUs usually contribute little if any to glycemic control and may be stopped. Eventually—especially after having diabetes for many years—patients may need full basal-bolus insulin therapy, much like patients with type 1 diabetes.

The best way to use injections of pramlintide or exenatide is not yet well defined. Pramlintide may help some patients who are taking both basal and mealtime insulin but who cannot obtain good postprandial glycemic control without gaining too much weight. Exenatide may postpone the need for insulin in some patients for whom oral agents are no longer effective, and it has the advantage of causing weight loss rather than weight gain. Whether exenatide will prove psychologically more acceptable as injection therapy than insulin in general use remains to be seen. Moreover, the long-term balance between the desired effects and the unwanted effects of these agents is not fully tested. The potential safety and effectiveness of combining exenatide with a TZD or insulin is also not established.

Monitoring Glycemic Outcomes

Self-Measurement of Blood Glucose

Patients with type 2 diabetes need to test their blood glucose levels regularly. Relatively frequent SMBG may be desirable in patients with newly diagnosed diabetes, because the results can teach these patients about their daily patterns of glucose and the effect of meals, exercise, stress, and hypoglycemic drugs on these patterns. Seeing the effect of specific food choices on SMBG readings contributes powerfully to learning. Once treatment is established, some patients with type 2 diabetes may be able to reduce the frequency of SMBG, particularly if they have stable glycemic patterns and are taking agents that pose only modest risk of hypoglycemia. For example, a patient with stable control on one or two oral agents may need to test glucose once daily, or even less often. On the other hand, patients who start insulin should perform SMBG at least as many times a day as they inject insulin. Specifically, a patient who is taking a single bedtime dose of NPH or glargine insulin should test once daily before breakfast—and occasionally at 3 A.M., if nocturnal hypoglycemia is suspected—whereas a patient who takes twice-daily injections of premixed insulin may need to test both before breakfast and before the evening meal. Postprandial tests help guide therapy with rapid-action or regular insulin and with acute beta cell stimulants. All patients should also test glucose whenever they have symptoms they believe might be caused by hypoglycemia, in order to confirm this suspicion, guide treatment for the present event, and gain information that can be used to prevent a recurrence. Patients using full basal-bolus treatment should test at least three times a day and possibly up to six times a day, as do patients with type 1 diabetes who use this regimen.

Measurement of Hemoglobin A_1c

Monitoring of HbA_1c is a critical supplement to SMBG. This product of nonenzymatic glycation provides an excellent index of average blood glucose levels for the preceding 2 to 3 months.^99,100 Whereas SMBG promotes success in reaching short-term glycemic goals and identifies glycemic patterns, HbA_1c can measure long-term success in reaching targeted levels of control that will reduce the risk of long-term complications. The typical patient with type 2 diabetes should have HbA_1c tested at least every 6 months. Use of rapid-turnaround, point-of-service HbA_1c assays improves the efficiency with which diabetes caregivers can modify regimens during office visits and improves treatment results.^101–103 Assays of other products of nonenzymatic glycation (such as fructosamine and glycated albumin) that reflect shorter periods of chronic hyperglycemia are generally less useful.¹⁰²

Management of Hyperglycemia during Acute Illness

Hyperosmolar Hyperglycemic Nonketotic Coma

Type 2 diabetes mellitus seldom gives rise to diabetic ketoacidosis unless the patient experiences a severe medical stress. On the other hand, hyperosmolar hyperglycemic nonketotic coma (HHNC) is an infrequent but feared acute complication of type 2 diabetes. It is characterized by extreme hyperglycemia (over 600 mg/dl) and serum hyperosmolarity (over 320 mOsm/L) but with little or no ketosis.^104,105 The main clinical effect of extreme hyperosmolarity is somnolence or confusion, which can progress to coma, but focal or generalized seizures or transitory focal neurologic deficits may occur as well. The absence of severe ketonemia is usually attributed to residual insulin secretion that is sufficient to restrain lipolysis, although other factors may contribute. HHNC is marked by extreme dehydration, with both a marked deficit of free water and serious compromise of intravascular volume and tissue perfusion. Thus, most patients with HHNC have hypotension, extremely dry skin and mucous membranes, and gross elevation of hematocrit, urea nitrogen, creatinine, and albumin levels. Secondary lactic acidosis is not uncommon, with a low serum bicarbonate level and an increased anion gap.¹⁰⁴ Increased viscosity and coagulability of the blood predisposes to thrombotic events in the cerebral and coronary artery circulations or elsewhere. Conversely, stroke and myocardial infarction may precipitate HHNC, as may pancreatitis, sepsis, and drugs such as hydrochlorothiazide, phenytoin, and glucocorticoids. Elderly patients living in nursing homes are particularly vulnerable because their thirst mechanisms are less sensitive to a rising serum osmolality and because dementia, decreased alertness, or institutional conditions may combine to reduce water intake to less than urinary and insensible water losses. At presentation of HHNC, serum sodium is usually elevated or normal in the face of extreme hyperglycemia (i.e., the expected pseudohyponatremia is absent). Whatever the presenting level of serum sodium, it will rise, sometimes markedly, when glucose levels decline with insulin treatment.

Fluid replacement is the most important component of therapy for HHNC. Restoration of circulating volume is an urgent first priority and is accomplished by rapid intravenous infusion of 1 to 2 liters of 0.9% saline, followed by 0.45% saline. Later, when plasma glucose levels have declined to 250 to 300 mg/dl, 5% glucose in water or in 0.2% saline is given. Total fluid deficits of as much as 12 liters may have to be replaced. Insulin treatment, as for diabetic ketoacidosis, is started immediately after administration of isotonic saline. Potassium must be added to intravenous fluids to prevent hypokalemia caused by insulin action, but it should not be started until urine flow is verified or hypokalemia is proven, because potassium levels can be high initially. The patient may require days of fluid replacement, the tonicity of which must be carefully adjusted to achieve a gradual steady decrease in serum osmolality and sodium levels, before central nervous system function returns to normal or at least to baseline. The mortality from HHNC is still high. Infection, especially of the urinary tract, even if only suspected, should be treated with broad-spectrum antibiotics. Papillary necrosis may be seen. Patients with a history of arterial or venous thrombosis can benefit from low-dose prophylactic heparin administration.

Other Illness in Hospitalized Patients

Patients with type 2 diabetes who are hospitalized for other conditions are at high risk for complications, in part because of the frequent presence of vascular and neural disorders, which may not have been previously identified. Oral antihyperglycemic agents usually should be discontinued in patients admitted to hospital with acute illness, both because these agents are relatively ineffective during acute illness and because their side effects may be especially problematic in this setting. Insulin is the preferred treatment of hyperglycemia in the hospital; it is most effective when given by continuous intravenous infusion. Studies have shown significant reductions of morbidity and mortality among patients in intensive care units when plasma glucose is kept below approximately 120 mg/dl with insulin infusions.¹⁰⁶ The transition from infused insulin to subcutaneous regimens may be complicated by variable oral and parenteral intake of nutrients and the use of glucocorticoids. The best results are achieved when an experienced team follows the patient through this process and when multiple daily injections of insulin are given according to a predefined plan rather than as a so-called sliding-scale reaction to excessively high glucose levels. Hospitalization offers the opportunity for reinforced patient education by a diabetes nurse educator and, if the admission HbA_1c is well above target, for establishment of a new home treatment regimen.

Complications

The complications of diabetes mellitus are discussed in detail elsewhere [see 9:III Complications of Diabetes Mellitus].

Matthew C. Riddle, M.D., F.A.C.P., has received honoraria for consulting or speaking, or research grant support from Amylin, GlaxoSmithKline, Lilly, Novo-Nordisk, Sanofi-Aventis, and Pfizer.

Saul Genuth, M.D., F.A.C.P., has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.