Nutritional Management of Diabetes Mellitus1
Susan Oh
Rita Rastogi Kalyani
Adrian Dobs
1Abbreviations: ACSM, American College of Sports Medicine; ADA, American Diabetes Association; BMI, body mass index; CKD, chronic kidney disease; CVD, cardiovascular disease; DCCT, Diabetes Control and Complications Trial; DKA, diabetic ketoacidosis; DM, diabetes mellitus; DRI, dietary reference intake; FDA, Food and Drug Administration; FPG, fasting plasma glucose; GDM, gestational diabetes mellitus; GLUT4, glucose transporter-4; HDL-C, high-density lipoprotein cholesterol; HHS, hyperglycemic hyperosmolar state; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LDL-C, low-density lipoprotein cholesterol; MNT, medical nutrition therapy; NDDG, National Diabetes Data Group; OGTT, oral glucose tolerance test; UKPDS, UK Prospective Diabetes Study; WHO, World Health Organization.
Diabetes mellitus (DM) is a metabolic disorder characterized primarily by abnormally high levels of glucose (sugar) in the blood, with other multiple metabolic abnormalities often present. It is one of the most prominent epidemics worldwide. DM afflicts 25.8 million people of all ages in the United States and more than 220 million in the world, with the rate of DM-related deaths predicted to double between 2005 and 2030 (1, 2, 3, 4). DM and its complications have serious health and economic impacts. DM is the seventh leading cause of death in the United States (5). It is the leading cause of blindness among working-age adults (6), nontraumatic amputations (7), end stage renal disease and dialysis (3, 8), and peripheral neuropathy (9, 10). Further, having DM significantly increases the risk for heart disease and stroke (11, 12, 13). In particular, with the growing presence of decreased physical activity and the increased availability of calorically dense foods, the prevalence of DM is increasing worldwide, especially in developing countries and in adolescents, as with obesity.
As demonstrated by the Diabetes Prevention Program (14), the most successful strategy in the treatment and prevention of DM is lifestyle modification. Because most serum glucose depends on dietary intake, medical nutrition therapy (MNT) remains a cornerstone in the treatment of DM and continues to prove quite effective in the overall management of the disease (15). Physical activity is also very important in achieving lifestyle changes. Self-monitoring of blood glucose levels and appropriate adjustments of food intake, exercise, and medications can facilitate optimal glycemic control (16). In all cases, an integrated health care team is essential for persons with DM to maintain quality of life and longevity.
HISTORICAL OVERVIEW
Classic symptoms of DM, such as polyuria and polydipsia, have been observed and treated with dietary interventions for more than thousands of years in early Egyptian, Indian, and Greek civilizations. One of the earliest reports, the Ebers Papyrus written in 1500 BC (discovered in a tomb in the Thebes region in southern Egypt in 1862 and named after the Egyptologist Geary Ebers), describes a common symptom, polyuria, of the “sugar disease” (17). Egyptians suggested various dietary remedies for this syndrome, including a diet of beer, fruits, grains, and
honey (17). Early Indians described DM-like symptoms and recommended the freshly harvested cereals and bituminous preparations containing benzoates and silica as a remedy for DM (18). Aretaeus of Cappadocia (81 to 138 AD) first used the Greek word “diabetes,” literally meaning “to run through” or siphon. He described the disease as the “melting down of flesh and limbs into the urine.” He concluded that diabetes was a disease of the stomach and should be treated with milk, gruel, cereals, fruits, and sweet wines. Milk, water, wine, and beer were also used as the main fluids to relieve excessive thirst until the second century AD, when diabetes was thought to be a disease of the kidneys (19). A London physician, Thomas Willis, added “mellitus,” meaning honeylike, after noticing the sweet taste of urine.
honey (17). Early Indians described DM-like symptoms and recommended the freshly harvested cereals and bituminous preparations containing benzoates and silica as a remedy for DM (18). Aretaeus of Cappadocia (81 to 138 AD) first used the Greek word “diabetes,” literally meaning “to run through” or siphon. He described the disease as the “melting down of flesh and limbs into the urine.” He concluded that diabetes was a disease of the stomach and should be treated with milk, gruel, cereals, fruits, and sweet wines. Milk, water, wine, and beer were also used as the main fluids to relieve excessive thirst until the second century AD, when diabetes was thought to be a disease of the kidneys (19). A London physician, Thomas Willis, added “mellitus,” meaning honeylike, after noticing the sweet taste of urine.
In the late 1700s, a French physician began prescribing undernutrition or semistarvation diets, interspersed with frequent periods of fasting, for patients with DM (19). In the early 1900s, Dr. Frederick M. Allen, in the United States, developed his starvation diet and was one of the first to customize or “individualize” diets to his patients’ preference while still providing only 1000 calories a day. Although many of his patients were malnourished, Allen is credited with helping many survive before the introduction of insulin therapy in 1921 (19). The discovery of insulin in the 1920s dramatically increased survival for those afflicted with DM. However, diet recommendations still remained controversial. Similar to the present day, whereas some physicians were proponents of highcarbohydrate and low-fat diets, others were proponents of low-carbohydrate, high-protein, and high-fat diets (19). The second approach has generally fallen out of favor because of the increased risk of heart disease.
In 1994, shortly after clinical findings from the Diabetes Control and Complications Trial (DCCT) were published, the American Diabetes Association (ADA) published a revised set of nutrition guidelines, to refocus on an “individualized approach to nutrition self-management that is appropriate for the personal life-style and diabetes management goals of the individual with diabetes” (20). Although the core emphasis of these nutrition guidelines remains, the guidelines have continued to evolve.
CLASSIFICATION
The classification of DM has moved away from a system based, in large part, on the type of pharmacologic treatment to a system based on disease origin (21). The terms insulin-dependent DM (IDDM) and non-insulindependent DM (NIDDM) should no longer be used (21, 22, 23), because some patients who initially have type 2 NIDDM can eventually develop insulin dependence. DM is a clinically heterogeneous group of disorders that share hyperglycemia in common and that result from insulin insufficiency, insulin resistance, or both (24). An appropriate system of classification is important for the clinical management of DM (21). No systematic categorization had been generally accepted until the National Diabetes Data Group (NDDG) classification system was published in 1979 (21, 22). The World Health Organization (WHO) Expert Committee on Diabetes in 1980 and, later, the WHO Study Group on Diabetes Mellitus endorsed the recommendations of the NDDG (21, 23). Currently, the ADA and the WHO classify DM into four main clinical classifications: type 1, type 2, other specific types of DM, and gestational diabetes mellitus (GDM) (25). Most cases are type 1 or type 2 DM (24).
Type 1 DM is characterized by absolute insulin deficiency caused by autoimmune-mediated destruction of the pancreatic β cells, and it accounts for 5% of all cases. Type 2 DM, which accounts for about 90% to 95% of cases, is characterized by two primary defects: insulin resistance (diminished peripheral tissue sensitivity to insulin) and relatively impaired β-cell function (delayed or inadequate insulin release). GDM is defined as abnormal glucose status that is first recognized during pregnancy. The other types (i.e., unusual genetic forms or secondary causes of DM) account for the remaining cases in the United States. The origin and classification can be found in Table 61.1.
EPIDEMIOLOGY
The worldwide prevalence of DM has risen dramatically since the 1990s. DM is one of the most common chronic diseases in most countries, and it continues to increase in number and significance as changing lifestyles lead to reduced physical activity, increased intake of energydense foods, and increased obesity (26, 27). An estimated 25.8 million people are affected by DM (7 million of these people have undiagnosed cases), and 1.9 million people 20 years old or older were newly diagnosed with DM in 2010 in the United States (3). This number will almost double to 44.1 million by 2035 (26). Along with the United States, the global epidemic is also growing. Worldwide, 220 million people have DM; and the overall total predicted increase in numbers with DM from 2010 to 2030 is 54% at an annual growth of 2.2%, nearly twice the annual growth of the total world adult population (27). Developing countries have an anticipated disproportionate 69% increase compared with a 20% increase in developed countries between 2010 and 2030 (27). Thirtysix percent of the anticipated global increase of DM (154 million people) is projected to occur in India and China alone (27).
The economic impact of DM and its complications is great. Research suggests that the total cost of diabetes in 2007 for the United States was $174 billion, including $116 billion in excess medical expenditures and $58 billion in reduced national productivity. Medical costs attributed to DM included $27 billion for care to treat DM directly, $58 billion to treat DM-related chronic complications, and $31 billion in general medical costs. Indirect costs include absenteeism from work, reduced
work productivity, unemployment from disease-related comorbidity, and lost productive capacity from early mortality (26, 28, 29, 30). Further, total estimated global health care expenditures on DM were $376 billion in 2010 and are $490 billion in 2030 (31).
work productivity, unemployment from disease-related comorbidity, and lost productive capacity from early mortality (26, 28, 29, 30). Further, total estimated global health care expenditures on DM were $376 billion in 2010 and are $490 billion in 2030 (31).
TABLE 61.1 ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS | |||
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Considerable geographic and genetic variation is noted in the incidence of both type 1 and type 2 DM. The global age-adjusted incidence of type 1 DM ranges between the lowest incidence (0.1 per 100,000/year) in China and Venezuela to the highest incidence (40.9 per 100,000/ year) Finland and Sardinia (Italy) (32, 33). This incidence is increasing 3% to 4% per year worldwide, a finding possibly suggesting an environmental contribution to the disease (32). Soltesz et al (34) analyzed numerous epidemiologic studies and found environmental risk factors early in life to be possibly contributors to the increasing incidence of type 1 DM, including enteroviral infections in pregnant women (35, 36, 37, 38, 39), older maternal age (39, 40, 41), preeclampsia (42), cesarean section delivery (41, 42), increased birth weight (43), early introduction of cow’s milk proteins, and an increased rate of postnatal growth (weight and height) (44, 45). Vitamin D supplementation may be protective (46). Viruses may initiate autoimmunity toward the β cell, whereas other exposures may overload the β cell and accelerate DM development (34). Assuming that present trends in Europe continue, scientists predict doubling of new cases of type 1 DM in European children less than 5 years of age between 2005 and 2020 and a 70% rise in prevalent cases in patients less than 15 years of age (47).
Type 2 DM affects 90% to 95% of people with DM around the world, and it is associated with excess body weight and decreased physical inactivity. The prevalence of type 2 DM in the United States is increasing as the obesity epidemic is exploding. The onset is usually in older adults more than 35 years old, although type 2 DM is occurring more often in youth. Risk factors include physical inactivity (exercising less than three times per week), high-risk ethnicity (e.g., African-American, Latin American, Native American, Asian American, or Pacific Islander), delivery of a baby weighing more than 9 lb (4 kg) or a diagnosis of GDM, hypertension, high-density lipoprotein cholesterol (HDL-C) levels less than 35 mg/dL (0.90 mmol/L) and/or triglyceride levels higher than 250 mg/dL (2.82 mmol/L), polycystic ovarian syndrome, previously identified impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), clinical conditions associated with insulin resistance, and history of cardiovascular disease (CVD). Having a firstdegree relative with type 2 DM (i.e., a parent or sibling) increases the risk of DM by 40%. Abdominal obesity
confers higher risk, and waist circumference cutoffs may vary by ethnicity (48).
confers higher risk, and waist circumference cutoffs may vary by ethnicity (48).
Some other risk factors for type 2 DM include the following: older age (1); greater parity (49); low (versus moderate) alcohol use (50); cigarette smoking (51), as well as (transiently) stopping smoking (52); stress (53); low socioeconomic status, particularly among Latin Americans and African-Americans (54, 55); diet (i.e., high-fat, lowfiber, Western diet) (56); low magnesium intake (57); and soda consumption (58). Strong urbanization trends also associated with type 2 DM are clearly depicted in the following two epidemiologic cases. For example, in the Pacific island of Nauru, Pima Indians took on a more Western lifestyle leading to more obesity, and their DM incidence increased from nearly 0% to about 50% (59). In India, Asian Indians living in rural communities had a DM prevalence of 2%, which increased to 10% after they moved to an urban environment (60).
Prediabetes or intermediate DM is an emerging concern. Persons with prediabetes have an increased risk of developing type 2 DM, CVDs, and microvascular diseases such as peripheral neuropathy. In 2005 to 2008, based on fasting glucose or hemoglobin A1c levels, 35% of US adults 20 years old or older had prediabetes (61). According to the Centers for Disease Control and Prevention (CDC), applying this percentage to the entire US population in 2010 yields an estimated 79 million US residents 20 years old or older with prediabetes (3).
GDM affects an estimated 170,000 (1% to 14%) pregnancies each year in the United States (62). For those women who are diagnosed with GDM, 30% to 50% will have recurrent GDM in a future pregnancy (63, 64). Of particular concern, up to 50% of women with GDM will develop type 2 DM in the 5 to 10 years after delivery of their baby (62). In a metaanalysis, Bellamy et al reported that GDM corresponded to a 7.4-fold increased risk for developing future type 2 DM (63).
DIAGNOSIS
For the past several decades, the diagnosis of DM was based only on glucose criteria, either the fasting plasma glucose (FPG) or the 2-hour 75-g oral glucose tolerance test (OGTT). In 1997, the diagnostic criteria were revised after observing associations between FPG levels and the presence of retinopathy as the key factor on which to base the threshold glucose level (24). These analyses helped define the diagnostic cut point of FPG at greater than 126 mg/dL (7.0 mmol/L) and confirmed the long-standing diagnostic 2-hour plasma glucose value of greater than 200 mg/dL (11.1 mmol/L) for DM, still used today (24). The more recent diagnostic criteria, based on a hemoglobin A1c cut point of 6.5% or greater, are similarly associated with an inflection point for retinopathy prevalence (24). To be classified as having DM, a patient needs to satisfy at least one diagnostic criterion. Table 61.2 contains a summary of criteria.
TABLE 61.2 DIAGNOSTIC CRITERIA FOR THE DIAGNOSIS OF DIABETES | |||||||||
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Diagnostic criteria also exist for persons with an increased risk for DM but whose serum glucose levels do not yet meet the criteria for DM. The terms IGT and IFG refer to a stage intermediate between normal glucose homeostasis and DM (24). IFG is defined as FPG levels between 100 mg/dL (5.6 mmol/L) and 125 mg/dL (6.9 mmol/L) by the ADA, or between 110 mg/dL (6.1 mmol/L) and 125 mg/dL (6.9 mmol/L) by the International Diabetes Federation (IDF). IGT refers to a 2-hour glucose level of 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L). The ADA refers to these conditions as “prediabetes,” whereas the WHO prefers the term “intermediate diabetes” (24, 25). A criterion for a “category of increased risk of diabetes” based on a hemoglobin A1c level of 5.7% to 6.0% was also introduced (29).
The diagnosis of GDM is based on an OGTT performed during pregnancy. In the revised ADA guidelines (29), all women regardless of their risk factors are recommended to undergo a 75-g OGTT during weeks 24 to 28 of pregnancy. In women at high risk of DM, OGTT should also be considered at the beginning of pregnancy for the diagnosis of overt DM.
BODY FUEL REGULATION
Physiology of Normal Blood Glucose Regulation
Carbohydrate metabolism, or glucose homeostasis, depends on the interaction of several hormones. Insulin has a central role in maintaining this homeostasis as the only hormone that lowers blood glucose, but glucagon, glucocorticoids, catecholamines, and growth hormone also have significant glucose-raising effects that are interactive with insulin (65). Following the ingestion of a meal, nutrients are digested; broken down into glucose, amino
acids, and fatty acids; and rapidly absorbed by the small intestine. Glucose is first carried to the liver by the portal vein, where a substantial portion (30% to 70%) enters the liver by facilitated (carrier-mediated) diffusion driven by the concentration gradient that exists in the fed state (65, 66). The majority of this glucose is transformed into glycogen and stored, although some is converted to lipid or consumed by energy-generating pathways. A small portion of glucose in the liver is metabolized through glycolytic pathways to produce adenosine triphosphate. The remainder of the glucose enters the peripheral circulation, where regulated insulin secretion and target skeletal tissue responses to insulin contribute to insulin-mediated glucose clearance and control of blood glucose levels. Skeletal muscle represents the main peripheral tissue site for removal of this circulating blood glucose (65, 66, 67).
acids, and fatty acids; and rapidly absorbed by the small intestine. Glucose is first carried to the liver by the portal vein, where a substantial portion (30% to 70%) enters the liver by facilitated (carrier-mediated) diffusion driven by the concentration gradient that exists in the fed state (65, 66). The majority of this glucose is transformed into glycogen and stored, although some is converted to lipid or consumed by energy-generating pathways. A small portion of glucose in the liver is metabolized through glycolytic pathways to produce adenosine triphosphate. The remainder of the glucose enters the peripheral circulation, where regulated insulin secretion and target skeletal tissue responses to insulin contribute to insulin-mediated glucose clearance and control of blood glucose levels. Skeletal muscle represents the main peripheral tissue site for removal of this circulating blood glucose (65, 66, 67).
The main regulator of insulin secretion by the pancreatic β cells is the plasma glucose concentration. Intestinal factors called incretins (e.g., gastrointestinal-inhibitory peptide [GIP] and glucagon-like peptide-1 [GLP-1]) and neural (vagal) factors augment insulin secretion such that the insulin secretory response to oral glucose greatly exceeds the response to an equivalent intravenous glucose infusion (68, 69). High insulin concentrations stimulate transport of glucose and amino acids into muscle and adipose tissue. Insulin also facilitates the conversion of glucose products to fatty acids for storage as triglycerides in fat cells.
The overall effects of the increase in insulin levels, in response to increased glucose entry into the circulation, are suppression of glucose production by the liver and stimulation of glucose transport into the muscle and adipose tissue, where it is consumed as a metabolic fuel or stored. Insulin also inhibits the catabolism of the alternative energy sources, fat, and protein. This is an appropriate response to the abundance of circulating nutrients that occurs after meals (66).
During the fasting state, low serum insulin levels permit mobilization of fuel and energy from storage forms. For example, under stressful circumstances, hypoglycemia, or trauma, glucagon and other counterregulatory hormones, including catecholamines, glucocorticoids, and growth hormone, act specifically to decrease peripheral glucose uptake, to promote hepatic glucose production, and to mobilize fatty acids (70).
During periods of starvation, maintenance of glucose homeostasis is critically important (see also the chapter on the metabolic consequences of starvation). The brain cannot synthesize glucose or store fuel as glycogen for more than a few minutes supply. Thus, the brain depends on a continuous supply of glucose from plasma. Only the liver and kidneys contain glucose-6-phosphatase, the enzyme necessary for release of glucose into the circulation. Starvation is associated with a decline in insulin and a rise in glucagon concentrations that result in increased rates of gluconeogenesis. The change from a glucose-based to a lipid-based (free fatty acids and ketone bodies) energy supply in prolonged starvation helps minimize skeletal muscle protein catabolism by reducing the need for amino acid-derived gluconeogenesis (70).
This provides a brief overview of the impact of insulin on multiple tissues and its specific actions that result in lowering blood glucose and inhibiting the mobilization of alternative metabolic fuels such as fat and protein (Fig. 61.1). The disruption in glucose homeostasis and other metabolic derangements observed with DM can be explained by the loss of these actions of insulin. As previously mentioned, DM can be caused by either a relative or absolute deficiency of insulin and/or diminished tissue responsiveness to insulin that ultimately results in hyperglycemia (66).
 Figure 61.1. Metabolic effects of insulin on macronutrients. |
Pathophysiology of Diabetes
In the fed state, insulin is secreted from the pancreatic β cells in response to the increased circulating glucose concentrations, thus promoting glycogen synthesis in liver and muscle, lipid formation in adipocytes, and amino acid uptake and protein synthesis in most cells. In the postabsorptive state, during starvation, and in response to stress, decreased insulin levels and increased glucagon contribute to glycogen breakdown, lipolysis, hepatic ketogenesis, and decreased synthesis and increased degradation of protein. This decline in insulin levels also results in an increased hepatic release of glucose into the systemic circulation to maintain glucose levels (66, 67).
In DM, decreased insulin action poses a range of metabolic abnormalities that span from the effects of mild insulin deficiency, as seen in hyperglycemia, to the effects of insulinopenia, as seen in diabetic ketoacidosis (DKA) associated with fluid and electrolyte depletion (68). In postabsorptive or fasted states, hyperglycemia does not resolve and often worsens. Low insulin activity results in exaggerated counterregulatory responses that normally serve to protect against the development of hypoglycemia (69). The result of decreased insulin action and elevated counterregulatory hormones (glucagon, catecholamines and to a lesser extent, growth hormone and cortisol) includes, initially, the conversion of stored glycogen to glucose. Glucagon is a potent activator of glycogenolysis and gluconeogenesis (in the liver) and is able to increase endogenous glucose production.
In DM, relative or absolute insulin deficiency leads to a marked decrease in activity of the glucose transporter-4 (GLUT4) largely as a consequence of decreased insulinstimulated GLUT4 localization to the surface membranes of skeletal muscle. The results are a decrease in the normal postmeal flux of glucose into skeletal muscle and increased circulating plasma glucose (65).
DM is also associated with increased activity of enzymes involved in gluconeogenesis and decreased activity of glycolytic and oxidative enzymes. In addition, DM is often associated with relative or absolute hyperglucagonemia, resulting from loss of the suppressive effect of insulin on glucagon secretion by the pancreatic α cell.
COMPLICATIONS
DM is a chronic disease that can cause complications leading to significant morbidity and premature death, particularly if it is not well treated.
Acute Complications
Symptoms of hyperglycemia include increased polyuria (frequent urination), polydipsia (excessive thirst), fatigue, irritability, blurred vision, and weight loss. Blurry vision results from osmolar shifts from hyperglycemia within the lens (67). Polyuria and polydipsia occur when blood glucose increases above the urinary filtering threshold of 180 mg/dL. In normal glucose states, all glucose filtered at the glomerulus is reabsorbed by the tubules. However, the elevated plasma glucose in DM may lead to an increase in the filtered load of glucose that exceeds the maximum tubular reabsorptive capacity, and large amounts of glucose may be excreted (71). For the same reason, large amounts of ketones may also appear in the urine. These urinary losses further deplete the body of nutrients and lead to weight loss. Far worse, however, is the effect of these solutes on sodium and water excretion.
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