Biochemistry_Lippinco

Biochemistry_Lippinco. brain that is guided by two priorities: 1) the need to maintain adequate plasma levels of glucose to sustain energy metabolism in the brain, red blood cells, and other glucose-requiring tissues and 2) the need to mobilize FA from TAG in WAT for the synthesis and release of ketone bodies by the liver to supply energy to other tissues and spare body protein. As a result, blood glucose levels are maintained within a narrow range in fasting, while FA and ketone body levels increase. [Note: Maintaining glucose requires that the substrates for gluconeogenesis (such as pyruvate, alanine, and glycerol) be available.]


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Fuel stores The metabolic fuels available in a normal 70-kg man at the beginning of a fast are shown in Figure 24.10. Observe the enormous caloric stores available in the form of TAG compared with those contained in glycogen. [Note: Although protein is listed as an energy source, each protein also has a function unrelated to energy metabolism (for example, as a structural component of the body or as an enzyme). Therefore, only about one third of the body’s protein can be used for energy production without fatally compromising vital functions.] B. Enzymic changes


Biochemistry_Lippinco

Biochemistry_Lippinco. In fasting (as in the well-fed state), the flow of intermediates through the pathways of energy metabolism is controlled by four mechanisms: 1) the availability of substrates, 2) allosteric regulation of enzymes, 3) covalent modification of enzymes, and 4) induction-repression of enzyme synthesis. The metabolic changes observed in fasting are generally opposite those described for the absorptive state (see Fig. 24.9). For example, although most of the enzymes regulated by covalent modification are dephosphorylated and active in the well-fed state, they are phosphorylated and inactive in the fasted state. Three exceptions are glycogen phosphorylase (see p. 132), glycogen phosphorylase kinase (see p. 132), and HSL (see p. 189), which are active in their phosphorylated states. In fasting, substrates are not provided by the diet but are available from the breakdown of stores and/or tissues, such as glycogenolysis with release of glucose from the liver, lipolysis with release of FA and


Biochemistry_Lippinco

Biochemistry_Lippinco. substrates are not provided by the diet but are available from the breakdown of stores and/or tissues, such as glycogenolysis with release of glucose from the liver, lipolysis with release of FA and glycerol from TAG in adipose tissue, and proteolysis with release of amino acids from muscle. Recognition that the changes in fasting are the reciprocal of those in the fed state is helpful in understanding the ebb and flow of metabolism.


Biochemistry_Lippinco

Biochemistry_Lippinco. VIII. LIVER IN FASTING The primary role of the liver in fasting is maintenance of blood glucose through the production of glucose (from glycogenolysis and gluconeogenesis) for glucose-requiring tissues and the synthesis and distribution of ketone bodies for use by other tissues. Therefore, hepatic metabolism is distinguished from peripheral (or extrahepatic) metabolism. A. Carbohydrate metabolism


Biochemistry_Lippinco

Biochemistry_Lippinco. The liver first uses glycogen degradation and then gluconeogenesis to maintain blood glucose levels to sustain energy metabolism of the brain and other glucose-requiring tissues in the fasted state. [Note: Recall that the presence of glucose-6-phosphatase in the liver allows the production of free glucose both from glycogenolysis and from gluconeogenesis (see Fig. 24.4).] 1. Increased glycogenolysis: Figure 24.11 shows the sources of blood glucose after ingestion of 100 g of glucose. During the brief absorptive period, ingested glucose is the major source of blood glucose. Several hours later, blood glucose levels have declined sufficiently to cause increased secretion of glucagon and decreased secretion of insulin. The increased glucagon/insulin ratio causes a rapid mobilization of liver glycogen stores (which contain ~80 g of glycogen in the fed state) because of PKA-mediated phosphorylation (and activation) of glycogen phosphorylase kinase that phosphorylates (and activates)


Biochemistry_Lippinco

Biochemistry_Lippinco. liver glycogen stores (which contain ~80 g of glycogen in the fed state) because of PKA-mediated phosphorylation (and activation) of glycogen phosphorylase kinase that phosphorylates (and activates) glycogen phosphorylase (see p. 132). Figure 24.11 shows that because liver glycogen is exhausted by 24 hours of fasting, hepatic glycogenolysis is a transient response to early fasting. Figure 24.12, , shows glycogen degradation as part of the overall metabolic response of the liver during fasting. [Note: Phosphorylation of glycogen synthase simultaneously inhibits glycogenesis.]


Biochemistry_Lippinco

Biochemistry_Lippinco. See Section B.2 for an explanation of the decline in gluconeogenesis.] 2. Increased gluconeogenesis: The synthesis of glucose and its release into the circulation are vital hepatic functions during short-and long-term fasting (see Fig. 24.12, ). The carbon skeletons for gluconeogenesis are derived primarily from glucogenic amino acids and lactate from muscle and glycerol from adipose tissue. Gluconeogenesis, favored by activation of fructose 1,6-bisphosphatase (because of decreased availability of its inhibitor fructose 2,6-bisphosphate; see p. 121) and by induction of PEPCK by glucagon (see p. 122), begins 4–6 hours after the last meal and becomes fully active as stores of liver glycogen are depleted (see Fig. 24.11). [Note: The decrease in fructose 2,6-bisphosphate simultaneously inhibits glycolysis at PFK-1 (see p. 99).]


Biochemistry_Lippinco

Biochemistry_Lippinco. B. Fat metabolism 1. Increased fatty acid oxidation: The oxidation of FA obtained from TAG hydrolysis in adipose tissue is the major source of energy in hepatic tissue in the fasted state (see Fig. 24.12, ). The fall in malonyl CoA because of phosphorylation (inactivation) of ACC by AMPK removes the brake on CPT-I, allowing β-oxidation to occur (see p. 191). FA oxidation generates NADH, flavin adenine dinucleotide (FADH2), and acetyl CoA. The NADH inhibits the TCA cycle and shifts OAA to malate. This results in acetyl CoA being available for ketogenesis. The acetyl CoA is also an allosteric activator of PC and an allosteric inhibitor of PDH, thereby favoring use of pyruvate in gluconeogenesis (see Fig. 10.9, p. 122). [Note: Acetyl CoA cannot be used as a substrate for gluconeogenesis, in part because the PDH reaction is irreversible.] Oxidation of NADH and FADH2 coupled with oxidative phosphorylation supplies the energy required by the PC and PEPCK reactions of gluconeogenesis.


Biochemistry_Lippinco

Biochemistry_Lippinco. 2. Increased ketogenesis: The liver is unique in being able to synthesize and release ketone bodies, primarily 3-hydroxybutyrate but also acetoacetate, for use as fuel by peripheral tissues but not by the liver itself because liver lacks thiophorase (see p. 197). Ketogenesis, which starts during the first days of fasting (Fig. 24.13), is favored when the concentration of acetyl CoA from FA oxidation exceeds the oxidative capacity of the TCA cycle. [Note: Ketogenesis releases CoA, insuring its availability for continued FA oxidation.] The availability of circulating water-soluble ketone bodies is important in fasting because they can be used for fuel by most tissues, including the brain, once their blood level is high enough. Ketone body concentration in blood increases from ~50 µM to ~6 mM in fasting. This reduces the need for gluconeogenesis from amino acid carbon skeletons, thus preserving essential protein (see Fig. 24.11). Ketogenesis as part of the overall hepatic response to


Biochemistry_Lippinco

Biochemistry_Lippinco. mM in fasting. This reduces the need for gluconeogenesis from amino acid carbon skeletons, thus preserving essential protein (see Fig. 24.11). Ketogenesis as part of the overall hepatic response to fasting is shown in Figure 24.12, . [Note: Ketone bodies are organic acids and, when present at high concentrations, can cause ketoacidosis.]


Biochemistry_Lippinco

Biochemistry_Lippinco. IX. A. Glucose transport by insulin-sensitive GLUT-4 into the adipocyte and its subsequent metabolism are decreased because of low levels of circulating insulin. This results in decreased TAG synthesis. B. Fat metabolism 1. Increased fat degradation: The PKA-mediated phosphorylation and activation of HSL (see p. 189) and subsequent hydrolysis of stored fat (TAG) are enhanced by the elevated catecholamines norepinephrine and epinephrine. These hormones, which are secreted from the sympathetic nerve endings in adipose tissue and/or from the adrenal medulla, are physiologically important activators of HSL (Fig. 24.14, ). 2.


Biochemistry_Lippinco

Biochemistry_Lippinco. 2. Increased fatty acid release: FA obtained from hydrolysis of TAG stored in adipocytes are primarily released into the blood (see Fig. 24.14, ). Bound to albumin, they are transported to a variety of tissues for use as fuel. The glycerol produced from TAG degradation is used as a gluconeogenic precursor by the liver, which contains glycerol kinase. [Note: FA can also be oxidized to acetyl CoA, which can enter the TCA cycle, thereby producing energy for the adipocyte. They also can be reesterified to glycerol 3-phosphate (from glyceroneogenesis, see p. 190), generating TAG and reducing plasma FA concentration.] 3. Decreased fatty acid uptake: In fasting, LPL activity of adipose tissue is low. Consequently, FA in circulating TAG of lipoproteins are less available to adipose tissue than to muscle. X. RESTING SKELETAL MUSCLE IN FASTING


Biochemistry_Lippinco

Biochemistry_Lippinco. X. RESTING SKELETAL MUSCLE IN FASTING Resting muscle switches from glucose to FA as its major fuel source in fasting. [Note: By contrast, exercising muscle initially uses creatine phosphate and its glycogen stores. During intense exercise, glucose 6-phosphate from glycogenolysis is converted to lactate by anaerobic glycolysis (see p. 118). The lactate is used by the liver for gluconeogenesis (Cori cycle; see p. 118). As these glycogen reserves are depleted, free FA provided by the degradation of TAG in adipose tissue become the dominant energy source. The contraction-based rise in AMP activates AMPK that phosphorylates and inactivates the muscle isozyme of ACC, decreasing malonyl CoA and allowing FA oxidation (see p. 183).] A. Carbohydrate metabolism p. 97) and subsequent glucose metabolism are decreased because circulating insulin levels are low. Therefore, the glucose from hepatic gluconeogenesis is unavailable to muscle and adipose. B. Lipid metabolism


Biochemistry_Lippinco

Biochemistry_Lippinco. B. Lipid metabolism Early in fasting, muscle uses FA from adipose tissue and ketone bodies from the liver as fuels (Fig. 24.15, and ). In prolonged fasting, muscle decreases its use of ketone bodies (thus sparing them for the brain) and oxidizes FA almost exclusively. [Note: The acetyl CoA from FA oxidation indirectly inhibits PDH (by activation of PDH kinase) and spares pyruvate, which is transaminated to alanine and used by the liver for gluconeogenesis (glucose–alanine cycle; see p. 253).] C. Protein metabolism


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Protein metabolism During the first few days of fasting, there is a rapid breakdown of muscle protein (for example, glycolytic enzymes), providing amino acids that are used by the liver for gluconeogenesis (see Fig. 24.15, ). Because muscle does not have glucagon receptors, muscle proteolysis is initiated by a fall in insulin and sustained by a rise in glucocorticoids. [Note: Alanine and glutamine are quantitatively the most important glucogenic amino acids released from muscle. They are produced by the catabolism of BCAA (see p. 267). The glutamine is used as a fuel by enterocytes, for example, which send out alanine that is used in hepatic gluconeogenesis (glucose–alanine cycle)]. In the second week of fasting, the rate of muscle proteolysis decreases, paralleling a decline in the need for glucose as a fuel for the brain, which has begun using ketone bodies as a source of energy. XI. BRAIN IN FASTING


Biochemistry_Lippinco

Biochemistry_Lippinco. XI. BRAIN IN FASTING During the early days of fasting, the brain continues to use only glucose as a fuel (Fig. 24.16, ). Blood glucose is maintained by hepatic gluconeogenesis from glucogenic precursors, such as amino acids from proteolysis and glycerol from lipolysis. In prolonged fasting (beyond 2–3 weeks), plasma ketone bodies (see Fig. 24.12) reach significantly elevated levels and replace glucose as the primary fuel for the brain (see Figs. 24.16, and 24.17). This reduces the need for protein catabolism for gluconeogenesis: Ketone bodies spare glucose and, thus, muscle protein. [Note: As the duration of a fast extends from overnight to days to weeks, blood glucose levels initially drop and then are maintained at the lower level (65–70 mg/dl).] The metabolic changes that occur during fasting insure that all tissues have an adequate supply of fuel molecules. The response of the major tissues involved in energy metabolism during fasting is summarized in Figure 24.18.


Biochemistry_Lippinco

XII. KIDNEY IN LONG-TERM FASTING

Biochemistry_Lippinco. XII. KIDNEY IN LONG-TERM FASTING


Biochemistry_Lippinco

Biochemistry_Lippinco. As fasting continues into early starvation and beyond, the kidney plays important roles. The renal cortex expresses the enzymes of gluconeogenesis, including glucose 6-phosphatase, and, in late fasting, ~50% of gluconeogenesis occurs here. [Note: A portion of this glucose is used by the kidney itself.] The kidney also provides compensation for the acidosis that accompanies the increased production of ketone bodies (organic acids). The glutamine released from the muscle’s metabolism of BCAA is taken up by the kidney and acted upon by renal glutaminase and glutamate dehydrogenase (see p. 256), producing αketoglutarate, which can be used as a substrate for gluconeogenesis, plus ammonia (NH3). The NH3 picks up protons from ketone body dissociation and is excreted in the urine as ammonium (NH4+), thereby decreasing the acid load in the body (Fig. 24.19). Therefore, in long-term fasting, there is a switch from nitrogen disposal in the form of urea to disposal in the form of NH4 . [Note: As


Biochemistry_Lippinco

Biochemistry_Lippinco. thereby decreasing the acid load in the body (Fig. 24.19). Therefore, in long-term fasting, there is a switch from nitrogen disposal in the form of urea to disposal in the form of NH4 . [Note: As ketone body concentration rises, enterocytes, typically consumers of glutamine, become consumers of ketone bodies. This allows more glutamine to be available to the kidney.]


Biochemistry_Lippinco

XIII. CHAPTER SUMMARY

Biochemistry_Lippinco. XIII. CHAPTER SUMMARY


Biochemistry_Lippinco

Biochemistry_Lippinco. The flow of intermediates through metabolic pathways is controlled by four regulatory mechanisms: 1) the availability of substrates, 2) allosteric activation and inhibition of enzymes, 3) covalent modification of enzymes, and 4) induction-repression of enzyme synthesis. In the absorptive state, the 2-to 4-hour period after ingestion of a meal, these mechanisms insure that available nutrients are captured as glycogen, triacylglycerol (TAG), and protein (Fig. 24.20). During this interval, transient increases in plasma glucose, amino acids, and TAG occur, the last primarily as components of chylomicrons synthesized by the intestinal mucosal cells. The pancreas responds to the elevated levels of glucose with an increased secretion of insulin and a decreased secretion of glucagon. The elevated insulin/glucagon ratio and the ready availability of circulating substrates make the absorptive state an anabolic period during which virtually all tissues use glucose as a fuel. In addition, the


Biochemistry_Lippinco

Biochemistry_Lippinco. insulin/glucagon ratio and the ready availability of circulating substrates make the absorptive state an anabolic period during which virtually all tissues use glucose as a fuel. In addition, the liver replenishes its glycogen stores, replaces any needed hepatic proteins, and increases TAG synthesis. The latter are packaged in very-low-density lipoproteins, which are exported to the peripheral tissues. Adipose tissue increases TAG synthesis and storage, whereas muscle increases protein synthesis to replace protein degraded since the previous meal. In the fed state, the brain uses glucose exclusively as a fuel. In fasting, plasma levels of glucose, amino acids, and TAG fall, triggering a decline in insulin secretion and an increase in glucagon and epinephrine secretion. The decreased insulin/counterregulatory hormone ratio and the decreased availability of circulating substrates make the fasting state a catabolic period. This sets into motion an exchange of substrates among the liver,


Biochemistry_Lippinco

Biochemistry_Lippinco. hormone ratio and the decreased availability of circulating substrates make the fasting state a catabolic period. This sets into motion an exchange of substrates among the liver, adipose tissue, skeletal muscle, and brain that is guided by two priorities: 1) the need to maintain adequate plasma levels of glucose to sustain energy metabolism of the brain and other glucose-requiring tissues and 2) the need to mobilize fatty acids (FA) from adipose tissue and release ketone bodies from liver to supply energy to other tissues. To accomplish these goals, the liver degrades glycogen and initiates gluconeogenesis, using increased FA oxidation to supply the energy and reducing equivalents needed for gluconeogenesis and the acetyl coenzyme A building blocks for ketogenesis. The adipose tissue degrades stored TAG, thus providing FA and glycerol to the liver. The muscle can also use FA as fuel as well as ketone bodies supplied by the liver. The liver uses the glycerol for gluconeogenesis. Muscle


Biochemistry_Lippinco

Biochemistry_Lippinco. stored TAG, thus providing FA and glycerol to the liver. The muscle can also use FA as fuel as well as ketone bodies supplied by the liver. The liver uses the glycerol for gluconeogenesis. Muscle protein is degraded to supply amino acids for the liver to use in gluconeogenesis but decreases as ketone bodies increase. The brain can use both glucose and ketone bodies as fuels. From late fasting into starvation, the kidneys play important roles by synthesizing glucose and excreting the protons from ketone body dissociation as ammonium (NH4+).


Biochemistry_Lippinco

Biochemistry_Lippinco. Choose the ONE best answer. 4.1. Which one of the following is elevated in plasma during the absorptive (well-fed) state as compared with the postabsorptive (fasted) state? A. Acetoacetate B. Chylomicrons C. Free fatty acids D. Glucagon Correct answer = B. Triacylglycerol-rich chylomicrons are synthesized in (and released from) the intestine following ingestion of a meal. Acetoacetate, free fatty acids, and glucagon are elevated in the fasted state, not the absorptive state. 4.2. Which one of the following statements concerning liver in the absorptive state is correct? A. Fructose 2,6-bisphosphate is elevated. B. Insulin stimulates the uptake of glucose. C. Most enzymes that are regulated by covalent modification are in the phosphorylated state. D. The oxidation of acetyl coenzyme A is increased. E. The synthesis of glucokinase is repressed.


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Most enzymes that are regulated by covalent modification are in the phosphorylated state. D. The oxidation of acetyl coenzyme A is increased. E. The synthesis of glucokinase is repressed. Correct answer = A. The increased insulin and decreased glucagon levels characteristic of the absorptive state promote the synthesis of fructose 2,6bisphosphate, which allosterically activates phosphofructokinase-1 of glycolysis. Most covalently modified enzymes are in the dephosphorylated state and are active. Acetyl coenzyme A is not oxidized in the well-fed state because it is being used in fatty acid synthesis. Uptake of glucose (by glucose transporter-2) into the liver is insulin independent. Synthesis of glucokinase is induced by insulin in the well-fed state. 4.3. Which one of the following enzymes is phosphorylated and active in an individual who has been fasting for 12 hours? A. Arginase B. Carnitine palmitoyltransferase-I C. Fatty acid synthase D. Glycogen synthase


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Arginase B. Carnitine palmitoyltransferase-I C. Fatty acid synthase D. Glycogen synthase E. Hormone-sensitive lipase F. Phosphofructokinase-1 G. Pyruvate dehydrogenase Correct answer = E. Hormone-sensitive lipase of adipocytes is phosphorylated and activated by protein kinase A in response to epinephrine. Choices A, B, C, and F are not regulated covalently. Choices D and G are regulated covalently but are inactive if phosphorylated. 4.4. For a 70-kg man, in which one of the periods listed below do ketone bodies supply the major portion of the caloric needs of brain? A. Absorptive period B. Overnight fast C. Three-day fast D. Four-week fast E. Five-month fast


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Absorptive period B. Overnight fast C. Three-day fast D. Four-week fast E. Five-month fast Correct answer = D. Ketone bodies, made from the acetyl coenzyme A product of fatty acid oxidation, increase in the blood in fasting but must reach a critical level to cross the blood–brain barrier. Typically, this occurs in the second to third week of a fast. Fat stores in a 70-kg (~154-lb) man would not be able to supply his energy needs for 5 months. 24.5. The diagram below shows inputs to and outputs from pyruvate, a central molecule in energy metabolism. Which letter on the diagram represents a reaction that requires biotin and is activated by acetyl coenzyme A?


Biochemistry_Lippinco

Biochemistry_Lippinco. Which letter on the diagram represents a reaction that requires biotin and is activated by acetyl coenzyme A? Correct answer = C. Pyruvate carboxylase, a mitochondrial enzyme of gluconeogenesis, requires biotin (and ATP) and is allosterically activated by acetyl coenzyme A from fatty acid oxidation. None of the other choices meets these criteria. A = pyruvate kinase; B = pyruvate dehydrogenase complex; D = aspartate aminotransferase; E = alanine aminotransferase; F = lactate dehydrogenase. For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW


Biochemistry_Lippinco

Biochemistry_Lippinco. I. OVERVIEW Diabetes mellitus (diabetes) is not one disease but rather is a heterogeneous group of multifactorial, primarily polygenic syndromes characterized by an elevated fasting blood glucose (FBG) caused by a relative or absolute deficiency in insulin. Over 29 million people in the United States (~9% of the population) have diabetes. Of this number, ~8 million are as yet undiagnosed. Diabetes is the leading cause of adult blindness and amputation and a major cause of renal failure, nerve damage, heart attacks, and strokes. Most cases of diabetes mellitus can be separated into two groups (Fig. 25.1), type 1 ([T1D] formerly called insulin-dependent diabetes mellitus) and type 2 ([T2D] formerly called non– insulin-dependent diabetes mellitus). The incidence and prevalence of T2D is increasing because of the aging of the U.S. population and the increasing prevalence of obesity and sedentary lifestyles (see p. 349). The increase in children with T2D is particularly disturbing.


Biochemistry_Lippinco

II. TYPE 1

Biochemistry_Lippinco. II. TYPE 1


Biochemistry_Lippinco

Biochemistry_Lippinco. T1D constitutes <10% of the ~21 million known cases of diabetes in the United States. The disease is characterized by an absolute deficiency of insulin caused by an autoimmune attack on the islet β cells of the pancreas. In T1D, the islets of Langerhans become infiltrated with activated T lymphocytes, leading to a condition called insulitis. Over a period of years, this autoimmune attack on the β cells leads to gradual depletion of the β-cell population (Fig. 25.2). However, symptoms appear abruptly when 80%–90% of the β cells have been destroyed. At this point, the pancreas fails to respond adequately to ingestion of glucose, and insulin therapy is required to restore metabolic control and prevent life-threatening ketoacidosis. β-Cell destruction requires both a stimulus from the environment (such as a viral infection) and a genetic determinant that causes the β cells to be mistakenly identified as “nonself.” [Note: Among monozygotic (identical) twins, if one sibling develops T1D,


Biochemistry_Lippinco

Biochemistry_Lippinco. (such as a viral infection) and a genetic determinant that causes the β cells to be mistakenly identified as “nonself.” [Note: Among monozygotic (identical) twins, if one sibling develops T1D, the other twin has only a 30%– 50% chance of developing the disease. This contrasts with T2D (see p. 341), in which the genetic influence is stronger and, in virtually all monozygotic twinships, the disease eventually develops in both individuals.]


Biochemistry_Lippinco

A. Diagnosis

Biochemistry_Lippinco. A. Diagnosis


Biochemistry_Lippinco

Biochemistry_Lippinco. The onset of T1D is typically during childhood or puberty, and symptoms develop suddenly. Individuals with T1D can usually be recognized by the abrupt appearance of polyuria (frequent urination), polydipsia (excessive thirst), and polyphagia (excessive hunger), often triggered by physiologic stress such as an infection. These symptoms are usually accompanied by fatigue and weight loss. The diagnosis is confirmed by a FBG ≥126 mg/dl (normal is 70–99). [Note: Fasting is defined as no caloric intake for at least 8 hours.] A FBG of 100–125 mg/dl is categorized as an impaired FBG. Individuals with impaired FBG are considered prediabetic and are at increased risk for developing T2D. Diagnosis can also be made on the basis of a nonfasting (random) blood glucose level >200 mg/dl or a glycated hemoglobin (see p. 340) concentration ≥6.5 mg/dl (normal is <5.7) in an individual with symptoms of hyperglycemia. [Note: The oral glucose tolerance test, in which blood glucose is measured 2 hours after


Biochemistry_Lippinco

Biochemistry_Lippinco. (see p. 340) concentration ≥6.5 mg/dl (normal is <5.7) in an individual with symptoms of hyperglycemia. [Note: The oral glucose tolerance test, in which blood glucose is measured 2 hours after ingestion of a solution containing 75 g of glucose, also is used but is less convenient. It is most typically used to screen pregnant women for gestational diabetes (see p. 342).]


Biochemistry_Lippinco

Biochemistry_Lippinco. When blood glucose is >180 mg/dl, the ability of renal sodium-dependent glucose transporters (SGLT) to reclaim glucose is impaired, and glucose “spills” into urine. The loss of glucose is accompanied by the loss of water, resulting in the characteristic polyuria (with dehydration) and polydipsia of diabetes. B. Metabolic changes The metabolic abnormalities of T1D result from a deficiency of insulin that profoundly affects metabolism in three tissues: liver, skeletal muscle, and white adipose (Fig. 25.3). 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. Hyperglycemia and ketonemia: Elevated levels of blood glucose and ketone bodies are the hallmarks of untreated T1D (see Fig. 25.3). Hyperglycemia is caused by increased hepatic production of glucose via gluconeogenesis, combined with diminished peripheral utilization (muscle and adipose tissue have the insulin-regulated glucose transporter GLUT-4; see p. 97). Ketonemia results from increased mobilization of fatty acids (FA) from triacylglycerol (TAG) in adipose tissue, combined with accelerated hepatic FA β-oxidation and synthesis of 3hydroxybutyrate and acetoacetate (ketone bodies; see p. 196). [Note: Acetyl coenzyme A from β-oxidation is the substrate for ketogenesis and the allosteric activator of pyruvate carboxylase, a gluconeogenic enzyme.] Diabetic ketoacidosis (DKA), a type of metabolic acidosis caused by an imbalance between ketone body production and use, occurs in 25%–40% of those newly diagnosed with T1D and may recur if the patient becomes ill (most commonly with an


Biochemistry_Lippinco

Biochemistry_Lippinco. metabolic acidosis caused by an imbalance between ketone body production and use, occurs in 25%–40% of those newly diagnosed with T1D and may recur if the patient becomes ill (most commonly with an infection) or does not comply with therapy. DKA is treated by replacing fluid and electrolytes and administering short-acting insulin to gradually correct hyperglycemia without precipitating hypoglycemia.


Biochemistry_Lippinco

Biochemistry_Lippinco. 2. Hypertriacylglycerolemia: Not all of the FA flooding the liver can be disposed of through oxidation and ketone body synthesis. These excess FA are converted to TAG, which are packaged and secreted in very-lowdensity lipoproteins ([VLDL] see p. 230). Chylomicrons rich in dietary TAG are secreted by the intestinal mucosal cells following a meal (see p. 227). Because lipoprotein TAG degradation catalyzed by lipoprotein lipase in the capillary beds of adipose tissue (see p. 228) is low in diabetes (synthesis of the enzyme is decreased when insulin levels are low), the plasma chylomicron and VLDL levels are elevated, resulting in hypertriacylglycerolemia (see Fig. 25.3). C. Treatment


Biochemistry_Lippinco

Biochemistry_Lippinco. Individuals with T1D must rely on exogenous insulin delivered subcutaneously (subq) either by periodic injection or by continuous pump-assisted infusion to control the hyperglycemia and ketonemia. Two types of therapeutic injection regimens are currently used, standard and intensive. [Note: Pump delivery is also considered intensive therapy.] 1. Standard versus intensive treatment: Standard treatment is typically two to three daily injections of recombinant human insulin. Mean blood glucose levels obtained are typically 225–275 mg/dl, with a glycated hemoglobin (HbA1c) level (see p. 33) of 8%–9% of the total hemoglobin (blue arrow in Fig. 25.4). [Note: The rate of formation of HbA1c is proportional to the average blood glucose concentration over the previous 3 months. Thus, HbA1c provides a measure of how well treatment has normalized blood glucose over that time in a patient with diabetes.] In contrast to standard therapy, intensive treatment seeks to more closely normalize blood


Biochemistry_Lippinco

Biochemistry_Lippinco. a measure of how well treatment has normalized blood glucose over that time in a patient with diabetes.] In contrast to standard therapy, intensive treatment seeks to more closely normalize blood glucose through more frequent monitoring and subsequent injections of insulin, typically ≥4 times a day. Mean blood glucose levels of 150 mg/dl can be achieved, with HbA1c ~7% of the total hemoglobin (see red arrow in Fig. 25.4). [Note: Normal mean blood glucose is ~100 mg/dl, and HbA1c is ≤6% (see black arrow in Fig. 25.4).] Therefore, normalization of glucose values (euglycemia) is not achieved even in intensively treated patients. Nonetheless, patients on intensive therapy show a ≥50% reduction in the long-term microvascular complications of diabetes (that is, retinopathy, nephropathy, and neuropathy) compared with patients receiving standard care. This confirms that the complications of diabetes are related to an elevation of plasma glucose.


Biochemistry_Lippinco

Biochemistry_Lippinco. therapy. [Note: Nondiabetic individuals are included for comparison.] 2. Hypoglycemia: One of the therapeutic goals in cases of diabetes is to decrease blood glucose levels in an effort to minimize the development of long-term complications of the disease (see p. 345 for a discussion of the chronic complications of diabetes). However, appropriate dosage of insulin is difficult to achieve. Hypoglycemia caused by excess insulin is the most common complication of insulin therapy, occurring in >90% of patients. The frequency of hypoglycemic episodes, seizures, and coma is particularly high with intensive treatment regimens designed to achieve tight control of blood glucose (Fig. 25.5). In normal individuals, hypoglycemia triggers a compensatory secretion of counterregulatory hormones, most notably glucagon and epinephrine, which promote hepatic production of glucose (see p. 315). However, patients with T1D also develop a deficiency of glucagon secretion. This defect occurs early in the


Biochemistry_Lippinco

Biochemistry_Lippinco. notably glucagon and epinephrine, which promote hepatic production of glucose (see p. 315). However, patients with T1D also develop a deficiency of glucagon secretion. This defect occurs early in the disease and is almost universally present 4 years after diagnosis. Therefore, these patients rely on epinephrine secretion to prevent severe hypoglycemia. However, as the disease progresses, T1D patients show diabetic autonomic neuropathy and impaired ability to secrete epinephrine in response to hypoglycemia. The combined deficiency of glucagon and epinephrine secretion creates a symptom-free condition sometimes called “hypoglycemia unawareness.” Thus, patients with long-standing T1D are particularly vulnerable to hypoglycemia. Hypoglycemia can also be caused by strenuous exercise. Because exercise promotes glucose uptake into muscle and decreases the need for exogenous insulin, patients are advised to check blood glucose levels before or after intensive exercise to prevent or abort


Biochemistry_Lippinco

Biochemistry_Lippinco. exercise promotes glucose uptake into muscle and decreases the need for exogenous insulin, patients are advised to check blood glucose levels before or after intensive exercise to prevent or abort hypoglycemia.


Biochemistry_Lippinco

Biochemistry_Lippinco. 3. Contraindications for tight control: Children are not put on a program of tight control of blood glucose before age 8 years because of the risk that episodes of hypoglycemia may adversely affect brain development. Elderly people typically do not go on tight control because hypoglycemia can cause strokes and heart attacks in this population. Also, the major goal of tight control is to prevent complications many years later. Tight control, then, is most worthwhile for otherwise healthy people who can expect to live at least 10 more years. [Note: For most nonpregnant adults with diabetes, the individual treatment strategies and goals are based on the duration of diabetes, age/life expectancy, and known comorbid conditions.] III. TYPE 2


Biochemistry_Lippinco

Biochemistry_Lippinco. III. TYPE 2 T2D is the most common form of the disease, afflicting >90% of the U.S. population with diabetes. [Note: American Indians, Alaskan Natives, Hispanic and Latino Americans, African Americans, and Asian Americans have the highest prevalence.] Typically, T2D develops gradually without obvious symptoms. The disease is often detected by routine screening tests. However, many individuals with T2D have symptoms of polyuria and polydipsia of several weeks’ duration. Polyphagia may be present but is less common. Patients with T2D have a combination of insulin resistance and dysfunctional β cells (Fig.


Biochemistry_Lippinco

Biochemistry_Lippinco. 25.6) but do not require insulin to sustain life. However, in >90% of these patients, insulin eventually will be required to control hyperglycemia and keep HbA1c <7%. The metabolic alterations observed in T2D are milder than those described for type 1, in part because insulin secretion in T2D, although inadequate, does restrain ketogenesis and blunts the development of DKA. [Note: Insulin suppresses the release of glucagon (see p. 314).] Diagnosis is based on the presence of hyperglycemia as described above. The pathogenesis does not involve viruses or autoimmune antibodies and is not completely understood. [Note: An acute complication of T2D in the elderly is a hyperosmolar hyperglycemic state characterized by severe hyperglycemia and dehydration and altered mental status.]


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Biochemistry_Lippinco. T2D is characterized by hyperglycemia, insulin resistance, impaired insulin secretion, and, ultimately, β-cell failure. The eventual need for insulin therapy has eliminated the designation of T2D as non–insulin-dependent diabetes. A. Insulin resistance Insulin resistance is the decreased ability of target tissues, such as the liver, white adipose, and skeletal muscle, to respond properly to normal (or elevated) circulating concentrations of insulin. For example, insulin resistance is characterized by increased hepatic glucose production, decreased glucose uptake by muscle and adipose tissue, and increased adipose lipolysis with production of free fatty acids (FFA).


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Biochemistry_Lippinco. 1. Insulin resistance and obesity: Although obesity is the most common cause of insulin resistance and increases the risk of T2D, most people with obesity and insulin resistance do not develop diabetes. In the absence of a defect in β-cell function, obese individuals can compensate for insulin resistance with elevated levels of insulin. For example, Figure 25.7A shows that insulin secretion is two to three times higher in obese subjects than it is in lean individuals. This higher insulin concentration compensates for the diminished effect of the hormone (as a result of insulin resistance) and produces blood glucose levels similar to those observed in lean individuals (Fig. 25.7B). 2.


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Biochemistry_Lippinco. 2. Insulin resistance and type 2 diabetes: Insulin resistance alone will not lead to T2D. Rather, T2D develops in insulin-resistant individuals who also show impaired β-cell function. Insulin resistance and subsequent risk for the development of T2D is commonly observed in individuals who are obese, physically inactive, or elderly and in the 3%–5% of pregnant women who develop gestational diabetes. These patients are unable to sufficiently compensate for insulin resistance with increased insulin release. Figure 25.8 shows the time course for the development of hyperglycemia and the loss of β-cell function. 3.


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Biochemistry_Lippinco. Causes of insulin resistance: Insulin resistance increases with weight gain and decreases with weight loss, and excess adipose tissue (particularly in the abdomen) is key in the development of insulin resistance. Adipose is not simply an energy storage tissue, but also a secretory tissue. With obesity, there are changes in adipose secretions that result in insulin resistance (Fig. 25.9). These include secretion of proinflammatory cytokines such as interleukin 6 and tumor necrosis factor-α by activated macrophages (inflammation is associated with insulin resistance); increased synthesis of leptin, a protein with proinflammatory effects (see p. 353 for additional effects of leptin); and decreased secretion of adiponectin (see p. 350), a protein with anti-inflammatory effects. The net result is chronic, low-grade inflammation. One effect of insulin resistance is increased lipolysis and production of FFA (see Fig. 25.9). FFA availability decreases use of glucose, contributing to


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Biochemistry_Lippinco. result is chronic, low-grade inflammation. One effect of insulin resistance is increased lipolysis and production of FFA (see Fig. 25.9). FFA availability decreases use of glucose, contributing to hyperglycemia, and increases ectopic deposition of TAG in liver (hepatic steatosis). [Note: Steatosis results in nonalcoholic fatty liver disease (NAFLD). If accompanied by inflammation, a more serious condition, nonalcoholic steatohepatitis (NASH), can develop.] FFA also have a proinflammatory effect. In the long term, FFA impair insulin signaling. [Note: Adiponectin increases FA β-oxidation (see p. 349). Consequently, a decrease in this adipocyte protein contributes to FFA availability.]


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Biochemistry_Lippinco. B. Dysfunctional β cells In T2D, the pancreas initially retains β-cell capacity, resulting in insulin levels that vary from above normal to below normal. However, with time, the β cell becomes increasingly dysfunctional and fails to secrete enough insulin to correct the prevailing hyperglycemia. For example, insulin levels are high in typical, obese, T2D patients but not as high as in similarly obese individuals who do not have diabetes. Thus, the natural progression of the disease results in a declining ability to control hyperglycemia with endogenous secretion of insulin (Fig. 25.10). Deterioration of β-cell function may be accelerated by the toxic effects of sustained hyperglycemia and elevated FFA and a proinflammatory environment. C. Metabolic changes The abnormalities of glucose and TAG metabolism in T2D are the result of insulin resistance expressed primarily in liver, skeletal muscle, and white adipose tissue (Fig. 25.11). 1.


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Biochemistry_Lippinco. The abnormalities of glucose and TAG metabolism in T2D are the result of insulin resistance expressed primarily in liver, skeletal muscle, and white adipose tissue (Fig. 25.11). 1. Hyperglycemia: Hyperglycemia is caused by increased hepatic production of glucose, combined with diminished use of glucose by muscle and adipose tissues. Ketonemia is usually minimal or absent in patients with T2D because the presence of insulin, even in the presence of insulin resistance, restrains hepatic ketogenesis. 2.


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Biochemistry_Lippinco. 2. Dyslipidemia: In the liver, FFA are converted to TAG, which are packaged and secreted in VLDL. Dietary TAG–rich chylomicrons are synthesized and secreted by the intestinal mucosal cells following a meal. Because lipoprotein TAG degradation catalyzed by lipoprotein lipase in adipose tissue is low in diabetes, the plasma chylomicron and VLDL levels are elevated, resulting in hypertriacylglycerolemia (see Fig. 25.10). Low levels of high-density lipoproteins are also associated with T2D, likely as a result of increased degradation. D. Treatment


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Biochemistry_Lippinco. D. Treatment The goal in treating T2D is to maintain blood glucose concentrations within normal limits and to prevent the development of long-term complications. Weight reduction, exercise, and medical nutrition therapy (dietary modifications) often correct the hyperglycemia of newly diagnosed T2D. Oral hypoglycemic agents, such as metformin (decreases hepatic gluconeogenesis), sulfonylureas (increase insulin secretion; see p. 310), thiazolidinediones (decrease FFA levels and increase peripheral insulin sensitivity), α-glucosidase inhibitors (decrease absorption of dietary carbohydrate), and SGLT inhibitors (decrease renal reabsorption of glucose), or subq insulin therapy may be required to achieve satisfactory plasma glucose levels. [Note: Bariatric surgery in morbidly obese individuals with T2D has been shown to result in disease remission in most patients. Remission may not be permanent.] IV. CHRONIC EFFECTS AND PREVENTION


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Biochemistry_Lippinco. As noted previously, available therapies moderate the hyperglycemia of diabetes but fail to completely normalize metabolism. The long-standing elevation of blood glucose is associated with the chronic vascular complications of diabetes including cardiovascular disease (CVD) and stroke (macrovascular complications) as well as retinopathy, nephropathy, and neuropathy (microvascular). Intensive insulin treatment (see p. 340) delays the onset and slows the progression of some long-term complications. For example, the incidence of retinopathy decreases as control of blood glucose improves and HbA1c levels decrease (Fig. 25.12). [Note: Data concerning the effect of tight control on CVD in T2D are less clear.] The benefits of tight control of blood glucose outweigh the increased risk of severe hypoglycemia in most patients. How hyperglycemia causes the chronic complications of diabetes is unclear. In cells in which glucose uptake is not dependent on insulin, elevated blood glucose leads to


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Biochemistry_Lippinco. hypoglycemia in most patients. How hyperglycemia causes the chronic complications of diabetes is unclear. In cells in which glucose uptake is not dependent on insulin, elevated blood glucose leads to increased intracellular glucose and its metabolites. For example, increased intracellular sorbitol contributes to cataract formation (see p. 140) in diabetes. Additionally, hyperglycemia promotes glycation of cellular proteins in a reaction analogous to the formation of HbA1c. These glycated proteins undergo additional reactions and become advanced glycation end products (AGE) that mediate some of the early microvascular changes of diabetes and can reduce wound healing. Some AGE bind to a membrane receptor (RAGE), causing the release of proinflammatory molecules. There is currently no preventative treatment for T1D. The risk for T2D can be significantly decreased by a combined regimen of medical nutrition therapy, weight loss, exercise, and aggressive control of hypertension and


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Biochemistry_Lippinco. preventative treatment for T1D. The risk for T2D can be significantly decreased by a combined regimen of medical nutrition therapy, weight loss, exercise, and aggressive control of hypertension and dyslipidemias. For example, Figure 25.13 shows the incidence of disease in normal and overweight individuals with varying degrees of exercise.


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V. CHAPTER SUMMARY

Biochemistry_Lippinco. V. CHAPTER SUMMARY


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Biochemistry_Lippinco. Diabetes mellitus is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose that is caused by a relative or absolute deficiency of insulin (Fig. 25.14). Diabetes is the leading cause of adult blindness and amputation and a major cause of renal failure, nerve damage, heart attacks, and stroke. Diabetes can be classified into two groups, type 1 (T1D) and type 2 (T2D). T1D constitutes ~10% of >29 million cases of diabetes in the United States. The disease is characterized by an absolute deficiency of insulin caused by an autoimmune attack on the pancreatic β cells. This destruction requires an environmental stimulus (such as a viral infection) and a genetic determinant that causes the β cell to be mistakenly identified as “nonself.” The metabolic abnormalities of T1D include hyperglycemia, diabetic ketoacidosis (DKA), and hypertriacylglycerolemia that result from a deficiency of insulin. Those with T1D must rely on exogenous insulin delivered


Biochemistry_Lippinco

Biochemistry_Lippinco. abnormalities of T1D include hyperglycemia, diabetic ketoacidosis (DKA), and hypertriacylglycerolemia that result from a deficiency of insulin. Those with T1D must rely on exogenous insulin delivered subcutaneously to control hyperglycemia and ketoacidosis. T2D has a strong genetic component. It results from a combination of insulin resistance and dysfunctional β cells. Insulin resistance is the decreased ability of target tissues, such as liver, white adipose, and skeletal muscle, to respond properly to normal (or elevated) circulating concentrations of insulin. Obesity is the most common cause of insulin resistance. However, most people with obesity and insulin resistance do not develop diabetes. In the absence of a defect in β-cell function, obese individuals without diabetes can compensate for insulin resistance with elevated levels of insulin. Insulin resistance alone will not lead to T2D. Rather, T2D develops in insulin-resistant individuals who also show impaired β-cell


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Biochemistry_Lippinco. compensate for insulin resistance with elevated levels of insulin. Insulin resistance alone will not lead to T2D. Rather, T2D develops in insulin-resistant individuals who also show impaired β-cell function. The acute metabolic alterations observed in T2D are milder than those described for the insulin-dependent form of the disease, in part because insulin secretion in T2D, although inadequate, does restrain ketogenesis and blunts the development of DKA. Available treatments for diabetes moderate the hyperglycemia but fail to completely normalize metabolism. The long-standing elevation of blood glucose is associated with the chronic complications of diabetes including cardiovascular disease and stroke (macrovascular) as well as retinopathy, nephropathy, and neuropathy (microvascular).


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Biochemistry_Lippinco. Choose the ONE best answer. 5.1. Three patients being evaluated for gestational diabetes are given an oral glucose tolerance test. Based on the data shown below, which patient is prediabetic? A. Patient #1 B. Patient #2 C. Patient #3 D. None Correct answer = B. Patient #2 has a normal fasting blood glucose (FBG) but an impaired glucose tolerance (GT) as reflected in her blood glucose level at 2 hours and, so, is described as prediabetic. Patient #1 has a normal FBG and GT, whereas patient #3 has diabetes. 5.2. Relative or absolute lack of insulin in humans would result in which one of the following reactions in the liver? A. Decreased activity of hormone-sensitive lipase B. Decreased gluconeogenesis from lactate C. Decreased glycogenolysis D. Increased formation of 3-hydroxybutyrate E. Increased glycogenesis


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Biochemistry_Lippinco. A. Decreased activity of hormone-sensitive lipase B. Decreased gluconeogenesis from lactate C. Decreased glycogenolysis D. Increased formation of 3-hydroxybutyrate E. Increased glycogenesis Correct answer = D. Low insulin levels favor the liver producing ketone bodies, using acetyl coenzyme A generated by β-oxidation of the fatty acids provided by hormone-sensitive lipase (HSL) in adipose tissue (not liver). Low insulin also causes activation of HSL, decreased glycogen synthesis, and increased gluconeogenesis and glycogenolysis. 5.3. Which one of the following is characteristic of untreated diabetes regardless of the type? A. Hyperglycemia B. Ketoacidosis C. Low levels of hemoglobin A1c D. Normal levels of C-peptide E. Obesity F. Simple inheritance pattern


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Biochemistry_Lippinco. A. Hyperglycemia B. Ketoacidosis C. Low levels of hemoglobin A1c D. Normal levels of C-peptide E. Obesity F. Simple inheritance pattern Correct answer = A. Elevated blood glucose occurs in type 1 diabetes (T1D) as a result of a lack of insulin. In type 2 diabetes (T2D), hyperglycemia is due to a defect in β-cell function and insulin resistance. The hyperglycemia results in elevated hemoglobin A1c levels. Ketoacidosis is rare in T2D, whereas obesity is rare in T1D. C (connecting)-peptide is a measure of insulin synthesis. It would be virtually absent in T1D and initially increased then decreased in T2D. Both forms of the disease show complex genetics. 5.4. An obese individual with type 2 diabetes typically: A. benefits from receiving insulin about 6 hours after a meal. B. has a lower plasma level of glucagon than does a normal individual. C. has a lower plasma level of insulin than does a normal individual early in the disease process.


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Biochemistry_Lippinco. B. has a lower plasma level of glucagon than does a normal individual. C. has a lower plasma level of insulin than does a normal individual early in the disease process. D. shows improvement in glucose tolerance if body weight is reduced. E. shows sudden onset of symptoms. Correct answer = D. Many individuals with type 2 diabetes are obese, and almost all show some improvement in blood glucose with weight reduction. Symptoms usually develop gradually. These patients have elevated insulin levels and usually do not require insulin (certainly not 6 hours after a meal) until late in the disease. Glucagon levels are typically normal. For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW


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Biochemistry_Lippinco. Obesity is a disorder of body weight regulatory systems characterized by an accumulation of excess body fat. In primitive societies, in which daily life required a high level of physical activity and food was only available intermittently, a genetic tendency favoring storage of excess calories as fat may have had a survival value. Today, however, the sedentary lifestyle and abundance and wide variety of palatable, inexpensive foods in industrialized societies has undoubtedly contributed to an obesity epidemic. As adiposity has increased, so has the risk of developing associated diseases, such as type 2 diabetes (T2D), cardiovascular disease (CVD), hypertension, cancer, and arthritis. Particularly alarming is the explosion of obesity in children and adolescents, which has shown a threefold increase in prevalence over the last four decades. [Note: Approximately 17% of those age 2–19 years are obese.] In the United States, the lifetime risk of becoming overweight or obese is ~50% and


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Biochemistry_Lippinco. increase in prevalence over the last four decades. [Note: Approximately 17% of those age 2–19 years are obese.] In the United States, the lifetime risk of becoming overweight or obese is ~50% and 25%, respectively. Obesity has increased globally, and, by some estimates, there are more obese than undernourished individuals worldwide.


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Biochemistry_Lippinco. II. ASSESSMENT Because the amount of body fat is difficult to measure directly, it is usually determined from an indirect measure, the body mass index (BMI), which has been shown to correlate with the amount of body fat in most individuals. [Note: Exceptions are athletes who have large amounts of lean muscle mass.] Measuring the waist size with a tape measure is also used to screen for obesity, because this measurement reflects the amount of fat in the central abdominal area of the body. The presence of excess central fat is associated with an increased risk for morbidity and mortality, independent of the BMI. [Note: A waist size ≥40 in (men) and ≥35 in (women) is considered a risk factor.] A. Body mass index


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Body mass index The BMI (defined as weight in kg/[height in m]2) provides a measure of relative weight, adjusted for height. This allows comparisons within and between populations. The healthy range for the BMI is between 18.5 and 24.9. Individuals with a BMI between 25 and 29.9 are considered overweight, those with a BMI ≥30 are defined as obese, and a BMI >40 is considered severely (morbidly) obese (Fig. 26.1). These cutoffs are based on studies examining the relationship of BMI to premature death and are similar in men and women. Nearly two thirds of U.S. adults are overweight, and more than one third of those are obese. Children with a BMI-for-age above the 95th percentile are considered obese. B. Anatomic differences in fat deposition


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Biochemistry_Lippinco. B. Anatomic differences in fat deposition The anatomic distribution of body fat has a major influence on associated health risks. A waist/hip ratio (WHR) >0.8 for women and >1.0 for men is defined as android, apple-shaped, or upper-body obesity and is associated with more fat deposition in the trunk (Fig. 26.2A). In contrast, a lower WHR reflects a preponderance of fat distributed in the hips and thighs and is called gynoid, pear-shaped, or lower-body obesity. It is defined as a WHR of <0.8 for women and <1.0 for men. The pear shape, more commonly found in women, presents a much lower risk of metabolic disease, and some studies indicate that it may actually be protective. Thus, the clinician can use simple indices of body shape to identify those who may be at higher risk for metabolic diseases associated with obesity.


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Biochemistry_Lippinco. About 80%–90% of human body fat is stored in subcutaneous (subq) depots in the abdominal (upper body) and the gluteal-femoral (lower body) regions. The remaining 10%–20% is in visceral depots located deep within the abdominal cavity (Fig. 26.2B). Excess fat in visceral and abdominal subq stores increases health risks associated with obesity. C. Biochemical differences in regional fat depots


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Biochemistry_Lippinco. C. Biochemical differences in regional fat depots The regional types of fat described above are biochemically different. Subq adipocytes from the lower body, particularly in women, are larger, very efficient at fat (triacylglycerol [TAG]) deposition, and tend to mobilize fatty acids (FA) more slowly than subq adipocytes from the upper body. Visceral adipocytes are the most metabolically active. In obese individuals, both abdominal subcutaneous and visceral depots have high rates of lipolysis and contribute to increased availability of free fatty acids (FFA). These metabolic differences may contribute to the higher health risk found in individuals with upper body (abdominal) obesity. [Note: FFA impair insulin signaling and are proinflammatory (see p. 343).] 1.


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Biochemistry_Lippinco. Endocrine function: White adipose tissue, once thought to be a passive reservoir of TAG, is now known to play an active role in body weight regulatory systems. For example, the adipocyte is an endocrine cell that secretes a number of protein regulators (adipokines), such as the hormones leptin and adiponectin. Leptin regulates appetite as well as metabolism (see p. 352). Adiponectin reduces FFA levels in the blood (by increasing FA oxidation in muscles) and has been associated with improved lipid profiles, increased insulin sensitivity resulting in better glycemic control, and reduced inflammation in patients with diabetes. [Note: Adiponectin levels decrease as body weight increases, whereas leptin levels increase.] 2.


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Biochemistry_Lippinco. Importance of portal circulation: With obesity, there is increased release of FFA and secretion of proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), from adipose tissue. [Note: Cytokines are small proteins that regulate the immune system.] One hypothesis for why abdominal adipose depots have such a large influence on metabolic dysfunction in obesity is that the FFA and cytokines released from these depots enter the portal vein and, therefore, have direct access to the liver. In the liver, they may lead to insulin resistance (see p. 343) and increased hepatic synthesis of TAG, which are released as components of very-low-density lipoprotein particles and contribute to the hypertriacylglycerolemia associated with obesity. By contrast, FFA from lower body subq adipose depots enter the general circulation, where they can be oxidized in muscle and, therefore, reach the liver in lower concentration. D. Adipocyte size and number


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Biochemistry_Lippinco. As TAG are stored, adipocytes can expand to an average of two to three times their normal volume (Fig. 26.3). However, the ability of fat cells to expand is limited. With prolonged overnutrition, preadipocytes within adipose tissue are stimulated to proliferate and differentiate into mature fat cells, increasing the number of adipocytes. Thus, most obesity is due to a combination of increased fat cell size (hypertrophy) and number (hyperplasia). Obese individuals can have up to five times the normal number of adipocytes. [Note: Like other tissues, the adipose tissue undergoes continuous remodeling. Contrary to early dogma, we now know that adipocytes can die. The estimated average lifespan of an adipocyte is 10 years.] If excess calories cannot be accommodated within adipose tissue, the excess FA “spill over” into other tissues, such as muscle and the liver. The amount of this ectopic fat is strongly associated with insulin resistance. With weight loss in an obese individual, the size


Biochemistry_Lippinco

Biochemistry_Lippinco. FA “spill over” into other tissues, such as muscle and the liver. The amount of this ectopic fat is strongly associated with insulin resistance. With weight loss in an obese individual, the size of the fat cells is reduced, but the number is not usually affected. Thus, a normal amount of body fat is achieved by decreasing the size of the fat cell below normal. However, small fat cells are very efficient at reaccumulating fat, and this may drive appetite and weight regain.


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Biochemistry_Lippinco. III. BODY WEIGHT REGULATION The body weight of most individuals tends to be relatively stable over time. This observation prompted the hypothesis that each individual has a biologically predetermined “set point” for body weight. The body attempts to add to adipose stores when the body weight falls below the set point and to lose adipose from stores when the body weight rises above the set point. Thus, the body defends the set point. For example, with weight loss, appetite increases and energy expenditure falls, whereas with overfeeding, appetite falls and energy expenditure may slightly increase (Fig. 26.4). However, a strict set point model explains neither why some individuals fail to revert to their starting weight after a period of overeating nor the current epidemic of obesity. A. Genetic contributions It is now evident that genetic mechanisms play a major role in determining body weight. 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Genetic contributions It is now evident that genetic mechanisms play a major role in determining body weight. 1. Biologic origin: The importance of genetics as a determinant of obesity is indicated by the observation that children who are adopted usually show a body weight that correlates with their biologic rather than adoptive parents. Furthermore, identical twins have very similar BMI (Fig. 26.5), whether reared together or apart, and their BMI are more similar than those of nonidentical, dizygotic twins. 2.


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Biochemistry_Lippinco. 2. Mutations: Rare, single gene mutations can cause human obesity. For example, mutations in the gene for leptin (causing decreased production) or its receptor (decreased function) result in hyperphagia (increased appetite for and consumption of food) and severe obesity (Fig. 26.6), underscoring the importance of the leptin system in regulating human body weight (see IV below). [Note: Most obese humans have elevated leptin levels but are resistant to the appetite-regulating effects of this hormone.] B. Environmental and behavioral contributions


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Biochemistry_Lippinco. The epidemic of obesity occurring over the last several decades cannot be simply explained by changes in genetic factors, which are stable on this short time scale. Clearly, environmental factors, such as the ready availability of palatable, energy-dense foods, play a role. Furthermore, sedentary lifestyles decrease physical activity and enhance the tendency to gain weight. Eating behaviors, such as portion size, variety of foods consumed, an individual’s food preferences, and the number of people present during eating, also influence food consumption. However, it is important to note that many individuals in this same environment do not become obese. The susceptibility to obesity appears to be explained, at least in part, by an interaction of an individual’s genes and his or her environment and can be influenced by additional factors such as maternal under-or overnutrition that may “set” the body regulatory systems to defend a higher or lower level of body fat. Thus, epigenetic


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Biochemistry_Lippinco. and can be influenced by additional factors such as maternal under-or overnutrition that may “set” the body regulatory systems to defend a higher or lower level of body fat. Thus, epigenetic changes (see p.


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Biochemistry_Lippinco. 476) likely influence the risk for obesity. IV. MOLECULAR INFLUENCES The cause of obesity can be summarized in a deceptively simple application of the first law of thermodynamics: Obesity results when energy (caloric) intake exceeds energy expenditure. However, the mechanism underlying this imbalance involves a complex interaction of biochemical, neurologic, environmental, and psychologic factors. The basic neural and humoral pathways that regulate appetite, energy expenditure, and body weight involve systems that regulate short-term food intake (meal to meal), and signals for the long-term (day to day, week to week, year to year) regulation of body weight (Fig. 26.7). and overnourished (B) states. CCK = cholecystokinin; PYY = peptide YY. A. Long-term signals reflect the status of fat (TAG) stores. 1.


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Biochemistry_Lippinco. and overnourished (B) states. CCK = cholecystokinin; PYY = peptide YY. A. Long-term signals reflect the status of fat (TAG) stores. 1. Leptin: Leptin is an adipocyte peptide hormone that is made and secreted in proportion to the size of fat stores. It acts on the brain to regulate food intake and energy expenditure. When we consume more calories than we need, body fat increases, and leptin production by adipocytes increases. The body adapts by increasing energy use (increasing activity) and decreasing appetite (an anorexigenic effect). When body fat decreases, the opposite effects occur. Unfortunately, most obese individuals are leptin resistant, and the leptin system may be better at preventing weight loss than preventing weight gain. [Note: Leptin’s effects are mediated through binding to receptors in the arcuate nucleus of the hypothalamus.] 2.


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Biochemistry_Lippinco. Insulin: Obese individuals are also hyperinsulinemic. Like leptin, insulin acts on hypothalamic neurons to dampen appetite. (See Chapter 23 for the effects of insulin on metabolism.) [Note: Obesity is associated with insulin resistance (see p. 342).] B. Short-term signals


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Biochemistry_Lippinco. Short-term signals from the gastrointestinal (GI) tract control hunger and satiety, which affect the size and number of meals over a time course of minutes to hours. In the absence of food intake (between meals), the stomach produces ghrelin, an orexigenic (appetite-stimulating) hormone that drives hunger. As food is consumed, GI hormones, including cholecystokinin and peptide YY, among others, induce satiety (an anorexigenic effect), thereby terminating eating, through actions on gastric emptying and neural signals to the hypothalamus. Within the hypothalamus, neuropeptides (such as orexigenic neuropeptide Y [NPY] and anorexigenic α-melanocyte–stimulating hormone [α-MSH]) and neurotransmitters (such as anorexigenic serotonin and dopamine) are important in regulating hunger and satiety. Long-term and short-term signals interact, insofar as leptin increases secretion of α-MSH and decreases secretion of NPY. Thus, there are many complex regulatory loops that control the size and number


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Biochemistry_Lippinco. and short-term signals interact, insofar as leptin increases secretion of α-MSH and decreases secretion of NPY. Thus, there are many complex regulatory loops that control the size and number of meals in relationship to the status of body fat stores. [Note: α-MSH, a cleavage product of proopiomelanocortin, binds to the melanocortin-4 receptor (MC4R). Loss-of-function mutations to MC4R are associated with early-onset obesity.]


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Biochemistry_Lippinco. V. METABOLIC EFFECTS The primary metabolic effects of obesity include dyslipidemias, glucose intolerance, and insulin resistance expressed primarily in the liver, skeletal muscle, and adipose tissue. These metabolic abnormalities reflect molecular signals originating from the increased mass of adipocytes (see Fig. 25.9, p. 343, and Fig. 26.7). [Note: About 30% of obese individuals do not show these metabolic abnormalities.] A. Metabolic syndrome


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Biochemistry_Lippinco. A. Metabolic syndrome Abdominal obesity is associated with a cluster of metabolic abnormalities (hyperglycemia, insulin resistance, hyperinsulinemia, dyslipidemia [low levels of high-density lipoprotein (HDL) and elevated TAG], and hypertension) that is referred to as the metabolic syndrome (Fig. 26.8). It is a risk factor for CVD and T2D. The low-grade, chronic, systemic inflammation seen with obesity contributes to the pathogenesis of insulin resistance and T2D and likely plays a role in metabolic syndrome. In obesity, adipocytes release proinflammatory mediators such as IL-6 and TNF-α. Additionally, levels of adiponectin, which normally dampens inflammation and sensitizes tissues to insulin, are low. B. Nonalcoholic liver disease Obesity is associated with ectopic deposition of TAG in the liver (hepatic steatosis) and results in increased risk for nonalcoholic fatty liver disease ([NAFLD], see p. 343). VI. OBESITY AND HEALTH


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Biochemistry_Lippinco. VI. OBESITY AND HEALTH Obesity is correlated with an increased risk of death (Fig. 26.9) and is a risk factor for a number of chronic conditions, including T2D, dyslipidemias, hypertension, CVD, some cancers, gallstones, arthritis, gout, pelvic floor disorders (for example, urinary incontinence), NAFLD, and sleep apnea. The relationship between obesity and associated morbidities is stronger among individuals age <55 years. After age 74 years, there is no longer an association between increased BMI and mortality. [Note: Obesity also has social consequences (for example, stigmatization and discrimination).] Weight loss in obese individuals leads to decreased blood pressure, plasma TAG, and blood glucose levels. HDL increase. VII. WEIGHT REDUCTION


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Biochemistry_Lippinco. VII. WEIGHT REDUCTION Weight reduction can help reduce the complications of obesity. To achieve weight reduction, the obese patient must decrease energy intake or increase energy expenditure, although decreasing energy intake is thought to contribute more to inducing weight loss. Typically, a plan for weight reduction combines dietary change; increased physical activity; and behavioral modification, which can include nutrition education and meal planning, recording food intake through food diaries, modifying factors that lead to overeating, and relearning cues to satiety. Medications or surgery may be recommended. Once weight loss is achieved, weight maintenance is a separate process that requires vigilance because the majority of patients regain weight after they stop their weight-loss efforts. B. Caloric restriction


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Biochemistry_Lippinco. B. Caloric restriction Dieting is the most commonly practiced approach to weight control. Because 1 lb of adipose tissue corresponds to ~3,500 kcal, the effect that caloric restriction will have on the amount of adipose tissue can be estimated. Weight loss on calorie-restricted diets is determined primarily by caloric intake and not nutrient composition. [Note: However, compositional aspects can affect glycemic control and the blood lipid profile.] Caloric restriction is ineffective over the long term for many individuals. Over 90% of people who attempt to lose weight regain the lost weight when dietary intervention is suspended. Nonetheless, although few individuals will reach their ideal weight with treatment, weight losses of 10% of body weight over a 6-month period often reduce blood pressure and lipid levels and enhance control of T2D. A. Physical activity


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Biochemistry_Lippinco. A. Physical activity An increase in physical activity can create an energy deficit. Although adding exercise to a hypocaloric regimen may not produce a greater weight loss initially, exercise is a key component of programs directed at maintaining weight loss. In addition, physical activity increases cardiopulmonary fitness and reduces the risk of CVD, independent of weight loss. Persons who combine caloric restriction and exercise with behavioral treatment may expect to lose ~5%–10% of initial body weight over a period of 4–6 months. Studies show that individuals who maintain their exercise program regain less weight after their initial weight loss. C. Pharmacologic treatment


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Biochemistry_Lippinco. C. Pharmacologic treatment The U.S. Food and Drug Administration has approved several weight-loss medications for use in adults. They include orlistat (decreases absorption of dietary fat), lorcaserin and phentermine in combination with topiramate (promote satiety through serotonin signaling), liraglutide (decreases appetite by activating the glucagon-like peptide 1 receptor), and buproprion in combination with naltrexone (increase metabolism by increasing norepinephrine). Their effects on weight reduction tend to be modest. [Note: Pharmacologic activation of brown adipocytes (see p. 79) is being explored.] D. Surgical treatment


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Biochemistry_Lippinco. D. Surgical treatment Gastric bypass and restriction surgeries are effective in causing weight loss in severely obese individuals. Through mechanisms that remain poorly understood, these operations greatly improve glycemic control in morbidly obese diabetic individuals. [Note: Implantation of a device that electrically stimulates the vagus nerve to decrease food intake has been approved.] VIII. CHAPTER SUMMARY


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Biochemistry_Lippinco. Obesity, the accumulation of excess body fat, results when energy (caloric) intake exceeds energy expenditure (Fig. 26.10). Obesity is increasing in industrialized countries because of a reduction in daily energy expenditure and an increase in energy intake resulting from the increasing availability of palatable, inexpensive foods. The body mass index (BMI) is easy to determine and highly correlated to body fat. Nearly 69% of U.S. adults are overweight (BMI ≥25), and >33% of this group are obese (BMI ≥30). The anatomic distribution of body fat has a major influence on associated health risks. Excess fat located in the abdomen (upper body, apple shape), as reflected in waist size, is associated with greater risk for hypertension, insulin resistance, diabetes, dyslipidemia, and coronary heart disease as compared to fat located in the hips and thighs (lower body, pear shape). A person’s weight is determined by genetic and environmental factors. Appetite is influenced by afferent, or


Biochemistry_Lippinco

Biochemistry_Lippinco. heart disease as compared to fat located in the hips and thighs (lower body, pear shape). A person’s weight is determined by genetic and environmental factors. Appetite is influenced by afferent, or incoming, signals (that is, neural signals, circulating hormones such as leptin, and metabolites) that are integrated by the hypothalamus. These diverse signals prompt release of hypothalamic peptides (such as neuropeptide Y and α-melanocyte– stimulating hormone) and activate outgoing, efferent neural signals. Obesity is correlated with an increased risk of death and is also a risk factor for a number of chronic conditions. Weight reduction is achieved best with negative energy balance, that is, by decreasing caloric intake and increasing physical activity. Virtually all diets that limit particular groups of foods or macronutrients lead to short-term weight loss. Long-term maintenance of weight loss is difficult to achieve. Modest reduction in food intake occurs with pharmacologic


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Biochemistry_Lippinco. particular groups of foods or macronutrients lead to short-term weight loss. Long-term maintenance of weight loss is difficult to achieve. Modest reduction in food intake occurs with pharmacologic treatment. Surgical procedures, such as gastric bypass, designed to limit food intake are an option for the severely obese patient who has not responded to other treatments.


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Biochemistry_Lippinco. Choose the ONE best answer. For Questions 26.1 and 26.2, use the following scenario. A 40-year-old woman, 5 ft, 1 in (155 cm) tall and weighing 188 lb (85.5 kg), seeks your advice on how to lose weight. Her waist measured 41 in and her hips 39 in. The remainder of the physical examination and the blood laboratory data were all within the normal range. Her only child (who is age 14 years), her sister, and both of her parents are overweight. The patient recalls being overweight throughout her childhood and adolescence. Over the past 15 years, she had been on seven different diets for periods of 2 weeks to 3 months, losing from 5 to 25 lb each time. On discontinuation of the diets, she regained weight, returning to 185–190 lb. 6.1. Calculate and interpret the body mass index for the patient. Body mass index (BMI) = weight in kg/(height in m)2 = 85.5/1.552 = 35.6. Because her BMI is >30, the patient is classified as obese.


Biochemistry_Lippinco

Biochemistry_Lippinco. Body mass index (BMI) = weight in kg/(height in m)2 = 85.5/1.552 = 35.6. Because her BMI is >30, the patient is classified as obese. 6.2. Which one of the following statements best describes the patient? A. She has approximately the same number of adipocytes as an individual of normal weight, but each adipocyte is larger. B. She shows an apple pattern of fat distribution. C. She would be expected to show higher-than-normal levels of adiponectin. D. She would be expected to show lower-than-normal levels of circulating leptin. E. She would be expected to show lower-than-normal levels of circulating triacylglycerols.


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Biochemistry_Lippinco. Correct answer = B. Her waist/hip ratio (WHR) is 1.05 (41/39). Apple shape is defined as a WHR of >0.8 for women and >1.0 for men. Therefore, she has an apple pattern of fat distribution, more commonly seen in males. Compared with other women of the same body weight who have a gynoid (pear-shaped) fat pattern, her android fat pattern places her at greater risk for diabetes, hypertension, dyslipidemia, and coronary heart disease. Individuals with marked obesity and a history dating to early childhood have a fat depot made up of too many adipocytes, each fully loaded with triacylglycerol (TAG). Plasma leptin levels are proportional to fat mass, suggesting that resistance to leptin, rather than its deficiency, occurs in human obesity. Adiponectin levels decrease with increasing fat mass. The elevated circulating free fatty acids characteristic of obesity are carried to the liver and converted to TAG. The TAG are released as components of very-low-density lipoproteins, resulting in


Biochemistry_Lippinco

Biochemistry_Lippinco. The elevated circulating free fatty acids characteristic of obesity are carried to the liver and converted to TAG. The TAG are released as components of very-low-density lipoproteins, resulting in elevated plasma TAG levels, or are stored in the liver, resulting in hepatic steatosis.


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Biochemistry_Lippinco. Nutrition: Overview and Macronutrients For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW Nutrients are the constituents of food necessary to sustain the normal functions of the body. All energy (calories) is provided by three classes of nutrients: fats, carbohydrates, and protein (Fig. 27.1). Because the intake of these energy-rich molecules is larger (g amounts) than that of the other dietary nutrients, they are called macronutrients. This chapter focuses on the kinds and amounts of macronutrients that are needed to maintain optimal health and prevent chronic disease. Those nutrients needed in lesser amounts (mg or µg), vitamins and minerals, are called micronutrients and are considered in Chapters 28 and 29. II. DIETARY REFERENCE INTAKES


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Biochemistry_Lippinco. II. DIETARY REFERENCE INTAKES Committees of U.S. and Canadian experts organized by the Food and Nutrition Board of the Institute of Medicine of the National Academy of Sciences have compiled Dietary Reference Intakes (DRI), which are estimates of the amounts of nutrients required to prevent deficiencies and maintain optimal health and growth. The DRI expands on the Recommended Dietary Allowances (RDA), which have been published with periodic revisions since 1941. Unlike the RDA, the DRI establishes upper limits on the consumption of some nutrients and incorporates the role of nutrients in lifelong health, going beyond deficiency diseases. Both the DRI and the RDA refer to long-term average daily nutrient intakes, because it is not necessary to consume the full RDA every day. A. Definition The DRI consists of four dietary reference standards for the intake of nutrients designated for specific life stage (age) groups, physiologic states, and gender (Fig. 27.2). 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Definition The DRI consists of four dietary reference standards for the intake of nutrients designated for specific life stage (age) groups, physiologic states, and gender (Fig. 27.2). 1. Estimated average requirement: The average daily nutrient intake level estimated to meet the requirement of one half of the healthy individuals in a particular life stage and gender group is the Estimated Average Requirement (EAR). It is useful in estimating the actual requirements in groups and individuals. 2.


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Biochemistry_Lippinco. 2. Recommended dietary allowance: The RDA is the average daily nutrient intake level that is sufficient to meet the requirements of nearly all (97%– 98%) individuals in a particular life stage and gender group. The RDA is not the minimal requirement for healthy individuals, but it is intentionally set to provide a margin of safety for most individuals. The EAR serves as the foundation for setting the RDA. If the standard deviation (SD) of the EAR is available and the requirement for the nutrient is normally distributed, the RDA is set at 2 SD above the EAR (that is, RDA = EAR + 2 SDEAR). 3.


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Biochemistry_Lippinco. 3. Adequate intake: An Adequate Intake (AI) is set instead of an RDA if sufficient scientific evidence is not available to calculate an EAR or RDA. The AI is based on estimates of nutrient intake by a group (or groups) of apparently healthy people. For example, the AI for young infants, for whom human milk is the recommended sole source of food for the first 6 months, is based on the estimated daily mean nutrient intake supplied by human milk for healthy, full-term infants who are exclusively breast-fed. 4.


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Biochemistry_Lippinco. 4. Tolerable upper intake level: The highest average daily nutrient intake level that is likely to pose no risk of adverse health effects to almost all individuals in the general population is the Tolerable Upper Intake Level (UL, or TUL). As intake increases above the UL, the potential risk of adverse effects may increase. The UL is useful because of the increased availability of fortified foods and the increased use of dietary supplements. For some nutrients, there may be insufficient data on which to develop a UL. B. Using the dietary reference intakes


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Biochemistry_Lippinco. B. Using the dietary reference intakes Most nutrients have a set of DRI (Fig. 27.3). Usually a nutrient has an EAR and a corresponding RDA. Most are set by age and gender and may be influenced by special factors, such as pregnancy and lactation in women (see p. 372). When the data are not sufficient to estimate an EAR (or an RDA), an AI is designated. Intakes below the EAR need to be improved because the probability of adequacy is ≤50% (Fig. 27.4). Intakes between the EAR and RDA likely need to be improved because the probability of adequacy is <98%, and intakes at or above the RDA can be considered adequate. Intakes above the AI can be considered adequate. Intakes between the UL and the RDA can be considered to have no risk for adverse effects. [Note: Because the DRI is designed to meet the nutritional needs of the healthy, it does not include any special needs of the sick.] III. ENERGY REQUIREMENT IN HUMANS


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Biochemistry_Lippinco. III. ENERGY REQUIREMENT IN HUMANS The Estimated Energy Requirement (EER) is the average dietary energy intake predicted to maintain an energy balance (that is, the calories consumed are equal to the energy expended) in a healthy adult of a defined age, gender, and height whose weight and level of physical activity are consistent with good health. Differences in the genetics, body composition, metabolism, and behavior of individuals make it difficult to accurately predict a person’s caloric requirements. However, some simple approximations can provide useful estimates. For example, sedentary adults require ~30 kcal/kg/day to maintain body weight, moderately active adults require 35 kcal/kg/day, and very active adults require 40 kcal/kg/day. A. Energy content of food


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Energy content of food The energy content of food is calculated from the heat released by the total combustion of food in a calorimeter. It is expressed in kilocalories (kcal, or Cal). The standard conversion factors for determining the metabolic caloric value of fat, protein, and carbohydrate are shown in Figure 27.5. Note that the energy content of fat is more than twice that of carbohydrate or protein, whereas the energy content of ethanol is intermediate between those of fat and carbohydrate. [Note: The joule (J) is a unit of energy widely used in countries other than the United States. One cal = 4.2 J; 1 kcal (1 Cal, 1 food calorie) = 4.2 kJ. For uniformity, many scientists are promoting the use of joules rather than calories in the United States. However, kcal still predominates and is used throughout this text.] Figure27.5Averageenergyavailablefromthemacronutrientsandalcohol. B. Use of food energy in the body


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Biochemistry_Lippinco. Figure27.5Averageenergyavailablefromthemacronutrientsandalcohol. B. Use of food energy in the body The energy generated by metabolism of the macronutrients is used for three energy-requiring processes that occur in the body: resting metabolic rate (RMR), physical activity, and the thermic effect of food. The number of kcal expended by these processes in a 24-hour period is the total energy expenditure (TEE).


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Biochemistry_Lippinco. 1. Resting metabolic rate: RMR is the energy expended by an individual in a resting, postabsorptive state. It represents the energy required to carry out the normal body functions, such as respiration, blood flow, and ion transport. RMR can be determined by measuring oxygen (O2) consumed or carbon dioxide (CO2) produced (indirect calorimetry). [Note: The ratio of CO2 to O2 is the respiratory quotient (RQ). It reflects the substrate being oxidized for energy (Fig. 27.6).] RMR also can be estimated using equations that include sex and age (RMR reflects lean muscle mass, which is highest in men and the young) as well as height and weight. A commonly used rough estimate is 1 kcal/kg/hour for men and 0.9 kcal/kg/hour for women. [Note: A basal metabolic rate (BMR) can be determined if more stringent environmental conditions are used, but it is not routinely done. RMR is ~10% higher than the BMR.] In an adult, the 24-hour RMR, known as the resting energy expenditure (REE), is ~1,800 kcal for


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Biochemistry_Lippinco. environmental conditions are used, but it is not routinely done. RMR is ~10% higher than the BMR.] In an adult, the 24-hour RMR, known as the resting energy expenditure (REE), is ~1,800 kcal for men (70 kg) and 1,300 kcal for women (50 kg). From 60%–75% of the TEE in sedentary individuals is attributable to the REE (Fig. 27.7). [Note: Hospitalized individuals are commonly hypercatabolic, and the RMR is multiplied by an injury factor that ranges from 1.0 (mild infection) to 2.0 (severe burns) in calculating their TEE.] 2.


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Biochemistry_Lippinco. Physical activity: Muscular activity provides the greatest variation in the TEE. The amount of energy consumed depends on the duration and intensity of the exercise. This energy cost is expressed as a multiple of the RMR (range is 1.1 to >8.0) that is referred to as the physical activity ratio (PAR) or the metabolic equivalent of the task (MET). In general, a lightly active person requires ~30%–50% more calories than the RMR (see Fig. 27.7), whereas a highly active individual may require ≥100% calories above the RMR. 3. Thermic effect of food: The production of heat by the body increases as much as 30% above the resting level during the digestion and absorption of food. This is called the thermic effect of food, or diet-induced thermogenesis. The thermic response to food intake may amount to 5%– 10% of the TEE. IV. ACCEPTABLE MACRONUTRIENT DISTRIBUTION RANGES


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Biochemistry_Lippinco. IV. ACCEPTABLE MACRONUTRIENT DISTRIBUTION RANGES Acceptable Macronutrient Distribution Ranges (AMDR) are defined as a range of intakes for a particular macronutrient that is associated with reduced risk of chronic disease while providing adequate amounts of essential nutrients. The AMDR for adults is 45%–65% of their total calories from carbohydrates, 20%– 35% from fat, and 10%–35% from protein (Fig. 27.8). The biologic properties of dietary fat, carbohydrate, and protein are described below. V. DIETARY FATS The incidence of a number of chronic diseases is significantly influenced by the kinds and amounts of nutrients consumed (Fig. 27.9). Dietary fats most strongly influence the incidence of coronary heart disease (CHD), but evidence linking dietary fat and the risk for cancer or obesity is much weaker.


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Biochemistry_Lippinco. Earlier recommendations emphasized decreasing the total amount of dietary fat. Unfortunately, this resulted in increased consumption of refined grains and added sugars. Data now show that the type of fat is a more important risk factor than the total amount of fat. A. Plasma lipids and coronary heart disease Plasma cholesterol may arise from the diet or from endogenous biosynthesis. In either case, cholesterol is transported between the tissues in combination with protein and phospholipids as lipoproteins.


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Biochemistry_Lippinco. 1. Low-density and high-density lipoproteins: The level of plasma cholesterol is not precisely regulated but, rather, varies in response to diet. Elevated levels of total cholesterol (hypercholesterolemia) result in an increased risk for CHD (Fig. 27.10). A much stronger correlation exists between CHD and the level of cholesterol in low-density lipoproteins ([LDL-C] see p. 234). As LDL-C increases, CHD increases. In contrast, elevated levels of high-density lipoprotein cholesterol (HDL C) have been associated with a decreased risk for heart disease (see p. 235). [Note: Elevated plasma triacylglycerol (TAG) is associated with CHD, but a causative relationship has yet to be demonstrated.] Abnormal levels of plasma lipids (dyslipidemias) act in combination with smoking, obesity, sedentary lifestyle, insulin resistance, and other risk factors to increase the risk of CHD.


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Biochemistry_Lippinco. 2. Benefits of lowering plasma cholesterol: Dietary or drug treatment of hypercholesterolemia has been shown to be effective in decreasing LDLC, increasing HDL-C, and reducing the risk for cardiovascular events. The diet-induced changes in plasma cholesterol concentrations are modest, typically 10%–20%, whereas treatment with statin drugs decreases plasma cholesterol by 30%–60% (see p. 224). [Note: Dietary and drug treatment can also lower TAG.] B. Dietary fats and plasma lipids TAG are quantitatively the most important class of dietary fats. The influence of TAG on blood lipids is determined by the chemical nature of their constituent fatty acids. The absence or presence and number of double bonds (saturated versus mono-and polyunsaturated), the location of the double bonds (ω-6 versus ω-3), and the cis versus trans configuration of the unsaturated fatty acids are the most important structural features that influence blood lipids.


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Biochemistry_Lippinco. 1. Saturated fats: TAG composed primarily of fatty acids whose hydrocarbon chains do not contain any double bonds are referred to as saturated fats. Consumption of saturated fats is positively associated with high levels of total plasma cholesterol and LDL-C and an increased risk of CHD. The main sources of saturated fatty acids are dairy and meat products and some vegetable oils, such as coconut and palm oils (a major source of fat in Latin America and Asia, although not in the United States). Many experts strongly advise limiting intake of saturated fats to <10% of total caloric intake and replacing them with unsaturated fats (and whole grains). Saturated fatty acids with carbon chain lengths of 14 (myristic) and 16 (palmitic) are most potent in increasing the plasma cholesterol level. Stearic acid (18 carbons, found in many foods including chocolate) has little effect on blood cholesterol.


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Biochemistry_Lippinco. 2. Monounsaturated fats: TAG containing primarily fatty acids with one double bond are referred to as monounsaturated fats. Monounsaturated fatty acids (MUFA) are generally obtained from plant-based oils. When substituted for saturated fatty acids in the diet, MUFA lower both total plasma cholesterol and LDL-C and maintain or increase HDL-C. This ability of MUFA to favorably modify lipoprotein levels may explain, in part, the observation that Mediterranean cultures, with diets rich in olive oil (high in monounsaturated oleic acid), show a low incidence of CHD. [Note: Although there is no AMDR for MUFA, a common recommendation is 10%–20% of caloric intake.] a. The Mediterranean diet: The Mediterranean diet is an example of a diet rich in MUFA (from olive oil) and polyunsaturated fatty acids or PUFA (from fish oils, plant oils, and some nuts) but low in saturated fat. For example, Figure 27.11 shows the composition of the Mediterranean diet in comparison with both a Western diet similar


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Biochemistry_Lippinco. or PUFA (from fish oils, plant oils, and some nuts) but low in saturated fat. For example, Figure 27.11 shows the composition of the Mediterranean diet in comparison with both a Western diet similar to that consumed in the United States and a typical low-fat diet. The Mediterranean diet contains seasonally fresh food, with an abundance of plant material, low amounts of red meat, and olive oil as the principal source of fat. The Mediterranean diet is associated with decreased plasma total cholesterol and LDL-C, decreased TAG, and increased HDL-C when compared with a typical Western diet higher in saturated fats.


Biochemistry_Lippinco

Biochemistry_Lippinco. 3. Polyunsaturated fats: TAG containing primarily fatty acids with more than one double bond are referred to as polyunsaturated fats. The effects of PUFA on cardiovascular disease are influenced by the location of the double bonds within the molecule.


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Biochemistry_Lippinco. a. ω-6 Fatty acids: These are long-chain PUFA, with the first double bond beginning at the sixth bond position when starting from the methyl (ω) end of the fatty acid molecule. [Note: They are also called n-6 fatty acids (see p. 182).] Consumption of fats containing ω-6 PUFA, principally linoleic acid (18:2 [9,12]), obtained from vegetable oils, lowers plasma cholesterol when substituted for saturated fats. Plasma LDL-C is lowered, but HDL-C, which protects against CHD, is also lowered, partially offsetting the benefits of lowering LDL-C. Nuts, avocados, olives, soybeans, and various oils, including sunflower and corn oil, are common sources of these fatty acids. The AMDR for linoleic acid is 5%–10%. [Note: The lower recommendation for intake of PUFA relative to MUFA is because of concern that free radical– mediated oxidation (peroxidation) of PUFA may lead to deleterious products.] b. ω-3 Fatty acids: These are long-chain PUFA, with the first double bond beginning at the third bond


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Biochemistry_Lippinco. that free radical– mediated oxidation (peroxidation) of PUFA may lead to deleterious products.] b. ω-3 Fatty acids: These are long-chain PUFA, with the first double bond beginning at the third bond position from the methyl (ω) end. Dietary ω-3 PUFA suppress cardiac arrhythmias, reduce plasma TAG, decrease the tendency for thrombosis, lower blood pressure, and substantially reduce risk of cardiovascular mortality (Fig. 27.12), but they have little effect on LDL-C or HDL-C levels. Evidence suggests that they have anti-inflammatory effects. The ω-3 PUFA, principally α-linolenic acid, 18:3(9,12,15), are found in plant oils, such as flaxseed and canola, and some nuts, such as walnuts. The AMDR for αlinolenic acid is 0.6%–1.2%. Fish oil contains the long-chain ω-3 docosahexaenoic acid (DHA, 22:6) and eicosapentaenoic acid (EPA, 20:5). Two fatty fish (for example, salmon) meals per week are recommended. For patients with documented CHD, 1 g/day of fish oils is recommended, while 2–4 g/day is


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Biochemistry_Lippinco. and eicosapentaenoic acid (EPA, 20:5). Two fatty fish (for example, salmon) meals per week are recommended. For patients with documented CHD, 1 g/day of fish oils is recommended, while 2–4 g/day is prescribed to lower TAG. [Note: DHA is included in infant formulas to promote brain development.] Linoleic and α-linolenic acids are essential fatty acids (EFA) required for membrane fluidity and synthesis of eicosanoids (see p. 213). EFA deficiency, caused primarily by fat malabsorption, is characterized by scaly dermatitis as a result of the depletion of skin ceramides with long-chain fatty acids (see p. 206).


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Biochemistry_Lippinco. = eicosapentaenoic acid (20:5); DHA = docosahexaenoic acid (22:6). 4. Trans fatty acids: Trans fatty acids (Fig. 27.13) are chemically classified as unsaturated fatty acids but behave more like saturated fatty acids in the body because they elevate LDL-C and lower HDL-C, thereby increasing the risk of CHD. Trans fatty acids do not occur naturally in plants but occur in small amounts in animals. However, trans fatty acids are formed during the hydrogenation of vegetable oils (for example, in the manufacture of margarine and partially hydrogenated vegetable oil). Trans fatty acids are a major component of many commercial baked goods, such as cookies, and most deep-fried foods. Many manufacturers have reformulated their products to be free of trans fats. In 2006, the U.S. Food and Drug Administration required that Nutrition Facts labels (see p. 370) portray the trans fat content of packaged food. By 2018, virtually no industrial trans fatty acids will be permitted in food.