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Biochemistry_Lippincott_1183	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. 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_Lippincott_1184	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. 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_Lippincott_1185	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. 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_Lippincott_1186	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. 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_Lippincott_1187	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. 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_Lippincott_1188	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. 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_Lippincott_1189	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. 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_Lippincott_1190	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. 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_Lippincott_1191	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.]	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.]
Biochemistry_Lippincott_1192	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).	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).
Biochemistry_Lippincott_1193	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.	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.
Biochemistry_Lippincott_1194	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.	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.
Biochemistry_Lippincott_1195	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	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
Biochemistry_Lippincott_1196	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.]	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.]
Biochemistry_Lippincott_1197	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.	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.
Biochemistry_Lippincott_1198	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.	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.
Biochemistry_Lippincott_1199	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	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
Biochemistry_Lippincott_1200	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	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
Biochemistry_Lippincott_1201	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	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
Biochemistry_Lippincott_1202	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	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
Biochemistry_Lippincott_1203	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.	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.
Biochemistry_Lippincott_1204	Biochemistry_Lippinco	V. CHAPTER SUMMARY	Biochemistry_Lippinco. V. CHAPTER SUMMARY
Biochemistry_Lippincott_1205	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. 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_Lippincott_1206	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	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
Biochemistry_Lippincott_1207	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).	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).
Biochemistry_Lippincott_1208	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	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
Biochemistry_Lippincott_1209	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	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
Biochemistry_Lippincott_1210	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.	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.
Biochemistry_Lippincott_1211	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	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
Biochemistry_Lippincott_1212	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	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
Biochemistry_Lippincott_1213	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.	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.
Biochemistry_Lippincott_1214	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. 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_Lippincott_1215	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	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
Biochemistry_Lippincott_1216	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.	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.
Biochemistry_Lippincott_1217	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	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
Biochemistry_Lippincott_1218	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.	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.
Biochemistry_Lippincott_1219	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.	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.
Biochemistry_Lippincott_1220	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	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
Biochemistry_Lippincott_1221	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. 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_Lippincott_1222	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.	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.