Robbins & Cotran Pathologic Basis of Disease (Robbins Pathology)

1096 C H A P T E R 24 The Endocrine System Bone disease and bone pain secondary to fractures of bones weakened by osteoporosis or osteitis fibrosa cystica Nephrolithiasis (renal stones) in 20% of newly diagnosed patients, with attendant pain and obstructive uropathy. Chronic renal insufficiency and...

1096 C H A P T E R 24 The Endocrine System Bone disease and bone pain secondary to fractures of bones weakened by osteoporosis or osteitis fibrosa cystica Nephrolithiasis (renal stones) in 20% of newly diagnosed patients, with attendant pain and obstructive uropathy. Chronic renal insufficiency and abnormalities in renal function lead to polyuria and secondary polydipsia. Gastrointestinal disturbances, including constipation, nausea, peptic ulcers, pancreatitis, and gallstones Central nervous system alterations, including depression, lethargy, and eventually seizures Neuromuscular abnormalities, including weakness and fatigue Cardiac manifestations, including aortic or mitral valve calcifications (or both) The abnormalities most directly related to hyperparathyroidism are nephrolithiasis and bone disease, whereas those attributable to hypercalcemia include fatigue, weakness, pancreatitis, metastatic calcifications, and constipation. Secondary Hyperparathyroidism Secondary hyperparathyroidism is caused by any condition that gives rise to chronic hypocalcemia, which, in turn, leads to compensatory overactivity of the parathyroid glands. Renal failure is by far the most common cause of secondary hyperparathyroidism, although several other diseases, including inadequate dietary intake of calcium, steatorrhea, and vitamin D deficiency, may also cause this disorder. The mechanisms by which chronic renal failure induces secondary hyperparathyroidism are complex and not fully understood. Chronic renal insufficiency is associated with decreased phosphate excretion, which, in turn, results in hyperphosphatemia. The elevated serum phosphate levels directly depress serum calcium levels and thereby stimulate parathyroid gland activity. In addition, loss of renal substance reduces the availability of α1-hydroxylase, which is necessary for the synthesis of the active form of vitamin D, leading in turn to reduced intestinal absorption of calcium (Chapter 9). Because vitamin D has suppressive effects on parathyroid growth and PTH secretion, its deficiency compounds the hyperparathyroidism in renal failure. MORPHOLOGY The parathyroid glands in secondary hyperparathyroidism are hyperplastic. As in primary hyperparathyroidism, the degree of glandular enlargement may be asymmetric. Microscopically, the hyperplastic glands contain an increased number of chief cells, or water-clear cells in a diffuse or multinodular distribution. Fat cells are decreased in number. Metastatic calcification may be seen in many tissues, including the lungs, heart, stomach, and blood vessels. Clinical Features The clinical features of secondary hyperparathyroidism are usually dominated by the inciting chronic renal failure. Secondary hyperparathyroidism is usually not as severe or as prolonged as primary hyperparathyroidism, hence the skeletal abnormalities (referred to as renal osteodystrophy) tend to be milder. Control of the hyperparathyroidism allows the bony changes to regress significantly or disappear completely. The vascular calcification associated with secondary hyperparathyroidism may occasionally result in significant ischemic damage to skin and other organs, a process referred to as calciphylaxis. Patients with secondary hyperparathyroidism often respond to dietary vitamin D supplementation as well as phosphate binders, which decrease the prevailing hyperphosphatemia. In a minority of patients, parathyroid activity may become autonomous and excessive, with resultant hypercalcemia, a process termed tertiary hyperparathyroidism. Parathyroidectomy may be necessary to control the hyperparathyroidism in such patients. KEY CONCEPTS HYPERPARATHYROIDISM Primary hyperparathyroidism is the most common cause of asymptomatic hypercalcemia. In a majority of cases, primary hyperparathyroidism is caused by a sporadic parathyroid adenoma and, less commonly, by parathyroid hyperplasia. Parathyroid adenomas are solitary, while hyperplasia typically is a multiglandular process. Skeletal manifestations of hyperparathyroidism include bone resorption, osteitis fibrosa cystica, and brown tumors. Renal changes include nephrolithiasis (stones) and nephrocalcinosis. The clinical manifestations of hyperparathyroidism have been classically summarized as “painful bones, renal stones, abdominal groans, and psychic moans.” Secondary hyperparathyroidism most often is caused by renal failure, which lowers serum calcium levels, resulting in reactive hyperplasia of parathyroid glands. Malignancies are the most important cause of symptomatic hypercalcemia, which results from osteolytic metastases or release of PTH-related protein from nonparathyroid tumors. HYPOPARATHYROIDISM Hypoparathyroidism is far less common than is hyperparathyroidism. Acquired hypoparathyroidism is almost always an inadvertent consequence of surgery; in addition, there are several genetic causes of hypoparathyroidism. Surgically induced hypoparathyroidism occurs with inadvertent removal of all parathyroid glands during thyroidectomy, excision of parathyroid glands in the mistaken belief that they are lymph nodes during radical neck dissection for some form of malignant disease, or removal of too large a proportion of parathyroid tissue in the treatment of primary hyperparathyroidism. Autoimmune hypoparathyroidism is often associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency; this syndrome is known as APS-1 and is caused by mutations in the autoimmune regulator (AIRE) gene. The syndrome typically presents in childhood with the onset of candidiasis, followed several years later by hypoparathyroidism and then adrenal insufficiency during adolescence. APS-1 is discussed further later in this chapter. The endocrine pancreas Autosomal-dominant hypoparathyroidism is caused by gain-of-function mutations in the calcium-sensing receptor (CASR) gene. Inappropriate CASR activity due to heightened calcium sensing suppresses PTH, resulting in hypocalcemia and hypercalciuria. Recall that loss-offunction CASR mutations are a rare cause of familial parathyroid adenomas. Familial isolated hypoparathyroidism (FIH) is a rare condition with either autosomal dominant or autosomal recessive patterns of inheritance. Autosomal dominant FIH is caused by a mutation in the gene encoding PTH that impairs PTH processing to the mature active hormone. Autosomal recessive FIH is caused by loss-of-function mutations in the transcription factor gene GCM2, which is essential for development of the parathyroid. Congenital absence of parathyroid glands can occur in conjunction with other malformations, such as thymic aplasia and cardiovascular defects, or as a component of the 22q11 deletion syndrome. As discussed in Chapter 6, when thymic defects are present, the condition is called DiGeorge syndrome. Clinical Features The major manifestations of hypoparathyroidism are related to the severity and chronicity of the hypocalcemia. The hallmark of hypocalcemia is tetany, which is characterized by neuromuscular irritability, resulting from decreased serum calcium levels. The symptoms range from circumoral numbness or paresthesias (tingling) of the distal extremities and carpopedal spasm, to lifethreatening laryngospasm and generalized seizures. The classic findings on physical examination are Chvostek sign and Trousseau sign. Chvostek sign is elicited in subclinical disease by tapping along the course of the facial nerve, which induces contractions of the muscles of the eye, mouth, or nose. Trousseau sign refers to carpal spasms produced by occlusion of the circulation to the distal arm with a blood pressure cuff for several minutes. Mental status changes include emotional instability, anxiety and depression, confusional states, hallucinations, and frank psychosis. Intracranial manifestations include calcifications of the basal ganglia, parkinsonian-like movement disorders, and increased intracranial pressure with resultant papilledema. The paradoxical association of hypocalcemia with calcifications may be because of an increase in phosphate levels, leading to deposition of calcium phosphate in vulnerable tissues. Ocular disease takes the form of calcification of the lens and cataract formation. Cardiovascular manifestations include a conduction defect that produces a characteristic prolongation of the QT interval in the electrocardiogram. Dental abnormalities occur when hypocalcemia is present during early development. These findings are highly characteristic of hypoparathyroidism and include dental hypoplasia, failure of eruption, defective enamel and root formation, and abraded carious teeth. Pseudohypoparathyroidism In this condition, hypoparathyroidism occurs because of end-organ resistance to the actions of PTH. Indeed, serum PTH levels are normal or elevated. In one form of pseudohypoparathyroidism, there is end-organ resistance to TSH and FSH/LH as well as PTH. All of these hormones signal via G-protein–coupled receptors, and the disorder results from genetic defects in components of this pathway that are shared across endocrine tissues. PTH resistance is the most obvious clinical manifestation. It presents as hypocalcemia, hyperphosphatemia, and elevated circulating PTH. TSH resistance is generally mild, while LH/FSH resistance manifests as hypergonadotropic hypogonadism in females. The Endocrine Pancreas The endocrine pancreas consists of about 1 million clusters of cells, the islets of Langerhans, which contain four major and two minor cell types. The four main types are β, α, δ, and PP (pancreatic polypeptide) cells. They can be differentiated by the ultrastructural characteristics of their granules, and by their hormone content (Fig. 24.27). The β cells produce insulin, which regulates glucose utilization in tissues and reduces blood glucose levels, as will be detailed in the discussion of diabetes. The α cells secrete glucagon, which stimulates glycogenolysis in the liver and thus increases blood sugar. The δ cells secrete somatostatin, which suppresses both insulin and glucagon release. The PP cells secrete pancreatic polypeptide, which exerts several gastrointestinal effects, such as stimulation of secretion of gastric and intestinal enzymes and inhibition of intestinal motility. These cells not only are present in islets but also are scattered throughout the exocrine pancreas. There are also two rare cell types, D1 cells and enterochromaffin cells. D1 cells elaborate vasoactive intestinal polypeptide (VIP), a hormone that induces glycogenolysis and hyperglycemia; it also stimulates gastrointestinal fluid secretion and causes secretory diarrhea. Enterochromaffin cells synthesize serotonin and are the source of pancreatic tumors that cause the carcinoid syndrome (Chapter 19). The following discussion focuses on the two main disorders of islet cells: diabetes mellitus and pancreatic endocrine tumors. DIABETES MELLITUS Diabetes mellitus is a group of metabolic disorders sharing the common feature of hyperglycemia caused by defects in insulin secretion, insulin action, or, most 1097 1098 C H A P T E R 24 The Endocrine System A b cells: insulin B a cells: glucagon D C d cells: somatostatin E Figure 24.27 Hormone production in pancreatic islet cells. Immunoperoxidase staining shows insulin in β cells (A), glucagon in α cells (B), and somatostatin in δ cells (C). (D) Electron micrograph of a β cell shows the characteristic membrane-bound granules, each containing a dense, often rectangular core and distinct halo. (E) Portions of an α cell (left) and a δ cell (right) also show granules, but with closely apportioned membranes. The α-cell granule shows a dense, round center. (Electron micrographs courtesy Dr. Arthur Like, University of Massachusetts Medical School, Worcester, Mass.) commonly, both. The chronic hyperglycemia and attendant metabolic deregulation may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels. In the United States, diabetes is the leading cause of end-stage renal disease, adult-onset blindness, and nontraumatic lower extremity amputations. Diabetes and related disorders of glucose metabolism are common. According to the American Diabetes Association, diabetes affects more than 30 million children and adults, or more than 9% of the population, in the United States, of which about 1.2 million have the form of diabetes called type 1 and the remainder have type 2. Astonishingly, nearly one-fourth of these individuals are currently unaware that they have hyperglycemia. Approximately 1.5 million new cases of adult diabetes are diagnosed each year in the United States. Furthermore, a staggering 84 million adults in this country have impaired glucose tolerance or “prediabetes,” which is defined as elevated blood sugar that does not reach the criterion used for an outright diagnosis of type 2 diabetes (T2D; see later), and individuals with prediabetes are at risk for developing frank T2D. Compared to non-Hispanic Caucasians, Native Americans, African Americans, and Hispanics are 1.5 to 2 times more likely to develop diabetes in their lifetimes. The World Health Organization estimates that as many as 422 million people suffer from diabetes worldwide, with India and China being the largest contributors to the world’s diabetic burden. Increasingly sedentary lifestyles and poor eating habits have contributed to the simultaneous escalation of T2D and obesity, which some have called the diabesity epidemic. Sadly, this epidemic has now spread to children living in “food deserts” who subsist on highly processed foods rich in carbohydrates and sugar and do not exercise adequately. The mortality rate from diabetes varies across countries, with middle- and low-income nations accounting for almost 80% of diabetes-related deaths and nearly double the mortality rates observed in high-income nations. Nonetheless, diabetes remains in the top 10 “killers” in the United States. The total yearly cost related to diabetes in the United States is estimated to be an astounding $327 billion, including $237 billion in direct medical costs and $90 billion in indirect costs stemming from the reduced productivity of individuals with diabetes. Diagnosis Blood glucose is normally maintained in a very narrow range of 70 to 120 mg/dL. According to the ADA and WHO, diagnostic criteria for diabetes include the following: 1. A fasting plasma glucose ≥126 mg/dL 2. A random plasma glucose ≥200 mg/dL (in a patient with classic hyperglycemic signs, as discussed later) The endocrine pancreas 3. A 2-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test (OGTT) with a loading dose of 75 g 4. A glycated hemoglobin (HbA1c) level ≥6.5% (glycated hemoglobin is further discussed later in the chapter) All tests, except the random blood glucose test in a patient with classic hyperglycemic signs, need to be repeated and confirmed on a separate day. If there is discordance between two assays (e.g., fasting glucose and HbA1c level), the result with the greatest degree of abnormality is considered the “readout.” Of note, many acute stresses, such as severe infections, burns, or trauma, can lead to transient hyperglycemia due to secretion of hormones such as catecholamines and cortisol that oppose the action of insulin. The diagnosis of diabetes requires persistence of hyperglycemia following resolution of the acute illness. Prediabetes, a state of dysglycemia that often precedes development of frank T2D, is defined by one or more of the following: 1. A fasting plasma glucose between 100 and 125 mg/dL (“impaired fasting glucose”), 2. A 2-hour plasma glucose between 140 and 199 mg/dL following a 75-g oral glucose tolerance test (OGTT) (“impaired glucose tolerance”), and/or 3. A glycated hemoglobin (HbA1c) level between 5.7% and 6.4% As many as one-fourth of individuals with impaired glucose tolerance will develop overt diabetes over 5 years, with additional factors such as obesity and family history compounding the risk. In addition, individuals with prediabetes also are at significant risk for cardiovascular complications. Classification Although all forms of diabetes have hyperglycemia as a common feature, the underlying abnormalities involved in its development vary widely. The previous classification schemes of diabetes were based on clinical features, such as the age of onset of disease and the mode of therapy; in contrast, the current classification reflects our greater understanding of the pathogenesis of each variant (Table 24.6). The vast majority of cases of diabetes fall into one of two broad classes: Type 1 diabetes (T1D) is an autoimmune disease characterized by pancreatic β-cell destruction and an absolute deficiency of insulin. It accounts for approximately 5% to 10% of diabetes and is the most common subtype diagnosed in patients younger than 20 years of age. Type 2 diabetes (T2D) is caused by a combination of peripheral resistance to insulin action and a secretory response by pancreatic β cells that is inadequate to overcome insulin resistance (“relative insulin deficiency”). Approximately 90% to 95% of diabetes patients have T2D, and the vast majority of such individuals are overweight. Although classically considered “adult-onset,” the prevalence of T2D in children and adolescents has been increasing at an alarming pace due to the increasing rates of obesity in children and young adults, particularly in Hispanic, Native American, and Asian ethnic groups. Table 24.6 Classification of Diabetes Type 1 Diabetes (β-Cell Destruction, Usually Leading to Absolute Insulin Deficiency) Immune-mediated Idiopathic (autoantibody-negative) Type 2 Diabetes (Combination of Insulin Resistance and β-Cell Dysfunction) Other Types Genetic Defects of β-Cell Function Maturity-onset diabetes of the young (MODY) caused by mutations in: Hepatocyte nuclear factor 4α (HNF4A) (MODY1) Glucokinase (GCK) (MODY2) Hepatocyte nuclear factor 1α (HNF1A), (MODY3) Pancreatic and duodenal homeobox 1 (PDX1) (MODY4) Hepatocyte nuclear factor 1β (HNF1B) (MODY5) Neurogenic differentiation factor 1 (NEUROD1) (MODY6) Neonatal diabetes (activating mutations in KCNJ11 and ABCC8, encoding Kir6.2 and SUR1, respectively) Maternally inherited diabetes and deafness (MIDD) due to mitochondrial DNA mutations (m.3243A→G) Defects in proinsulin conversion Insulin gene mutations Genetic Defects in Insulin Action Type A insulin resistance Lipoatrophic diabetes Exocrine Pancreatic Defects (“Pancreatogenic” or Type 3C Diabetes) Chronic pancreatitis Pancreatectomy/trauma Pancreatic cancer Cystic fibrosis Hemochromatosis Fibrocalculous pancreatopathy Endocrinopathies Acromegaly Cushing syndrome Hyperthyroidism Pheochromocytoma Glucagonoma Infections Cytomegalovirus Coxsackie B virus Congenital rubella Drugs Glucocorticoids Thyroid hormone Interferon-α Protease inhibitors β-adrenergic agonists Thiazides Nicotinic acid Phenytoin (Dilantin) Vacor Genetic Syndromes Associated With Diabetes Down syndrome Klinefelter syndrome Turner syndrome Prader-Willi syndrome Gestational Diabetes Mellitus Modified from American Diabetes Association: Diagnosis and classification of diabetes mellitus, Diabetes Care 37(Suppl 1):S81–S90, 2014. 1099 1100 C H A P T E R 24 The Endocrine System Table 24.7 Comparative Features of Type 1 and Type 2 Glucose Diabetes Type 1 Diabetes Clinical Onset: usually childhood and adolescence GLUT-2 Type 2 Diabetes Onset: usually adult; increasing incidence in childhood and adolescence Normal weight or weight loss preceding diagnosis Vast majority are obese (80%) Progressive decrease in insulin levels Increased blood insulin (early); normal or moderate decrease in insulin (late) Circulating islet autoantibodies (anti-insulin, anti-GAD, anti-ICA512) No islet autoantibodies Diabetic ketoacidosis in absence of insulin therapy Nonketotic hyperosmolar coma more common Sulfonylurea receptor Glucose K+ K+ channel protein inactivated Membrane depolarization ATP Insulin Mitochondria No HLA linkage; linkage to candidate diabetogenic and obesity-related genes (e.g., TCF7L2, PPARG, FTO) Influx of Ca2+ Ca2+ channel Genetics Major linkage to MHC class II genes; also linked to polymorphisms in CTLA4 and PTPN22, and insulin gene VNTRs Insulin Ca2+ Figure 24.28 Insulin synthesis and secretion. The influx of glucose into β cells through the GLUT-2 receptors initiates a cascade of signaling events that culminates in Ca2+-induced release of stored insulin (see text for details). Pathogenesis Dysfunction in T-cell selection and regulation leading to breakdown in self-tolerance to islet autoantigens Insulin resistance in peripheral tissues, failure of compensation by β cells Pathology Insulitis (inflammatory infiltrate of T cells and macrophages) β-cell depletion, islet atrophy No insulitis; amyloid deposition in islets Mild β-cell depletion HLA, Human leukocyte antigen; MHC, major histocompatibility complex; VNTRs, variable number of tandem repeats. The important similarities and differences between T1D and T2D are summarized in Table 24.7. A variety of monogenic and secondary causes are responsible for the remaining cases (discussed later). Before discussing the pathogenesis of the two major types, we will first briefly review normal insulin secretion and the mechanism of insulin action, since these are critical to understanding the pathogenesis of diabetes. Glucose Homeostasis Glucose homeostasis is tightly regulated by three interrelated processes: glucose production in the liver; glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle; and actions of insulin and counter-regulatory hormones, including glucagon, on glucose uptake and metabolism. Insulin and glucagon have opposing effects on glucose homeostasis. During fasting states, low insulin and high glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, thereby preventing hypoglycemia. Thus, fasting plasma glucose levels are determined primarily by hepatic glucose output. Following a meal, insulin levels rise and glucagon levels fall in response to the large glucose load. Insulin promotes glucose uptake and utilization in tissues (discussed later). The skeletal muscle is the major insulin-responsive site for postprandial glucose utilization, and it is critical for preventing hyperglycemia and maintaining glucose homeostasis. Although less dependent on insulin, brain and adipose tissues also extract a significant amount of glucose from the circulation. Regulation of Insulin Release Insulin is produced in the β cells of the pancreatic islets (see Fig. 24.27) as a precursor protein and is proteolytically cleaved in the Golgi complex to generate the mature hormone and a peptide byproduct, C-peptide. Both insulin and C-peptide are then stored in secretory granules and secreted in equimolar quantities after physiologic stimulation; thus, C-peptide levels serve as a surrogate for β-cell function, decreasing with loss of β-cell mass in T1D and increasing with insulin resistance–associated hyperinsulinemia. The most important stimulus for insulin synthesis and release is glucose. An increase in blood glucose levels results in glucose uptake into pancreatic β cells, facilitated by an insulin-independent glucose transporter, GLUT2 (Fig. 24.28). Metabolism of glucose generates ATP, which leads to the influx of Ca2+ through plasma membrane calcium channels. The resultant increase in intracellular Ca2+ stimulates secretion of insulin, presumably from hormone stored in β-cell granules. This is the phase of immediate insulin release, sometimes called the first phase of β-cell insulin secretion. If the secretory stimulus persists, a delayed and protracted response follows that involves active synthesis of insulin, the second phase. Oral intake of food leads to secretion of multiple hormones that play a role in glucose homeostasis and satiety. Of these, the most important class of hormones responsible for promoting insulin secretion from pancreatic β cells following feeding is the incretins, which act by binding G-protein–coupled receptors that are expressed on pancreatic β cells. The two most important incretins are glucose-dependent insulinotropic polypeptide (GIP) and The endocrine pancreas glucagon-like peptide-1 (GLP-1), both secreted by cells in the intestines following oral food intake. The elevation in GIP and GLP-1 levels is known as the “incretin effect.” In addition to increasing insulin secretion from β cells, these hormones reduce glucagon secretion from pancreatic α cells and delay gastric emptying, which promotes satiety. Once released, circulating GIP and GLP-1 are degraded in the circulation by a class of enzymes known as dipeptidyl peptidases (DPPs), especially DPP-4. The “incretin effect” is significantly blunted in patients with T2D, and efforts to restore incretin function can improve glycemic control and promote weight loss (through restoration of satiety). These insights have led to the recent development of two classes of drugs for treating T2D: GLP-1 receptor agonists, which are synthetic GLP-1 mimetics that bind to and activate the GLP-1 receptor on islet and extrapancreatic cells; and DPP-4 inhibitors, which enhance levels of endogenous incretins by delaying their degradation. GLP-1 also increases energy expenditure, so the weight-loss–inducing effects are likely multifactorial. Indeed, GLP-1 receptor agonists are also now approved for treatment of obesity. Insulin Action and Insulin-Signaling Pathways Insulin is the most potent anabolic hormone known, with multiple synthetic and growth-promoting effects (Fig. 24.29). The principal metabolic function of insulin is to increase the rate of glucose transport into certain cells in the body, thus providing a major source of energy and metabolic intermediates derived from glucose that are used in the biosynthesis of cellular building blocks such as lipids, nucleotides, and amino acids. The most important targets of insulin action are striated muscle cells (including cardiomyocytes) and, to a lesser extent, adipocytes, which together normally represent about two-thirds of the body’s weight. The type of adipose tissue that utilizes the most glucose is Adipose tissue “beige” adipose tissue, which develops with exercise, and not the “white” adipose tissue that accumulates in obese individuals. This is one reason why exercise is beneficial and obesity detrimental to glucose control. In muscle cells, glucose is either stored as glycogen or oxidized to generate ATP. In adipose tissue, glucose is primarily used as a substrate for synthesis of lipids, which are stored as triglycerides. Besides promoting lipid synthesis, insulin also inhibits triglyceride hydrolysis and lipid release by adipocytes. Similarly, insulin promotes amino acid uptake and protein synthesis, while inhibiting protein degradation. Thus, the anabolic effects of insulin are attributable to increased synthesis and reduced degradation of glycogen, lipids, and proteins. In addition, insulin has several mitogenic activities, including initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation. The metabolic effects of insulin are exerted through its binding to the insulin receptor, which, in turn, sets into motion a series of signaling events through an array of mediators, the more pertinent of which are summarized in Fig. 24.30. The insulin receptor is a tetrameric protein composed of two α-subunits and two β-subunits. The βsubunit cytosolic domain possesses tyrosine kinase activity. Insulin binding to the α-subunit extracellular domain activates the β-subunit tyrosine kinase, which autophosphorylates itself and also phosphorylates several intracellular docking or bridging proteins, including so-called insulin receptor substrate (IRS) proteins. These molecules in turn activate downstream factors such as PI-3-kinase and Akt, a serine/threonine kinase that serves as a central signaling hub that mediates many insulin-dependent activities, including increased glucose uptake, reduced glucose synthesis, and increased glycogen and protein synthesis. Pathogenesis of Type 1 Diabetes T1D is an autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting against endogenous β-cell antigens. T1D most commonly develops in childhood, becomes manifest at puberty, and progresses with age. Because the disease can develop at any age, including late adulthood, the old moniker “juvenileonset diabetes” is no longer used. Similarly, “insulindependent diabetes mellitus” has been excluded from the current classification of diabetes because many forms of diabetes eventually require treatment with insulin. Nevertheless, most patients with T1D require insulin for survival; without insulin, they may develop serious metabolic complications such as ketoacidosis and coma. As with most autoimmune diseases, the pathogenesis of T1D involves an interplay of genetic and environmental factors. Glucose uptake Lipogenesis Lipolysis Insulin Genetic Susceptibility Striated muscle Glucose uptake Glycogen synthesis Protein synthesis Liver Gluconeogenesis Glycogen synthesis Lipogenesis Figure 24.29 Metabolic actions of insulin in striated muscle, adipose tissue, and liver. Epidemiologic studies, such as those demonstrating higher concordance rates in monozygotic versus dizygotic twins, have convincingly established a genetic basis for T1D. More recently, GWAS have identified multiple genetic susceptibility loci for T1D, as well as for T2D (see later). Of these, the most important locus is the HLA gene cluster, which according to some estimates contributes as much as 50% of the genetic susceptibility for T1D. Ninety percent to 95% 1101 1102 C H A P T E R 24 The Endocrine System Insulin Glucose Insulin receptor α P β α GLUT-4 β P IRS Glucose uptake PI3K P P GLUT-4 vesicle Akt P P P P P TSC1 TSC2 mTOR P P P P FOXO GSK3 Glucose synthesis Glycogen synthesis Protein synthesis Figure 24.30 Insulin action on a target cell. Insulin binding to the tetrameric receptor initiates a cascade of phosphorylation events that result in activation of PI-3-kinase/Akt signaling. Akt is a serine threonine kinase that mediates its effector functions via phosphorylation-dependent events. For example, Akt phosphorylates and inhibits the function of the tuberous sclerosis complex (TSC) proteins, leading to activation of the downstream mammalian TOR (mTOR) complex, which enhances protein synthesis. Akt also inhibits the function of Forkhead box O (FOXO) protein, which, in turn, reduces glucose synthesis, while inhibition of glycogen synthase kinase 3 (GSK3) enhances glycogen production. Finally, Akt enhances intracellular glucose uptake by translocation of GLUT-4 vesicles to the cell membrane. IRS, Insulin receptor substrate; PI3K, phosphoinositide 3-kinase. (Modified from Brendan Manning, Harvard T.H. Chan School of Public Health.) of Caucasians with this disease have either an HLA-DR3 or HLA-DR4 haplotype, in contrast to about 40% of normal subjects; moreover, 40% to 50% of patients with T1D are DR3/DR4 compound heterozygotes, in contrast to 5% of normal subjects. Individuals who have either DR3 or DR4 concurrently with a DQ8 haplotype demonstrate one of the highest inherited risks for T1D in sibling studies. Predictably, the polymorphisms in the HLA molecules that are associated with risk are located in or adjacent to the peptide-binding pockets, consistent with the notion that disease-associated alleles code for HLA molecules that have the capacity to display particular antigens. However, as discussed in Chapter 6, it is still not known how particular HLA alleles contribute to the pathogenesis of T1D (and other autoimmune diseases). Several non-HLA genes also confer susceptibility to T1D. The first disease-associated non-MHC gene variant to be identified consisted of variable number of tandem repeats in the promoter region of the insulin gene. The mechanism underlying this association is unknown. It is possible that these polymorphisms influence insulin expression by thymic antigen-presenting cells, thus affecting the negative selection of insulin-reactive T cells (Chapter 6). The association between polymorphisms in CTLA4 and PTPN22 and autoimmune thyroiditis was mentioned earlier; not surprisingly, these genes have also been linked with susceptibility to T1D. The relationship of T1D to altered T-cell selection and regulation is also underscored by the striking prevalence of this disease in individuals with rare germline defects in genes that code for immune regulators, such as AIRE, mutations of which cause APS-1 (discussed later). Environmental Factors As in other autoimmune diseases, genetic susceptibility contributes to only a part of diabetes risk, and the concordance rate in monozygotic twins is only about 50%, so environmental factors must play a role. The nature of these environmental influences remains an enigma. Although antecedent viral infections have been suggested as triggers, neither the type of virus nor how it promotes islet-specific autoimmunity is established. Some studies suggest that viruses might share epitopes with islet antigens, and the immune response to the virus results in cross-reactivity and destruction of islet tissues, a phenomenon known as molecular mimicry. On the other hand, certain infections are also thought to be protective against T1D. Mechanisms of β-Cell Destruction While the clinical onset of T1D is often abrupt, there is a lengthy lag period between initiation of the autoimmune process and the appearance of symptomatic disease, during which there is progressive loss of insulin reserves. Three distinct stages of T1D are now recognized (Fig. 24.31). In stage 1 (autoimmunity positive, normoglycemia, presymptomatic T1D), individuals have developed two or more islet autoantibodies but are still normoglycemic. In stage 2 (autoimmunity positive, dysglycemia, presymptomatic T1D), there is increasingly severe loss of glucose tolerance due to progressive loss of β-cell mass, but frank symptoms are absent. Nonetheless, the 5-year risk of developing symptomatic T1D increases from less than 50% in stage 1 to 75% in stage 2. Finally, in stage 3 (autoimmunity positive, dysglycemia, symptomatic T1D), classic manifestations of the disease (polyuria, polydipsia, polyphagia, ketoacidosis; see later) appear, typically after more than 90% of the β cells have been destroyed. The fundamental immune abnormality in T1D is a failure of self-tolerance in T cells specific for islet antigens. This failure of tolerance may be a result of some combination of defective clonal deletion of self-reactive T cells in the thymus, as well as defects in the functions of regulatory T cells or abnormal resistance of effector T cells to suppression by regulatory cells. Thus, autoreactive T cells not only survive, but are poised to respond to self antigens. The initial activation of these cells is thought to occur in the peripancreatic lymph nodes, perhaps in response to antigens that are released from damaged islets. The activated T cells then traffic to the pancreas, where they cause β-cell injury. Multiple T-cell populations have been implicated in this damage, including Th1 cells (which may secrete cytokines, including IFN-γ and TNF, that injure β cells), and CD8+ CTLs (which kill β cells directly). The islet autoantigens that are the targets of immune attack may include insulin, the β-cell enzyme glutamic acid decarboxylase (GAD), and others. Consistent with the idea that failure of self-tolerance is fundamental to the pathogenesis of T1D, cancer patients The endocrine pancreas Proposed nomenclature Phenotypic characteristics Stage 1 Stage 2 Stage 3 β-Cell autoimmunity Normogylcemia Presymptomatic β-Cell autoimmunity Dysgylcemia Presymptomatic β-Cell autoimmunity Dysgylcemia Symptomatic Individual at risk for Type 1 diabetes Presymptomatic Type 1 diabetes Symptomatic Type 1 diabetes Phase in natural history Functional β-Cell mass 100% 0% Time Figure 24.31 The three stages of type 1 diabetes. (Modified with permission from Insel RA, Dunne JL, Atkinson MA, et al: Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association, Diabetes Care 38(10):1964–1974, 2015.) treated with immune checkpoint blockade therapy, which disrupts tolerance mechanisms, sometimes develop the disease. A role for antibodies in T1D is suspected because autoantibodies against islet antigens are found in the vast majority of patients with T1D, including at the presymptomatic stages of disease, as described earlier. However, it is not clear if the autoantibodies cause injury or are merely a consequence of islet injury. Pathogenesis of Type 2 Diabetes T2D is a complex disease that involves the interplay of genetic and environmental factors and a pro-inflammatory state. Unlike T1D, there is no evidence of an autoimmune basis. Genetic Factors Genetic susceptibility contributes to the pathogenesis, as evidenced by the disease concordance rate of greater than 90% in monozygotic twins, a rate higher than in T1D. Furthermore, first-degree relatives have 5- to 10-fold higher risk of developing T2D than those without a family history, when matched for age and weight. GWAS performed over the past decade have identified at least 30 loci that individually confer a minimal to modest increase in the lifetime risk for T2D. Many of these genes are involved in adipose tissue function (through effects on bodily fat distribution [visceral vs. subcutaneous]), islet β-cell function, and obesity. It is believed that together, these genetic polymorphisms conspire to provide the genetic basis for T2D risk. However, heritable risk remains a minor player impacting disease susceptibility, and environmental factors are the major contributors. Environmental Factors The most important environmental risk factor for T2D is obesity, particularly central or visceral obesity. Greater than 80% of individuals with T2D are obese, and the incidence of diabetes worldwide has risen in proportion to obesity. Obesity contributes to the cardinal metabolic abnormalities of diabetes (see later) and to insulin resistance early in disease. In fact, even modest weight loss through dietary modifications can reduce insulin resistance and improve glucose tolerance. A sedentary lifestyle (typified by lack of exercise) is another risk factor for diabetes, independent of obesity. Weight loss and exercise usually increase insulin sensitivity additively and are often first-line interventions in patients with milder T2D. The combination of obesity, hyperglycemia, increased serum cholesterol and triglycerides, and hypertension is called the metabolic syndrome. Despite this general risk, several populations worldwide in which T2D rates are increasing most rapidly (e.g., East Asian, South Asian, and Middle Eastern) do not show comparable increases in obesity (increased body mass index [BMI], a measure of total body fat). This has suggested that risk is related not only to the amount of body fat but also to its anatomic distribution, as discussed later. Sleep disorders (such as obstructive sleep apnea) and circadian disruption are additional environmental risk factors for T2D. Circadian disruption is defined as misalignment between the endogenous circadian rhythm and the cycle or rhythm created by individual behaviors. Those at risk for circadian disruption include shift workers and those with sleep disorders or other conditions that restrict nighttime sleep and daytime wakefulness. Studies have shown that circadian disruption impairs glucose homeostasis by affecting both insulin secretion and insulin action. In addition, GWAS have shown an association between circadian-controlled genes and T2D. Disruption of “clock” genes not only affects insulin secretion and action but also activity level and feeding behaviors, resulting in increased risk for hyperglycemia and diabetes. 1103 1104 C H A P T E R 24 The Endocrine System Metabolic Defects in Type 2 Diabetes The development of T2D involves two key abnormalities: Insulin resistance: Decreased response of peripheral tissues, especially skeletal muscle, adipose tissue, and liver, to insulin β-cell dysfunction: Inadequate insulin secretion in the face of insulin resistance and hyperglycemia Insulin resistance predates the development of hyperglycemia and is usually accompanied by compensatory β-cell hyperfunction and hyperinsulinemia in the early stages of the evolution of T2D (Fig. 24.32). Over time, the inability of β cells to adapt to increasing secretory needs for maintaining a euglycemic state results in chronic hyperglycemia and the resulting long-standing complications of diabetes. Insulin Resistance Insulin resistance is the failure of target tissues to respond normally to insulin. The liver, skeletal muscle, and adipose tissue are the major tissues where insulin resistance gives rise to abnormal glucose tolerance. Insulin resistance results in the following: Failure to inhibit endogenous glucose production (gluconeogenesis) in the liver, which contributes to high fasting blood glucose levels Obesity Vasculature Adipocytes Adipokines FFAs Inflammation Insulin resistance Pancreatic islet β-cell compensation β-cell failure β-cells Insulin secretion by β-cells Normal Increased Decreased Blood glucose Normal Normal to impaired glucose tolerance Diabetes mellitus Figure 24.32 Development of type 2 diabetes. Insulin resistance associated with obesity is induced by adipokines, free fatty acids (FFAs), and chronic inflammation in adipose tissue. Pancreatic β cells compensate for insulin resistance by hypersecretion of insulin. However, at some point, β-cell compensation is followed by β-cell failure, and diabetes ensues. (Reproduced with permission from Kasuga M: Insulin resistance and pancreatic β-cell failure, J Clin Invest 116(7):1756–1760, 2006.) Failure of glucose uptake and glycogen synthesis to occur in skeletal muscle following a meal, which contributes to high postprandial blood glucose level Failure to inhibit activation of “hormone-sensitive” lipases in adipose tissue, leading to excess triglyceride breakdown in adipocytes and high levels of circulating free fatty acids (FFAs). A variety of functional defects in the insulin-signaling pathway underlie insulin resistance. For example, reduced tyrosine phosphorylation of the insulin receptor and IRS proteins is observed in peripheral tissues, which compromises insulin signaling and reduces the level of the glucose transporter GLUT-4 on the cell surface (see Fig. 24.30). In fact, one of the mechanisms by which exercise improves insulin sensitivity is by increasing the translocation of GLUT-4 to the plasma membrane of skeletal muscle cells. Obesity Multiple factors contribute to insulin resistance, of which obesity is probably the most important. The risk for diabetes rises as the BMI increases. Not only the absolute amount of fat but also its distribution determines insulin sensitivity: central obesity (abdominal fat) is more likely to be linked with insulin resistance than is peripheral (gluteal/ subcutaneous) obesity. In fact, individuals from Asia and the Middle East who develop diabetes without overt obesity have primarily visceral adiposity, and it is this increase in visceral fat that appears to engender T2D risk for them. By contrast, individuals who develop primarily subcutaneous adiposity may be relatively protected from T2D. Studies of these so-called “metabolically healthy obese” individuals is an emerging field. Obesity can adversely impact insulin sensitivity in numerous ways (see Fig. 24.32): Free fatty acids (FFAs). Cross-sectional studies have demonstrated an inverse correlation between fasting plasma FFAs and insulin sensitivity. Central adipose tissue is more “lipolytic” than peripheral sites, which might explain the particularly deleterious consequences of this pattern of fat distribution. Excess FFAs overwhelm the intracellular fatty acid oxidation pathways, leading to the accumulation of cytoplasmic intermediates like diacylglycerol (DAG), phospholipids, and sphingolipids, including ceramides. These “toxic” lipid metabolites can attenuate signaling through the insulin receptor and activate inflammatory pathways in the islets, which further promote β-cell abnormalities. In liver cells, insulin normally inhibits gluconeogenesis by blocking the activity of phosphoenolpyruvate carboxykinase, the first enzymatic step in this process. Attenuated insulin signaling allows phosphoenolpyruvate carboxykinase to “ramp up” gluconeogenesis. Excess FFAs also compete with glucose as substrates for oxidation, further exacerbating the reduced glucose utilization. Adipokines. You will recall that adipose tissue is not merely a storage depot for fat but is also an endocrine organ that releases hormones in response to changes in metabolism (Chapter 9). A variety of proteins secreted into the circulation by adipose tissue have been identified that are collectively termed adipokines (or adipose cytokines). Some of these promote hyperglycemia, while others (such The endocrine pancreas as leptin and adiponectin) decrease blood glucose, in part by increasing insulin sensitivity in peripheral tissues. Adiponectin levels are reduced in obesity, thus contributing to insulin resistance. Inflammation: Over the past several years, inflammation has emerged as an important factor in the pathogenesis of T2D. It is now known that an inflammatory milieu— mediated not by an autoimmune process, as in T1D, but rather by pro-inflammatory cytokines that are secreted in response to excess nutrients such as FFAs and glucose— results in both insulin resistance and β-cell dysfunction. Excess FFAs within macrophages and β cells can activate the inflammasome, a multiprotein cytoplasmic complex that leads to secretion of the cytokine interleukin IL-1β (Chapter 3). IL-1β, in turn, mediates the secretion of additional pro-inflammatory cytokines from macrophages, islet cells, and other cells. IL-1 and other cytokines act on the major sites of insulin action to promote insulin resistance. Thus, excess FFAs can impede insulin signaling directly within peripheral tissues, as well as indirectly through the release of pro-inflammatory cytokines. Liver steatosis: High circulating levels of FFAs may result in the accumulation of excess fat (steatosis) in hepatocytes. This form of nonalcoholic fatty liver disease (NAFLD) ranges in severity from hepatic steatosis without evidence of liver injury to nonalcoholic steatohepatitis (NASH) with evidence of inflammation and hepatocyte injury with or without fibrosis (Chapter 18). NAFLD is common in those with metabolic syndrome and T2D, an association that cuts both ways: NAFLD promotes the development of T2D, which in turn increases the risk of developing the more severe forms of NAFLD. β-Cell Dysfunction While insulin resistance by itself can lead to impaired glucose tolerance, β-cell dysfunction is a requirement for the development of overt diabetes. In contrast to the severe genetic defects in β-cell function that occur in monogenic forms of diabetes (see later), β-cell function actually increases early in the disease process in most patients with “sporadic” T2D as a compensatory measure to counter insulin resistance and maintain euglycemia. Eventually, however, β cells seemingly exhaust their capacity to adapt to the long-term demands posed by insulin resistance, and the hyperinsulinemic state gives way to a state of relative insulin deficiency, that is, insulin levels are deficient for the level of blood glucose. Several mechanisms have been implicated in promoting β-cell dysfunction in T2D, including the following: Excess FFAs that compromise β-cell function and attenuate insulin release (lipotoxicity) The impact of chronic hyperglycemia (glucotoxicity) An abnormal incretin effect, leading to reduced secretion of GIP and GLP-1, hormones that promote insulin release (see earlier) Amyloid deposition within islets. This is a characteristic finding in individuals with long-standing T2D, being present in more than 90% of diabetic islets examined, but it is unclear whether it is a cause or an effect of β-cell “burnout.” Finally, the impact of genetics cannot be discounted, as many of the polymorphisms associated with an increased lifetime risk for T2D occur in genes that control insulin secretion (see earlier). Monogenic Forms of Diabetes Although genetically defined causes of diabetes are uncommon, they have been intensively studied in the hope of gaining insights into the disease. As Table 24.6 illustrates, monogenic forms of diabetes are classified separately from types 1 and 2 diabetes. Monogenic forms of diabetes result from either a primary defect in β-cell function or a defect in insulin receptor signaling (described later). Genetic Defects in β-Cell Function Approximately 1% to 2% of patients with diabetes harbor a primary defect in β-cell function that affects either β-cell mass and/or insulin production. This form of monogenic diabetes is caused by a heterogeneous group of genetic defects. The largest subgroup of patients in this category was designated as having “maturity-onset diabetes of the young” (MODY) because of its superficial resemblance to T2D and its occurrence in younger patients. MODY can result from germline loss-of-function mutations in one of six genes (see Table 24.6), of which mutations of glucokinase (GCK) are the most common. Glucokinase is a rate-limiting step in oxidative glucose metabolism, which, in turn, is coupled to insulin secretion within islet β cells (see Fig. 24.28). Genetic Defects That Impair Tissue Response to Insulin Rare insulin receptor mutations that affect receptor synthesis, insulin binding, or RTK activity can cause severe insulin resistance, accompanied by hyperinsulinemia and diabetes (type A insulin resistance). Such patients often show a velvety hyperpigmentation of the skin known as acanthosis nigricans. Females with type A insulin resistance also frequently have polycystic ovaries and elevated androgen levels. Diabetes and Pregnancy Pregnancy can be complicated by diabetes in one of two settings: when women with preexisting diabetes become pregnant (“pregestational” or overt diabetes) or women who were previously euglycemic develop impaired glucose tolerance and diabetes for the first time during pregnancy (“gestational” diabetes). Approximately 5% to 9% of pregnancies occurring in the United States are complicated by hyperglycemia, and the incidence of both pregestational and gestational diabetes is increasing in the general population. Pregnancy is a “diabetogenic” state in which the prevailing hormonal milieu favors insulin resistance. In a previously euglycemic woman who is otherwise susceptible due to concurrent genetic and environmental factors, the consequence may be gestational diabetes. Of even greater concern, women with pregestational diabetes have an increased risk of stillbirth and congenital malformations in the fetus. Poorly controlled diabetes that arises later in pregnancy, regardless of prior history, can lead to excessive birth weight in the newborn (macrosomia) and may have long-term sequelae for the child later in life, including an increased risk of obesity and diabetes. Gestational diabetes typically resolves following delivery; however, the majority of affected women develop overt diabetes over the next 10 to 20 years. 1105 1106 C H A P T E R 24 The Endocrine System Clinical Features of Diabetes It is difficult to sketch with brevity the diverse clinical presentations of diabetes. We will discuss the most common initial presentation or mode of diagnosis for each of the two major subtypes, followed by a discussion of acute and then chronic (long-term) complications of the disease. T1D may arise at any age. In the initial 1 or 2 years following the onset of overt T1D, exogenous insulin requirements may be minimal because of residual endogenous insulin secretion (referred to as the honeymoon period). Eventually, however, β-cell function declines to a tipping point, and insulin requirements increase dramatically. Although β-cell destruction is a prolonged process, the transition from impaired glucose tolerance (stage 2, see earlier) to overt diabetes (stage 3) may be abrupt and is often brought on by a superimposed stress, such as infection, because of associated increase in insulin requirements. In contrast to T1D, T2D is typically seen in obese patients older than 40 years of age; however, it is now being diagnosed in children and adolescents with increasing frequency due to increases in obesity and sedentary lifestyle. In some cases, medical attention is sought because of unexplained fatigue, dizziness, or blurred vision. Most frequently, however, the diagnosis of T2D is made after routine blood testing in asymptomatic persons. In fact, in light of the large number of asymptomatic individuals with undiagnosed hyperglycemia in the United States, routine blood glucose testing is recommended for everyone older than 45 years of age, and in younger individuals with obesity, family history, or the presence of the metabolic syndrome. The Classic Triad of Diabetes The onset of T1D is usually marked by the triad of polyuria, polydipsia, polyphagia, and, when severe, diabetic ketoacidosis, all resulting from metabolic derangements. Because insulin is a major anabolic hormone, its deficiency results in a catabolic state that affects glucose, fat, and protein metabolism. Unopposed secretion of counterregulatory hormones (such as glucagon) also plays a role in these metabolic derangements. The assimilation of glucose into muscle and adipose tissue is sharply diminished or abolished. Not only does storage of glycogen in liver and muscle cease, but reserves are depleted by glycogenolysis. The resultant hyperglycemia leads to filtration of so much glucose in the kidney that the renal tubular threshold for reabsorption is exceeded. This leads to glycosuria, which induces an osmotic diuresis and thus polyuria, causing a profound loss of water and electrolytes (Fig. 24.33). The renal water loss combined with the hyperosmolarity owing to increased levels of glucose in the blood depletes intracellular water, triggering the osmoreceptors of the thirst centers of the brain. Thus, intense thirst (polydipsia) appears. With a deficiency of insulin, the scales swing from insulin-promoted anabolism to catabolism of proteins and fats. Proteolysis follows, releasing gluconeogenic amino acids that are removed by the liver and used as building blocks for glucose. The catabolism of proteins and fats tends to induce a negative energy balance, which in turn leads to increasing appetite (polyphagia), thus completing the classic triad of polyuria, polydipsia, and polyphagia. Despite the increased appetite, catabolic effects prevail, resulting in weight loss and muscle weakness. The combination of polyphagia and weight loss is paradoxical and should always raise the suspicion of diabetes. Acute Metabolic Complications of Diabetes Diabetic ketoacidosis is a severe acute metabolic complication of T1D; it is not as common or as severe in T2D. The most frequent precipitating factor is a failure to take insulin, although other stressors such as infections, other illnesses, trauma, and certain drugs may also serve as triggers. It may also occur less commonly in T2D but only under condition of very severe stress such as caused by serious infections and trauma. Many of these factors are associated with the release of the catecholamine epinephrine, which blocks residual insulin action and stimulates the secretion of glucagon. The insulin deficiency coupled with glucagon excess decreases peripheral utilization of glucose while increasing gluconeogenesis, severely exacerbating hyperglycemia (the plasma glucose levels are usually in the range of 250 to 600 mg/dL). The hyperglycemia causes an osmotic diuresis and dehydration characteristic of the ketoacidotic state. A second major effect of insulin deficiency is increased synthesis of ketone bodies. Insulin deficiency stimulates hormone-sensitive lipase, with a resultant breakdown of adipose stores and an increase in levels of FFAs. When these FFAs reach the liver, they are esterified to fatty acyl coenzyme A. Oxidation of fatty acyl coenzyme A molecules within the hepatic mitochondria produces ketone bodies (acetoacetic acid and β-hydroxybutyric acid). The rate at which ketone bodies are formed may exceed the rate at which they can be utilized by peripheral tissues, leading to ketonemia and ketonuria. If the urinary excretion of ketones is compromised by dehydration, the result is a systemic metabolic ketoacidosis. Release of ketogenic amino acids by protein catabolism aggravates the ketotic state. The clinical manifestations of diabetic ketoacidosis include fatigue, nausea and vomiting, severe abdominal pain, a characteristic fruity odor, and deep, labored breathing (also known as Kussmaul breathing). Persistence of the ketotic state eventually leads to depressed consciousness and coma. Reversal of ketoacidosis requires administration of insulin, correction of metabolic acidosis, and treatment of any underlying precipitating factors, such as infection. The lower frequency of ketoacidosis in T2D is believed to be due to higher portal vein insulin levels in these patients, which prevents unrestricted hepatic fatty acid oxidation and keeps the formation of ketone bodies in check. Instead, patients with T2D may develop a condition known as hyperosmolar hyperglycemic state due to severe dehydration resulting from sustained osmotic diuresis (particularly in patients who do not drink enough water to compensate for urinary losses from chronic hyperglycemia). Typically, this occurs in an older patient who has diabetes and is disabled by a stroke or an infection and thus unable to maintain adequate water intake. Furthermore, the absence of ketoacidosis and its symptoms (nausea, vomiting, Kussmaul breathing) delays the seeking of medical attention until severe dehydration and impairment of mental status occur. The hyperglycemia is usually more severe than in diabetic ketoacidosis, in the range of 600 to 1200 mg/dL. Once treatment commences, ironically, the most common acute metabolic complication in either type of diabetes is The endocrine pancreas Insulin deficiency and/or insulin resistance Leads to decreased tissue glucose utilization spillover into blood Glucagon excess Muscle Adipose tissue Increased lipolysis (free fatty acids) Increased protein catabolism (amino acids) Gluconeogenesis Ketogenesis Liver POLYPHAGIA KETOACIDOSIS HYPERGLYCEMIA DIABETIC COMA Kidney Ketonuria Glycosuria POLYURIA VOLUME DEPLETION POLYDIPSIA Figure 24.33 Sequence of metabolic derangements underlying the clinical manifestations of diabetes. An absolute insulin deficiency leads to a catabolic state, culminating in ketoacidosis and severe volume depletion. These cause sufficient central nervous system compromise to lead to coma and eventual death if left untreated. hypoglycemia. Causes include missing a meal, excessive physical exertion, excessive insulin administration, or “misdosing” during the phase of dose finding for antidiabetic agents such as sulfonylureas. The signs and symptoms of hypoglycemia include dizziness, confusion, sweating, palpitations, and tachycardia; if hypoglycemia persists, loss of consciousness may occur. Rapid reversal of hypoglycemia through oral or intravenous glucose intake is critical for preventing permanent neurologic damage. Chronic Complications of Diabetes The morbidity associated with long-standing diabetes of either type is due to damage induced in large- and mediumsized muscular arteries (diabetic macrovascular disease) and in small vessels (diabetic microvascular disease) by chronic hyperglycemia. Macrovascular disease causes accelerated atherosclerosis among patients with diabetes, resulting in increased risk of myocardial infarction, stroke, and lower extremity ischemia. The effects of microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively (see later). Pathogenesis Persistent hyperglycemia (glucotoxicity) seems to be responsible for the long-term complications of diabetes. Much of the evidence supporting a role for glycemic control in ameliorating the long-term complications of diabetes has come from large randomized trials. The assessment of glycemic control in these trials has been based on the percentage of glycated hemoglobin, also known as HbA1c, which is formed by nonenzymatic covalent addition of glucose moieties to hemoglobin in red cells. Unlike blood glucose levels, HbA1c provides a measure of glycemic control over the lifespan of a red cell (120 days) and is affected little by day-to-day variation in glucose levels. It is recommended that HbA1c be maintained below 7% in patients with diabetes. The emergence of new technology, including 1107 1108 C H A P T E R 24 The Endocrine System continuous glucose-monitoring systems, has introduced a new goal, increasing “time-in-range” (set at 70 to 180 mg/ dL), which may be a better predictor of the risk of chronic complications than HbA1c level. It is important to stress, however, that hyperglycemia is not the only factor responsible for the long-term complications of diabetes, and that other underlying abnormalities, such as insulin resistance, and comorbidities like obesity, also play an important role. At least four distinct mechanisms have been implicated in the deleterious effects of persistent hyperglycemia on peripheral tissues. In each proposed mechanism, increased flux through metabolic pathways due to hyperglycemia is thought to generate harmful precursors that contribute to end-organ damage. Formation of advanced glycation end products. Advanced glycation end products (AGEs) are formed as a result of nonenzymatic reactions between glucose-derived metabolites (glyoxal, methylglyoxal, and 3-deoxyglucosone) and the amino groups of intracellular and extracellular proteins. The rate of AGE formation is accelerated by hyperglycemia. AGEs bind to a specific receptor (RAGE) that is expressed on inflammatory cells (macrophages and T cells), endothelium, and vascular smooth muscle. The detrimental effects of the AGE-RAGE signaling axis within the vascular compartment include the following: Release of cytokines and growth factors, including transforming growth factor-β (TGF-β), which leads to deposition of excess basement membrane material, and vascular endothelial growth factor (VEGF), implicated in diabetic retinopathy (see later) Generation of reactive oxygen species (ROS) in endothelial cells Increased procoagulant activity on endothelial cells and macrophages Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix Not surprisingly, endothelium-specific overexpression of RAGE in diabetic mice accelerates large vessel injury and microangiopathy, while RAGE-null mice show attenuation of these features. Antagonists of RAGE have emerged as therapeutic agents in diabetes and are being tested in clinical trials. In addition to receptor-mediated effects, AGEs can directly cross-link extracellular matrix proteins. Crosslinking of collagen type I molecules in large vessels decreases their elasticity, which may predispose these vessels to shear stress and endothelial injury (Chapter 11). Similarly, AGE-induced cross-linking of type IV collagen in basement membrane decreases endothelial cell adhesion and increases extravasation of fluid. Proteins cross-linked by AGEs are resistant to proteolytic digestion. Thus, cross-linking decreases protein removal, enhancing protein accumulation. AGE-modified matrix components also trap nonglycated plasma or interstitial proteins. In large vessels, trapping of LDL, for example, retards its efflux from the vessel wall and contributes to the deposition of cholesterol in the intima, thus accelerating atherogenesis (Chapter 11). In capillaries, including those of renal glomeruli, plasma proteins such as albumin bind to the glycated basement membrane, accounting in part for the basement membrane thickening that is characteristic of diabetic microangiopathy. Activation of protein kinase C. Calcium-dependent activation of intracellular protein kinase C (PKC) and the second messenger diacyl glycerol (DAG) is an important signal transduction pathway. Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic intermediates, and hence causes excessive PKC activation. The downstream effects of PKC activation are numerous, including production of VEGF, TGF-β, and the procoagulant protein plasminogen activator inhibitor-1 (PAI-1) (Chapter 4) by the vascular endothelium. It should be evident that some effects of AGEs and activated PKC are overlapping, and both likely contribute to diabetic microangiopathy. Oxidative stress and disturbances in polyol pathways. Even in tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys, blood vessels), persistent hyperglycemia leads to an increase in intracellular glucose. This excess glucose is metabolized by the enzyme aldose reductase to sorbitol, a polyol, and eventually to fructose, in a reaction that uses NADPH (the reduced form of nicotinamide dinucleotide phosphate) as a cofactor. NADPH is also required by the enzyme glutathione reductase in a reaction that regenerates reduced glutathione (GSH). GSH is one of the important antioxidant mechanisms in the cell (Chapter 2), and any reduction in GSH increases cellular susceptibility to reactive oxygen species (“oxidative stress”). In the face of sustained hyperglycemia, progressive depletion of intracellular NADPH by aldose reductase compromises GSH regeneration, increasing cellular susceptibility to oxidative stress. Sorbitol accumulation in the lens contributes to cataract formation. Hexosamine pathways and generation of fructose-6-phosphate. Finally, it is postulated that hyperglycemia induces flux of glycolytic intermediates through the hexosamine pathway, which results in cell damage and enhanced oxidative stress. Morphology of Chronic Complications of Diabetes The important morphologic changes are related to the many late systemic complications of diabetes. As discussed earlier, these changes are seen in both T1D and T2D (Fig. 24.34). MORPHOLOGY PANCREAS Alterations in the pancreas are inconstant and often subtle. Distinctive changes are more commonly associated with T1D than with T2D. One or more of the following alterations may be present: Reduction in the number and size of islets. This is most often seen in T1D, particularly with rapidly advancing disease. Most of the islets are small and inconspicuous. Leukocytic infiltrates in the islets (insulitis) are principally composed of T lymphocytes and are also seen in animal models of autoimmune diabetes (Fig. 24.35A). Lymphocytic infiltrates may be present in T1D at the time of clinical presentation. In T2D there may be a subtle reduction in islet cell mass, demonstrated only by special morphometric studies. Amyloid deposition within islets in T2D begins in and around capillaries and between cells. At advanced stages, the The endocrine pancreas Microangiopathy Cerebral vascular infarcts Hemorrhage Retinopathy Cataracts Glaucoma Hypertension Myocardial infarct Atherosclerosis Nephrosclerosis Glomerulosclerosis Arteriosclerosis Pyelonephritis Islet cell loss Insulitis (Type 1) Amyloid (Type 2) Peripheral vascular atherosclerosis Gangrene Peripheral neuropathy Autonomic neuropathy Infections Figure 24.34 Long-term complications of diabetes. islets may be virtually obliterated (see Fig. 24.35B); fibrosis may also be observed. Similar lesions may be found in older individuals without diabetes, apparently as part of normal aging. An increase in the number and size of islets is especially characteristic of nondiabetic newborns of mothers with diabetes. Presumably, fetal islets undergo hyperplasia in response to the maternal hyperglycemia. Diabetic Macrovascular Disease Diabetes exacts a heavy toll on the vascular system. Endothelial dysfunction (Chapter 11), which predisposes to atherosclerosis and other cardiovascular morbidities, is widespread in diabetes, as a consequence of the deleterious effects of persistent hyperglycemia and insulin resistance on the vascular compartment. The hallmark of diabetic macrovascular disease is accelerated atherosclerosis involving the aorta and large- and medium-sized arteries. The morphology of atherosclerosis in patients with diabetes is indistinguishable from that in individuals without diabetes (Chapter 11). Myocardial infarction, caused by atherosclerosis of the coronary arteries, is the most common cause of death in diabetes. Gangrene of the lower extremities, as a result of advanced vascular disease, is about 100 times more common in diabetes patients than in the general population. The larger renal arteries are also subject to severe atherosclerosis, but the most damaging effect of diabetes on the kidneys is exerted at the level of the glomeruli and the microcirculation (discussed later). Hyaline arteriolosclerosis, the vascular lesion associated with essential hypertension (Chapters 11 and 20), is both more prevalent and more severe in patients with diabetes than those without, but it is not specific for diabetes and may be seen in older patients without hypertension. It takes the form of an amorphous, hyaline thickening of the wall of the arterioles, which causes narrowing of the lumen (Fig. 24.36). Not surprisingly, in diabetic patients, it is related not only to the duration of the disease but also to the level of blood pressure. Diabetic Microangiopathy One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes. The thickening is most evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla. However, it may also be seen in such nonvascular structures as renal tubules, the Bowman capsule, peripheral nerves, and placenta. It should be noted that despite the increase in the thickness of basement membranes, capillaries in patients with diabetes are leakier than normal to plasma proteins. The microangiopathy underlies the development of 1109 1110 C H A P T E R 24 The Endocrine System U B A L Figure 24.37 Electron micrograph of a renal glomerulus showing markedly thickened glomerular basement membrane (B) in a diabetic. L, Glomerular capillary lumen; U, urinary space. (Courtesy Dr. Michael Kashgarian, Department of Pathology, Yale University School of Medicine, New Haven, Conn.) B Figure 24.35 (A) Insulitis, shown here from a rat (BB) model of autoimmune diabetes, also seen in type 1 human diabetes. (B) Amyloidosis of a pancreatic islet in type 2 diabetes. (A, Courtesy Dr. Arthur Like, University of Massachusetts, Worchester, Mass.) Figure 24.38 Renal cortex showing thickening of tubular basement membranes in a diabetic patient (periodic acid–Schiff stain). from this disease. Three lesions are encountered: (1) glomerular lesions; (2) renal vascular lesions, principally arteriolosclerosis; and (3) pyelonephritis, including necrotizing papillitis. The most important glomerular lesions are capillary basement membrane thickening, diffuse mesangial sclerosis, and nodular glomerulosclerosis. Figure 24.36 Severe renal hyaline arteriolosclerosis. Note a markedly thickened, tortuous afferent arteriole. The amorphous nature of the thickened vascular wall is evident (periodic acid–Schiff stain). (Courtesy M.A. Venkatachalam, MD, Department of Pathology, University of Texas Health Science Center, San Antonio, Texas.) diabetic nephropathy, retinopathy, and some forms of neuropathy. Diabetic Nephropathy The kidneys are prime targets of diabetes. Renal failure is second only to myocardial infarction as a cause of death Capillary Basement Membrane Thickening. Widespread thickening of the glomerular capillary basement membrane (GBM) occurs in virtually all cases of diabetic nephropathy and is part and parcel of diabetic microangiopathy. Capillary basement membrane thickening is best appreciated by electron microscopy (Fig. 24.37). Morphometric studies demonstrate that thickening begins as early as 2 years after the onset of T1D and by 5 years amounts to about a 30% increase. These progressive changes in the GBM are usually accompanied by mesangial widening and thickening of the tubular basement membranes (Fig. 24.38). The endocrine pancreas Figure 24.39 Diffuse and nodular diabetic glomerulosclerosis (periodic acid–Schiff [PAS] stain). Note the diffuse increase in mesangial matrix and characteristic acellular PAS-positive nodules. Diffuse Mesangial Sclerosis. This lesion consists of diffuse increase in mesangial matrix. The matrix depositions are PAS-positive (Fig. 24.39). As the disease progresses, the mesangial matrix deposits may take on a nodular appearance. The progressive expansion of the mesangium has been shown to correlate well with measures of deteriorating renal function such as increasing proteinuria. Nodular Glomerulosclerosis. This is also known as intercapillary glomerulosclerosis or Kimmelstiel-Wilson disease. The glomerular lesions take the form of ovoid or spherical, often laminated, PAS-positive nodules of matrix situated in the periphery of the glomerulus. They lie within the mesangial core of the glomerular lobules and may be surrounded by patent peripheral capillary loops (see Fig. 24.39) or loops that are markedly dilated. The nodules often show features of mesangiolysis, defined by disruption of anchoring interactions between the capillaries and the mesangial stalks. The loss of these support structures may lead to the formation of capillary microaneurysms. While not all the lobules in individual glomeruli are involved by nodular lesions, even uninvolved lobules and glomeruli show striking diffuse mesangial sclerosis. The nodular lesions are frequently accompanied by prominent accumulations of hyaline material in capillary loops (“fibrin caps”) or adherent to Bowman capsules (“capsular drops”). Both afferent and efferent glomerular hilar arterioles show hyalinosis. As a consequence of the glomerular and arteriolar lesions, the kidney becomes ischemic, develops tubular atrophy and interstitial fibrosis, and usually contracts in size (Fig. 24.40). Approximately 15% to 30% of individuals with long-term diabetes develop nodular glomerulosclerosis, and in most instances it is associated with renal failure. Renal atherosclerosis and arteriolosclerosis also contribute to renal dysfunction in patients with diabetes. Hyaline arteriolosclerosis affects not only the afferent but also the efferent arteriole. Such efferent arteriolosclerosis is rarely, if ever, encountered in individuals who do not have diabetes. Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to affect the tubules. Both the acute and chronic forms of this disease are more common and more severe Figure 24.40 Nephrosclerosis in a patient with long-standing diabetes. The kidney has been bisected to demonstrate both diffuse granular transformation of the surface (left) and marked thinning of the cortical tissue (right). Additional features include some irregular depressions, the result of pyelonephritis, and an incidental cortical cyst (far right). in patients with diabetes than in the general population. One special pattern of acute pyelonephritis, papillary necrosis, is much more prevalent in diabetes patients than in those without diabetes. Diabetic Ocular Complications The eye is profoundly affected by diabetes mellitus. The architecture and microanatomy of the eye are discussed in Chapter 29. Diabetes-induced hyperglycemia leads to acquired opacification of the lens, a condition known as cataract. Longstanding diabetes is also associated with increased intraocular pressure (glaucoma; see later), and resulting damage to the optic nerve. The most profound ocular changes of diabetes are seen in the retina. The retinal vasculopathy of diabetes mellitus can be classified into background (preproliferative) diabetic retinopathy and proliferative diabetic retinopathy (Chapter 29). Diabetic Neuropathy The prevalence of peripheral neuropathy in individuals with diabetes depends on the duration of the disease; up to 50% of diabetes patients overall have peripheral neuropathy clinically, and up to 80% of those who have had the disease for more than 15 years. This is discussed further in Chapter 27. Clinical Manifestations of Chronic Diabetes Table 24.7 summarizes some of the pertinent clinical, genetic, and histopathologic features that distinguish T1D and T2D. In both types, it is the long-term effects of diabetes, rather than acute metabolic complications, that are responsible for much of the morbidity and mortality. In most instances, these complications appear approximately 15 to 20 years after the onset of hyperglycemia. The severity of chronic 1111 1112 C H A P T E R 24 The Endocrine System complications is related to both the degree and the duration of hyperglycemia, as evidenced by the attenuation of endorgan damage by effective glycemic control in prospective studies. Macrovascular complications such as myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the most common causes of mortality in long-standing diabetes. Patients with diabetes have a two to four times greater incidence of coronary artery disease and a fourfold higher risk of dying from cardiovascular complications than age-matched individuals without diabetes. An elevated risk for cardiovascular disease is even observed in patients with prediabetes. Significantly, myocardial infarction is almost as common in women with diabetes as in men. In contrast, myocardial infarction is uncommon in women of reproductive age without diabetes. Diabetes is often accompanied by underlying conditions that favor the development of adverse cardiovascular events. For example, hypertension is found in approximately 75% of individuals with T2D and potentiates the effects of hyperglycemia and insulin resistance on endothelial dysfunction and atherosclerosis. Another cardiovascular risk frequently seen in diabetes patients is dyslipidemia, which includes both increased triglycerides and LDL levels and decreased levels of the “protective” lipoprotein, high-density lipoprotein (Chapter 11). Insulin resistance is believed to contribute to “diabetic dyslipidemia” by favoring the hepatic production of atherogenic lipoproteins and by suppressing the uptake of circulating lipids in peripheral tissues. Diabetic nephropathy is a leading cause of end-stage renal disease in the United States. Approximately 30% to 40% of all patients with diabetes develop clinical evidence of nephropathy. Development of end-stage renal disease is more likely with T1D than T2D, but because of the greater prevalence of T2D, these patients constitute slightly over one-half of the patients with diabetes starting dialysis each year. The progression from overt nephropathy to end-stage renal disease is highly variable, but by 20 years, more than 75% of patients with T1D and approximately 20% of those with T2D with overt nephropathy will develop end-stage renal disease, requiring dialysis or renal transplantation. The likelihood of diabetic nephropathy is greatly influenced by ethnicity; for example, Native Americans, Hispanics, and African Americans have a greater risk of developing end-stage renal disease than do non-Hispanic Caucasians with T2D. These differences are suspected to be genetic in origin, but responsible genes have yet to be identified. The earliest manifestation of diabetic nephropathy is the appearance of low amounts of albumin (microalbuminuria) in the urine (>30 mg and 300 mg/day of urinary albumin) over 10 to 15 years, usually accompanied by the appearance of hypertension. Visual impairment, including total blindness, is one of the more feared consequences of long-standing diabetes. Approximately 60% to 80% of patients develop some form of diabetic retinopathy approximately 15 to 20 years after diagnosis, and diabetic retinopathy is the leading cause of adult blindness in the United States. The fundamental lesion of retinopathy—neovascularization—is attributable to hypoxia-induced expression of VEGF in the retina. Current treatment for this condition includes administration of antiangiogenic agents that block the action of VEGF. As stated earlier, patients with diabetes also have an increased propensity for glaucoma and cataract formation, which also contribute to visual impairment. Diabetic neuropathy can result in damage to the central nervous system, peripheral sensorimotor nerves, and the autonomic nervous system. It most frequently takes the form of a distal symmetric polyneuropathy of the lower extremities that affects both motor and sensory function. Over time, the upper extremities may be involved as well, thus approximating a “glove-and-stocking” pattern of polyneuropathy. Other forms include autonomic neuropathy, which produces disturbances in bowel and bladder function and sometimes erectile dysfunction, and diabetic mononeuropathy, which may manifest as sudden footdrop, wristdrop, or isolated cranial nerve palsies. Patients with diabetes are plagued by enhanced susceptibility to infections of the skin and to tuberculosis, pneumonia, and pyelonephritis. Such infections cause the deaths of about 5% of these patients. In an individual with diabetic neuropathy, a trivial infection in a toe may be the first event in a long succession of complications (gangrene, bacteremia, pneumonia) that ultimately leads to death. The basis of enhanced susceptibility is multifactorial and includes decreased neutrophil function (chemotaxis, adherence to the endothelium, phagocytosis, and microbicidal activity) and impaired cytokine production by macrophages. The vascular compromise also impairs the delivery of immune cells and molecules to sites of infection. The staggering societal and economic impact of diabetes has already been discussed. For the most part, diabetes remains a lifelong disease, although pancreatic islet cell transplantation has the potential to ameliorate T1D for many patients. For some individuals with T2D, dietary modifications, exercise, and weight-loss regimens can reduce insulin resistance and hyperglycemia at least early in the disease. However, all patients will ultimately require some form of therapeutic intervention to maintain glycemic control. KEY CONCEPTS DIABETES MELLITUS: PATHOGENESIS AND LONG-TERM COMPLICATIONS T1D is an autoimmune disease characterized by progressive destruction of islet β cells, leading to absolute insulin deficiency. T1D stems from a failure of self-tolerance in T cells, and circulating autoantibodies to islet cell antigens (including insulin) often are detected in affected patients. T2D has no autoimmune basis; instead, features central to its pathogenesis are insulin resistance and β-cell dysfunction, resulting in relative insulin deficiency. Obesity has an important relationship with insulin resistance (and hence T2D), mediated through multiple factors including excess FFAs, cytokines released from adipose tissues (adipocytokines), and inflammation. The endocrine pancreas Monogenic forms of diabetes are uncommon and are caused by single-gene defects that result in primary β-cell dysfunction (e.g., glucokinase mutation) or lead to abnormalities of insulin-insulin receptor signaling (e.g., insulin receptor gene mutations). The long-term complications of diabetes are similar in both types and involve four potential mechanisms resulting from sustained hyperglycemia: formation of AGEs, activation of PKC, disturbances in the polyol pathways leading to oxidative stress, and overload of the hexosamine pathway. Long-term complications of diabetes include both large-vessel disease (macroangiopathy), such as atherosclerosis, ischemic heart disease, and lower extremity ischemia, as well as small vessel disease (microangiopathy), the latter manifesting mainly as retinopathy, nephropathy, and neuropathy. PANCREATIC NEUROENDOCRINE TUMORS The preferred term for tumors of the pancreatic islet cells (“islet cell tumors”) is pancreatic neuroendocrine tumors or PanNETs. They are rare in comparison with tumors of the exocrine pancreas, accounting for 2% of all pancreatic neoplasms. PanNETs can occur anywhere within the pancreas or in the immediate peripancreatic tissues. They resemble their counterparts, carcinoid tumors, found elsewhere in the alimentary tract (Chapter 17). These tumors may be single or multiple and benign or malignant. Pancreatic endocrine neoplasms often elaborate pancreatic hormones, but are sometimes nonfunctional. Like other endocrine neoplasms, it is difficult to predict the behavior of a PanNET based on its light microscopic appearance alone, although tumors with a higher proliferation index (measured as 3% or more neoplastic nuclei expressing Ki-67) can have an aggressive biological potential. Unequivocal criteria for malignancy include metastases, vascular invasion, and local infiltration. The functional status of the tumor has some impact on prognosis, in that approximately 90% of insulin-producing tumors are benign, and 60% to 90% of other functioning and nonfunctioning pancreatic endocrine neoplasms are malignant. Fortunately, insulinomas are the most common subtype of pancreatic endocrine neoplasms. Pathogenesis The genome of sporadic PanNETs recently has been sequenced, with identification of recurrent somatic alterations in three major genes or pathways: MEN1, which causes familial MEN syndrome, type 1, also is mutated in some sporadic neuroendocrine tumors Loss-of-function mutations in tumor suppressor genes such PTEN and TSC2 (Chapter 7), which result in activation of the oncogenic mammalian TOR (mTOR) signaling pathway. Inactivating mutations in two genes, alpha-thalassemia/ mental retardation syndrome, X-linked (ATRX) and death-domain–associated protein (DAXX), which have multiple cellular functions, including telomere maintenance. PanNETs with DAXX or ATRX mutations demonstrate a phenomenon known as “alternative lengthening of telomeres” (ALT), which allows telomeres to be maintained in noeplastic cells that do not express telomerase (Chapter 7). Of note, nearly one-half of PanNETs have a somatic mutation in either ATRX or DAXX, but not both, consistent with their function in the same oncogenic pathway. The three most common and distinctive clinical syndromes associated with functional pancreatic endocrine neoplasms are (1) hyperinsulinism, (2) hypergastrinemia and the ZollingerEllison syndrome, and (3) MEN (described later). Hyperinsulinism (Insulinoma) β-cell tumors (insulinomas) are the most common pancreatic endocrine neoplasms and often produce sufficient insulin to induce clinically significant hypoglycemia. The characteristic clinical picture is dominated by hypoglycemic episodes, which occur when the blood glucose level falls below 50 mg/dL. Clinical manifestations include confusion, stupor, and loss of consciousness. These episodes are precipitated by fasting or exercise and are promptly relieved by feeding or parenteral administration of glucose. MORPHOLOGY Insulinomas are most often found within the pancreas and are usually benign. Most are solitary, although multiple tumors may be encountered. Bona fide carcinomas, making up only about 10% of cases, are diagnosed on the basis of local invasion and distant metastases. On rare occasions an insulinoma may arise in ectopic pancreatic tissue. In such cases, electron microscopy reveals the distinctive granules of β cells (see Fig. 24.27). Solitary tumors are usually small (often