The Endocrine Pancreas PDF

The endocrine pancreas 1097 Autosomal-dominant hypoparathyroidism is caused by Mental status changes include emotional instability, anxiety gain-of-function mutations in the calcium-sensing recep- and depression, confusional states, hallucinations, and tor (C...

The endocrine pancreas 1097 Autosomal-dominant hypoparathyroidism is caused by Mental status changes include emotional instability, anxiety gain-of-function mutations in the calcium-sensing recep- and depression, confusional states, hallucinations, and tor (CASR) gene. Inappropriate CASR activity due to frank psychosis. heightened calcium sensing suppresses PTH, resulting Intracranial manifestations include calcifications of the basal in hypocalcemia and hypercalciuria. Recall that loss-of- ganglia, parkinsonian-like movement disorders, and function CASR mutations are a rare cause of familial increased intracranial pressure with resultant papilledema. parathyroid adenomas. The paradoxical association of hypocalcemia with calcifica- Familial isolated hypoparathyroidism (FIH) is a rare condition tions may be because of an increase in phosphate levels, with either autosomal dominant or autosomal recessive leading to deposition of calcium phosphate in vulnerable patterns of inheritance. Autosomal dominant FIH is caused tissues. by a mutation in the gene encoding PTH that impairs Ocular disease takes the form of calcification of the lens PTH processing to the mature active hormone. Autosomal and cataract formation. recessive FIH is caused by loss-of-function mutations in Cardiovascular manifestations include a conduction defect the transcription factor gene GCM2, which is essential that produces a characteristic prolongation of the QT for development of the parathyroid. interval in the electrocardiogram. Congenital absence of parathyroid glands can occur in Dental abnormalities occur when hypocalcemia is present conjunction with other malformations, such as thymic during early development. These findings are highly aplasia and cardiovascular defects, or as a component characteristic of hypoparathyroidism and include dental of the 22q11 deletion syndrome. As discussed in Chapter hypoplasia, failure of eruption, defective enamel and root 6, when thymic defects are present, the condition is called formation, and abraded carious teeth. DiGeorge syndrome. Clinical Features Pseudohypoparathyroidism The major manifestations of hypoparathyroidism are related In this condition, hypoparathyroidism occurs because to the severity and chronicity of the hypocalcemia. of end-organ resistance to the actions of PTH. Indeed, The hallmark of hypocalcemia is tetany, which is char- serum PTH levels are normal or elevated. In one form of acterized by neuromuscular irritability, resulting from pseudohypoparathyroidism, there is end-organ resistance decreased serum calcium levels. The symptoms range to TSH and FSH/LH as well as PTH. All of these hormones from circumoral numbness or paresthesias (tingling) signal via G-protein–coupled receptors, and the disorder of the distal extremities and carpopedal spasm, to life- results from genetic defects in components of this pathway threatening laryngospasm and generalized seizures. The that are shared across endocrine tissues. PTH resistance classic findings on physical examination are Chvostek sign is the most obvious clinical manifestation. It presents as and Trousseau sign. Chvostek sign is elicited in subclinical hypocalcemia, hyperphosphatemia, and elevated circulat- disease by tapping along the course of the facial nerve, ing PTH. TSH resistance is generally mild, while LH/FSH which induces contractions of the muscles of the eye, resistance manifests as hypergonadotropic hypogonadism in mouth, or nose. Trousseau sign refers to carpal spasms females. produced by occlusion of the circulation to the distal arm with a blood pressure cuff for several minutes. The Endocrine Pancreas The endocrine pancreas consists of about 1 million clusters There are also two rare cell types, D1 cells and entero- of cells, the islets of Langerhans, which contain four major chromaffin cells. D1 cells elaborate vasoactive intestinal and two minor cell types. The four main types are β, α, δ, polypeptide (VIP), a hormone that induces glycogenolysis and PP (pancreatic polypeptide) cells. They can be differenti- and hyperglycemia; it also stimulates gastrointestinal ated by the ultrastructural characteristics of their granules, fluid secretion and causes secretory diarrhea. and by their hormone content (Fig. 24.27). Enterochromaffin cells synthesize serotonin and are the The β cells produce insulin, which regulates glucose source of pancreatic tumors that cause the carcinoid utilization in tissues and reduces blood glucose levels, syndrome (Chapter 19). as will be detailed in the discussion of diabetes. The α cells secrete glucagon, which stimulates glyco- The following discussion focuses on the two main dis- genolysis in the liver and thus increases blood sugar. orders of islet cells: diabetes mellitus and pancreatic The δ cells secrete somatostatin, which suppresses both endocrine tumors. insulin and glucagon release. The PP cells secrete pancreatic polypeptide, which exerts several gastrointestinal effects, such as stimulation of DIABETES MELLITUS secretion of gastric and intestinal enzymes and inhibition of intestinal motility. These cells not only are present in Diabetes mellitus is a group of metabolic disorders islets but also are scattered throughout the exocrine sharing the common feature of hyperglycemia caused pancreas. by defects in insulin secretion, insulin action, or, most 1098 C H A P T E R 24 The Endocrine System A b cells: insulin B a cells: glucagon C d cells: somatostatin D 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 suffer from diabetes worldwide, with India and China being metabolic deregulation may be associated with secondary the largest contributors to the world’s diabetic burden. damage in multiple organ systems, especially the kidneys, Increasingly sedentary lifestyles and poor eating habits have eyes, nerves, and blood vessels. In the United States, contributed to the simultaneous escalation of T2D and diabetes is the leading cause of end-stage renal disease, obesity, which some have called the diabesity epidemic. Sadly, adult-onset blindness, and nontraumatic lower extremity this epidemic has now spread to children living in “food amputations. deserts” who subsist on highly processed foods rich in Diabetes and related disorders of glucose metabolism carbohydrates and sugar and do not exercise adequately. are common. According to the American Diabetes Associa- The mortality rate from diabetes varies across countries, tion, diabetes affects more than 30 million children and with middle- and low-income nations accounting for almost adults, or more than 9% of the population, in the United 80% of diabetes-related deaths and nearly double the mortal- States, of which about 1.2 million have the form of diabetes ity rates observed in high-income nations. Nonetheless, called type 1 and the remainder have type 2. Astonishingly, diabetes remains in the top 10 “killers” in the United States. nearly one-fourth of these individuals are currently unaware The total yearly cost related to diabetes in the United States that they have hyperglycemia. Approximately 1.5 million is estimated to be an astounding $327 billion, including new cases of adult diabetes are diagnosed each year in the $237 billion in direct medical costs and $90 billion in indirect United States. Furthermore, a staggering 84 million adults costs stemming from the reduced productivity of individuals in this country have impaired glucose tolerance or “predia- with diabetes. betes,” which is defined as elevated blood sugar that does not reach the criterion used for an outright diagnosis of Diagnosis type 2 diabetes (T2D; see later), and individuals with pre- Blood glucose is normally maintained in a very narrow diabetes are at risk for developing frank T2D. Compared range of 70 to 120 mg/dL. According to the ADA and WHO, to non-Hispanic Caucasians, Native Americans, African diagnostic criteria for diabetes include the following: Americans, and Hispanics are 1.5 to 2 times more likely to 1. A fasting plasma glucose ≥126 mg/dL develop diabetes in their lifetimes. The World Health 2. A random plasma glucose ≥200 mg/dL (in a patient with Organization estimates that as many as 422 million people classic hyperglycemic signs, as discussed later)  The endocrine pancreas 1099 3. A 2-hour plasma glucose ≥200 mg/dL during an oral Table 24.6 Classification of Diabetes glucose tolerance test (OGTT) with a loading dose of Type 1 Diabetes (β-Cell Destruction, Usually Leading to 75 g Absolute Insulin Deficiency) 4. A glycated hemoglobin (HbA1c) level ≥6.5% (glycated Immune-mediated hemoglobin is further discussed later in the chapter) Idiopathic (autoantibody-negative) Type 2 Diabetes (Combination of Insulin Resistance and All tests, except the random blood glucose test in a patient β-Cell Dysfunction) with classic hyperglycemic signs, need to be repeated and confirmed on a separate day. If there is discordance between Other Types two assays (e.g., fasting glucose and HbA1c level), the result Genetic Defects of β-Cell Function with the greatest degree of abnormality is considered the Maturity-onset diabetes of the young (MODY) caused by mutations in: “readout.” Of note, many acute stresses, such as severe Hepatocyte nuclear factor 4α (HNF4A) (MODY1) infections, burns, or trauma, can lead to transient hyper- Glucokinase (GCK) (MODY2) glycemia due to secretion of hormones such as catecholamines Hepatocyte nuclear factor 1α (HNF1A), (MODY3) Pancreatic and duodenal homeobox 1 (PDX1) (MODY4) and cortisol that oppose the action of insulin. The diagnosis Hepatocyte nuclear factor 1β (HNF1B) (MODY5) of diabetes requires persistence of hyperglycemia following Neurogenic differentiation factor 1 (NEUROD1) (MODY6) resolution of the acute illness. Neonatal diabetes (activating mutations in KCNJ11 and ABCC8, Prediabetes, a state of dysglycemia that often precedes encoding Kir6.2 and SUR1, respectively) development of frank T2D, is defined by one or more of Maternally inherited diabetes and deafness (MIDD) due to the following: mitochondrial DNA mutations (m.3243A→G) Defects in proinsulin conversion 1. A fasting plasma glucose between 100 and 125 mg/dL Insulin gene mutations (“impaired fasting glucose”), 2. A 2-hour plasma glucose between 140 and 199 mg/dL Genetic Defects in Insulin Action following a 75-g oral glucose tolerance test (OGTT) Type A insulin resistance (“impaired glucose tolerance”), and/or Lipoatrophic diabetes 3. A glycated hemoglobin (HbA1c) level between 5.7% Exocrine Pancreatic Defects (“Pancreatogenic” or Type 3C and 6.4% Diabetes) Chronic pancreatitis As many as one-fourth of individuals with impaired Pancreatectomy/trauma glucose tolerance will develop overt diabetes over 5 years, Pancreatic cancer with additional factors such as obesity and family history Cystic fibrosis Hemochromatosis compounding the risk. In addition, individuals with pre- Fibrocalculous pancreatopathy diabetes also are at significant risk for cardiovascular complications. Endocrinopathies Acromegaly Classification Cushing syndrome Hyperthyroidism Although all forms of diabetes have hyperglycemia as a Pheochromocytoma common feature, the underlying abnormalities involved in Glucagonoma its development vary widely. The previous classification Infections schemes of diabetes were based on clinical features, such as the age of onset of disease and the mode of therapy; in Cytomegalovirus contrast, the current classification reflects our greater Coxsackie B virus Congenital rubella understanding of the pathogenesis of each variant (Table 24.6). The vast majority of cases of diabetes fall into one of Drugs two broad classes: Glucocorticoids Type 1 diabetes (T1D) is an autoimmune disease character- Thyroid hormone ized by pancreatic β-cell destruction and an absolute Interferon-α Protease inhibitors deficiency of insulin. It accounts for approximately 5% β-adrenergic agonists to 10% of diabetes and is the most common subtype Thiazides diagnosed in patients younger than 20 years of age. Nicotinic acid Type 2 diabetes (T2D) is caused by a combination of Phenytoin (Dilantin) peripheral resistance to insulin action and a secretory Vacor response by pancreatic β cells that is inadequate to Genetic Syndromes Associated With Diabetes overcome insulin resistance (“relative insulin deficiency”). Down syndrome Approximately 90% to 95% of diabetes patients have Klinefelter syndrome T2D, and the vast majority of such individuals are over- Turner syndrome weight. Although classically considered “adult-onset,” Prader-Willi syndrome the prevalence of T2D in children and adolescents has Gestational Diabetes Mellitus been increasing at an alarming pace due to the increasing Modified from American Diabetes Association: Diagnosis and classification of rates of obesity in children and young adults, particu- diabetes mellitus, Diabetes Care 37(Suppl 1):S81–S90, 2014. larly in Hispanic, Native American, and Asian ethnic groups. 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 GLUT-2 Type 1 Diabetes Type 2 Diabetes Clinical Sulfonylurea receptor Onset: usually childhood and Onset: usually adult; increasing adolescence incidence in childhood and Glucose adolescence K+ Normal weight or weight loss Vast majority are obese (80%) preceding diagnosis K+ channel protein ATP Progressive decrease in insulin Increased blood insulin (early); inactivated Insulin levels normal or moderate decrease in Insulin insulin (late) Circulating islet autoantibodies No islet autoantibodies Membrane Influx (anti-insulin, anti-GAD, Mitochondria of Ca2+ depolarization anti-ICA512) Diabetic ketoacidosis in Nonketotic hyperosmolar coma absence of insulin therapy more common Ca2+ channel Genetics Ca2+ Major linkage to MHC class II No HLA linkage; linkage to genes; also linked to candidate diabetogenic and Figure 24.28 Insulin synthesis and secretion. The influx of glucose into β polymorphisms in CTLA4 and obesity-related genes (e.g., cells through the GLUT-2 receptors initiates a cascade of signaling events PTPN22, and insulin gene TCF7L2, PPARG, FTO) that culminates in Ca2+-induced release of stored insulin (see text for VNTRs details). Pathogenesis Dysfunction in T-cell selection Insulin resistance in peripheral insulin-responsive site for postprandial glucose utilization, and regulation leading to tissues, failure of compensation breakdown in self-tolerance by β cells and it is critical for preventing hyperglycemia and maintain- to islet autoantigens ing glucose homeostasis. Although less dependent on insulin, brain and adipose tissues also extract a significant amount Pathology of glucose from the circulation. Insulitis (inflammatory infiltrate No insulitis; amyloid deposition in of T cells and macrophages) islets Regulation of Insulin Release β-cell depletion, islet atrophy Mild β-cell depletion Insulin is produced in the β cells of the pancreatic islets HLA, Human leukocyte antigen; MHC, major histocompatibility complex; VNTRs, variable number of tandem repeats. (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 The important similarities and differences between C-peptide are then stored in secretory granules and secreted T1D and T2D are summarized in Table 24.7. A variety of in equimolar quantities after physiologic stimulation; thus, monogenic and secondary causes are responsible for the C-peptide levels serve as a surrogate for β-cell function, remaining cases (discussed later). Before discussing the decreasing with loss of β-cell mass in T1D and increasing pathogenesis of the two major types, we will first briefly with insulin resistance–associated hyperinsulinemia. review normal insulin secretion and the mechanism of The most important stimulus for insulin synthesis and insulin action, since these are critical to understanding the release is glucose. An increase in blood glucose levels results pathogenesis of diabetes. in glucose uptake into pancreatic β cells, facilitated by an insulin-independent glucose transporter, GLUT2 (Fig. 24.28). Glucose Homeostasis Metabolism of glucose generates ATP, which leads to the influx of Ca2+ through plasma membrane calcium channels. Glucose homeostasis is tightly regulated by three inter- The resultant increase in intracellular Ca2+ stimulates secre- related processes: glucose production in the liver; glucose tion of insulin, presumably from hormone stored in β-cell uptake and utilization by peripheral tissues, chiefly skeletal granules. This is the phase of immediate insulin release, muscle; and actions of insulin and counter-regulatory sometimes called the first phase of β-cell insulin secretion. hormones, including glucagon, on glucose uptake and If the secretory stimulus persists, a delayed and protracted metabolism. Insulin and glucagon have opposing effects response follows that involves active synthesis of insulin, on glucose homeostasis. During fasting states, low insulin the second phase. and high glucagon levels facilitate hepatic gluconeogenesis Oral intake of food leads to secretion of multiple and glycogenolysis (glycogen breakdown) while decreasing hormones that play a role in glucose homeostasis and glycogen synthesis, thereby preventing hypoglycemia. Thus, satiety. Of these, the most important class of hormones fasting plasma glucose levels are determined primarily by responsible for promoting insulin secretion from pancre- hepatic glucose output. Following a meal, insulin levels rise atic β cells following feeding is the incretins, which act by and glucagon levels fall in response to the large glucose binding G-protein–coupled receptors that are expressed on load. Insulin promotes glucose uptake and utilization in pancreatic β cells. The two most important incretins are tissues (discussed later). The skeletal muscle is the major glucose-dependent insulinotropic polypeptide (GIP) and  The endocrine pancreas 1101 glucagon-like peptide-1 (GLP-1), both secreted by cells in “beige” adipose tissue, which develops with exercise, and the intestines following oral food intake. The elevation in not the “white” adipose tissue that accumulates in obese GIP and GLP-1 levels is known as the “incretin effect.” In individuals. This is one reason why exercise is beneficial addition to increasing insulin secretion from β cells, these and obesity detrimental to glucose control. In muscle cells, hormones reduce glucagon secretion from pancreatic α glucose is either stored as glycogen or oxidized to generate cells and delay gastric emptying, which promotes satiety. ATP. In adipose tissue, glucose is primarily used as a Once released, circulating GIP and GLP-1 are degraded in substrate for synthesis of lipids, which are stored as triglyc- the circulation by a class of enzymes known as dipeptidyl erides. Besides promoting lipid synthesis, insulin also inhibits peptidases (DPPs), especially DPP-4. The “incretin effect” triglyceride hydrolysis and lipid release by adipocytes. is significantly blunted in patients with T2D, and efforts to Similarly, insulin promotes amino acid uptake and protein restore incretin function can improve glycemic control and synthesis, while inhibiting protein degradation. Thus, the promote weight loss (through restoration of satiety). These anabolic effects of insulin are attributable to increased insights have led to the recent development of two classes synthesis and reduced degradation of glycogen, lipids, and of drugs for treating T2D: GLP-1 receptor agonists, which proteins. In addition, insulin has several mitogenic activities, are synthetic GLP-1 mimetics that bind to and activate the including initiation of DNA synthesis in certain cells and GLP-1 receptor on islet and extrapancreatic cells; and DPP-4 stimulation of their growth and differentiation. inhibitors, which enhance levels of endogenous incretins The metabolic effects of insulin are exerted through its by delaying their degradation. GLP-1 also increases energy binding to the insulin receptor, which, in turn, sets into expenditure, so the weight-loss–inducing effects are likely motion a series of signaling events through an array of multifactorial. Indeed, GLP-1 receptor agonists are also now mediators, the more pertinent of which are summarized in approved for treatment of obesity. Fig. 24.30. The insulin receptor is a tetrameric protein composed of two α-subunits and two β-subunits. The β- Insulin Action and Insulin-Signaling Pathways subunit cytosolic domain possesses tyrosine kinase activity. Insulin is the most potent anabolic hormone known, with Insulin binding to the α-subunit extracellular domain multiple synthetic and growth-promoting effects (Fig. activates the β-subunit tyrosine kinase, which autophos- 24.29). The principal metabolic function of insulin is to phorylates itself and also phosphorylates several intracellular increase the rate of glucose transport into certain cells in docking or bridging proteins, including so-called insulin the body, thus providing a major source of energy and receptor substrate (IRS) proteins. These molecules in turn metabolic intermediates derived from glucose that are used activate downstream factors such as PI-3-kinase and Akt, in the biosynthesis of cellular building blocks such as lipids, a serine/threonine kinase that serves as a central signaling nucleotides, and amino acids. The most important targets hub that mediates many insulin-dependent activities, includ- of insulin action are striated muscle cells (including cardio- ing increased glucose uptake, reduced glucose synthesis, myocytes) and, to a lesser extent, adipocytes, which together and increased glycogen and protein synthesis. normally represent about two-thirds of the body’s weight. The type of adipose tissue that utilizes the most glucose is Pathogenesis of Type 1 Diabetes Adipose tissue T1D is an autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting Glucose uptake against endogenous β-cell antigens. T1D most commonly Lipogenesis develops in childhood, becomes manifest at puberty, and Lipolysis progresses with age. Because the disease can develop at any age, including late adulthood, the old moniker “juvenile- onset diabetes” is no longer used. Similarly, “insulin- dependent diabetes mellitus” has been excluded from the current classification of diabetes because many forms of diabetes eventually require treatment with insulin. Neverthe- less, most patients with T1D require insulin for survival; without insulin, they may develop serious metabolic Insulin complications such as ketoacidosis and coma. As with most autoimmune diseases, the pathogenesis of T1D involves an interplay of genetic and environmental factors. Genetic Susceptibility Epidemiologic studies, such as those demonstrating higher Striated muscle Liver concordance rates in monozygotic versus dizygotic twins, Glucose uptake have convincingly established a genetic basis for T1D. More Gluconeogenesis recently, GWAS have identified multiple genetic susceptibil- Glycogen synthesis Glycogen synthesis ity loci for T1D, as well as for T2D (see later). Of these, Protein synthesis Lipogenesis the most important locus is the HLA gene cluster, which Figure 24.29 Metabolic actions of insulin in striated muscle, adipose according to some estimates contributes as much as 50% of tissue, and liver. the genetic susceptibility for T1D. Ninety percent to 95% 1102 C H A P T E R 24 The Endocrine System Insulin between polymorphisms in CTLA4 and PTPN22 and Glucose autoimmune thyroiditis was mentioned earlier; not surpris- Insulin ingly, these genes have also been linked with susceptibility receptor to T1D. The relationship of T1D to altered T-cell selection α α and regulation is also underscored by the striking prevalence of this disease in individuals with rare germline defects in P β β P GLUT-4 genes that code for immune regulators, such as AIRE, Glucose mutations of which cause APS-1 (discussed later). IRS PI3K uptake P P Environmental Factors As in other autoimmune diseases, genetic susceptibility Akt GLUT-4 contributes to only a part of diabetes risk, and the con- vesicle P P cordance 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 P P P P P P P antecedent viral infections have been suggested as triggers, TSC1 FOXO GSK3 neither the type of virus nor how it promotes islet-specific autoimmunity is established. Some studies suggest that TSC2 viruses might share epitopes with islet antigens, and the Glucose Glycogen synthesis synthesis 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 Protein also thought to be protective against T1D. mTOR synthesis Mechanisms of β-Cell Destruction While the clinical onset of T1D is often abrupt, there is a Figure 24.30 Insulin action on a target cell. Insulin binding to the lengthy lag period between initiation of the autoimmune tetrameric receptor initiates a cascade of phosphorylation events that process and the appearance of symptomatic disease, during result in activation of PI-3-kinase/Akt signaling. Akt is a serine threonine which there is progressive loss of insulin reserves. Three kinase that mediates its effector functions via phosphorylation-dependent distinct stages of T1D are now recognized (Fig. 24.31). In stage events. For example, Akt phosphorylates and inhibits the function of the 1 (autoimmunity positive, normoglycemia, presymptomatic T1D), tuberous sclerosis complex (TSC) proteins, leading to activation of the downstream mammalian TOR (mTOR) complex, which enhances protein individuals have developed two or more islet autoantibodies synthesis. Akt also inhibits the function of Forkhead box O (FOXO) but are still normoglycemic. In stage 2 (autoimmunity posi- protein, which, in turn, reduces glucose synthesis, while inhibition of tive, dysglycemia, presymptomatic T1D), there is increasingly glycogen synthase kinase 3 (GSK3) enhances glycogen production. Finally, severe loss of glucose tolerance due to progressive loss of Akt enhances intracellular glucose uptake by translocation of GLUT-4 β-cell mass, but frank symptoms are absent. Nonetheless, vesicles to the cell membrane. IRS, Insulin receptor substrate; PI3K, the 5-year risk of developing symptomatic T1D increases phosphoinositide 3-kinase. (Modified from Brendan Manning, Harvard T.H. Chan School of Public Health.) 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, of Caucasians with this disease have either an HLA-DR3 polyphagia, ketoacidosis; see later) appear, typically after or HLA-DR4 haplotype, in contrast to about 40% of normal more than 90% of the β cells have been destroyed. subjects; moreover, 40% to 50% of patients with T1D are The fundamental immune abnormality in T1D is a DR3/DR4 compound heterozygotes, in contrast to 5% of failure of self-tolerance in T cells specific for islet antigens. normal subjects. Individuals who have either DR3 or DR4 This failure of tolerance may be a result of some combination concurrently with a DQ8 haplotype demonstrate one of the of defective clonal deletion of self-reactive T cells in the highest inherited risks for T1D in sibling studies. Predictably, thymus, as well as defects in the functions of regulatory T the polymorphisms in the HLA molecules that are associated cells or abnormal resistance of effector T cells to suppres- with risk are located in or adjacent to the peptide-binding sion by regulatory cells. Thus, autoreactive T cells not only pockets, consistent with the notion that disease-associated survive, but are poised to respond to self antigens. The alleles code for HLA molecules that have the capacity to initial activation of these cells is thought to occur in the display particular antigens. However, as discussed in Chapter peripancreatic lymph nodes, perhaps in response to antigens 6, it is still not known how particular HLA alleles contribute that are released from damaged islets. The activated T cells to the pathogenesis of T1D (and other autoimmune diseases). then traffic to the pancreas, where they cause β-cell injury. Several non-HLA genes also confer susceptibility to T1D. Multiple T-cell populations have been implicated in this The first disease-associated non-MHC gene variant to be damage, including Th1 cells (which may secrete cytokines, identified consisted of variable number of tandem repeats including IFN-γ and TNF, that injure β cells), and CD8+ in the promoter region of the insulin gene. The mechanism CTLs (which kill β cells directly). The islet autoantigens underlying this association is unknown. It is possible that that are the targets of immune attack may include insulin, these polymorphisms influence insulin expression by thymic the β-cell enzyme glutamic acid decarboxylase (GAD), and antigen-presenting cells, thus affecting the negative selection others. Consistent with the idea that failure of self-tolerance of insulin-reactive T cells (Chapter 6). The association is fundamental to the pathogenesis of T1D, cancer patients  The endocrine pancreas 1103 Proposed nomenclature Stage 1 Stage 2 Stage 3 β-Cell autoimmunity β-Cell autoimmunity β-Cell autoimmunity Phenotypic characteristics Normogylcemia Dysgylcemia Dysgylcemia Presymptomatic Presymptomatic Symptomatic 100% Functional β-Cell mass Phase in natural history Individual at risk Presymptomatic Symptomatic for Type 1 diabetes Type 1 diabetes Type 1 diabetes 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 than 80% of individuals with T2D are obese, and the inci- disrupts tolerance mechanisms, sometimes develop the dence of diabetes worldwide has risen in proportion to disease. obesity. Obesity contributes to the cardinal metabolic A role for antibodies in T1D is suspected because auto- abnormalities of diabetes (see later) and to insulin resistance antibodies against islet antigens are found in the vast majority early in disease. In fact, even modest weight loss through of patients with T1D, including at the presymptomatic stages dietary modifications can reduce insulin resistance and of disease, as described earlier. However, it is not clear if improve glucose tolerance. A sedentary lifestyle (typified the autoantibodies cause injury or are merely a consequence by lack of exercise) is another risk factor for diabetes, of islet injury. independent of obesity. Weight loss and exercise usually increase insulin sensitivity additively and are often first-line Pathogenesis of Type 2 Diabetes interventions in patients with milder T2D. The combination of obesity, hyperglycemia, increased serum cholesterol and T2D is a complex disease that involves the interplay of triglycerides, and hypertension is called the metabolic genetic and environmental factors and a pro-inflammatory syndrome. state. Unlike T1D, there is no evidence of an autoimmune Despite this general risk, several populations world- basis. wide in which T2D rates are increasing most rapidly (e.g., East Asian, South Asian, and Middle Eastern) do Genetic Factors not show comparable increases in obesity (increased body Genetic susceptibility contributes to the pathogenesis, as mass index [BMI], a measure of total body fat). This has evidenced by the disease concordance rate of greater than suggested that risk is related not only to the amount of 90% in monozygotic twins, a rate higher than in T1D. Fur- body fat but also to its anatomic distribution, as discussed thermore, first-degree relatives have 5- to 10-fold higher risk later. of developing T2D than those without a family history, when Sleep disorders (such as obstructive sleep apnea) and matched for age and weight. GWAS performed over the circadian disruption are additional environmental risk factors past decade have identified at least 30 loci that individually for T2D. Circadian disruption is defined as misalignment confer a minimal to modest increase in the lifetime risk for between the endogenous circadian rhythm and the cycle T2D. Many of these genes are involved in adipose tissue or rhythm created by individual behaviors. Those at risk function (through effects on bodily fat distribution [visceral for circadian disruption include shift workers and those vs. subcutaneous]), islet β-cell function, and obesity. It is with sleep disorders or other conditions that restrict nighttime believed that together, these genetic polymorphisms conspire sleep and daytime wakefulness. Studies have shown that to provide the genetic basis for T2D risk. However, heritable circadian disruption impairs glucose homeostasis by affecting risk remains a minor player impacting disease susceptibility, both insulin secretion and insulin action. In addition, GWAS and environmental factors are the major contributors. have shown an association between circadian-controlled genes and T2D. Disruption of “clock” genes not only affects Environmental Factors insulin secretion and action but also activity level and feeding The most important environmental risk factor for T2D is behaviors, resulting in increased risk for hyperglycemia and obesity, particularly central or visceral obesity. Greater diabetes. 1104 C H A P T E R 24 The Endocrine System Failure of glucose uptake and glycogen synthesis to occur Metabolic Defects in Type 2 Diabetes in skeletal muscle following a meal, which contributes The development of T2D involves two key abnormalities: to high postprandial blood glucose level Insulin resistance: Decreased response of peripheral tissues, Failure to inhibit activation of “hormone-sensitive” lipases especially skeletal muscle, adipose tissue, and liver, to in adipose tissue, leading to excess triglyceride breakdown insulin in adipocytes and high levels of circulating free fatty β-cell dysfunction: Inadequate insulin secretion in the face acids (FFAs). of insulin resistance and hyperglycemia A variety of functional defects in the insulin-signaling Insulin resistance predates the development of hyper- pathway underlie insulin resistance. For example, reduced glycemia and is usually accompanied by compensatory β-cell tyrosine phosphorylation of the insulin receptor and IRS hyperfunction and hyperinsulinemia in the early stages of proteins is observed in peripheral tissues, which compromises the evolution of T2D (Fig. 24.32). Over time, the inability insulin signaling and reduces the level of the glucose of β cells to adapt to increasing secretory needs for maintain- transporter GLUT-4 on the cell surface (see Fig. 24.30). In ing a euglycemic state results in chronic hyperglycemia and fact, one of the mechanisms by which exercise improves the resulting long-standing complications of diabetes. insulin sensitivity is by increasing the translocation of GLUT-4 to the plasma membrane of skeletal muscle cells. Insulin Resistance Insulin resistance is the failure of target tissues to respond Obesity normally to insulin. The liver, skeletal muscle, and adipose Multiple factors contribute to insulin resistance, of which tissue are the major tissues where insulin resistance gives obesity is probably the most important. The risk for rise to abnormal glucose tolerance. Insulin resistance results diabetes rises as the BMI increases. Not only the absolute in the following: amount of fat but also its distribution determines insulin Failure to inhibit endogenous glucose production (glu- sensitivity: central obesity (abdominal fat) is more likely to coneogenesis) in the liver, which contributes to high be linked with insulin resistance than is peripheral (gluteal/ fasting blood glucose levels 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 Obesity adiposity may be relatively protected from T2D. Studies of these so-called “metabolically healthy obese” individuals Vasculature is an emerging field. Obesity can adversely impact insulin sensitivity in numer- Adipocytes ous 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 Adipokines FFAs Inflammation tissue is more “lipolytic” than peripheral sites, which might explain the particularly deleterious consequences of this pattern of fat distribution. Excess FFAs overwhelm Insulin resistance the intracellular fatty acid oxidation pathways, leading to the accumulation of cytoplasmic intermediates like β-cell β-cell diacylglycerol (DAG), phospholipids, and sphingolipids, Pancreatic compensation failure including ceramides. These “toxic” lipid metabolites can islet attenuate signaling through the insulin receptor and activate inflammatory pathways in the islets, which further β-cells promote β-cell abnormalities. In liver cells, insulin nor- mally inhibits gluconeogenesis by blocking the activity of phosphoenolpyruvate carboxykinase, the first enzymatic Insulin secretion Normal Increased Decreased step in this process. Attenuated insulin signaling allows by β-cells phosphoenolpyruvate carboxykinase to “ramp up” gluconeogenesis. Excess FFAs also compete with glucose Blood Normal Normal to impaired Diabetes as substrates for oxidation, further exacerbating the glucose glucose tolerance mellitus reduced glucose utilization. Adipokines. You will recall that adipose tissue is not Figure 24.32 Development of type 2 diabetes. Insulin resistance merely a storage depot for fat but is also an endocrine associated with obesity is induced by adipokines, free fatty acids (FFAs), organ that releases hormones in response to changes in and chronic inflammation in adipose tissue. Pancreatic β cells compensate for insulin resistance by hypersecretion of insulin. However, at some point, metabolism (Chapter 9). A variety of proteins secreted into β-cell compensation is followed by β-cell failure, and diabetes ensues. the circulation by adipose tissue have been identified that (Reproduced with permission from Kasuga M: Insulin resistance and are collectively termed adipokines (or adipose cytokines). pancreatic β-cell failure, J Clin Invest 116(7):1756–1760, 2006.) Some of these promote hyperglycemia, while others (such  The endocrine pancreas 1105 as leptin and adiponectin) decrease blood glucose, in part lifetime risk for T2D occur in genes that control insulin by increasing insulin sensitivity in peripheral tissues. secretion (see earlier). Adiponectin levels are reduced in obesity, thus contribut- ing to insulin resistance. Monogenic Forms of Diabetes Inflammation: Over the past several years, inflammation has emerged as an important factor in the pathogenesis Although genetically defined causes of diabetes are uncom- of T2D. It is now known that an inflammatory milieu— mon, they have been intensively studied in the hope of mediated not by an autoimmune process, as in T1D, but gaining insights into the disease. As Table 24.6 illustrates, rather by pro-inflammatory cytokines that are secreted monogenic forms of diabetes are classified separately from in response to excess nutrients such as FFAs and glucose— types 1 and 2 diabetes. Monogenic forms of diabetes result results in both insulin resistance and β-cell dysfunction. from either a primary defect in β-cell function or a defect Excess FFAs within macrophages and β cells can activate in insulin receptor signaling (described later). the inflammasome, a multiprotein cytoplasmic complex that leads to secretion of the cytokine interleukin IL-1β Genetic Defects in β-Cell Function (Chapter 3). IL-1β, in turn, mediates the secretion of Approximately 1% to 2% of patients with diabetes harbor additional pro-inflammatory cytokines from macrophages, a primary defect in β-cell function that affects either β-cell islet cells, and other cells. IL-1 and other cytokines act mass and/or insulin production. This form of monogenic on the major sites of insulin action to promote insulin diabetes is caused by a heterogeneous group of genetic resistance. Thus, excess FFAs can impede insulin signaling defects. The largest subgroup of patients in this category directly within peripheral tissues, as well as indirectly was designated as having “maturity-onset diabetes of the through the release of pro-inflammatory cytokines. young” (MODY) because of its superficial resemblance to Liver steatosis: High circulating levels of FFAs may result T2D and its occurrence in younger patients. MODY can result in the accumulation of excess fat (steatosis) in hepatocytes. from germline loss-of-function mutations in one of six genes This form of nonalcoholic fatty liver disease (NAFLD) (see Table 24.6), of which mutations of glucokinase (GCK) ranges in severity from hepatic steatosis without evidence are the most common. Glucokinase is a rate-limiting step in of liver injury to nonalcoholic steatohepatitis (NASH) oxidative glucose metabolism, which, in turn, is coupled to with evidence of inflammation and hepatocyte injury insulin secretion within islet β cells (see Fig. 24.28). with or without fibrosis (Chapter 18). NAFLD is common in those with metabolic syndrome and T2D, an association Genetic Defects That Impair Tissue Response to Insulin that cuts both ways: NAFLD promotes the development Rare insulin receptor mutations that affect receptor synthesis, of T2D, which in turn increases the risk of developing insulin binding, or RTK activity can cause severe insulin the more severe forms of NAFLD. resistance, accompanied by hyperinsulinemia and diabetes (type A insulin resistance). Such patients often show a velvety β-Cell Dysfunction hyperpigmentation of the skin known as acanthosis nigricans. While insulin resistance by itself can lead to impaired glucose Females with type A insulin resistance also frequently have tolerance, β-cell dysfunction is a requirement for the polycystic ovaries and elevated androgen levels. development of overt diabetes. In contrast to the severe genetic defects in β-cell function that occur in monogenic Diabetes and Pregnancy forms of diabetes (see later), β-cell function actually increases early in the disease process in most patients with “sporadic” Pregnancy can be complicated by diabetes in one of two T2D as a compensatory measure to counter insulin resistance settings: when women with preexisting diabetes become and maintain euglycemia. Eventually, however, β cells pregnant (“pregestational” or overt diabetes) or women who seemingly exhaust their capacity to adapt to the long-term were previously euglycemic develop impaired glucose demands posed by insulin resistance, and the hyperinsu- tolerance and diabetes for the first time during pregnancy linemic state gives way to a state of relative insulin deficiency, (“gestational” diabetes). Approximately 5% to 9% of pregnan- that is, insulin levels are deficient for the level of blood cies occurring in the United States are complicated by glucose. hyperglycemia, and the incidence of both pregestational Several mechanisms have been implicated in promoting and gestational diabetes is increasing in the general popula- β-cell dysfunction in T2D, including the following: tion. Pregnancy is a “diabetogenic” state in which the prevail- Excess FFAs that compromise β-cell function and attenuate ing hormonal milieu favors insulin resistance. In a previously insulin release (lipotoxicity) euglycemic woman who is otherwise susceptible due to The impact of chronic hyperglycemia (glucotoxicity) concurrent genetic and environmental factors, the conse- An abnormal incretin effect, leading to reduced secretion quence may be gestational diabetes. Of even greater concern, of GIP and GLP-1, hormones that promote insulin release women with pregestational diabetes have an increased risk (see earlier) of stillbirth and congenital malformations in the fetus. Poorly Amyloid deposition within islets. This is a characteristic controlled diabetes that arises later in pregnancy, regardless finding in individuals with long-standing T2D, being of prior history, can lead to excessive birth weight in the present in more than 90% of diabetic islets examined, newborn (macrosomia) and may have long-term sequelae but it is unclear whether it is a cause or an effect of β-cell for the child later in life, including an increased risk of “burnout.” obesity and diabetes. Gestational diabetes typically resolves Finally, the impact of genetics cannot be discounted, as following delivery; however, the majority of affected women many of the polymorphisms associated with an increased develop overt diabetes over the next 10 to 20 years. 1106 C H A P T E R 24 The Endocrine System Clinical Features of Diabetes combination of polyphagia and weight loss is paradoxical and should always raise the suspicion of diabetes. It is difficult to sketch with brevity the diverse clinical presentations of diabetes. We will discuss the most common Acute Metabolic Complications of Diabetes initial presentation or mode of diagnosis for each of the Diabetic ketoacidosis is a severe acute metabolic complica- two major subtypes, followed by a discussion of acute and tion of T1D; it is not as common or as severe in T2D. The then chronic (long-term) complications of the disease. most frequent precipitating factor is a failure to take insulin, T1D may arise at any age. In the initial 1 or 2 years although other stressors such as infections, other illnesses, following the onset of overt T1D, exogenous insulin require- trauma, and certain drugs may also serve as triggers. It may ments may be minimal because of residual endogenous also occur less commonly in T2D but only under condition insulin secretion (referred to as the honeymoon period). of very severe stress such as caused by serious infections Eventually, however, β-cell function declines to a tipping and trauma. Many of these factors are associated with the point, and insulin requirements increase dramatically. release of the catecholamine epinephrine, which blocks Although β-cell destruction is a prolonged process, the residual insulin action and stimulates the secretion of transition from impaired glucose tolerance (stage 2, see glucagon. The insulin deficiency coupled with glucagon earlier) to overt diabetes (stage 3) may be abrupt and is excess decreases peripheral utilization of glucose while often brought on by a superimposed stress, such as infection, increasing gluconeogenesis, severely exacerbating hyper- because of associated increase in insulin requirements. glycemia (the plasma glucose levels are usually in the range In contrast to T1D, T2D is typically seen in obese patients of 250 to 600 mg/dL). The hyperglycemia causes an osmotic older than 40 years of age; however, it is now being diag- diuresis and dehydration characteristic of the ketoacidotic nosed in children and adolescents with increasing frequency state. due to increases in obesity and sedentary lifestyle. In some A second major effect of insulin deficiency is increased cases, medical attention is sought because of unexplained synthesis of ketone bodies. Insulin deficiency stimulates fatigue, dizziness, or blurred vision. Most frequently, hormone-sensitive lipase, with a resultant breakdown of however, the diagnosis of T2D is made after routine blood adipose stores and an increase in levels of FFAs. When testing in asymptomatic persons. In fact, in light of the large these FFAs reach the liver, they are esterified to fatty acyl number of asymptomatic individuals with undiagnosed coenzyme A. Oxidation of fatty acyl coenzyme A molecules hyperglycemia in the United States, routine blood glucose within the hepatic mitochondria produces ketone bodies testing is recommended for everyone older than 45 years (acetoacetic acid and β-hydroxybutyric acid). The rate at of age, and in younger individuals with obesity, family which ketone bodies are formed may exceed the rate at history, or the presence of the metabolic syndrome. which they can be utilized by peripheral tissues, leading to ketonemia and ketonuria. If the urinary excretion of ketones The Classic Triad of Diabetes is compromised by dehydration, the result is a systemic The onset of T1D is usually marked by the triad of poly- metabolic ketoacidosis. Release of ketogenic amino acids by uria, polydipsia, polyphagia, and, when severe, diabetic protein catabolism aggravates the ketotic state. ketoacidosis, all resulting from metabolic derangements. The clinical manifestations of diabetic ketoacidosis include Because insulin is a major anabolic hormone, its deficiency fatigue, nausea and vomiting, severe abdominal pain, a results in a catabolic state that affects glucose, fat, and protein characteristic fruity odor, and deep, labored breathing (also metabolism. Unopposed secretion of counterregulatory known as Kussmaul breathing). Persistence of the ketotic state hormones (such as glucagon) also plays a role in these eventually leads to depressed consciousness and coma. metabolic derangements. The assimilation of glucose into Reversal of ketoacidosis requires administration of insulin, muscle and adipose tissue is sharply diminished or abolished. correction of metabolic acidosis, and treatment of any Not only does storage of glycogen in liver and muscle cease, underlying precipitating factors, such as infection. but reserves are depleted by glycogenolysis. The resultant The lower frequency of ketoacidosis in T2D is believed hyperglycemia leads to filtration of so much glucose in the to be due to higher portal vein insulin levels in these patients, kidney that the renal tubular threshold for reabsorption which prevents unrestricted hepatic fatty acid oxidation is exceeded. This leads to glycosuria, which induces an and keeps the formation of ketone bodies in check. Instead, osmotic diuresis and thus polyuria, causing a profound patients with T2D may develop a condition known as loss of water and electrolytes (Fig. 24.33). The renal water hyperosmolar hyperglycemic state due to severe dehydration loss combined with the hyperosmolarity owing to increased resulting from sustained osmotic diuresis (particularly in levels of glucose in the blood depletes intracellular water, patients who do not drink enough water to compensate for triggering the osmoreceptors of the thirst centers of the brain. urinary losses from chronic hyperglycemia). Typically, this Thus, intense thirst (polydipsia) appears. With a deficiency of occurs in an older patient who has diabetes and is disabled insulin, the scales swing from insulin-promoted anabolism to by a stroke or an infection and thus unable to maintain catabolism of proteins and fats. Proteolysis follows, releasing adequate water intake. Furthermore, the absence of keto- gluconeogenic amino acids that are removed by the liver acidosis and its symptoms (nausea, vomiting, Kussmaul and used as building blocks for glucose. The catabolism of breathing) delays the seeking of medical attention until proteins and fats tends to induce a negative energy balance, severe dehydration and impairment of mental status occur. which in turn leads to increasing appetite (polyphagia), thus The hyperglycemia is usually more severe than in diabetic completing the classic triad of polyuria, polydipsia, and ketoacidosis, in the range of 600 to 1200 mg/dL. polyphagia. Despite the increased appetite, catabolic effects Once treatment commences, ironically, the most common prevail, resulting in weight loss and muscle weakness. The acute metabolic complication in either type of diabetes is  The endocrine pancreas 1107 Insulin deficiency and/or insulin resistance Leads to decreased tissue glucose utilization spillover into blood Glucagon Muscle excess Adipose tissue Increased protein Increased lipolysis catabolism (free fatty acids) (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 disease are most profound in the retina, kidneys, and physical exertion, excessive insulin administration, or peripheral nerves, resulting in diabetic retinopathy, nephropathy, “misdosing” during the phase of dose finding for antidiabetic and neuropathy, respectively (see later). agents such as sulfonylureas. The signs and symptoms of hypoglycemia include dizziness, confusion, sweating, palpita- Pathogenesis tions, and tachycardia; if hypoglycemia persists, loss of Persistent hyperglycemia (glucotoxicity) seems to be consciousness may occur. Rapid reversal of hypoglycemia responsible for the long-term complications of diabetes. through oral or intravenous glucose intake is critical for Much of the evidence supporting a role for glycemic control preventing permanent neurologic damage. in ameliorating the long-term complications of diabetes has come from large randomized trials. The assessment of Chronic Complications of Diabetes glycemic control in these trials has been based on the percent- The morbidity associated with long-standing diabetes of age of glycated hemoglobin, also known as HbA1c, which is either type is due to damage induced in large- and medium- formed by nonenzymatic covalent addition of glucose sized muscular arteries (diabetic macrovascular disease) moieties to hemoglobin in red cells. Unlike blood glucose and in small vessels (diabetic microvascular disease) by levels, HbA1c provides a measure of glycemic control over chronic hyperglycemia. Macrovascular disease causes the lifespan of a red cell (120 days) and is affected little by accelerated atherosclerosis among patients with diabetes, day-to-day variation in glucose levels. It is recommended resulting in increased risk of myocardial infarction, stroke, that HbA1c be maintained below 7% in patients with dia- and lower extremity ischemia. The effects of microvascular betes. The emergence of new technology, including 1108 C H A P T E R 24 The Endocrine System continuous glucose-monitoring systems, has introduced a Activation of protein kinase C. Calcium-dependent activation new goal, increasing “time-in-range” (set at 70 to 180 mg/ of intracellular protein kinase C (PKC) and the second dL), which may be a better predictor of the risk of chronic messenger diacyl glycerol (DAG) is an important signal complications than HbA1c level. It is important to stress, transduction pathway. Intracellular hyperglycemia however, that hyperglycemia is not the only factor respon- stimulates the de novo synthesis of DAG from glycolytic sible for the long-term complications of diabetes, and that intermediates, and hence causes excessive PKC activation. other underlying abnormalities, such as insulin resistance, The downstream effects of PKC activation are numerous, and comorbidities like obesity, also play an important role. including production of VEGF, TGF-β, and the proco- At least four distinct mechanisms have been implicated agulant protein plasminogen activator inhibitor-1 (PAI-1) in the deleterious effects of persistent hyperglycemia on (Chapter 4) by the vascular endothelium. It should be peripheral tissues. In each proposed mechanism, increased evident that some effects of AGEs and activated PKC flux through metabolic pathways due to hyperglycemia are overlapping, and both likely contribute to diabetic is thought to generate harmful precursors that contribute microangiopathy. to end-organ damage. Oxidative stress and disturbances in polyol pathways. Even Formation of advanced glycation end products. Advanced in tissues that do not require insulin for glucose transport glycation end products (AGEs) are formed as a result of (e.g., nerves, lenses, kidneys, blood vessels), persistent nonenzymatic reactions between glucose-derived metabo- hyperglycemia leads to an increase in intracellular glucose. lites (glyoxal, methylglyoxal, and 3-deoxyglucosone) This excess glucose is metabolized by the enzyme aldose and the amino groups of intracellular and extracellular reductase to sorbitol, a polyol, and eventually to fructose, proteins. The rate of AGE formation is accelerated by in a reaction that uses NADPH (the reduced form of hyperglycemia. AGEs bind to a specific receptor (RAGE) nicotinamide dinucleotide phosphate) as a cofactor. that is expressed on inflammatory cells (macrophages NADPH is also required by the enzyme glutathione and T cells), endothelium, and vascular smooth muscle. reductase in a reaction that regenerates reduced gluta- The detrimental effects of the AGE-RAGE signaling axis thione (GSH). GSH is one of the important antioxidant within the vascular compartment include the following: mechanisms in the cell (Chapter 2), and any reduction Release of cytokines and growth factors, including in GSH increases cellular susceptibility to reactive oxygen transforming growth factor-β (TGF-β), which leads to species (“oxidative stress”). In the face of sustained deposition of excess basement membrane material, hyperglycemia, progressive depletion of intracellular and vascular endothelial growth factor (VEGF), NADPH by aldose reductase compromises GSH regenera- implicated in diabetic retinopathy (see later) tion, increasing cellular susceptibility to oxidative stress. Generation of reactive oxygen species (ROS) in endothelial Sorbitol accumulation in the lens contributes to cataract cells formation. Increased procoagulant activity on endothelial cells and Hexosamine pathways and generation of fructose-6-phosphate. macrophages Finally, it is postulated that hyperglycemia induces flux Enhanced proliferation of vascular smooth muscle cells of glycolytic intermediates through the hexosamine and synthesis of extracellular matrix pathway, which results in cell damage and enhanced Not surprisingly, endothelium-specific overexpression oxidative stress. of RAGE in diabetic mice accelerates large vessel injury and microangiopathy, while RAGE-null mice show attenuation Morphology of Chronic Complications of Diabetes of these features. Antagonists of RAGE have emerged as The important morphologic changes are related to the therapeutic agents in diabetes and are being tested in clinical many late systemic complications of diabetes. As dis- trials. cussed earlier, these changes are seen in both T1D and T2D In addition to receptor-mediated effects, AGEs can (Fig. 24.34). directly cross-link extracellular matrix proteins. Cross- linking of collagen type I molecules in large vessels MORPHOLOGY decreases their elasticity, which may predispose these vessels to shear stress and endothelial injury (Chapter PANCREAS 11). Similarly, AGE-induced cross-linking of type IV Alterations in the pancreas are inconstant and often subtle. Distinc- collagen in basement membrane decreases endothelial tive changes are more commonly associated with T1D than with cell adhesion and increases extravasation of fluid. Proteins T2D. One or more of the following alterations may be present: cross-linked by AGEs are resistant to proteolytic digestion. Reduction in the number and size of islets. This is most Thus, cross-linking decreases protein removal, enhancing often seen in T1D, particularly with rapidly advancing disease. protein accumulation. AGE-modified matrix components Most of the islets are small and inconspicuous. also trap nonglycated plasma or interstitial proteins. In Leukocytic infiltrates in the islets (insulitis) are principally large vessels, trapping of LDL, for example, retards its composed of T lymphocytes and are also seen in animal models efflux from the vessel wall and contributes to the deposi- of autoimmune diabetes (Fig. 24.35A). Lymphocytic infiltrates tion of cholesterol in the intima, thus accelerating ath- may be present in T1D at the time of clinical presentation. erogenesis (Chapter 11). In capillaries, including those In T2D there may be a subtle reduction in islet cell of renal glomeruli, plasma proteins such as albumin bind mass, demonstrated only by special morphometric studies. to the glycated basement membrane, accounting in part Amyloid deposition within islets in T2D begins in and for the basement membrane thickening that is charac- around capillaries and between cells. At advanced stages, the teristic of diabetic microangiopathy.  The endocrine pancreas 1109 Microangiopathy Cerebral vascular infarcts Hemorrhage Retinopathy Hypertension Cataracts Glaucoma Myocardial infarct Atherosclerosis Islet cell loss Insulitis (Type 1) Amyloid (Type 2) Nephrosclerosis Glomerulosclerosis Arteriosclerosis Pyelonephritis Peripheral vascular atherosclerosis Gangrene Peripheral neuropathy Infections Autonomic neuropathy Figure 24.34 Long-term complications of diabetes. larger renal arteries are also subject to severe atherosclerosis, islets may be virtually obliterated (see Fig. 24.35B); fibrosis may but the most damaging effect of diabetes on the kidneys is also be observed. Similar lesions may be found in older individuals exerted at the level of the glomeruli and the microcirculation without diabetes, apparently as part of normal aging. (discussed later). An increase in the number and size of islets is especially Hyaline arteriolosclerosis, the vascular lesion associated characteristic of nondiabetic newborns of mothers with diabetes. with essential hypertension (Chapters 11 and 20), is both Presumably, fetal islets undergo hyperplasia in response to the more prevalent and more severe in patients with diabetes maternal hyperglycemia. 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 Diabetic Macrovascular Disease of the arterioles, which causes narrowing of the lumen (Fig. Diabetes exacts a heavy toll on the vascular system. Endo- 24.36). Not surprisingly, in diabetic patients, it is related thelial dysfunction (Chapter 11), which predisposes to ath- not only to the duration of the disease but also to the level erosclerosis and other cardiovascular morbidities, is of blood pressure. widespread in diabetes, as a consequence of the deleterious effects of persistent hyperglycemia and insulin resistance Diabetic Microangiopathy on the vascular compartment. The hallmark of diabetic One of the most consistent morphologic features of diabetes macrovascular disease is accelerated atherosclerosis involving is diffuse thickening of basement membranes. The thickening is the aorta and large- and medium-sized arteries. The morphol- most evident in the capillaries of the skin, skeletal muscle, ogy of atherosclerosis in patients with diabetes is indistin- retina, renal glomeruli, and renal medulla. However, it guishable from that in individuals without diabetes (Chapter may also be seen in such nonvascular structures as renal 11). Myocardial infarction, caused by atherosclerosis of tubules, the Bowman capsule, peripheral nerves, and pla- the coronary arteries, is the most common cause of death centa. It should be noted that despite the increase in the in diabetes. Gangrene of the lower extremities, as a result of thickness of basement membranes, capillaries in patients advanced vascular disease, is about 100 times more common with diabetes are leakier than normal to plasma proteins. in diabetes patients than in the general population. The The microangiopathy underlies the development of 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) glo- merular lesions; (2) renal vascular lesions, principally arteriolosclerosis; and (3) pyelonephritis, including nec- rotizing 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 Capillary Basement Membrane Thickening. Widespread thickened vascular wall is evident (periodic acid–Schiff stain). (Courtesy thickening of the glomerular capillary basement membrane M.A. Venkatachalam, MD, Department of Pathology, University of Texas (GBM) occurs in virtually all cases of diabetic nephropathy Health Science Center, San Antonio, Texas.) and is part and parcel of diabetic microangiopathy. Capillary basement membrane thickening is best appreciated by diabetic nephropathy, retinopathy, and some forms of electron microscopy (Fig. 24.37). Morphometric studies neuropathy. demonstrate that thickening begins as early as 2 years after the onset of T1D and by 5 years amounts to about a 30% Diabetic Nephropathy increase. These progressive changes in the GBM are usually The kidneys are prime targets of diabetes. Renal failure is accompanied by mesangial widening and thickening of the second only to myocardial infarction as a cause of death tubular basement membranes (Fig. 24.38).  The endocrine pancreas 1111 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 Figure 24.40 Nephrosclerosis in a patient with long-standing diabetes. increase in mesangial matrix. The matrix depositions are The kidney has been bisected to demonstrate both diffuse granular PAS-positive (Fig. 24.39). As the disease progresses, the transformation of the surface (left) and marked thinning of the cortical tissue (right). Additional features include some irregular depressions, the mesangial matrix deposits may take on a nodular appearance. result of pyelonephritis, and an incidental cortical cyst (far right). The progressive expansion of the mesangium has been shown to correlate well with measures of deteriorating renal function such as increasing proteinuria. in patients with diabetes than in the general population. One special pattern of acute pyelonephritis, papillary Nodular Glomerulosclerosis. Thi