Alterations of Hormonal Regulation

The cardinal features of SIADH are the result of enhanced renal free water retention. ADH induces the insertion of a water channel protein, called aquaporin-2, into the tubular luminal membrane, which increases water reabsorption by the kidneys (renal function is discussed in Chapter 37). This results in an expansion of extracellular fluid volume that leads to dilutional hyponatremia (low serum sodium concentration), high urinary osmolarity, high urinary sodium concentration, absence of edema, or clinical signs of volume depletion.³ Urine is inappropriately concentrated with respect to serum osmolarity because water is reabsorbed that normally would be excreted.

The symptoms of SIADH result from hyponatremia (see Chapter 3) and are determined by its severity and rapidity of onset. Thirst, impaired taste, anorexia, dyspnea on exertion, fatigue, and dulled sensorium occur when the serum sodium level decreases rapidly. Gastrointestinal (GI) symptoms, including vomiting and abdominal cramps, occur with a drop in sodium concentration from 130 to 120 mEq/L. There is weight gain from water retention, but peripheral edema is absent. Serum sodium levels below 115 mEq/L cause confusion, lethargy, muscle twitching, and convulsions; severe and sometimes irreversible neurologic damage may occur. Symptoms usually resolve with correction of hyponatremia.

A diagnosis of SIADH is based on these findings: (1) serum hypoosmolality and hyponatremia, (2) urine hyperosmolarity (i.e., urine osmolality is greater than expected for the concomitant serum osmolality), and (3) the absence of conditions that can alter volume status (e.g., adrenal or thyroid dysfunction, congestive heart failure, or renal insufficiency) (Table 22.2). It is important to remember that the diagnosis of SIADH requires normal renal, cardiac, hepatic, adrenal, and thyroid function. In particular, hypothyroidism and adrenal insufficiency must be excluded.⁴

The treatment of SIADH involves the correction of any underlying causal problems, as well as fluid restriction with careful monitoring of serum sodium and neurologic symptoms. In severe SIADH, emergency correction of severe hyponatremia by careful administration of hypertonic saline and administration of vasopressin receptor antagonists (vaptans) may be required. Resolution usually occurs within 3 days. If hyponatremia is corrected too rapidly, a severe neurologic syndrome called central pontine myelinolysis can ensue.

Individuals with DI have a partial to total inability to concentrate urine. Insufficient ADH activity causes excretion of large volumes of dilute urine, leading to increased plasma osmolality. In conscious individuals, the thirst mechanism is stimulated and induces polydipsia. Dehydration develops rapidly without ongoing fluid replacement. If the individual with DI cannot conserve as much water as is lost in the urine, serum hypernatremia and hyperosmolality occur. Concentrations of other serum electrolytes generally are not affected. Neurogenic (central) DI is the clinical manifestation of destruction of the neurons of the hypothalamus/posterior pituitary axis, with consequent loss of AVP secretion. The syndrome is caused by a wide variety of acquired or congenital lesions.6

The clinical manifestations of DI include polyuria, nocturia, continuous thirst, and polydipsia. The urine output is varied but can increase from the normal output of 1 to 2 L/day to as much as 8 to 12 L/day. Individuals with long-standing DI develop a large bladder capacity and hydronephrosis (see Chapter 38). Neurogenic DI usually has an abrupt onset, whereas nephrogenic DI usually has a more gradual onset. Table 22.2 compares the signs and symptoms of DI and SIADH. A history of lithium therapy may raise the possibility of NDI, whereas previous brain injury or neurosurgical intervention may indicate neurogenic (central) DI.⁶

Dipsogenic or primary polydipsia may be confused with DI, but it is particularly important not to misdiagnose primary polydipsia as neurogenic (central) DI, because inappropriate therapy with desmopressin can lead to dangerous hyponatremia in individuals who continue to drink excessively.6 Primary polydipsia is usually the result of a psychiatric condition that causes the chronic ingestion of extremely large quantities of fluid, which washes out the renal concentration gradient, resulting in partial resistance to ADH.

Treatment of neurogenic (central) DI is based on the extent of the ADH deficiency. Fluid replacement using oral or intravenous routes is usually adequate. Some individuals require ADH replacement with the synthetic vasopressin analog desmopressin (DDAVP). Once a diagnosis of neurogenic (central) DI is made, magnetic resonance imaging (MRI) of the hypothalamic-pituitary region is required to establish whether there is a structural lesion that is responsible for AVP deficiency. Management of nephrogenic DI requires treatment of any reversible underlying disorders, discontinuation of etiologic medications, and correction of associated electrolyte disorders.⁶ Drugs that potentiate the action of otherwise insufficient amounts of endogenous ADH, such as thiazide diuretics, chlorpropamide, carbamazepine, and clofibrate, may be used in individuals with incomplete ADH deficiency.

GH deficiency in children is manifested by growth failure and a condition known as hypopituitary dwarfism (Fig. 22.2). Symptoms of chronic adult GH deficiency syndrome include increased body fat, decreased strength and lean body mass, osteoporosis, reduced sweating, dry skin, and psychological problems, including depression, social withdrawal, fatigue, loss of motivation, and a diminished feeling of well-being. Dyslipidemias and atherosclerotic cardiovascular disease may occur.

A black-and-white historical photo shows the brothers, Hugo and Adrien, both 230 centimeters tall, standing together. While the brothers have pituitary giantism. Adrien, 69 centimeters, standing between them, has hypopituitary dwarfism and stands just as tall as the brothers’ knees.

With a GH-secreting neuroendocrine tumor, only slight elevations of GH and IGF-1 can stimulate growth. In children and adolescents whose epiphyseal plates have not yet closed, the effect of increased GH levels is termed giantism (see Fig. 22.2). Skeletal growth is excessive, with some individuals becoming 8 or 9 feet tall. In the adult, epiphyseal closure has occurred, and increased amounts of GH and IGF-1 cause connective tissue proliferation and increased cytoplasmic matrix, as well as bony proliferation that results in the characteristic appearance of acromegaly (Fig. 22.3).

A photo of the anterior profile of a person with acromegaly shows and labels the different conditions on the body, from the top to the bottom: transfrontal scar, frontal bossing, bitemporal hemianopia, papilledema, angioid streaks, prognathism (protruding jaw), enlarged tongue, molluscum fibrosum (skin tags), proximal myopathy, and spade-like hands.

GH also has significant effects on glucose, lipid, and protein metabolism. Hyperglycemia results from adipocyte inflammation and GH inhibition of peripheral glucose uptake and increased hepatic glucose production, followed by compensatory hyperinsulinism and, finally, insulin resistance. Diabetes mellitus occurs when the pancreas cannot secrete enough insulin to offset the effects of GH. Excessive levels of GH and IGF-1 also affect the cardiovascular system with calcium influx in cardiomyocytes, enhanced cardiac contractility, and cardiomyocyte growth. Hypertension, cardiomegaly, and left ventricular heart failure are seen in one-third to one-half of individuals with acromegaly. GH also acts on the renal tubules to increase phosphate reabsorption, leading to mild hyperphosphatemia. Approximately 20% of GH-secreting tumors also secrete prolactin. Because the adenoma becomes increasingly a space-occupying lesion, hypopituitarism may occur because of compression of surrounding hormone-secreting cells.

With connective tissue proliferation, individuals with acromegaly have an enlarged tongue, interstitial edema, enlarged and overactive sebaceous and sweat glands (leading to increased body odor), and coarse skin and body hair. Bony proliferation involves periosteal vertebral growth and enlargement of the bones of the face, hands, and feet (see Fig. 22.3). The lower jaw and forehead also protrude.

Increased IGF-1 levels cause ribs to elongate at the bone–cartilage junction, leading to a barrel-chested appearance, and increased proliferation of cartilage in joints, which causes backache and arthralgias. With bony and soft tissue overgrowth, nerve entrapment occurs, leading to peripheral nerve damage manifested by weakness, muscular atrophy, foot drop, and sensory changes in the hands.

Symptoms of diabetes mellitus, such as polyuria and polydipsia, may occur. Acromegaly-associated hypertension is usually asymptomatic until heart failure symptoms develop. Increased tumor size results in central nervous system symptoms of headache, seizure activity, visual disturbances, and papilledema. If compression hypopituitarism occurs, gonadotropin secretion may be affected, causing amenorrhea in women and sexual dysfunction in men. Increased prolactin results in hypogonadism.

The hallmark of a prolactinoma is sustained increases in the levels of serum prolactin, also known as hyperprolactinemia, which has multiple effects on female and male reproductive organs.12 Pathologic elevations of prolactin suppress LH and FSH, resulting in estrogen and progesterone deficiency in women and low testosterone levels in men.

Hypopituitarism may occur because of the compression of surrounding hormone-secreting cells. Central nervous system symptoms may develop because of growth and pressure of the tumor within the sella turcica. These complications are especially common with what are called macro (>1 cm in diameter) or giant (>4 cm in diameter) prolactinomas.

Thyrotoxicosis is a condition that results from any cause of increased TH levels and can result from dysfunction of the pituitary, the thyroid gland, ectopic thyroid tissue, or the ingestion of excessive amounts of TH medication. Hyperthyroidism is a form of thyrotoxicosis in which excess amounts of TH are secreted from the thyroid gland (Fig. 22.5).¹⁶Primary hyperthyroidism results from thyroid gland dysfunction and is most commonly caused by Graves disease, toxic multinodular goiter, and solitary toxic adenoma. Central (secondary) hyperthyroidism is less common and is caused by TSH-secreting pituitary adenomas. Each condition is associated with a specific pathophysiology and manifestations; however, all forms of thyrotoxicosis share some common characteristics.

An illustration of the thyroid highlights the following common causes of hyperthyroidism. 1. Graves disease (T S H receptor antibodies). T S H receptors attract T S H and I g G. 2. Nodular goiter. The illustration shows multiple fluid-filled lumps on the thyroid. 3. Adenoma. The illustration shows a large tumor on the thyroid. 4. Thyroid pill. The illustration shows that the ingestion of the pill results in a low T S H, leading to increased T 3 and T 4, which provides a feedback loop.

The clinical features of thyrotoxicosis are attributable to the metabolic effects of increased circulating levels of THs. This results in an increased metabolic rate, with heat intolerance and increased tissue sensitivity to stimulation by the sympathetic nervous system. The major manifestations are summarized in Fig. 22.6 and Table 22.3.

An illustration of the anterior view of a person highlights the manifestations for hypothyroidism and hyperthyroidism. The manifestations for hypothyroidism, identified from the top to the bottom, are as follows. • Loss of hair or coarse, brittle hair. • Periorbital edema. • Puffy face. • Normal or small thyroid. • Heart failure (bradycardia). • Constipation. • Cold intolerance. • Muscle weakness. • Edema of the extremities. The manifestations for hyperthyroidism, identified from the top to the bottom, are as follows. • Thin hair. • Exophthalmos. • Enlarged thyroid: diffuse (warm on palpation), nodular, solitary toxic nodule. • Heart failure (tachycardia). • Weight loss. • Diarrhea. • Warm, skin, sweaty palms. • Hyperreflexia. • Pretibial edema.

Evaluation and Treatment. Elevated serum thyroxine (T₄) and triiodothyronine (T₃) levels and suppressed serum TSH levels are diagnostic for primary hyperthyroidism. By contrast, central (secondary) hyperthyroidism caused by TSH-secreting pituitary tumors is characterized by normal to increased TSH levels despite elevated TH concentrations. Treatment is directed at controlling excessive TH production, secretion, or action and involves antithyroid drug therapy, radioactive iodine therapy (absorbed only by thyroid tissue, causing death of cells), or surgical removal of nodules or part of the thyroid gland. A major complication of all forms of treatment for hyperthyroidism is excessive ablation of the gland, leading to hypothyroidism.

In primary hypothyroidism, loss of thyroid function leads to decreased production of TH and increased secretion of TSH and TRH. The most common causes of primary hypothyroidism in adults include autoimmune thyroiditis (chronic lymphocytic thyroiditis), iatrogenic loss of thyroid tissue after surgical or radioactive treatment for hyperthyroidism or after head and neck radiation therapy, medications (e.g., lithium and amiodarone), and endemic iodine deficiency. Iodine, required for the production of TH, is not produced naturally by the body and is obtained through dietary intake. Iodine deficiency is relatively rare in the United States because of the use of iodized salt and fortified foods.19 Infants and children may present with hypothyroidism because of congenital defects. Central (secondary) hypothyroidism is caused by the pituitary's failure to synthesize adequate amounts of TSH or a lack of TRH. Pituitary tumors that compress surrounding pituitary cells or the consequences of their treatment are the most common causes of central hypothyroidism. Other causes include traumatic brain injury, subarachnoid hemorrhage, pituitary infarction, or metabolic disorders including insulin resistance or hyperglycemia, dyslipidemia, obesity, and endothelial dysfunction.²¹ Hypothalamic dysfunction results in low levels of TH, TSH, and TRH.

Hypothyroidism generally affects all body systems and occurs insidiously over months or years. Decreased TH levels lower energy metabolism and heat production. The individual develops a low basal metabolic rate, cold intolerance, lethargy, and slightly lowered basal body temperature (see Fig. 22.6). The decrease in the level of TH leads to excessive TSH production, which stimulates thyroid tissue and causes a goiter (Table 22.4).

The characteristic sign of severe or long-standing hypothyroidism is myxedema, which results from the altered composition of the dermis and other tissues. The connective tissue fibers are separated by large amounts of protein and mucopolysaccharide. This complex binds water, producing nonpitting, boggy edema, especially around the eyes, hands, and feet and in the supraclavicular fossae (Fig. 22.9). The tongue and laryngeal and pharyngeal mucous membranes thicken, producing thick, slurred speech and hoarseness. Myxedema coma, a medical emergency, is a diminished level of consciousness associated with severe hypothyroidism. Signs and symptoms include hypothermia without shivering, hypoventilation, hypotension, hypoglycemia, and lactic acidosis. Older individuals with comorbid conditions, such as pulmonary or urinary infections, congestive heart failure, or cerebrovascular accident, and with moderate or untreated hypothyroidism are particularly at risk for developing myxedema coma. It also may occur after overuse of narcotics or sedatives or after an acute illness in hypothyroid individuals. Symptoms of hypothyroidism in older adults should not be attributed to expected age-related changes.

The diagnosis of primary hypothyroidism is made by documentation of the clinical symptoms of hypothyroidism and measurement of increased serum levels of TSH and decreased serum levels of TH (total T₃ and both total and free T₄). Central hypothyroidism is diagnosed by finding low TH and low serum TSH levels. Alluded to earlier, subclinical hypothyroidism is diagnosed by an elevation in TSH level with normal levels of circulating TH. Hormone replacement therapy with the hormone levothyroxine is the treatment of choice for both primary and central thyroid disorders (Emerging Science Box: Combination Therapy for the Treatment of Hypothyroidism).

Primary hyperparathyroidism is characterized by inappropriate excess secretion of PTH by one or more of the parathyroid glands.24 It is one of the most common endocrine disorders. Approximately 80% to 85% of cases are caused by parathyroid adenomas, another 10% to 15% result from parathyroid hyperplasia, and approximately 1% of cases are caused by parathyroid carcinoma. In addition, primary hyperparathyroidism may be caused by a variety of genetic causes, especially the genes that cause multiple endocrine neoplasia.

In primary hyperparathyroidism, PTH secretion is increased and is not under the usual feedback control mechanisms. The calcium level in the blood rises because of increased bone resorption and GI absorption of calcium but fails to inhibit PTH secretion by the parathyroid gland. Some individuals with primary hyperparathyroidism maintain normal levels of calcium despite elevated levels of PTH and are diagnosed only when they develop osteoporosis.

Secondary hyperparathyroidism is a compensatory response of the parathyroid glands to chronic hypocalcemia, which is commonly associated with decreased activation of vitamin D in individuals with renal failure (see Chapter 38). Secretion of PTH is elevated, but not enough to achieve normal calcium levels because of insufficient levels of activated vitamin D. Other causes of secondary hyperparathyroidism include a dietary deficiency of vitamin D or calcium; decreased intestinal absorption of vitamin D or calcium; and ingestion of drugs, such as phenytoin, phenobarbital, and laxatives, which either accelerate the metabolism of vitamin D or decrease intestinal absorption of calcium.

Tertiary hyperparathyroidism can develop after any long-standing period of hypocalcemia, such as is seen with chronic dialysis, renal transplantation, or GI malabsorption. Parathyroid chief cell hyperplasia leads to excessive secretion of PTH and may cause hypercalcemia (cellular adaptation is discussed in Chapter 2).

Hypercalcemia and hypophosphatemia are the hallmarks of primary hyperparathyroidism. Hypercalcemia and hypophosphatemia may be asymptomatic or affected individuals may present with symptoms related to the muscular, nervous, and GI systems, including fatigue, headache, depression, anorexia, and nausea and vomiting. Excessive osteoclastic and osteocytic activity causes bone resorption, resulting in osteoporosis, pathologic fractures, kyphosis of the dorsal spine, and compression fractures of the vertebral bodies (bone resorption is discussed in Chapter 44).

Hypercalcemia means that the renal tubules must filter large amounts of calcium, leading to hypercalciuria and production of an abnormally alkaline urine. PTH hypersecretion enhances renal phosphate excretion and results in hypophosphatemia and hyperphosphaturia (see Chapter 3). The combination of these three variables—hypercalciuria, alkaline urine, and hyperphosphaturia—predisposes the individual to the formation of calcium stones, particularly in the renal pelvis or renal collecting ducts. These stones may be associated with infections and impaired renal function. Chronic hypercalcemia also is associated with mild insulin resistance, necessitating increased insulin secretion to maintain normal glucose levels (Table 22.5).

Secondary hyperparathyroidism, caused by renal disease, presents clinically not only with the complications of bone resorption but also with the symptoms of hypocalcemia and hyperphosphatemia, such as muscle spasms and cardiovascular complications (see Chapter 3).

Symptoms associated with hypopara thyroidism are primarily those of hypocalcemia (see Chapter 3). Hypocalcemia causes muscle spasms, which can progress to tetany, dry skin, and loss of body and scalp hair. Irreversible complications include hypoplasia of developing teeth, horizontal ridges on the nails, cataracts, basal ganglia calcifications (which may be associated with a parkinsonian syndrome), and bone deformities, including brachydactyly and bowing of the long bones.

Autoimmune diabetes mellitus type 1 is a slowly progressive disease that destroys β cells of the pancreas. There are strong genetic associations with histocompatibility leukocyte antigen (HLA) class II alleles HLA-DQ and HLA-DR. Environmental factors that have been implicated include exposure to certain drugs, foods, and viruses. These gene-environment interactions result in the formation of autoantigens that are expressed on the surface of pancreatic β cells and circulate in the bloodstream and lymphatics (see Fig. 22.11). Cellular immunity (T-cytotoxic cells and macrophages) and humoral immunity (autoantibodies against islet cells, insulin, glutamic acid decarboxylase [GAD], and other cytoplasmic proteins) are stimulated, resulting in β-cell destruction and apoptosis. Over time, 80% to 90% of the insulin-secreting β cells of the islet of Langerhans are destroyed, insulin synthesis declines, and hyperglycemia develops.

A flowchart represents the pathophysiology of type 1 diabetes mellitus. Genetic predisposition and environmental factors impact the autoantigens form on insulin-producing beta cells and circulate in the bloodstream and lymphatics, which leads to the following sequence. • Activation of cellular immunity (macrophages and T cytotoxic cells) and humoral immunity (autoantibodies) toward beta cells. • Destruction of beta cells with decreased insulin secretion.

Insulin normally suppresses secretion of glucagon, and thus hypoinsulinemia leads to a marked increase in glucagon secretion. In addition to the decline in insulin secretion, there is decreased secretion of amylin (another β-cell hormone), which also leads to an increase in glucagon. Glucagon, a hormone produced by the α cells of the islets, acts in the liver to increase the blood glucose level by stimulating glycogenolysis and gluconeogenesis. Thus, both a lack of insulin and a relative excess of glucagon contribute to hyperglycemia in type 1 diabetes.

The natural history of type 1 diabetes involves a long preclinical period before insulin deficiency and hyperglycemia develop. Glucose accumulates in the blood and appears in the urine as the renal threshold for glucose is exceeded, producing an osmotic diuresis and symptoms of polyuria and thirst (Table 22.8). Wide fluctuations in blood glucose levels occur. Insulin deficiency also causes protein and fat breakdown, resulting in weight loss. Excessive metabolism of fats and proteins leads to high levels of circulating ketones, causing a condition known as diabetic ketoacidosis (DKA) (see the Acute Complications of Diabetes section).

Although most individuals with type 1 diabetes are of normal or decreased weight, there are increasing numbers of individuals who have both type 1 diabetes and the clinical manifestations of metabolic syndrome, including obesity, dyslipidemia, and hypertension (Box 22.2). These individuals are at high risk for chronic complications of diabetes, including heart disease and stroke.

The common clinical manifestations of type 1 diabetes result from both insulin deficiency and hyperglycemia. These manifestations are described in Table 22.8. Acute complications also may include hypoglycemia and DKA, which are described later in this chapter. Chronic complications include renal, nervous system, cardiac, peripheral vascular, retinal, and bony tissue dysfunction.

The criteria for diagnosis of type 1 diabetes are the same as those for type 2 diabetes (see Box 22.1). To estimate the severity of β-cell destruction, C-peptide, a component of proinsulin released during insulin production, can be measured in the serum as a surrogate for insulin levels. An individual with residual pancreatic β cell function will have detectable levels of C-peptide, but a negligible amount of C-peptide can point to the diagnosis of type 1 diabetes. Individuals with hyperglycemia and at risk for type 1 diabetes can be tested for a variety of autoantibodies, such as zinc transporter 8 (ZnT8Ab) or tyrosine phosphatases. If two or more of the autoantibodies are positive in conjunction with diagnostic hyperglycemia, then the diagnosis of type 1 diabetes is confirmed. It is important to note that antibody testing itself is not a diagnostic requirement for type 1 diabetes. Other important aspects of evaluation include looking for evidence of acute and chronic complications of type 1 diabetes.

There are no approved treatments for preventing destruction of the β cells. Currently, treatment regimens are designed to achieve optimal glucose level control (as measured by the HbA_1C value) without causing episodes of significant hypoglycemia. A comprehensive, person-centered collaborative management plan is essential.²⁶ Management requires individual planning according to type of disease, age, and activity level, but all individuals require some combination of insulin therapy, meal planning, an exercise regimen, and glucose monitoring. There are several different types of insulin preparations available, and there are new technologies for more physiologic insulin delivery systems. Many different kinds of therapies are being tested to prevent the autoimmune destruction of β cells, including immunosuppression with antirejection drugs and stem cell transplantation (Emerging Science Box: Pancreatic β Cell Regeneration as a Plausible Diabetic Therapy).

Diabetes mellitus type 2 is a chronic and metabolic disease characterized by defects in pancreatic insulin secretion and (or) insulin effect on target tissues, generating a persistent state of hyperglycemia, inducing metabolic alteration, cell death, and inflammation.28 Insulin resistance is defined as a suboptimal response of insulin-sensitive tissues (especially liver, muscle, and adipose tissue) to insulin. Several mechanisms are involved in abnormalities of the insulin signaling pathway and contribute to insulin resistance. These include an abnormality of the insulin molecule, high amounts of insulin antagonists, down-regulation of the insulin receptor, and alteration of glucose transporter (GLUT) proteins.

Obesity is one of the most important contributors to insulin resistance and diabetes and acts through several important mechanisms:

Compensatory hyperinsulinemia prevents the clinical appearance of diabetes for many years. Eventually, however, a decrease in β-cell mass and a reduction in normal β-cell function develops and leads to a relative deficiency of insulin activity.

As you have learned, many organs contribute to insulin resistance, chronic hyperglycemia, and the consequences of type 2 diabetes. These causes and consequences are summarized in Fig. 22.13, and the complications of type 2 diabetes will be discussed later in this chapter.

An illustration lists the causes and consequences of chronic hyperglycemia. The causes of chronic hyperglycemia are as follows. • Pancreas. Decreased beta-cell insulin and amylin secretion. Increased alpha-cell glucagon secretion. • Adipose tissue. Decreased insulin-dependent glucose uptake. Increased lipolysis. Decreased adiponectin. Increased leptin and resistin. Macrophage accumulation and inflammation (T N F-alpha, I L-6). • Liver. Increased hepatic gluconeogenesis. • Digestive system. Decreased G L P-1 and G I P. Decreased stomach secretion of ghrelin. • Kidney. Increased glucose reabsorption and gluconeogenesis. • Muscle. Decreased insulin sensitivity. Decreased glucose uptake. Increased lipid accumulation. • Brain. Neurotransmitter dysfunction. Altered insulin-signaling. Altered lipid-sensing. The consequences of chronic hyperglycemia are as follows. • Decreased cognition. • Oxidative stress. Immunosuppression. Infection. Cancer. • Nephropathy. Glomerulosclerosis. Chronic kidney disease. • Gastroparesis. • Steatohepatitis. Biliary disease. • Heart disease. • Hypertension. P V D. Stroke. • Neuropathy. • Retinopathy and cataracts.

The clinical manifestations of type 2 diabetes are nonspecific. The individual with type 2 diabetes may show some classic symptoms of diabetes, such as polyuria and polydipsia, but more often will have nonspecific symptoms, such as fatigue, pruritus, recurrent infections, visual changes, or symptoms of neuropathy (paresthesia or weakness). The affected individual is often overweight, dyslipidemic, and hypertensive. The increased morbidity and mortality rates related to diabetes mellitus type 2 are often associated with vascular complications, such as cardiovascular diseases, nephropathy, retinopathy, endothelial dysfunction, dyslipidemia, and an increase of oxidative stress, which is also due to inflammation (Emerging Science Box: Inflammation and Its Importance to the Pathophysiology of Insulin Resistance in Prediabetes and Diabetes Mellitus Type 2).^29,30

The diagnostic criteria for type 2 diabetes are the same as those for type 1 (see Box 22.1). Metabolic syndrome is a constellation of disorders (central obesity, dyslipidemia, prehypertension, and an elevated FPG) that confer a high risk of developing type 2 diabetes and associated cardiovascular complications (see Box 22.2).

As with type 1 diabetes, the goal of treatment for individuals with type 2 diabetes (and metabolic syndrome) is the restoration of near-euglycemia (normal blood glucose) levels and correction of related metabolic disorders. Prevention and treatment of type 2 diabetes, especially in those individuals with prediabetes, focuses on lifestyle modifications as the cornerstone modality.³¹ Diet should match activity levels and include more complex carbohydrates (rather than simple sugars), foods low in fats, adequate protein, and fiber. Obesity management results in improved glucose tolerance. Bariatric surgery improves glycemic control, decreases the risk of cardiovascular disease, and promotes weight loss in those morbidly obese.²⁶

For individuals who require further intervention, oral and/or non-insulin antidiabetic agents are indicated (Table 22.9).²⁶ Currently, metformin is considered the primary pharmacologic choice for the treatment of type 2 diabetes. If the HbA_1C target is not maintained over 3 months, a GLP-1 receptor agonist (incretin) may be added.^26,31

If treatment goals are still not met, a combination of drugs, including SGLT2 inhibitors, may be required. Insulin therapy may be needed in the later stage of type 2 diabetes because of loss of β-cell function, which is progressive over time (Emerging Science Box: Smart Pens for Improved Safety and Efficacy of Insulin Therapy).