(1)  ↑ cortisol and androgen levels

(2)  ↓ ACTH (if caused by primary adrenal hyperplasia or pharmacologic doses of glucocorticosteroids); ↑ ACTH (if caused by overproduction of ACTH, as in Cushing

disease)

(3)  Hyperglycemia (caused by elevated cortisol levels)

(4)  ↑ protein catabolism and muscle wasting

(5)  Central obesity (round face, supraclavicular fat, buffalo hump)

(6)  Poor wound healing

(7)  Virilization of women (caused by elevated levels of adrenal androgens)

(8)  Hypertension (caused by elevated levels of cortisol and aldosterone)

(9)  Osteoporosis (elevated cortisol levels cause increased bone resorption) (10)  Striae

■Ketoconazole, an inhibitor of steroid hormone synthesis, can be used to treat Cushing disease.

c.  Hyperaldosteronism—Conn syndrome

■is caused by an aldosterone-secreting tumor.

■is characterized by the following:

(1)  Hypertension (because aldosterone increases Na+ reabsorption, which leads to

increases in ECF volume and blood volume)

(2)  Hypokalemia (because aldosterone increases K+ secretion)

(3)  Metabolic alkalosis (because aldosterone increases H+ secretion)

(4)  ↓ renin secretion (because increased ECF volume and blood pressure inhibit renin secretion by negative feedback)

d.  21b-Hydroxylase deficiency

■is the most common biochemical abnormality of the steroidogenic pathway (see Figure 7.11).

■belongs to a group of disorders characterized by adrenogenital syndrome.

■is characterized by the following:

(1)  ↓ cortisol and aldosterone levels (because the enzyme block prevents the production of 11-deoxycorticosterone and 11-deoxycortisol, the precursors for cortisol and aldosterone)

(2)  ↑ 17-hydroxyprogesterone and progesterone levels (because of accumulation of intermediates above the enzyme block)

(3)  ↑ ACTH (because of decreased feedback inhibition by cortisol)

(4)  Hyperplasia of zona fasciculata and zona reticularis (because of high levels of

ACTH)

(5)  ↑ adrenal androgens (because 17-hydroxyprogesterone is their major precursor) and ↑ urinary 17-ketosteroids

(6)  Virilization in women

(7)  Early acceleration of linear growth and early appearance of pubic and axillary hair

(8)  Suppression of gonadal function in both men and women e.  17a-Hydroxylase deficiency is characterized by the following:

(1)  ↓ androgen and glucocorticoid levels (because the enzyme block prevents the pro-

duction of 17-hydroxypregnenolone and 17-hydroxyprogesterone)

(2)  ↑ mineralocorticoid levels (because intermediates accumulate to the left of the enzyme block and are shunted toward the production of mineralocorticoids)

(3)  Lack of pubic and axillary hair (which depends on adrenal androgens) in women

(4)  Hypoglycemia (because of decreased glucocorticoids)

(5)  Metabolic alkalosis, hypokalemia, and hypertension (because of increased mineralocorticoids)

(6)  ↑ ACTH (because decreased cortisol levels stimulate ACTH secretion by negative feedback)

B. Adrenal medulla (see Chapter 2, I A 4)

vI. enDOCrIne PAnCreAs–GlUCAGOn AnD InsUlIn (TABle 7.7)

A.Organization of the endocrine pancreas

■The islets of Langerhans contain three major cell types (Table 7.8). Other cells secrete pancreatic polypeptide.

■Gap junctions link beta cells to each other, alpha cells to each other, and beta cells to alpha cells for rapid communication.

■The portal blood supply of the islets allows blood from the beta cells (containing insulin) to bathe the alpha and delta cells, again for rapid cell-to-cell communication.

B.Glucagon

1.regulation of glucagon secretion (Table 7.9)

■The major factor that regulates glucagon secretion is the blood glucose concentration.

Decreased blood glucose stimulates glucagon secretion.

■Increased blood amino acids stimulate glucagon secretion, which prevents hypoglycemia caused by unopposed insulin in response to a high protein meal.

2.Actions of glucagon

■Glucagon acts on the liver and adipose tissue.

■The second messenger for glucagon is CAmP.

a.Glucagon increases the blood glucose concentration.

(1)It increases glycogenolysis and prevents the recycling of glucose into glycogen.

(2)It increases gluconeogenesis. Glucagon decreases the production of fructose 2,6-bisphosphate, decreasing phosphofructokinase activity; in effect, substrate is directed toward glucose formation rather than toward glucose breakdown.

b.Glucagon increases blood fatty acid and ketoacid concentration.

■ Glucagon increases lipolysis. The inhibition of fatty acid synthesis in effect “shunts” substrates toward gluconeogenesis.

■Ketoacids (β-hydroxybutyrate and acetoacetate) are produced from acetyl coenzyme A (CoA), which results from fatty acid degradation.

c.Glucagon increases urea production.

■Amino acids are used for gluconeogenesis (stimulated by glucagon), and the resulting amino groups are incorporated into urea.

ACh = acetylcholine; cAMP = cyclic adenosine monophosphate; CCK = cholecystokinin; GIP = glucose-dependent insulinotropic peptide.

C.Insulin

■contains an A chain and a B chain, joined by two disulfide bridges.

■Proinsulin is synthesized as a single-chain peptide. Within storage granules, a connecting peptide (C peptide) is removed by proteases to yield insulin. The C peptide is packaged and secreted along with insulin, and its concentration is used to monitor beta cell function in diabetic patients who are receiving exogenous insulin.

1.  Regulation of insulin secretion (Table 7.10) a.  Blood glucose concentration

■is the major factor that regulates insulin secretion.

■Increased blood glucose stimulates insulin secretion. An initial burst of insulin is followed by sustained secretion.

b.  Mechanism of insulin secretion

■Glucose, the stimulant for insulin secretion, binds to the Glut 2 receptor on the beta cells.

■Inside the beta cells, glucose is oxidized to ATP, which closes K+ channels in the cell membrane and leads to depolarization of the beta cells. Similar to the action of ATP,

sulfonylurea drugs (e.g., tolbutamide, glyburide) stimulate insulin secretion by closing these K+ channels.

■Depolarization opens Ca2+ channels, which leads to an increase in intracellular [Ca2+] and then to secretion of insulin.

2.  Insulin receptor (see Figure 7.3)

■is found on target tissues for insulin.

■is a tetramer, with two α subunits and two β subunits.

a.  The α subunits are located on the extracellular side of the cell membrane.

b.  The β subunits span the cell membrane and have intrinsic tyrosine kinase activity. When insulin binds to the receptor, tyrosine kinase is activated and autophosphorylates the β subunits. The phosphorylated receptor then phosphorylates intracellular proteins.

t a b l e   7.9     Regulation of Glucagon Secretion

ACh = acetylcholine, CCK = cholecystokinin.