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• 1 • A researcher is designing an in vitro experimental system to study the kinetics of GLUT4-mediated glucose transport into mammalian cells of Insulin- IA•A] . 2 dependent organs. The system will measure radiolabeled glucose levels In cell culture media both before and at intervals after the addition of Insulin. • 3 Which of the following cell types is the best choice for use in this experimental system? · 4 • 5 : A. Adipocytes • 6 . 7 B. Cortica l neurons

· 8 c. Erythrocytes . 9 o. Hepatocytes • 10 E. Pancreatic f3 cells • 11 • 12 • 13 • 14 • 15 • 16

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1 The correct a nswer is A. 69% chose this. . 2 Adipocytes are the cells that comprise adipose (fat) tissue. GLUT4-mediated glucose transport occurs in only two tissue types: adipose tissue and skeletal muscle. In the fasting state, when insulin levels are low, there is decrea sed intake of glucose into adipose tissue and skeletal muscle, enabling glucose to • 3 be utilized by more pertinent organs. In this context, decrea sed glucose intake into fat and muscle cells will promote mobilization of stored precursors such as amino acids and free fatty acids. This is the only choice among those listed that could be used in the hypothetical experimental system described. . 4 Adipose tissue Skeletal muscle Glucose Insulin Adipocyte Amino acid Fasting Fatty acid Free fatty acids Muscle • 5 B is not correct. 4 % chose this. • 6 Cortical neurons are derived from the brain, where glucose transport occurs independent of insulin stimulation. Thus these cells could not be used in this hypothetical system . Brain and RBCs take up glucose via GLUT-1 transport. . 7 Glucose GlUTl Neuron Insulin Cerebral cortex Brain • 8 c is not correct. 5 % chose this. • 9 RBCs take up glucose independent of insulin levels using GLUT-1 transport . GlUTl Insulin Glucose • 10 D is not correct. 13 % chose this. · 11 Insulin has no effect on glucose uptake in hepatocytes, so this cell type could not be used in this hypothetical system . • 12 Insulin Hepatocyte Glucose Glucose uptake Cell type

• 13 E is not correct. 9 % chose this. • 14 Pancrea tic j3 cells express GLUT2 transporters, which serve as glucose sensors. These cells do not express GLUT4 transporters and would not be appropriate for use in this hypothetical system . • 15 GlUT2 GlUT4 Glucose • 16

Botto m Line: Skeletal muscle and adipose tissue depend on insulin for glucose uptake, wherea s the brain and RBCs take up glucose independent of insulin. Adipose tissue Insulin Skeletal muscle Glucose Glucose uptake Human brain Muscle Brain

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1 Bottom Line: . 2 Skeletal muscle and adipose tissue depend on insulin for glucose uptake, whereas the brain and RBCs take up glucose independent of insulin. Adipose tissue Insulin Skeletal muscle Glucose Glucose uptake Human brain Muscle Brain • 3 . 4 • 5 I iii I ;fi 1!1 I•J for year:l 2017 .. • 6 FIRST AID FACT S . 7 FA17p314.1 • 8 Insulin • 9 SYNTHESIS Preproinsulin (synthesized in RER) - cleavage • 10 of"presignal" - proinsulin (stored in secretory · 11 granules) - clea,·age of proinsulin - exocytosis Proinsulin • 12 of insul in and C-peptide equall y. Insuli n and C-peptide are t in insulinoma and sulfonylurea • 13 use, whereas exogenous insulin lacks C-peptide. • 14 ~chain • 15 SOURCE Released from pancreatic ~ cells. • 16 FUNCTION Binds insulin receptors (tyrosi ne kinase insulin-dependent glucose transporters: activity 0 ), inducing glucose uptake (carrier­ • GLUT4: adipose tissue, striated muscle mediated transport) into insulin-dependent (exercise can also increase GLUT4 tiss ue e and gene transcription. cx'Pression) Anabolic effects of insulin: Insulin-independent transporters: • t glucose transport in skeletal muscle and • GLUTl: RBCs, brain, cornea, placenta adipose tissue • GLUT2 (bidirectional): ~i sl et cells, liver, • t p)vcoPcn svnthesis and stora2c kidnev. small intestine 6 s 0 lock Suspend End Block Item: 2 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 380 2 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 • A 14-year-old high school athlete is rushed to the emergency department after being found unresponsive in his bedroom at home. His mother reports IA•A] . 2 that earlier in the day, he complained of feeling more tired than usual. She notes that in the past few days he had been drinking more fluids and urinating more than usual. His pulse is 125/min, respiratory rate is 32/mln, and blood pressure is 85/60 mm Hg. His pupils are dilated. Laboratory • 3 tests are as follows:

· 4 Sodium: 132 mEq/L • 5 Potassium: 5.1 mEq/L Chloride: 95 mEq/L • 6 Bicarbonate: 17 mEq/L Blood urea nitrogen: 18 mg/dl . 7 Creatinine: 0.6 mg/dl · 8 Urinalysis reveals a sodium level of 45 mmoi/dL. . 9

• 10 Which of the following is most likely associated with his clinical syndrome? • 11 : • 12 A • An autoimmune process

• 13 B • Drug overdose • 14 c . Immune complexes • 15 Insulin insensitivity • 16 o . E. Trauma to the pituitary stalk

F. Ventricular septal hypertrophy

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1 The correct a nswer is A. 46% chose this. 2 This patient's clinical syndrome is consistent with type 1 diabetes mellitus. The underlying pathophysiology is thought to be an autoimmune or viral process causing inflammation in the j3 islets. This patient unfortunately has developed diabetic ketoacidosis. He has gone without insulin for quite some • 3 time, allowing his liver to generate ketones. DKA is characteristic by the triad of hyperglycemia, anion gap acidosis, and ketonemia. The anion gap and . 4 serum glucose level are usually> 12 and 250 mmoi/L, respectively. The most concerning problem, however; is volume depletion; the hyperglycemia has caused an osmotic diuresis, lea ding to polyuria and polydipsia. Indeed, therapy begins with rehydration. Hyperkalemia is common in these patients • 5 because of the cellular H+;K+ exchange mechanism, but there is an overall total body K+ deficit. This patient's low serum Na + and normal urine Na + concentration is explained by the hyperglycemia. The patient's high serum glucose level lea ds to an osmotic shift and pulls fluid from cells into the • 6 bloodstrea m . This increa se in fluid lea ds to a relative decrea se in the mea sured Na + though the actual serum Na + level remains the same. . 7 Diabetic ketoacidosis Hyperkalemia Polyuria Diabetes mellitus type 1 Diabetes mellitus Osmotic diuresis Hyperglycemia Polydipsia Glucose Ketoacidosis Urine liver Blood sugar Acidosis Blood plasma Insulin Autoimmunity Ketosis liver function tests Diuretic Autoimmune disease Hypovolemia Pathophysiology Anion • 8 Serum (blood) Ketone Virus Inflammation Reference ranges for blood tests Circulatory system Anion gap Osmosis • 9 B is not correct. 13% chose this • • 10 This choice may be tempting because of the patient's dilated pupils. Amphetamines and cocaine do cause dilated pupils. However; in this case, extreme · 11 volume depletion is causing high sympathetic tone, lea ding to dilated pupils. One could also think that diuretic abuse potentially led to this patient's symptoms. However; most diuretics do not cause such profound salt wasting, and the hyponatremia seen in this patient's labs cannot be explained by • 12 diuretic abuse . Hyponatremia Diuretic Sympathetic nervous system Cocaine Substituted amphetamine Mydriasis Hypovolemia Pupillary response Salt (chemistry) Salt • 13 c is not correct. 5 % chose this • • 14 Many immune complex-driven processes, such as poststreptococcal glomerulonephritis, may cause renal failure, but they typically would be oliguric, not • 15 polyuric. Electrolyte disturbances would not be expected, and the patient would not be volume depleted to this degree (no tachycardia, hypotension, or high blood urea nitrogen). This patient's history does not suggest immune complex vasculitis. • 16 Hyperuricemia Immune complex Blood urea nitrogen Oliguria Urea Hypotension Electrolyte Uremia Tachycardia Vasculitis Glomerulonephritis Nitrogen Streptococcus Kidney

D is not correct. 13% chose this. This is the mechanism behind type 2 diabetes mellitus. Unfortunately, the incidence of type 2 diabetes is rising in this patient's demographic, but the most likely cause of his clinical syndrome is still type 1 diabetes mellitus. Type 2 diabetics are at risk for hyperosmolar hyperglycemic nonketotic state. The bicarbonate in this syndrome is normal. Similar to diabetic ketoacidosis, the volume deficit can be profound. Diabetic ketoacidosis Diabetes mellitus Diabetes mellitus type 1 Diabetes mellitus type 2 Ketoacidosis Hyperglycemia Bicarbonate 6 s 0 lock Suspend End Block Item: 2 of 16 ~ . , . M k <:] t> al ~· ~ QIO: 3802 .l. ar Previous Next lab 'Vfl1ues Notes Calculator p y 1 • D is not correct. 13% chose this. 2 This is the mechanism behind type 2 diabetes mellitus. Unfortunately, the incidence of type 2 diabetes is rising in this patient's demographic, but the most • 3 likely cause of his clinical syndrome is still type 1 diabetes mellitus. Type 2 diabetics are at risk for hyperosmolar hyperglycemic nonketotic state. The bicarbonate in this syndrome is normal. Similar to diabetic ketoacidosis, the volume deficit can be profound. . 4 Diabetic ketoacidosis Diabetes mellitus Diabetes mellitus type 1 Diabetes mellitus type 2 Ketoacidosis Hyperglycemia Bicarbonate • 5 E is not correct. 19% chose this • • 6 Tra uma to the posterior pituitary gland or to the pituitary stalk could produce an AOH deficiency, resulting in central diabetes insipidus ( 01). Central 01 . 7 would manifest with polyuria and hypernatremia, and hyperosmotic volume contra ction. Electrolyte disturbances would not be expected. Notably, some medications (eg, the va sopressin receptor 2 antagonist tolvaptan) used to trea t hyponatremia can transiently induce a form of nephrogenic • 8 01, thereby elevating Na + levels.

• 9 Vasopressin receptor antagonist Hyponatremia Hypernatremia Polyuria Diabetes insipidus Pituitary gland Posterior pituitary Pituitary stalk Tolvaptan

0 10 Neurogenic diabetes insipidus Electrolyte Vasopressin Diabetes mellitus Vasopressin receptor Gland Receptor antagonist Receptor (biochemistry)

· 11 F is not correct. 4 % chose this. • 12 Hypertrophic cardiomyopathy (HCM) is an autosomal dominant condition resulting from mutations of myosin hea vy chains. The left ventricle displays asymmetric hypertrophy, in particular affecting the interventricular septum. HCM is a cause of sudden dea th, particularly in young athletes, due to sudden • 13 left ventricular outflow obstruction lea ding to immediate cessation of cardiac output. Pa tient with HCM do not usually present with polydipsia or polyuria as is the case in this vignette . • 14 Hypertrophic cardiomyopathy Polyuria Interventricular septum Dominance (genetics) Myosin Polydipsia Ventricle (heart) Cardiomyopathy Cardiac output

0 15 Hypertrophy Autosome Ventricular hypertrophy Septum Mutation Ventricular system Heart • 16

Botto m Line: Young people with type 1 diabetes may present in diabetic ketoacidosis. j3 Islet cells are inflamed and destroyed by an autoimmune or viral process. A profound insulin deficit results. Diabetic ketoacidosis Diabetes mellitus type 1 Diabetes mellitus Ketoacidosis Insulin Autoimmune disease Autoimmunity Virus

6 s 0 lock Suspend End Block Item: 2 of 16 ~ . , . M k <:] t> al ~· ~ QIO: 3802 .l. ar Previous Next lab 'Vfl1ues Notes Calculator -- .,.-- 1 Hypertrophic cardiomyopathy Polyuria Interventricular septum Dominance (genetics) Myosin Polydipsia Ventricle (heart) Cardiomyopathy Cardiac output 2 Hypertrophy Autosome Ventricular hypertrophy Septum Mutation Ventricular system Heart • 3

. 4 Bottom Line: • 5 Young people with type 1 diabetes may present in diabetic ketoacidosis. j3 Islet cells are inflamed and destroyed by an autoimmune or viral process. A • 6 profound insulin deficit results. Diabetic ketoacidosis Diabetes mellitus type 1 Diabetes mellitus Ketoacidosis Insulin Autoimmune disease Autoimmunity Virus . 7 • 8

• 9 I ill ;fi 1!1 I•J for year:[ 2017 .. FI RST AI D FACTS • 10 · 11 FA17 p 336.1 • 12 Diabetes mellitus • 13 ACUTE MANIFESTATIONS Polydipsia, polyu ri a, polyphagia, weight loss, DKA (type 1), hyperosmolar coma (type Z). • 14 Rarely, can be caused by unopposed secretion of GH and epinephrine. Also seen in patients on • 15 glucocorticoid therap)' (steroid diabetes). • 16 CHRONIC COMPLICATIONS Nonenzymatic glycation: • Small ,·esse] disease (diffuse thickening of basement membrane) ..... retinopathy (hemorrhage, exudates, microaneurysms, vessel proli feration), glaucoma, neuropathy, nephropathy (nodular glomerulosclerosis, aka Kim melstiel-Wilson nodules ..... progressive proteinuria Iinitially microalbuminuria; ACE inhibitors are renoprotective) and arteriolosclerosis ..... hypertension; both lead to chronic renal fail ure). Large vessel atherosclerosis, CAD, peripheral vascular occlusive disease, gangrene ..... li mb loss, 6 s 0 lock Suspend End Block Item: 2 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 380 2 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 •

2 FA17p337.1 • 3 Type 1 vs type 2 diabetes mellitus · 4 Variable Type 1 Type2 • 5 1 DEFECT Autoimmune destmction of~ cells (eg, due to t resistance to insulin, progressi,·e pancreatic • 6 glutamic acid decarbox) lase antibodies) ~ -cel l fai lure . 7 INSULIN NECESSARY IN TREATMENT Always Sometimes · 8 AGE (EXCEPTIONS COMMONLY < 30 \'[ > 40n . 9 OCCUR) ' ' • 10 ASSOCIATION WITH OBESITY 'o Ye~ • 11 GENETIC PREDISPOSITION Rel ati vely wea k (50% concordance in identical Relati vely strong (90% concordance in identical • 12 t\\ ins), polygenic t" in s), polygenic • 13 ASSOCIATION WITH HLA SYSTEM Yes (HLA-DR3 and -OR4) 'o • 14 GLUCOSE INTOLERANCE Severe lild to moderate • 15 INSULI NSE NSI TIVITY lligh Low • 16 KETOACIDOSIS Common Rare

~- CEll NUMBERS IN THE ISLETS Variable (with amyloid deposits) SERUM INSULIN lEVEl Variable CLASSIC SYMPTOMS Of POLYURIA, Common Someti mes POLYDIPSIA, POLYPHAGIA, WEIGHT LOSS a s 8 Lock Suspend End Block Item: 2 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 380 2 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 SERUM INSUliN LEVEl ariable • 2 CLASSIC SYMPTOMS OF POLYURIA, Common' ometimes • 3 POLYDIPSIA, POLYPHAGIA, WEIGHT LOSS · 4 HISTOLOGY lsletleukocvtic infiltrate Islet am} loid polypeptide (lAPP) deposits • 5 ' • 6 . 7 FA17 p 337.2 · 8 Diabetic ketoacidosis One of the most feared complications of diabetes. Usuall~ due to insulin noncompliance or . 9 f insulin requirements from f stress (eg, infection). E:-.cess fat breakdown and f ketogenesis from f free fatty acids, which arc then made into ketone bodies ( ~-hydroxybutyrate >acetoacetate). • 10 Usually occurs in type I diabetes, as endogenous insulin in type 2 diabetes usually pre\'ents • 11 lipolysis . • 12 SIGNS/SYMPTOMS DKA is Deadly: Delirium/psychosis, Kussmaul respirations (rapid/deep breathing), Abdominal • 13 pain/nausea/vomiting, Dehyd ration. Fruity breath odor (due to exhaled acetone). • 14 LABS Hype rg lycemia, f J-l+, IT T C03- (f anion gap metabol ic acidosis), t blood ketone levels, • 15 leukocytosis. Hyperkalemia, but depleted intracellular K+ due to transcellular shift from I insulin • 16 and acidosis (therefore total body K+ is depleted) . COMPliCATIONS Life-threatening mucormycosis (usually caused by Rhizopus infection), cerebral edema, cardiac arrhythmias, heart failure. TREATMENT IV fluids, IV insulin, and K+ (to replete intracellular stores); glucose if necessary to pre,·ent hypoglycemia.

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1 • A 42-year-old woman, who has not seen her physician in years, presents complaining of a mild chronic headache. The physician remembers the IA•A] 2 patient but is struck by the change in her facial fea tures, which have become coarser. The physician notes a broadening of her brow and protrusion of her jaw. A surgical procedure was attempted, but her condition persisted. The doctor decided to attempt a pharmacalogic treatment. • 3

· 4 Administration of the treatment for her condition would be expected to directly Inhibit the release of which of the following other hormones? • 5 : • 6 A. Parathyroid hormone . 7 B. ACTH · 8 c. Cortisol . 9 • 10 o. Insulin

• 11 E. Testosterone • 12 • 13 • 14 • 15 • 16

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1 • The correct answ er i s D. 470/o chose this. 2 This patient has acromegaly, usually caused by excess growth hormone production from a pituitary adenoma. Ultimately, growth hormone's effects of 3 reducing insulin sensitivity plays a crucial role in the pathophysiology of this disease. Acromegaly is treated medically with octreotide, a somatostatin analog. Somatostatin has a variety of physiologic roles throughout the body, most of them inhibitory. In the hypothalamic-pituitary axis, both · 4 somatostatin and growth hormone-releasing hormone (GHRH) are released from the hypothalamus and act on the pituitary. GHRH stimulates the • 5 synthesis and release of growth hormone. Somatostatin, on the other hand, blocks GHRH's effect, thereby inhibiting growth hormone secretion. In the gastrointestinal system, somatostatin is released from mucosal D cells to Inhibit gastric acrd secretion and gastric emptying and to slow down motility. In • 6 the pancreas, somatostatin reduces glucagon and insulin secretion. As a result, exogenous administration of octreotide is expected to inhibit the release of insulin. In addition, octreotide may cause nausea, vomiting, diarrhea, and gallstone-related illness. . 7 Somatost. in ..lcromegaly Growth hormone-releasing hormone Pituitary adenoma G .agon Octreotide Hypothalamus Hypothalamic-pituitary hormone Gastric acio · 8 Insulin Pancreas Growth hormone Diarrhea Gastrointestinal tract Pituitary gland Hormone Insulin resistance Nausea Delta cell Adenoma GHRH Vomiting . 9 Hormona. the• apy oncology) Structural analog Secretion Pathophysiology Human gastrointestinal tract Physiology Stomach • 10 A is not correct. 70/o chose this• Parathyroid hormone (PTH ) is released from the parathyroid gland. Secretion Is Induced by low serum calcium concentration and inhibited by Increased • 11 calcium levels. When serum calcium levels are decreased, the parathyroid gland will release PTH, which in turn will increase calcium absorption from the PTH will also • 12 Intestine and kidney. In addition, PTH will induce osteoblasts to stimulate osteoclasts and break down bone, increasing serum calcium. upregulate 25-hydroxyvitamin-o-hydroxylase, which will increase the production of the active form of vitamin D. Paratyhroid hormone is not under the • 13 hormonal control of stomatostatin, making this answer choice incorrect . Parathyroid gland Parathyroid hormone Osteoclast Osteoblast Kidney Gastrointestinal tract Calcium Hormone Vitamin Blood plasma Serum calcium Gland • 14 Serum (blood) Bone Secretion • 15 B is not correct . 220/o chose this . • 16 Traditionally, It is thought that adrenocorticotropic hormone (ACTH ) Is not directly Inhibited by somatostatin. (For your own information, a few new studies have suggested that somatostatin may indeed have a mild inhibitory effect on ACTH, although don't expect to see this reflected on Step 1 just yet! ) Inhibition of corticotropin-releasing hormone (CRH) would cause downstream decrease of ACTH . Adrenocorticotropic hormone Somatostatin Corticotropin-releasing hormone Hormone

C is not correct. 140/o chose this. Cortisol release is not affected directly by somatostatin. Cortisol is regulated through a negative feedback loop. As cortisol levels increase, cortisol will Inhibit the release of corticotropin-releasing hormone from the hypothalamus, thus decreasing the amount of adrenocorticotropic hormone from the anterior pituitary.

-~ ~- ~ - .... - . .... ______-----~--'"'--.-.!- ..... --.! •• 1 ,.._~ __ ..._ ___ ._ ------... ___ -- a s 8 Lock Suspend End Block Item: 3 of 16 ~ . , . M k <:] t> al ~· ~ QIO: 3849 .l. ar Previous Next lab 'Vfl1ues Notes Calculator

• ...... ,...... w ...... w. 1 Inhibition of corticotropin-releasing hormone (CRH ) would cause downstream decrease of ACTH . Adrenocorticotropic hormone Somatostatin Corticotropin-releasing hormone Hormone 2 3 c is not correct. 14 % chose this. Cortisol release is not affected directly by somatostatin. Cortisol is regulated through a negative feedback loop. As cortisol levels increase, cortisol will . 4 inhibit the release of corticotropin-releasing hormone from the hypothalamus, thus decreasing the amount of adrenocorticotropic hormone from the anterior pituitary. • 5 Adrenocorticotropic hormone Somatostatin Cortisol Corticotropin-releasing hormone Hypothalamus Anterior pituitary Negative feedback Hormone Pituitary gland • 6 Feedback

. 7 E is not correct. 10 % chose this. • 8 Release of testosterone, the hormone responsible for the development of male secondary sexual characteristics and maturation of spermatocytes, is regulated by the hypothalamic-pituitary-gonadal axis. Its release is not influenced by somatostatin. The hypothalamus will release gonadotropin-releasing • 9 hormone (GnRH ), which in turn will release of luteinizing hormoine (LH) from the anterior pituitary, stimulating the testes to produce testosterone. As testosterone levels increase it will shut down GnRH and LH production via a negative feedback loop . • 10 Gonadotropin-releasing hormone Hypothalamic-pituitary-gonadal axis Somatostatin Hypothalamus Testosterone Anterior pituitary Testicle Negative feedback · 11 Hormone Pituitary gland Secondary sex characteristic Spermatocyte Feedback Sex organ Sexual characteristics luteinizing hormone • 12 • 13 Botto m Line: • 14 Somatostatin has a variety of physiologic roles throughout the body, most of them inhibitory. In the gastrointestinal system, somatostatin inhibits • 15 secretion of gastric acid, glucagon, and insulin, and decreases gastric emptying and intestinal motility. Somatostatin Glucagon Gastric acid Gastrointestinal tract Insulin Motility Human gastrointestinal tract Physiology Stomach • 16

lijl;fiiJI•l foryea r:[2017 • ] FI RST AID FACT S

FA17 p356.1 Gastrointestinal reaulatorv substances 6 s 0 lock Suspend End Block Item: 3 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 3849 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 • FA17p319.1 2 Cortisol 3 SOURCE Adrenal zona fasciculata. Bound to corticosteroid-binding globulin. · 4 FUNCTION t \ ppetite Cortisol is a ,\ BIG FIB. • 5 t Blood pressure: Exogenous corticosteroids can cause • 6 Upregulates cxrreceptors on arterioles rcacti,·ation ofTB and candidiasis (blocks IL-2 . 7 .... t sensiti,•ity to norepinephrine and production) . epinephrine (permissive action) · 8 • t high concentrations, can bind to . 9 mineralocorticoid (aldosterone) receptors • 10 t Insulin resistance (diabetogenic) • 11 t Gluconeogenesis, lipolysis, and proteolysis • 12 (l glucose uti lization) • 13 l Fibroblast activity (poor wound healing, l collagen srnthesis, t striae) • 14 l lnAammatory and Immune responses: • 15 • Inhibits production ofleukotriencs and • 16 prostaglandins • In hibits WBC adhesion .... neutrophilia • Blocks histamine release from mast cells • Eosinopenia, lymphopenia • Blocks IL-2 production l Bone formation (l osteoblast activi ty) REGULATION C RH Chmothalamus) stimulates CTH release Chronic stress induces orolonl!'ed secretion. a s 8 Lock Suspend End Block Item: 3 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 3849 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 ~ Bone formation ( ~ osteoblast agonists (eg, cabergol inc).

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1 • A 40-year-old nulligravid woman visits her gynecologist because of irregular periods for the past 6 months. She also complains of recent-onset 2 bilateral nipple discharge. Her medical history is significant for type 2 diabetes, hypothyroidism, Tourette's syndrome, and a seizure disorder. A urine pregnancy test is negative. 3

. 4 Treatment for which of the following conditions is most likely the cause of the patient's symptoms? • 5 : • 6 A. Hypothyroidism . 7 B. Seizure disorder · 8 c. Tourette's syndrome . 9 • 10 D. Type 2 diabetes mellitus

• 11 • 12 • 13 • 14 • 15 • 16

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1

2 3 The correct a nswer is c. 52% chose this. 4 This patient has galactorrhea and menstrual abnormalities, which in the absence of pregnancy is indicative of hyperprolactinemia. Hyperprolactinemia • 5 commonly is caused by tumors or antipsychotic drugs. Typical antipsychotic agents are dopamine antagonists and lea d to increa sed secretion of prolactin because dopamine tonically inhibits prolactin relea se under normal conditions. Typical antipsychotics are used in the trea tment of schizophrenia and • 6 Tourette's syndrome. . 7 Typical antipsychotic Galactorrhea Hyperprolactinaemia Prolactin Antipsychotic Schizophrenia Tourette syndrome Dopamine Pregnancy Dopamine antagonist • 8 A is not correct. 21% chose this • In addition to dopamine antagonism, prolactin relea se can be stimulated by high levels of thyrotropin-relea sing hormone (TRH ). High TRH levels are seen • 9 in primary hypothyroidism. Although untrea ted hypothyroidism could cause this patient's symptoms, the trea tment, levothyroxine, does not lea d to • 10 hyperprolactinemia . Thyrotropin-releasing hormone Prolactin Hyperprolactinaemia Dopamine levothyroxine Hypothyroidism Hormone · 11 B is not correct. 22% chose this • • 12 Generalized seizures can lea d to a tempora ry state of hyperprolactinemia, but prolactin levels typically return to normal within 2 hours of the seizure. Although there are many antiepileptic medications, none work through dopamine antagonism or cause elevated prolactin levels. • 13 Prolactin Hyperprolactinaemia Dopamine Anticonvulsant Epileptic seizure Seizure types Generalised epilepsy • 14 D is not correct. 5 % chose this • • 15 Drugs for trea ting type 2 diabetes include metformin, sulfonylurea s, glitazones, and a-glucosidase inhibitors. None of these drugs would produce • 16 hyperprolactinemia, though there are notable adverse effects to ea ch . Sulfonylurea s can cause hypoglycemia. Metformin rarely causes lactic acidosis . Glitazones may cause weight gain and hepatotoxicity. a-Glucosidase inhibitors may cause gastrointestinal disturbances. Metformin Hyperprolactinaemia Hypoglycemia Hepatotoxicity lactic acidosis Diabetes mellitus Diabetes mellitus type 2 Sulfonylurea Acidosis Gastrointestinal tract Weight gain Human gastrointestinal tract

Botto m Line: Typical antipsychotic agents can cause hyperprolactinemia, because these agents act as dopamine antagonists and under normal circumstances rlnn;::a min.o tnnir;::a lht inhihit~ nn'\brtin r·.ol.o;::a c::.o fr·nrn th.o ;::a nt.or·it'\f" nit11it;::a n1 6 s 0 lock Suspend End Block Item: 4 of 16 ~ . , . M k <:] t> al ~· ~ QIO: 2794 .l. ar Previous Next lab 'Vfl1ues Notes Calculator yp p yp g y p ty typ y 1 • • Weight gain Human gastrointestinal tract 2 3 Bottom Line: 4 Typical antipsychotic agents can cause hyperprolactinemia, because these agents act as dopamine antagonists and under normal circumstances • 5 dopamine tonically inhibits prolactin release from the anterior pituitary. • 6 Typical antipsychotic Prolactin Hyperprolactinaemia Antipsychotic Dopamine Anterior pituitary Pituitary gland Dopamine antagonist . 7 • 8 I iii I ;fi 1!1 I•J for year:l 2017 .. • 9 FI RST AID FACTS

0 10 · 11 FA11 p543.1 • 12 Typical antipsychotics Haloperidol, pimozide, trifluoperazine, fluphen azine, thioriclazine, chlorpromazine.

• 13 MECHANISM Block dopamine D2 receptor (t cAMP). • 14 CLINI CAL USE Schizophrenia (1° positive symptoms), psychosi s, bipolar disorder, delirium, Tourette syndrome, Huntington disease, OCD. 0 15 • 16 POTE NCY High potency: TriAuoperazine, Fluphenazine, Haloperidol (Try to Fly High)- neurologic side effects (eg, extrapyramidal symptoms [EPS]). Low potency: Chlorpromazi ne, Thioridazine (Cheating T hieves are low)-anticholinergic,

antihistamine, a 1-blockacle effects. ADVERSE EFFECTS Lipid soluble ~ stored in body fat ~ slow to be removed from body.

Endocrin e: dopamine receptor antagonism ~ hyperprolactinemia ~ galactorrh ea, n l i onn'lf'lnn tY"h ()~ O\/nPt•nn,~t: t-i ~ 6 s 0 lock Suspend End Block Item: 4 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 2794 ..L a r Previous Next Lab~lu es Notes Calculat o r -...... : •.: ,, 1 ·-·. . Encephalopathy, unstable Vitals, t Enzymes, muscle Rigidity. Treatment: dantrolene, 0 2 agonist 2 (eg, bromocriptine). 3 4 FA17p313.1 • 5 Pituitary gland • 6 Anterior pituitary Secretes F'SH, LI I, ACT! I, TSII , prolactin, ACT II and l\ ISH are deri,·ati,es of . 7 (adenohypophysis) G I-l . ~ l elanotropin (l\ ISII ) secreted from proopiomelanocortin (POYIC). · 8 intermediate lobe of pituitary. Deri,ed from I LA'I PiC: FSH, Ll-l , ACTI-I , T 1-1 , PRL, C H. . 9 oral ectoderm (Rathke pouch). 8 -FL.\T: Basophils-FSH, LH, \CTII , TSII. • 10 a subunit-hormone subunit common to Acidophils: Gil, PRL. TSH. LH, FSII, and hCC. • 11 • ~ subun i t-dete r mines hormone specificity. • 12 Posterior pituitary Stores and releases vasopressin (antidiuretic • 13 (neurohypophysis) hormone, or ADH) and oxytocin, both • 14 made in the hypothalamus (supraoptic and • 15 paravcntricular nuclei) and t rans portcd to • 16 posteri or pituita ry via neurophysins (caHier proteins). Derived from neuroectoderm.

FA17 p316.1 Prolactin

SOURCE Secreted mainl) b~ anterior pituitary. Structurally homologous to gro" th hormone. a s 8 Lock Suspend End Block Item: 5 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 3143 ..L a r Previous Next Lab~lu es Not es Calculat o r

1 • Steroid hormones are unique in that they enter the cell and act directly on DNA to effect gene expression level changes, rather than acting only 2 through Intermediary signaling proteins. 3 Which of the following steps in the steroid hormone mechanism directly precedes DNA binding within the nucleus? 4 • 5 : A. Conformational change of the hormone-receptor complex • 6 . 7 B. Hormone binding to a DNA enhancer element

· 8 C. Hormone binding to a hormone-spedfic globulin . 9 D. Hormone binding to a membrane receptor • 10 E. Hormone binding to its intracellular receptor • 11 • 12 • 13 • 14 • 15 • 16

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1 The correct a nsw er is A. 38% chose this. • 2 The steroid hormone circulates in the plasma bound to a hormone-specific binding globulin. At the target organ, it enters a cell at the cell membrane due to Its lipophilic properties and binds to an intracellular receptor either In the cytoplasm or within the nucleus. The hormone-receptor complex then 3 undergoes a conformational change, which reveals the hormone's DNA-binding domain; without this step, it is unable to carry out its action and bind to DNA. Once the binding domain is revealed, the hormone binds the DNA enhancer element and causes changes to gene expression at the transcriptional 4 level. 5 Ste oid hormone Cel. membrane Cytoplasm Gene lipophilicity DNA-binding domain Gene e~pression Steroid Hormone Intracellular Blood plasma Intrace lu eceptor eel nucleus Conformational change DNA Globulin Receptor (b1ochem1stry) Enhancer (genetics) Transcription (genetics) • 6 16% this. . 7 B is not correct. chose Binding to a DNA enhancer element is the desired action of the hormone and the final step in its signaling pathway; however, the question asks what step · 8 Immediately precedes this binding event. Hormone DNA Enhancer genetics) . 9 C is not correct. 7% chose this. • 10 Binding of the steroid hormone to a hormone-specific globulin in the plasma helps the hormone reach its target cell population but is not the step that • 11 directly precede its binding to DNA . Steroid hormone Blood plasma Steroid Hormone Globulin DNA • 12 0 is not correct. so;o chose t his • • 13 Steroid hormones do not act through transmembrane receptors and second messengers like protein hormones do, making this choice incorrect . • 14 Steroid Protein Transmembrane protein Second m essenger system Steroid hormone Cell surface receptor Hormone Receptor (biochemistry)

• 15 E is not correct. 340/o chose this. • 16 Binding to an Intracellular steroid receptor alone does not enable DNA binding. The steroid-receptor complex must alter its conformation to reveal the DNA-binding domain, which allows it to then bind to DNA enhancer elements. DNA-binding domain Steroid hormone receptor Steroid DNA Conformational isomerism Intracellular Protein structure Enhancer (genetics) Receptor {biochemistry)

Bottom Line: Before binding DNA in the nucleus, the hormone-receptor complex for steroid hormones undergoes a conformational change in order to reveal the hormone's DNA-binding domain. Ste oid ONA-bindina domain Hormone DNA Cell nucleus Conformationa chanae Ste• o1d ho1 mone a s 8 Lock Suspend End Block Item: 5 of 16 ~ . , . M k <:] t> al ~· ~ QIO: 3143 .l. ar Previous Next Lab'Vfllues Notes Calculator

1

2 Bottom Line: 3 Before binding DNA in the nucleus, the hormone-receptor complex for steroid hormones undergoes a conformational change in order to reveal the hormone's DNA -binding domain. 4 Steroid DNA-binding domain Hormone DNA Cell nucleus Conformational change Steroid hormone 5 • 6 . 7 lijj ;fi IJ l•l for year:l 2017 .. FI RST AID FACT S • 8

• 9 FA17 p 322.2 • 10 Signaling pathway of Steroid hormones arc lipoph il ic and therefore Cytoplasm · 11 steroid hormones must circulate bound to specific binding /--Nucleus • 12 globulins, which t their solubility. Bmdtng to enhancer­ ,... ~JT,...,... - In men, t sex hormone-binding globulin • 13 bkeelemenl____ in DNA __~ .. 0 Gene -" (SHBG) lowers free testosterone Pre-mRNA • 14 ( H ... - gynecomastia. Transformation of "'- mRNA • 15 ln women, ! SHBG raises free testosterone receptor to expose ONA· t bindmg domain mRNA • 16 - hirsutism . t Binding to receptor ~ Protetn OCPs, pregnancy - t SHBG. located in nucleus or in cytoplasm ~ t Response H Hormone

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1 • During a normal pregnancy, several changes take place in the mother's thyroid hormone system. 2

3 Compared with a nonpregnant woman, which of the following changes would be expected in a pregnant woman? 4 : 5 A. Decreased thyroid-binding globulin, decreased total T4, decreased free T4

• 6 B. Decreased thyroid-binding globulin, decreased total T4, unchanged free T4 . 7 c. Increased thyroid-binding globulin, increased total T4, increased free T4 · 8 total T , unchanged free T4 . 9 o. Increased thyroid-binding globulin, increased 4

• 10 E. Unchanged thyroid-binding globulin, unchanged total T4, unchanged free T4

• 11 • 12 • 13 • 14 • 15 • 16

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2 3 The correct answ er is o . 690/o chose this. 4 In part due to rising estrogen levels, there is an increase in hepatic synthesis of thyroid-binding globulin (TBG) in the pregnant female. The total amount 5 of thyroid hormone 1n the body (represented by total T4 ) subsequently Increases woth the rise in TBG. The unbound, active thyroid hormone (represented as free T4) typically remains unchanged during a normal pregnancy; therefore, a pregnant female generally remains euthyroid throughout her pregnancy. 6 Est ogen t: 1tl y ood Thyrood hormone Thyroid Hormone Liver Globu 1n Pregnancy -...,ro e-binding globulin

0 7 A i s not correct. 4 0/o chose this. o8 Thyroid-binding globulin increases during pregnancy therefore this is not the correct answer. In this answer the free T4 concentration is also decreased, Her symptoms could Include constipation, cold intolerance, difficulty with . 9 Indicating that this patient would be dinically hypothyroid. memory/ concentration, or potential weight gain, among others. Hypothyroidism Is not associated with normal pregnancy. • 10 Constipation Hypothyroidism Globulin Cold sensitivity Pregnancy Weight gain

• 11 B is not correct. 6 0/o chose this• Thyroid-binding globulin (TBG) increases during pregnancy therefore this Is not the correct answer. This presentation is possible in a patient who has a • 12 decrease In TBG, for example a patient with anorexia or chronic liver disease. The low TBG would decrease the total T4 but would leave the free T4 • 13 concentration unchanged. Therefore the patient would remain euthyroid . Liver Liver disease Pregnancy Anorexia nervosa Anorexia (symptom) Euthyroid

0 14 C is not co rrect. 190/o chose this. • 15 Although thyroid-binding globulin and total T4 does increa se during pregnancy, the concentration of free T4 should not increa se during a normal erthyroidism, which Is a complication that occurs in 1 out of 1000- 2000 pregnant women and Is most 0 16 pregnancy. An Increased free T4 would indicate hyp commonly caused by Graves disease. This is not a normal physiologic response to pregnancy and is therefore not the correct answer. Graves' disease Hyperthyroidism Pregnancy Globulin

E is not co rrect. 20/o chose this. The Increase In estrogen associated with pregnancy will cause thyroid binding globulin to increase, not remain unchanged as is described in this answer choice. It is therefore not the correct answer. Estrogen Thyroxine-binding globulin Thyroid Globulin Pregnancy

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1 Graves' disease Hyperthyroidism Pregnancy Globulin

2 E is not correct. 2 % chose this. The increase in estrogen associated with pregnancy will cause thyroid binding globulin to increase, not remain unchanged as is described in this answer 3 choice. It is therefore not the correct answer. 4 Estrogen Thyroxine-binding globulin Thyroid Globulin Pregnancy 5 6 Botto m Line: . 7 During pregnancy there is an increase in total thyroxine and thyroxine-binding globulin, but the amount of metabolically active free, or unbound, thyroxine remains unchanged. Consequently, pregnant women remain euthyroid . • 8 Thyroid hormone Thyroxine-binding globulin Euthyroid Globulin Pregnancy Metabolism • 9 • 10 · 11 I iii I ;fi 1!1 I•J fo r year:l 2 0 17 .. FIRST AID FACT S • 12

• 13 FA17 p 321.2 • 14 Thyroid hormones Iodine-containing hormones that control the body's metabolic rate. • 15 (Ti T4) • 16 SOURCE Follicles of thyroid. Most T 3 formed in target T 3 functions-4 B's: tissues. Brain maturation

FUNCTION Bone growth (sy nergism with GH) Bone growth C1 S maturation ~ -a dren e rg i c effects Basal metabolic rate t t ~ 1 receptors in heart = t CO, HR, SV, contractility Thyroxine-binding globulin (TBG) binds most t h.,c.,J """'"""1;,. "''"' ";" t .,+/I(+_ATP"c"' T tiT .. in blood; only free hormone is acti ve. 6 s 0 lock Suspend End Block Item: 7 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 3850 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 • A hormone normally secreted from the pancrea s causes glycogen breakdown, gluconeogenesis, and decreased glycolysis. 2

3 Which type of receptor mediates the function of this hormone? 4 : 5 A. G·prote1n-coupled receptor

6 B. Intracellular steroid receptor

0 7 c. Ion channel-linked receptor o8 . 9 o. Serine-threonine kinase receptor • 10 E. Tyrosine kinase receptor

• 11 • 12 • 13

0 14 • 15

0 16

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2 3 The correct answ er is A. 650/o chose this. 4 The hormone described in the question stem is glucagon. This hormone Is released from pancreatic a cells and opposes the actions of insulin. Glucagon's 5 function Is mediated through a G-protein-coupled receptor. There is downstream activation of adenylyl cyclase and an increase in cAMP, which serves as a second messenger that mediates subsequent physiologic actions. 6 G-p oteon-coupled receptor Glucagon Adenylyl cyclase Second messenger system Cy~ooc adenosine monophosphate Insulin Hormone Physiology 7 B is not correct. 60/o chose this. · 8 This mechanism of action is assodated with steroid hormones. Glucagon Is not a steroid hormone. An example of a steroid hormone is cortisol. Steroid inside the cytosol or the nucleus. The hormone-receptor complex then binds DNA to act as . 9 hormones diffuse across cell membranes to bind with receptors a transcription factor, regulating the rate of transcription of genes. • 10 Glucagon Cortisol Steroid hormone Cytosol Transcription factor Steroid ~ranscription (genetics) Hormone Mechanism of action Cell membrane Cell nucleus DNA

• 11 C is not correct. 4 0/o chose this• Glutamate is an example of a ligand that works through an ion channel-linked receptor, which causes a change in polarization across the cell membrane . • 12 Cell membrane Ugand-gated ion channel Ugand (biochemistry) Glutamic acid Ugand Ion channel linked receptors Ion • 13 0 is not correct. 60/o chose this• • 14 Transforming growth factor-13 is an example of a molecule that has its action mediated by a receptor serine-threonine kinase, which produces physiologic actions through phosphorylation . • 15 Phosphorylation Serine/threonine-specific protein kinase Molecule Kinase • 16 E is not co rrect. 190/o chose this. This mechanism of action is associated with insulin. Insulin's action is mediated through the tyrosine kinase activity of its receptor; which phosphorylates downstream proteins and enzymes to mediate physiologic actions. Insulin has many of the opposite actions of glucagon. Glucagon Insulin Tyrosine kinase Tyrosine Phosphorylation Mechanism of action Kinase Enzyme Protein

Bottom Line:

C.:lur11nnn rPiiP<; nn 11 C.:-rnuniPrl -nrntPin rPc:Pntnr thilt ilrtiviltP<; ilrlPnvlvl n~rlii<;P tn nrnrlurP 11n inc:rPiiSP in intrilrPIIOJiilr rAMP. a s 8 Lock Suspend End Block Item: 7 of 16 ~ . , . M k <:] t> al ~· ~ QIO: 3850 .l. ar Previous Next lab 'Vfl1ues Notes Calculator

1 This mechanism of action is associated with insulin. Insulin's action is mediated through the tyrosine kinase activity of its receptor; which phosphorylates downstrea m proteins and enzymes to mediate physiologic actions. Insulin has many of the opposite actions of glucagon. 2 Glucagon Insulin Tyrosine kinase Tyrosine Phosphorylation Mechanism of action Kinase Enzyme Protein 3

4 Bottom Line: 5 Glucagon relies on a G-coupled-protein receptor that activates adenylyl cyclase to produce an increa se in intracellular cAMP. Glucagon Adenylyl cyclase Intracellular Receptor (biochemistry) 6 7 • 8 I iii I ;fi 1!1 I•J for year:l 2017 .. • 9 FIRST AID FACT S • 10 · 11 FA17 p81.2 • 12 Glycogen regulation by insulin and glucagon/epinephrine • 13 • 14 Insulin {liver and muscle) • 15 a Receptor Tyrosine • 16 + p.<~en~\ate kinase \as dimer receptor Glucagon . . receptor cAMP Calcrum-calmodulrn Endoplasmrc n reticulum ATP r.k in muscle during t contraction 't1 Protein t nase A / ~----~ Ca lciu m Protein kinase A 1 I 6 s 0 lock Suspend End Block j '\-, 2 / Protein~ hosphatase 3 Glucose / 4 ------~ 5 FA17 p 322.1 6 Signaling pathways of endocrine hormones 7 cAMP FSH, LH, ACTH, T SH, C RI I, hCC, AD II FLA1 ChMIP · 8 ( 2-receptor), ~ I SH , PT H, calcitonin, C H RH, . 9 glucagon, histamine (H2-receplor) • 10 cGMP B lP, \ 'P, EDRF ('.JO) B\D G ra \IPa • 11 Thin!.. vasodilators • 12 IP3 GnRH, 0 "-ytocin, ADH (V1-rcceptor), T RH, GO\THAG • 13 H istamine (Hrrcceptor), Angiotensin II , • 14 Gastrin • 15 Intracellular receptor Progesterone, Estrogen, Testosterone, Cortisol, PET CAT on TV Aldosterone, T Vitami n D • 16 3rt 4, Receptor tyrosine Insulin ' IGF-l ' FGF' PDGF, EC F MAP kinase pathway kinase Think Growth Factors Non receptor tyrosine Prolactin, l mmunomodulators (eg, C) tokines JAK/STAT pathway kinase IL-2, IL-6, IFN), GH, G-CSF, Erythropoietin, Think acidophils and cytokines T hrombopoietin PICCLET a s 8 Lock Suspend End Block Item: 7 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 3850 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 cAMP FSH, LH, ACTH, TSH, C RII, hCC, AD! I FLAT ChAl\IP •

2 ( rreceptor), M SH, PT H, calci tonin, C HRH, glucagon, histamine (H -receptor) 3 2 cGMP B 'P, ,\1 P, EDRF' ( 0) B \I) Gra i\1Pa 4 Thin\.. ,·asodilators 5 G nRH, 0J~.)tocin, ADH (V -receptor), 1 RH , GO\TH\G 6 1 Histamine (H1-receptor), Angiotensin II, 7 Gastrin · 8 Intracellular receptor Progesterone, Estrogen, Testosterone, Corti sol, PET C.\T on T\ . 9 Aldosterone, T/ 14, \ itamin 0 • 10 Receptor tyrosine Insulin, lGF-1, FGF, PDC I ~ ECF lAP kinase pathway • 11 kinase Think G rowth Factors • 12 Non receptor tyrosine Prolactin, l mmunomodulators (eg, cytokines JAK/STAT pathway • 13 kinase IL-Z, IL-6, IF ), G H, G-CSF, Erythropoietin, Think acidophils and cytokines • 14 T hrombopoietin PICCI.F.T • 15 FA17p 315.1 • 16 Glucagon SOURCE lade by a cell s of pancreas. FUNCTION Glycogenolysis, gluconeogenesis, Iipolysis, ketone product ion. REGULATION Secreted in response to hypoglycemia. Inhibited by insulin, hyperglycem ia, and somatostatin.

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1 • A 17-year-old Asian boy with no significant medical history presents to the emergency department complaining of sudden onset of rapid deep 2 breathing, nausea, vomiting, and abdominal pain. He has lost 4.5 kg (10 lb) In the past few weeks and reports polyuria and polydipsia . on further questioning, he mentions a recent upper r espiratory infection. Physical examination Is notable for a fruity odor on his breath and abdominal 3 tenderness. Laboratory studies show:

4 Na+: 134 mEq/L 5 K+: 5.3 mEq/L c1·: 95 mEq/L 6 HCo3·: 12 mEq/L PC02: 28 mm Hg 7 pH: 7.30 · 8 Glucose: 320 mg/dL . 9 The patient's symptoms are due to a hormone deficiency. What is normally the stimulus for secretion of this hormone? • 10

• 11 : A. Cholecystokinin • 12 B. Decrease in blood glucose • 13 • 14 c. Epinephrine

• 15 D. Increase in blood glucose • 16 E. Increase in ketone bodies

F. Norepinephrine

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1 • The co rrect answ er i s D. 860/o chose this. 2 The patient most likely has diabetic ketoacidosis (DKA), a complication most often associated with type 1 diabetes mellitus. Her labs show hyperglycemia 3 and an anion gap metabolic acidosis (normal anion gap is 8-16 mEq/l, this patient has an anion gap of 27 mEq/L). The anion gap is determined by subtracting the sodium level from the chloride plus the bicarbonate (In this case, 134-(95+ 12)). Type 1 diabetes is characterized by insulin deficiency. OKA 4 occurs when there is relative insulin deficiency along with an increase In counterregulatory hormones such as glucagon and epinephrine. Hyperglycemia Is 5 the primary stimulus for insulin secretion. Other stimuli include an increase In fatty acids in the blood, an increase in amino acids in the blood, cortisol, growth hormone, and gastrointestinal inhibit ory peptide. 6 Diabetic 'etoacodosis Epinephrine Glucagon Cortisol Diabetes mel ;tus Metabo oc acldvs•s Diabetes mel ;tus type 1 Hyperglycemia Insulin Anion gap ..:etoacldos.s 7 Acidos;s Ho moo e Gro th hormone Bicarbonate Amino acid Sodium Fatty acid Peptide Anion Gastrointestinal tract Metabolism 8 A i s not correct. 2% chose this. Cholecystokinin is a gastrointestinal hormone that is important in normal digestion. This hormone is released in response to peptides, amino acids, . 9 monoglycerldes, and fatty acids entering the lumen of the duodenum. It acts primarily to facilitate the intestinal phase of digestion and to stimulate • 10 glucagon secretion, but it does not stimulate insulin secretion . Gastrointestinal hormone Cholecystokinin Glucagon Duodenum Peptide Insulin Amino acid Hormone Lumen (anatomy) Digestion Monoglyceride • 11 Human gastrointestinal tract Fatty acid Gastrointestinal tract Secretion • 12 B is not co rrect. 60/o chose this • • 13 Hypoglycemia stimulates glucagon, not insulin, secretion. In this scenario, glucagon Is released because of the impaired uptake of glucose Into the cell, leading to a perceived state of low glucose. Insulin deficiency and an Increase In glucagon lead to diabetic ketoacidosis. Insulin causes hypoglycemia by • 14 causing cellular uptake and utiliza tion of glucose. • 15 Diabetic ketoacidosis Glucagon Hypoglycemia I nsulin Glucose Ketoacidosis Diabetes mellitus Secretion • 16 C is not co rrect. 20/o chose this . like norepinephrine, epinephrine acts to stimulate glucagon secretion and provides energy substrate for the fight-or-flight response. Epinephrine does not stimulate Insulin secretion, as this would lea d to hypoglycemia and depletion of energy substrate. Fight-or-flight response Epinephrine Glucagon Hypoglycemia Norepinephrine Insulin Substrate (chemistry) Secretion

E is not correct. 40/o chose this. Ketone bodies are seen in diabetic ketoacidosis because, with reduced Insulin and increased glucagon, there is an increase of fatty acid breakdown, leading to excessive acetyl-coenzyme A going down the ketone body pathway. The presence of acetone leads to the fruity breath odor. Diabetic ketoacidosis Acetone Glucagon Ketone bodies Fatty acid Ketone Ketoacodosi3 Acety -CoA Insul n Fatty acid metabolism Diabetes me itus a s 8 Lock Suspend End Block Item: 8 of 16 ~ . , . M k <:] t> al ~· ~ QIO: 2800 .l. ar Previous Next lab 'Vfl1ues Notes Calculator

1 stimulate insulin secretion, as this would lea d to hypoglycemia and depletion of energy substrate. Fight-or-flight response Epinephrine Glucagon Hypoglycemia Norepinephrine Insulin Substrate (chemistry) Secretion 2 E is not correct. 4 % chose this. 3 Ketone bodies are seen in diabetic ketoacidosis because, with reduced insulin and increa sed glucagon, there is an increa se of fatty acid brea kdown, 4 lea ding to excessive acetyl-coenzyme A going down the ketone body pathway. The presence of acetone lea ds to the fruity brea th odor. Diabetic ketoacidosis Acetone Glucagon Ketone bodies Fatty acid Ketone Ketoacidosis Acetyi-CoA Insulin Fatty acid metabolism Diabetes mellitus 5 F is not correct. 0 % chose this. 6 Norepinephrine acts to stimulate glucagon secretion and provide energy substrate for the fight-or-flight response. Norepinephrine does not stimulate 7 insulin secretion, as this would lea d to hypoglycemia and depletion of energy substrate. Fight-or-flight response Glucagon Hypoglycemia Norepinephrine Insulin Substrate (chemistry) Secretion 8 • 9 • 10 Botto m Li ne: Hyperglycemia is a primary stimulus for insulin secretion. · 11 Hyperglycemia Insulin Secretion • 12 • 13

• 14 lijl;fiiJI•l to r year:[ 2017 • ] FIRST AI D FA CTS • 15 • 16 FA17 p 337.1 Type 1 vs type 2 diabetes mellitus Variable Type 1 Type2

Au toimmune destruction of ~ cells (eg, due to t resistance to insulin, progressive pancreatic glutamic acid decarboxylase antibod ies) ~-ce ll fa ilure INSULIN NECESSARY IN TREATMENT Alwavs Sometimes 6 s 0 lock Suspend End Block Item: 8 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 2800 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 •

2 FA17 p 337.2 3 Diabetic ketoacidosis One of the most feared complications of diabetes. Usually due to insulin noncompliance or 4 t insulin requirements from t stress (eg, infection). Excess fat breakdown and t ketogenesis from 5 t free fatty acids, which are then made into ketone bodies (J}-hydrox:·butyrate >acetoacetate). 6 Usually occurs in type l diabetes, as endogenous insulin in type 2 diabetes usually pre,·cnts 7 lipolysis. 8 SIGNS/SYMPTOMS DK \ is Deadly: Delirium/psychosis, Kussmaul respirations (rapid/deep breathing), \ bdominal . 9 pain/nausea/vomiting, Deh)dration. Fruit) breath odor (due to exhaled acetone). • 10 LABS Hyperglycemia, t H•, l HC03- (t anion gap metabolic acidosis}, t blood ketone levels, leukoc~'losis. Hyperkalemia, but depleted intracellular K+ due to transcellular shift from l insulin • 11 and acidosis (therefore total body K+ is depleted). • 12 COMPLICATIONS Life-threatening mucormycos is (usually caused by Hhizopus infection), cerebral edema, cardiac • 13 arrhythmias, heart failure . • 14 TREATMENT IV fluids, IV insulin, and K+ (to replete intracellular stores}; glucose if necessary to prevent • 15 hypoglycemia . • 16

FA17 p336.1 Diabetes mellitus ACUTE MANIFESTATIONS Polydipsia, polyuria, polyphagia, weight loss, DKA (type I), hyperosmolar coma (type 2). Rarel y, can be caused by unopposed secretion of Gil and epinephrine. Also seen in patients on glucocorticoid therapy (steroid diabetes). a s 8 Lock Suspend End Block Item: 9 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 3835 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 • A researcher is designing an experiment in order to develop new methods of treatment for hypertensive crisis in patients with pheochromocytoma. 2 She plans to simulate conditions of hypertensive crises that arise during surgery In mice. She plans to anesthetize the rats and then administer a high-potency injection that will lead to hyperstimulation of the adrenal gland. 3

4 If properly targeted, which of the following molecules could be used in this Injection? 5 : 6 A. Acetylcholine 7 B. Cortisol 8 c. Dopamine . 9 • 10 D. Epinephrine

• 11 E. Norepinephrine • 12 • 13 • 14 • 15 • 16

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1 The correct a nswer is A. 52% chose this. 2 Pheochromocytoma is a rare tumor of the adrenal gland that secretes catecholamines (epinephrine and norepinephrine) in response to sympathetic 3 stimulation. The adrenal medulla is innervated directly by the sympathetic nervous system, causing relea se of catecholamines. The adrenal medulla is a unique sympathetic organ in that the nerves that supply it do not first synapse in other sympathetic ganglia. Presynaptic neurons in sympathetic ganglia 4 use acetylcholine as their neurotransmitter; which in this case binds to nicotinic acetylcholine receptors in the adrenal medulla. Thus injection of high­ potency acetylcholine would theoretically lea d to excess relea se of catecholamines from the adrenal medulla. 5 Adrenal gland Pheochromocytoma Adrenal medulla Sympathetic nervous system Norepinephrine Acetylcholine Neurotransmitter Sympathetic ganglion Synapse 6 Medulla oblongata Catecholamine Chemical synapse Nicotinic acetylcholine receptor Ganglion Nervous system Neoplasm Neuron Gland Acetylcholine receptor 7 B is not correct. 12% chose this. 8 Cortisol is a steroid hormone produced in the adrenal zona fasciculata. The relea se of corticotropin-relea sing hormone from the hypothalamus, followed by ACTH relea se from the pituitary, lea ds to cortisol production. 9 Zona fasciculata Cortisol Corticotropin-releasing hormone Steroid hormone Hypothalamus Adrenocorticotropic hormone Steroid Hormone Pituitary gland

0 10 Adrenal gland oll c is not correct. 7 % chose this. Dopamine normally is not secreted by, nor does it stimulate, the adrenal gland. In pheochromocytoma, dopamine may sometimes be one of the 0 12 molecules secreted by the tumor. However; it would not trigger hyperstimulation of the adrenal gland. 0 13 Adrenal gland Pheochromocytoma Dopamine Neoplasm Gland

0 14 D is not correct. 15 % chose this. Epinephrine is a catecholamine secreted by the adrenal gland in response to sympathetic stimulation. It is the hormone relea sed by this stimulation, 0 15 rather than the molecule that would lea d to the relea se, which in this case is acetylcholine. 0 16 Adrenal gland Catecholamine Epinephrine Acetylcholine Hormone Sympathetic nervous system Molecule Gland

E is not correct. 14 % chose this. Norepinephrine is a catecholamine secreted by the adrenal gland in response to sympathetic stimulation. It is the hormone relea sed by this stimulation, rather than the molecule that would lea d to the relea se, which in this case is acetylcholine. Adrenal gland Catecholamine Norepinephrine Acetylcholine Hormone Sympathetic nervous system Molecule Gland

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1 E is not correct. 14% chose this. Norepinephrine is a catecholamine secreted by the adrenal gland in response to sympathetic stimulation. It is the hormone relea sed by this stimulation, 2 rather than the molecule that would lea d to the relea se, which in this case is acetylcholine. 3 Adrenal gland Catecholamine Norepinephrine Acetylcholine Hormone Sympathetic nervous system Molecule Gland 4 5 Bottom Line: 6 The adrenal medulla secretes catecholamines (epinephrine and norepinephrine) in response to direct stimulation by preganglionic sympathetic neurons. These neurons use the neurotransmitter acetylcholine to trigger catecholamine relea se from the adrenal medulla. 7 Catecholamine Adrenal medulla Norepinephrine Neurotransmitter Acetylcholine Medulla oblongata Neuron Preganglionic nerve fibers 8 9

0 10 I ill ;fi 1!1 I•J for year:[ 2017 .. FI RST AI D FACT S oll

0 12 FA17p229.1 0 13 Central and peripheral nervous system

0 14 Medulla 0 15 Smooth muscle. gland Parasympathetic M cells. nerve terminals. 0 ACh ~ACh 16 Pre (long) • {short) cardiac muscle

A Spinal cord u T 0 M Sweat glands N Pre !short) Post (long) 0 M Smooth muscle. gland cells, nerve terminals. I • ~ r~ n1i~r mu ~riP 6 s 0 lock Suspend End Block Item: 9 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 3835 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 •

2 FA17 p 326.1 Pheochromocytoma 3 ETIOLOGY 's: 4 r-. lost common tumor of the adrenal medulla in Rule of IO adults · . Derived from chromaffin cells (arise 10% malignant 5 from neural crest). I0 % bi Iat era I 6 ~lay be associated with germline mutations (eg, 10% extra-adrenal (eg, bladder wall, organ of 7 NF-1, VHL, RET [\ 1Et\ 2t\, 28]). Zuckerkandl) 8 10% ca lei fv 9 10% kids • 10

• 11 • 12 SYMPTOMS !\lost tumors secrete epinephrine, Episodic hyperadrenergic symptoms (5 P '~) : norepinephrine, and dopamine, which can (t BP) • 13 Pressure cause episodic hypertension . Pain (headache) • 14 Symptoms occur in "spells" - relapse a11 d re111il. Perspiration • 15 Palpitations (tachycardia) • 16 Pallor FINDINGS t catecholamines and metanephrines in urine and plasma. TREATMENT I rre,·ersible a-antagon ists (eg, Phenox} benzamine (16 letters) is given for phenoxybenzamine) followed by ~-blockers pheochromocytoma (also 16 letters). prior to tumor resection. a -blockade must be a s 8 Lock Suspend End Block Item: 10 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 2358 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 • A 42-year-old woman with a history of bipolar disorder presents to her physician with complaints of excessive urination over the past few weeks. The 2 patient Is currently taking lithium and states that she is compliant with the medication. The patient has no other complaints. Past medical history other than the bipolar disorder is unremarkable. A full blood and urine workup Is Initiated on this patient. lithium levels are found to be 1.21 mEq/l 3 [normal: 0.8 to 1.2 mEq/L]. Serum osmolality is 290 mosm/l. Given the patient's current medication, the physician initiates a water deprivation test. Initial deprivation shows no change in her urine osmolality. The physician then Injects desmopressin and measures urine osmolality which still does not show any 4 change. 5 6 Which of the following urine osmolality values most closely reflects her condition?

7 : 8 A. 100 mOsm/kg

9 B. 290 mOsm/kg • 10 c. 360 mOsm/kg • 11 o. 425 mOsm/kg • 12 • 13 E. 800 mOsm/kg • 14 • 15 • 16

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1

2 3 The correct a nswer is A. 63% chose this. 4 The patient has nephrogenic diabetes insipidus secondary to lithium use which is common side effect in patients taking this medication. Any patient taking this medication and exhibiting symptoms of constant polyuria with thirst should be worked up for diabetes insipidus. A commonly used test is the water 5 deprivation test. In this test, the patient is not allowed fluid intake while urine osmolality is being mea sured. In patients with primary polydipsia, there 6 will be an increa se in urine osmolality as kidney function is fine and they are able to concetrate urine. Pa tients who fail the water deprivation test, are given a bolus of desmopressin. If urine osmolality increa ses as a result of desmopressin, they have centra l diabetes insipidus in which ADH is not made. 7 Pa tients who still do not have an increa se in urine osmolality will have nephrogenic diabetes insipidus. 8 Nephrogenic diabetes insipidus is characterized by an inability of the kidney to concentrate urine effectively due to resistance to ADH . Concentration of urine normally is controlled by ADH , which regulates water pores in the renal collecting ducts. Thirst and resulting polydipsia are caused by increa sed 9 levels of plasma sodium and osmolality. This change in osmolality is due to loss of free water in the form of hypotonic urine. The kidney is not able to 10 rea bsorb the water; because it is not responding to ADH; therefore this water is simply excreted. This patient's plasma osmolality is 290 mOsm/kg, therefore only a urine osmolality less than this value would indicate hypotonic urine and diabetes insipidus. The correct answer of these choices is · 11 therefore 100 mo sm/kg. Desmopressin Polyuria Plasma osmolality Polydipsia Neurogenic diabetes insipidus Diabetes insipidus Collecting duct system Urine Nephrogenic diabetes insipidus • 12 Primary polydipsia Diabetes mellitus Osmolality Renal function Blood plasma Vasopressin Sodium Tonicity Kidney Adverse effect lithium Dehydration

• 13 Pharmaceutical drug • 14 B is not correct. 15% chose this • • 15 This osmolality would be present in a patient with a normal functioning kidney as this is an expected range of urine osmolality. It is important to remember that only urine osmolality less than serum osmolality could indicate a hypotonic urine and diabetes insipidus. • 16 Diabetes insipidus Kidney Urine Osmolality Diabetes mellitus Blood plasma Tonicity Urine osmolality Plasma osmolality

c is not correct. 8% chose this. A patient with a urine osmolality such as this would be present during dehydration or any state in which there is an increa se in water rea bsorption in the kidney. This osmolality is higher than the patient's serum osmolality so we would expect the patient to be in a state of dehydration. Dehydration Osmolality Kidney Urine Urine osmolality Blood plasma Plasma osmolality

D is not correct. 6 % chose this. A larger increa se in urine osmolality such as this can be present in patients with more severe dehydra tion or in disea ses such as SIADH or glycosuria or 6 s 0 lock Suspend End Block Item: 10 of 16 ~ . I • M k <:] t> al ~· ~ QIO: 2358 .l. ar Previous Next lab 'Vfl1ues Notes Calculator

1 c is not correct. 8% chose this. A patient with a urine osmolality such as this would be present during dehydration or any state in which there is an increa se in water rea bsorption in the 2 kidney. This osmolality is higher than the patient's serum osmolality so we would expect the patient to be in a state of dehydration. 3 Dehydration Osmolality Kidney Urine Urine osmolality Blood plasma Plasma osmolality

4 D is not correct. 6 % chose this. 5 A larger increa se in urine osmolality such as this can be present in patients with more severe dehydration or in disea ses such as SIADH or glycosuria or when ea ting a high-protein diet . It should be noted that SIADH can have a urine osmolality less than this va lue but grea ter than 100 mOsm/kg but a 6 value such as this would indicate a more adva nced stage. Glycosuria Osmolality Dehydration Urine Syndrome of inappropriate antidiuretic hormone secretion Urine osmolality 7 E is not correct. 8% chose this. 8 A urine osmolality such as this would be present if the patient had primary polydipsia and underwent a water depriva tion test. Since the main fea ture in 9 this disea se is that there is stimulation of the thirst response, the patient would increa se fluid intake. Since there is no pathology with the kidney, fluid restriction would drastically increa se the urine osmolality as the kidneys are functioning properly. This osmolality can also be seen in patients with central 10 diabetes insipidus after recieving desmopressin. In central diabetes insipidus, there is a lack of ADH secretion. Introducing ADH would enable the kidneys · 11 to concentrate urine and function properly. Desmopressin Diabetes insipidus Polydipsia Primary polydipsia Neurogenic diabetes insipidus Osmolality Urine Vasopressin Diabetes mellitus Kidney Pathology • 12 Fluid restriction • 13 • 14 Botto m Line: • 15 In diabetes insipidus, the kidney is unable to concentrate urine effectively; thus in diabetes insipidus, urine osmolality, as compared with plasma • 16 osmolality, must be hypo-osmolar. Diabetes insipidus Plasma osmolality Diabetes mellitus Osmolality Kidney Blood plasma Urine

lijl;fiiJI•l toryea r:[2017 • ] FI RST AID FACT S

r • ,..., - ..,..., .. ,. 6 s 0 lock Suspend End Block Item: 10 of 16 ~ . I • M k <:] t> al ~· ~ QIO: 2358 .l. ar Previous Next lab 'Vfl1ues Notes Calculator

1 Bottom Line: 2 In diabetes insipidus, the kidney is unable to concentrate urine effectively; thus in diabetes insipidus, urine osmolality, as compared with plasma 3 osmolality, must be hypo-osmolar. Diabetes insipidus Plasma osmolality Diabetes mellitus Osmolality Kidney Blood plasma Urine 4 5 6 lijl;fiiJI•l toryear:[2017 • ] 7 FI RST AID FACT S

8 FA17p334.1 9 Diabetes insipidus Characteri zed by intense thirst and polyuria with inability to concentrate urine due to lack of ADH 10 (central) or fa ilure of response to circulating ADH (nephrogenic). · 11 Central 01 Nephrogenic Dl • 12 ETIOLOGY Pituitary tumor, autoimmune, trauma, surgery, Hereditary (ADH receptor mutation), 2° • 13 ischemic encephalopathy, idiopathic to hypercalcemia, hypokalemia, lithium, • 14 demeclocycline (ADH antagonist) • 15 FINDINGS l ADH onnal or t ADH levels • 16 Urine specifi c gravity< 1.006 Urine specific gravity< 1.006 Serum osmolality> 290 mOsm/kg Serum osmolality> 290 mOsm/kg Hyperosmotic volume contraction Hyperosmoti c volume contraction WATERDEPRIVATION TEST' >50% t in urine osmolality only after Min imal change in urine osmola lity, even after administration of ADH analog administration of ADH analog TREATMENT Desmopressin acetate HCTZ, indomethacin, amiloride 't' T 1 • • -.--.- 'I •• ' . .. . ' r 6 s 0 lock Suspend End Block Item: 11 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 2790 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 • A 35-year-old man presents to his primary care physician with a chief complaint of palpitations and occasional chest pain. Further questioning reveals IA•A] 2 a recent history of weight loss, diarrhea, and hea t intolerance. Laboratory evaluation shows antithyroid-stimulating hormone (TSH) receptor antibodies In the patient's serum. 3 Thyroid- Total Free 4 stimulating Choice thyroxine hormone thyroxine 5 6 A t t t 7 B t ~ t 8 c 9 t ~ ~ 10 D ~ t t • 11 E ~ ~ ~ • 12

• 13 Using the table above, which of the following best describes this patient's TSH and thyroid hormone levels relative to normal baseline values? • 14 : • 15 A

• 16 B c

0

E

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1 The correct a nswer is D. 79% chose this. 2 The vignette describes a classic history of an autoimmune hyperthyroidism- Graves disea se. In this disorder; thyroid follicular cells are stimulated to synthesize and secrete thyroid hormone by anti-TSH receptor antibodies, which stimulate the TSH receptor; lea ding to increa sed levels of thyroxine (T 4) 3 and triiodothyronine (T3) in the blood. Negative feedback on the anterior pituitary by T4 and T3 results in suppression of TSH secretion. Thus, both free T4 and total T , which includes free T and T bound to proteins in the blood (eg, albumin and thyroxine-binding globulin) will be increa sed, wherea s blood 4 4 4 4 TSH levels will be low relative to the normal baseline. 5 Thyroid hormone Thyroxine-binding globulin Triiodothyronine Anterior pituitary Albumin Thyroid Thyroid-stimulating hormone Autoimmune disease 6 Thyrotropin receptor Hormone Pituitary gland Antibody Follicular cell Autoimmunity Negative feedback Globulin Receptor (biochemistry) Protein Secretion 7 A is not correct. 1 0 % chose this. The pattern of hormone levels seen in A suggests a central hyperthyroidism that could be caused by a pituitary adenoma. The elevated levels of thyroid 8 hormone in this condition are driven by an increa sed production of thyroid-stimulating hormone (TSH ) by the pituitary. This is not the case in Graves disea se, in which the elevated T levels lea ds to a suppression of TSH production due to negative feedback on the anterior pituitary. 9 4 Graves' disease Thyroid-stimulating hormone Pituitary adenoma Hyperthyroidism Thyroid hormone Anterior pituitary Thyroid Hormone Pituitary gland Adenoma

10 Negative feedback Feedback

11 B is not correct. 4 % chose this. • 12 An elevated TSH level is not characteristic of Graves disea se, and an eleva ted free T4 level should result in a lower TSH level due to negative feedback on the anterior pituitary. Furthermore, thyroid hormone binding to proteins in the blood should not be decrea sed but instea d should be increased in the • 13 setting of increa sed free T4 . Therefore, the total T4 1evel should be elevat ed rather than low. The pattern of hormone expression in this answer is not • 14 physiologic. Graves' disease Thyroid hormone Anterior pituitary Thyroid Thyroid-stimulating hormone Hormone Pituitary gland Negative feedback Protein • 15 c is not correct. 5 % chose this • • 16 Graves disea se is characterized by a low TSH level due to the circulating thyroid-stimulating immunoglobulins, which elevate T3 and T4l evels and, via negative feedback, downregulate the level of TSH . In this answer choice, the level of TSH is elevated, which would lea d to elevat ed, not diminished, levels of T3 and T4. The pattern of hormone levels in this answer represent hypothyroidism due to dysfunction of the thyroid gland which could be observed in the aftermath of a thyroiditis. Graves' disease Hypothyroidism Thyroid Thyroid-stimulating hormone Hormone Thyroiditis Negative feedback Antibody Downregulation and upregulation Gland

E is not correct. 2% chose this. Total and free thyroxine (T4 ) levels are expected to be low in the setting of low TSH levels. However; in Gra ves disea se, stimulation of TSH receptors on the thyroid follicular cells by anti-TSH receptor antibodies stimulates the secretion of thyroid hormones and results in increased total and free T4 levels in 6 s 0 lock Suspend End Block Item: 11 of 16 ~ . , . M k <:] t> al ~· ~ QIO: 2790 .l. ar Previous Next lab 'Vfl1ues Notes Calculator

.. • .. w ...... • • ...... • ... • .. ... • ...... • ...... 1 levels of T3 and T4. The pattern of hormone levels in this answer represent hypothyroidism due to dysfunction of the thyroid gland which could be observed in the aftermath of a thyroiditis. 2 Graves' disease Hypothyroidism Thyroid Thyroid-stimulating hormone Hormone Thyroiditis Negative feedback Antibody Downregulation and upregulation Gland 3 E is not correct. 2 % chose this. 4 Total and free thyroxine (T4 ) levels are expected to be low in the setting of low TSH levels. However; in Graves disease, stimulation of TSH receptors on the thyroid follicular cells by anti-TSH receptor antibodies stimulates the secretion of thyroid hormones and results in increased total and free T4 levels in 5 the setting of normal or even low TSH levels. The resulting negative feedback loop to the anterior pituitary leads to reduced TSH levels. The pattern of 6 hormone levels seen in this answer represents a central hypothyroidism which could be seen, for example, after pituitary surgery. For this reason, these patients are supplemented with thyroid hormone, as well as corticosteroids and sex hormones to replace the loss in pituitary function. 7 Graves' disease Thyroid hormone Hypothyroidism Anterior pituitary Corticosteroid Thyroid Thyroid-stimulating hormone Hormone Negative feedback 8 Pituitary gland Sex steroid Antibody Follicular cell Thyrotropin receptor Feedback Secretion Receptor (biochemistry) 9

10 Botto m Line:

11 In Graves disease, thyroid follicular cells are directly stimulated, so T4 and T3 levels are high, but TSH levels are low because of negative feedback on the anterior pituitary. • 12 Graves' disease Anterior pituitary Thyroid Thyroid-stimulating hormone Pituitary gland Follicular cell Negative feedback Feedback Ovarian follicle • 13 • 14

• 15 lijl;fiiJI•l to r year:[ 2 0 17 • ] FI RST AID FACT S • 16

FA17 p 329.1 Hyperthyroidism Graves disease Most common cause of hyperthyroidism. Thyroid-stimulating immunoglobulin (lgC; type ll hypersensitivity) stimulates TSH receptors on thyroid (hyperthyroidism, diffuse goiter) and dermal fibroblasts (pretibial myxedema). Infiltration of rctroorbi tal space by acti,·atcd T-cells • • 1 • , • 6 s 0 lock Suspend End Block 5 FA17 p 321 .2 6 Thyroid hormones 7 Iodine-containing hormones that cont rol the bod) 's metabolic rate. (T3IT4) 8 SOURCE Follicles of thyroid. :\lost T formed in target T fu nctions-4 B's: 9 3 3 tissues. Brain maturation 10 FUNCTION Bone growth (synergism with CJ J) Bone growth 11 C 15 maturation ~ -adrene rg i c effects • 12 Basal metabolic rate f f ~ 1 receptors in heart= f CO, HR, V, • 13 contractility Thyroxine-binding globulin (TBC) binds most T /T in blood; only free hormone is acti ve. • 14 f basal metabolic rate via f J a+fK'-A'I'Pase 3 4 ~ TBC in hepati c failure, steroids; f TBC in • 15 activity - f 0 2 consumption, RR, body temperature pregnancy or OCP use (estrogen f TBG). • 16 t glycogenolysis, gl uconeogenesis, I ipolys is T4 is major thyroid product·; convert ed to T 3 in peripheral tissue by 5'-deiodinase. REGULATION TRH (hypothalamus) stimnlates TSH T bi nds nuclear receptor with greater affinity (pituitary), which stimulates follicular cells. 3 than T-+. May also be stimulated by thyroid-stimulating Thyroid peroxidase is the enzyme responsible immunoglobulin (TSJ) in Cra,·es disease. for oxidation and organification of iodide as 1 egati' e feedback primarily by free T /T-+ to • • • • I I • • • • o , fT._ I "\ I t ,,·ell as coupling of monoiodotyrosine (MIT) ! s 8 Suspend End Block Item: 12 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 2798 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 • A researcher is investigating hormones that act via nuclear hormone receptors. She has developed an assay to analyze the activity of these hormones lA• A] 2 by assessing mRNA levels of known downstrea m products in various tissues. 3 What hormone can be studied by this technique? 4 5 : A. COrtiSOl 6 7 B. Glucagon 8 c. Histamine 9 D. Insulin 10 E. Norepinephrine 11 • 12 • 13 • 14 • 15 • 16

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1 The correct a nswer is A. 77% chose this. 2 Cortisol acts via a nuclea r steroid hormone receptor. Cortisol enters the cell and binds to its receptor in the cytoplasm. The receptor then translocates from the cytoplasm into the cell nucleus and the cortisol-receptor complex acts as a transcription factor. This results in gene tra nscription and new protein 3 synthesis. Other hormones that act through nuclea r steroid hormone receptors include aldosterone, vitamin D, testosterone, estrogen, and progesterone. It is important to note that the mechanism of binding its receptor differs between some of the steroid hormones. Some steroid hormones bind to 4 receptors located in the cytoplasm which then translocate to the nucleus due to nuclea r localization signals. Other steroid hormones have receptors that always remain in the nucleus and the hormone itself is targeted to the nucleus, where it binds the receptor once inside the nucleus. 5 Steroid hormone receptor Cortisol Aldosterone Steroid hormone Estrogen Testosterone Progesterone Cytoplasm Transcription factor Gene Vitamin D Steroid 6 Cell nucleus Transcription (genetics) Protein Hormone Protein biosynthesis Protein synthesis Nuclear localization sequence Protein targeting Hormone receptor 7 Vitamin Receptor (biochemistry)

8 B is not correct. 5 % chose this. 9 Glucagon acts via G-protein receptors located in the plasma membrane. G proteins are activa ted, and the a subunit activates adenylate cyclase. Glucagon does not act via nuclea r hormone receptors. 10 Glucagon Adenylyl cyclase Cell membrane G protein Hormone Nuclear receptor Blood plasma Receptor (biochemistry) Biological membrane Protein

11 c is not correct. 3 % chose this. 12 Histamine and vasopressin activa te phospholipase C, resulting in the clea vage of phosphatidylinositol diphosphate into inositol triphosphate and diacylglycerol. It does not act via nuclea r hormone receptors. • 13 Inositol trisphosphate Vasopressin Phospholipase c Diglyceride Histamine Inositol Phospholipase Phosphatidylinositol Hormone Nuclear receptor • 14 Receptor (biochemistry) • 15 D is not correct. 10 % chose this • Intracellular insulin acts via a tyrosine kinase cascade and not via nuclea r hormone receptors. • 16 Tyrosine kinase Intracellular Insulin Tyrosine Hormone Nuclear receptor Kinase Receptor (biochemistry)

E is not correct. 5 % chose this. Norepinephrine acts by binding to and activating adrenergic receptors. It does not bind to nuclea r hormone receptors. Norepinephrine Hormone Adrenergic receptor Nuclear receptor Receptor (biochemistry)

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1 E is not correct. 5 % chose this. 2 Norepinephrine acts by binding to and activating adrenergic receptors. It does not bind to nuclear hormone receptors. Norepinephrine Hormone Adrenergic receptor Nuclear receptor Receptor (biochemistry) 3 4 Bottom Line: 5 Cortisol and other steroid based hormones act via nuclear steroid hormone receptors. 6 Cortisol Steroid hormone Steroid Hormone Receptor (biochemistry) 7

8 9 lijj ;fi IJ l•l for year:l 2017 .. FI RST AI D FACTS 10

11 FA17 p 322.2 12 Signaling pathway of Steroid hormones arc lipoph il ic and therefore Cytoplasm • 13 steroid hormones must circulate bound to specific binding /--Nucleus • 14 globulins, which t their solubility. Bmdtng to enhancer­ ,... rw:'.ff ,... ,_ - • 15 In men, t sex hormone-binding globulin bkeelemenl______in DNA ~ .. 0 Gene -" (SHBG) lowers free testosterone Pre-mRNA • 16 ( H ... mRNA .... gynecomastia. Transformation of '<::: In women, ! SHBG raises free testosterone receptor to expose DNA· t bindmg domain mRNA --+ hirsutism. t Bindtng to receptor ~ Protetn OCPs, pregnancy .... t SHBG. located in nucleus or in cytoplasm ~ Response

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1 on cytoplasm t • Response 2 t H Hormone 3 4

5 FA17p322.1 6 Signaling pathways of endocrine hormones 7 cAMP FSH, LH, ACTH, T SH, CRH, hCC, AD II FL-\T ChAMP 8 ( 2-receptor), ~ I SH , PT H, calcitonin, C HR H, 9 glucagon, histamine (112-receptor) 10 cGMP B 'P, \ 'P, EDRP (\JO) B \D C ra \I Pa Thin!.. vasodilators 11 GnRH, Oxy tocin, ADH (V -rcceptor), T RH, CO\THAG 12 1 H istamine (H.-receptor), Angiotensin II, • 13 Gastrin • 14 Intracellular recept or Progesterone, Estrogen, Testosterone, Cortisol, PET CAT on TV • 15 Aldosterone, '1'/ 14, Vitami n D • 16 Receptor tyrosine Insulin, IGF-1, FG I~ PD G I ~ EC F MAP kinase pathway kinase T hink Growth Factors

Non receptor tyrosine Prolactin, l mmunomodulalors (eg, C) tokines JAK/STAT p athway kinase IL-2, IL-6, IFN), GH, G-CSF, Erythropoietin, Think acidophils and cytokines T hrombopoietin PICCLET

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1 • A 6-year-old girl whose parents just immigrated to the u.s . from Indonesia Is brought to the clinic because she has facial and neck swelling. She was lA• A] 2 developmentally normal at birth, but she then developed progressive Intellectual disability, growth delay, and abdominal protuberance. Below are pictures from when the patient was 3 months old. 3 4 5 6 7 8 9 10

11 12 • 13 • 14 • 15 • 16 A c I mages copyright ©2010 Rastogi and LaFranchi; licensee BioMed Central Ltd.

What other findings would be expected in this patient if more tests are ordered?

: A. Bone age that is less than chronologie age a s 8 Lock Suspend End Block 10 A c Images copyright ©2010 Rastogi and LaFranchi; licensee BioMed Central Ltd. 11 12 What other findings would be expected in this patient if more tests are ordered? • 13 : • 14 A. Bone age that is less than chronologie age • 15 B. Bone age that is more than chronologie age • 16 C. High oxygen consumption in body tissues

D. Severe protein deficiency

E. Thyroid-stimulating hormone value <0.5 IJU/ml

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1 The correct a nswer is A. 46% chose this. This patient is from a country where iodine deficiency is prevalent. Iodine is a substra te necessary for the proper synthesis of thyroid hormone. Iodide is 2 first taken up by thyroid follicular cells and condensed onto tyrosine residues, which reside along the polypeptide backbone of a protein called 3 thyroglobulin, forming either mono-iodinated or di-iodinated thyroglobulin. The molecules then undergo a coupling rea ction, forming either triiodothyronine (T3) or thyroxine (T4 ). These are then later relea sed as thyroid hormone into the blood strea m . T3 is the more active form of thyroid 4 hormone, and the inactive T4 is peripherally converted to form T3 · Thyroid hormone has a permissive action on growth hormone and nervous system maturation. Iodine is found in sea food (and iodized salt in the United States), and a lack of it in the diet lea ds to thyroid hormone deficiency. Thyroid 5 hormone is responsible for bone growth as well as central nervous system matura tion; therefore, this patient's bone age would prove to be less than her 6 rea l age. Thyroid hormone Thyroglobulin Triiodothyronine Iodine deficiency Central nervous system Iodine Hypothyroidism Thyroid Protein Iodised salt Hormone Tyrosine 7 Iodide Growth hormone Peptide Substrate (chemistry) Follicular cell Nervous system Bone age Bone Seafood Salt (chemistry)

8 B is not correct. 12% chose this. 9 Her bone growth would be delayed with a deficiency of thyroid hormone, and she would not show an older age of matura tion than expected. Thyroid hormone Thyroid Hormone Bone 10 c is not correct. 5 % chose this. 11 Thyroid hormone also is responsible for the basal metabolic rate (BMR). A low level of thyroid hormone would lea d to a depressed BMR and therefore less 12 oxygen consumption in tissues. Basal metabolic rate Thyroid hormone Thyroid Hormone Metabolism Kleiber's law Basal (phylogenetics) Oxygen 13 D is not correct. 13 % chose this • • 14 Protein deficiency, or kwashiorkor; is found in developing countries where the intake of mea t is minimal. Although it classically manifests with abdominal • 15 protuberance, this childb has een found to have an adequate intake of mea t . This condition is not associated with intellectual disability. Kwashiorkor Protein Intellectual disability Developing country Protein deficiency • 16 E is not correct. 24% chose this. Normal thyroid-stimulating hormone (TSH ) va lues vary between 0 .5 and 3 .0 IJU/ml. This patient would not be expected to have a borderline low TSH level, because she has thyroid hormone deficiency. Triiodothyronine (T3 ) and thyroxine (T4 ) normally exert negative feedback on the pituitary. The patient should have eleva ted TSH levels in the absence of T3 and T4 . Thyroid-stimulating hormone Thyroid hormone Triiodothyronine Hypothyroidism Thyroid Hormone Pituitary gland Negative feedback Feedback

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I ' 1 Protein deficiency, or kwashiorkor; is found in developing countries where the intake of meat is minimal. Although it classically manifests with abdominal 2 protuberance, this child has been found to have an adequate intake of meat. This condition is not associated with intellectual disability. Kwashiorkor Protein Intellectual disability Developing country Protein deficiency 3 E is not correct. 24% chose this. 4 Normal thyroid-stimulating hormone (TSH ) va lues vary between 0.5 and 3.0 IJU/ml. This patient would not be expected to have a borderline low TSH 5 level, because she has thyroid hormone deficiency. Triiodothyronine (T3 ) and thyroxine (T4 ) normally exert negative feedback on the pituitary. The patient should have elevated TSH levels in the absence of T3 and T4 . 6 Thyroid-stimulating hormone Thyroid hormone Triiodothyronine Hypothyroidism Thyroid Hormone Pituitary gland Negative feedback Feedback 7 8 Bottom Line: 9 Iodine deficiency is common in certain parts of the world. Thyroid hormone is has permissive action on growth hormone and nervous system maturation, 10 therefore younger patients with an iodine deficiency will typically present with symptoms of neurologic impairment and growth delay. Thyroid hormone Iodine deficiency Thyroid Iodine Growth hormone Hormone Nervous system Neurology 11 12 13 lijj ;fi IJ l•l for year:l 2017 .. • 14 FIRST AID FACT S • 15 FA17 p328.1 • 16 Hypothyroidism Hashimoto thyroiditis lost common cause of hypothyroidism in iodine-sufficient regions; an autoimmune disorder with antithyroid peroxidase (antimicrosomal) and antithyroglobulin antibodies. Associated with t risk of no n-Hodgkin lymphoma (typically of B-cell origin). May be hyperthyroid ea rly in course due to thyrotoxicosis during follicular rupture. Histologic find ings: Hi.ir thle cells, lymphoid aggregates with germinal centers rJ. 6 s 0 lock Suspend End Block 9 FA17 p 321 .2 10

11 Thyroid hormones Iodine-containing hormones that control the bod}'s metabolic rate. (Ti T4) 12 SOURCE Follicles of thyroid. Most T formed in target T functions-4 B's: 13 3 3 tissues. Brain maturation • 14 FUNCTION Bone growth (sy nergism with Cll) Bone growth • 15 C S maturation ~ -a d ren e rg i c effects • 16 Basal metabolic rate t t ~ 1 receptors in heart= t CO, H R, SV, contractility Thyroxine-bindi ng globulin (TBC) binds most t basal metabolic rate \•ia t 1 a+JK~ -ATPase T / T4 in blood; only free hormone is active. ! TBG in hepatic failure, steroids; t TBG in acti\·ity - t 0 2 consumption, RR, body temperature pregnancy or OCP use (estrogen t TBG). t glycogenolysis, gluconeogenesis, lipol)sis T-1 is major thyroid product; converted toT3 in peripheral tissue by 5'-deiodinase. OCt:lll ATtnN ! s 8 Suspend End Block Item: 14 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 2836 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 • A researcher is studying the signaling mechanism for hormone X. The molecular structure of the protein is analyzed and it appears that the hormone lA• A] 2 binds a polypeptide containing a zinc finger motif. To further understand the action of the hormone, it is tagged with a tracer to see its molecular activity. The experiment demonstrates that the free hormone passes through the cell membrane and then binds a receptor. The hormone-receptor 3 complex then transiocates to the nucleus. A diagram of the hormone signaling pathway is shown below. 4 5

6 ~ Hormone "- Receptor 7 8 9 ' \ 10

11 1 12 13 • 14 ...... __ ., • 15 • 16 This describes the mechanism of which of the following hormones?

A. Angiotensin II

B. Atrial natriuretic peptide

c. Insulin a s 8 Lock Suspend End Block 2 ' Receptor 3 4 5 ' \ 6 ) 7 8 9 ...... ,., 10 __ 11 12 This describes the mechanism of which of the following hormones? 13 : • 14 A . Angiotensin II • 15 8 . Atrial natriuretic peptide • 16 c. Insulin

o. Progesterone

E. Vasopressin

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1 The correct a nswer is D. 79% chose this. 2 The diagram shows the mechanism of a steroid hormone : (1) diffusing across the cell membrane, (2) binding to a cytosolic receptor; (3) binding to a nuclea r receptor; and ( 4) effecting change on DNA. The only "steroid" hormone among the choices is progesterone, made from a precursor cholesterol 3 molecule within the ovaries and to a smaller extent the adrenals. Steroid hormone receptors fall into the classification of zinc finger proteins (a polypeptide with a zinc atom bound to four cysteines), which have a hormone-binding region and a DNA-binding region that activates gene transcription. 4 Nuclear receptor Cell membrane Steroid hormone Progesterone Gene Zinc finger Steroid Transcription (genetics) Cytosol Ovary Cholesterol Hormone Peptide 5 Zinc DNA-binding domain DNA Molecule Atom Receptor (biochemistry) Protein

6 A is not correct. 4 % chose this.

7 Angiotensin II works via the angiotensin neuropeptide type I receptor (AT 1 receptor) on vascular smooth muscle, central nervous system, zona glomerulosa of the adrenal cortex, and renal tubuleAs. The T 1 receptor for antiogensin II is a Gq that works through the phospholipase C pathway to 8 increa se inositol triphosphate (I P3 ) and diacylglycerol (DAG ). Angiotensin II causes arteriolar vasoconstriction, thirst sensation, increa sed ADH and 9 aldosterone secretion, and increa sed sodium rea bsorption. Zona glomerulosa Inositol trisphosphate Aldosterone Angiotensin Adrenal cortex Central nervous system Angiotensin II Vasoconstriction Neuropeptide Diglyceride 10 Phospholipase C Smooth muscle tissue Vasopressin Sodium Phospholipase Arteriole Nervous system Vascular smooth muscle Blood vessel Inositol Muscle 11 Adrenal gland Receptor (biochemistry) Kidney Secretion

12 B is not correct. 4 % chose this. 13 Atrial natriuretic peptide (ANP ) works through the AN P receptor; which is a guanylate cyclase (GC) receptor. Intrinsic GC activity produces cGMP, which catalyzes protein kinase G to phosphorylate serine and threonine protein residues to produce arteriole vasodilation. 14 Arteriole Atrial natriuretic peptide Catalysis Guanylyl cyclase Threonine Vasodilation CGMP-dependent protein kinase Peptide Serine • 15 Cyclic guanosine monophosphate Protein Phosphorylation Protein kinase Receptor (biochemistry) Atrium (heart) Kinase • 16 c is not correct. 9 % chose this • Insulin works by binding to a receptor tyrosine kinase, which causes its intrinsic tyrosine kinase to catalyze autophosphorylation of tyrosine (producing phosophotyrosine) within the receptor. Intracellular proteins bind the SH2 domain of phosphotyrosine and the path ultimately activa tes mitogen-activated protein kinase (MAP kinase) by covalent phosphorylation of tyrosine and threonine, where the now activa ted MAP kinase enters the nucleus and alters gene transcription. Therefore, insulin binds a receptor and its second messenger MAP kinase actually enters the nucleus to alter gene transcription. Receptor tyrosine kinase Mitogen-activated protein kinase SH2 domain Threonine Gene Second messenger system Insulin Transcription (genetics) Tyrosine kinase Tyrosine Intracellular Phosphorylation Protein Autophosphorylation Protein kinase Kinase Covalent bond Catalysis Cell nucleus Receptor (biochemistry)

E is not correct. 4 % chose this. 6 s 0 lock Suspend End Block Item: 14 of 16 ~ . I • M k <:] t> al ~· ~ QIO: 2836 .l. ar Previous Next lab 'Vfl1ues Notes Calculator

1 E is not correct. 4 % chose this. 2 Vasopressin (ADH) can work by activating either V1 or V2 neuropeptide receptors on cell membranes. Stimulated V1 receptors on arterioles activate 3 phospholipase C, liberating DAG and IP3 from membrane lipids to elicit vasoconstriction (usually only seen with larger/supra physiologic doses). IP3 mobilizes calcium ions and, with DAG, activates protein kinase c. Stimulated V2 receptors on the principal cells of the cortical and medullary collecting 4 ducts activate G proteins that in turn activate adenylate cyclase, which produce cAMP. cAMP activates protein kinase A. The end result is an increased expression of aquaporin water channels available for water reabsorption in the collecting duct. Neither mechanism involves hormone diffusion across the 5 cell membrane. Vasopressin Neuropeptide Aquaporin Phospholipase c Vasoconstriction Adenylyl cyclase Cyclic adenosine monophosphate Cell membrane Collecting duct system 6 G protein Hormone Protein kinase Diglyceride Protein Biological membrane lipid Calcium Diffusion Arteriole Phospholipase lipid bilayer Cortex (anatomy) 7 Calcium in biology Kinase Cerebral cortex Receptor (biochemistry) 8 9 Bottom Line: 10 Steroid hormones exert their effects by diffusing through the cell membrane and binding to a zinc finger; which consists of a zinc atom bound to four 11 cysteine amino acids. Cell membrane Cysteine Zinc Zinc finger Amino acid Steroid Steroid hormone Hormone Atom 12 13 14 lijl;fiiJI•l toryear:[ 2017 • ] • 15 FI RST AI D FA CTS • 16 FA17 p 322.2 Signaling pathway of Steroid hormones arc lipoph il ic and therefore Cytoplasm steroid hormones must circulate bound to specific binding /--Nucleus globulins, which t their solubility. Bmdtng to enhancer­ r- ~ff"'" P" F" In men, t sex hormone-binding globulin ~keelemenl in DNA ~ 0 Gene -" Pre-mRNA (SHBG) lowers free testosterone _... ----~ J. 6 s 0 lock Suspend End Block Item: 14 of 16 ~ 1 • Ma rk -<:J 1>- Jil ~· !:';-~ QIO: 2836 ..L Prev ious Next Lab ~lu es Notes Calculat o r ,. 1 In women, ! SHBG raises free testosterone receptor to expose DNA· • b1nd1r1g domilln mRNA 2 --+ hirsutism. t ,. Bmd1ng to re<:eptor OCPs, pregnancy ..... t Sl IBG. Prote1n 3 located 111 nucleus or on cytoplasm t 4 Response 5 6 7 FA17 p 595.2 8 Progesterone 9 SOURCE Corpus luteum, placenta, adrenal corte>., testes. Fall in progesterone after deJi,er) disinhibits 10 FUNCTION Stimulation of endometrial glandular secretions prolactin ..... lactation. t progesterone is 11 and spiral artery development. ind icative of ovulation. 12 Maintenance of pregnancy. Progc~ terone is pro-gestation. 13 l myometrial excitability. ProhJCtin is pro-lactation. 14 Production of thick cervical mucus, which • 15 inhibits sperm entry into utems. t body temperature . • 16 Inhibition of gonadotropins (LH, FSII ). Uterine smooth muscle relaxation (preventing contractions). l estrogen receptor e>.pression. Pre,·ents endometrial hyperplasia.

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1 • A researcher is studying diabetes mellitus. The tea m is trying to understand the molecular pathways involved in insulin resistance. They create a 2 strain of genetically-altered mice with a mutated insulin receptor that Is only partially activated upon ligand binding. 3 In normal cellular function, binding of insulin to which molecular signaling system mediates its effects on the body? 4 5 : A. Adenylate cyclase 6 cyclase 7 B. Guanylate 8 c. Serine kinases 9 D. Threonine kinases 10 E. Tyrosine kinases 11 12 13 14

0 15

0 16

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1 The correct answer is E. 83 % chose this. 2 The actions of insulin are mediated at the cellular level by binding of insulin to its receptor followed by autophosphorylation of tyrosine residues on the insulin receptor; this generates a tyrosine kinase that participates in an intracellular signaling cascade. Inhibition of tyrosine kinase function would 3 preclude downstrea m signaling and block the physiologic changes associated with insulin action, regardless of the amount of insulin present in the blood. Insulin receptor Insulin Tyrosine kinase Tyrosine Second messenger system Signal transduction Intracellular Autophosphorylation Receptor (biochemistry) Kinase 4 Physiology 5 A is not correct. 8% chose this. 6 Adenylate cyclase and its product, cAMP, are involved in numerous important intracellular signaling systems, including the systems that mediate 7 autonomic sympathetic nervous stimulation, AD H action, renal calcium and phosphate transport, and glucagon action. However; adenylate cyclase and cAMP are not involved in the system that mediates insulin action. 8 Glucagon Adenylyl cyclase Cyclic adenosine monophosphate Intracellular Insulin Vasopressin Autonomic nervous system Calcium Phosphate

9 B is not correct. 4 % chose this. 10 Guanylate cyclase and its product, cGMP, are involved in many intracellular signaling systems, including those that mediate the transduction of visual stimuli into electrical signals in the nervous system, and the relaxation of vascular smooth muscle throughout the body. However; guanylate cyclase and 11 cGMP are not known to be involved in the system that mediates insulin action. Guanylyl cyclase Cyclic guanosine monophosphate Insulin Smooth muscle tissue Intracellular Vascular smooth muscle Guanosine monophosphate Nervous system 12 Signal transduction 13 c is not correct. 3 % chose this. 14 Serine kinases are involved in a number of intracellular signaling cascades, but they are not known to be involved in the signaling cascade that mediates 15 insulin action. Serine Insulin Serine/threonine-specific protein kinase Signal transduction Intracellular Kinase • 16 D is not correct. 2 % chose this. Threonine kinases are involved in a number of intracellular signaling cascades, but they are not known to be involved in the signaling cascade that mediates insulin action. Threonine Intracellular Insulin Signal transduction Kinase

Botto m Line:

" ...... -...... :.- ... -. 1: ... .- • •. -...... t •• -: ...... k -. ... : ...... -. ;,.. ...1,,,..1 ,... ;,...... 1; ... 1,.. - -: ...... • k ...... ; ...... 1,: ... -...... : ...... k.-:,...... 1-. - -: ...... -. ...t ...... ,_; ,...... k 6 s 0 lock Suspend End Block Item: 15 of 16 ~ . I • M k <:] t> al ~· ~ QIO: 2786 .l. ar Previous Next lab 'Vfl1ues Notes Calculator . . . . 1 Serine kinases are involved in a number of intracellular signaling cascades, but they are not known to be involved in the signaling cascade that mediates 2 insulin action. Serine Insulin Serine/threonine-specific protein kinase Signal transduction Intracellular Kinase 3 D is not correct. 2% chose this. 4 Threonine kinases are involved in a number of intracellular signaling cascades, but they are not known to be involved in the signaling cascade that 5 mediates insulin action. Threonine Intracellular Insulin Signal transduction Kinase 6 7 Bottom Line: 8 Important signaling transduction mechanisms include insulin's action on the tyrosine kinase receptor; epinephrine's action on adrenergic receptors such 9 as the a- and j3 -adrenergic receptors, and steroid hormone actions on intranuclea r receptors. Epinephrine Steroid hormone Insulin Tyrosine kinase Steroid Tyrosine Hormone Receptor tyrosine kinase Adrenergic receptor Kinase Signal transduction 10 Transduction (genetics) Receptor (biochemistry) 11 12

13 I ill ;fi 1!1 I•J for year:[ 2017 .. FI RST AI D FACTS 14 15 FA17p314.1 • 16 Insulin

SYNTHESIS Preproinsulin (synthesized in RER) - cleavage C peptide of"presignal" - proi nsulin (stored in secretory Proinsulin granules) - clea,·age of proinsulin - exocytosis a·chain of insul in and C-peptide equall y. Insulin and C-peptide are f in insulinoma and sulfonylurea / use, whereas exogenous insulin lacks C-pepti de. 6 s 0 lock Suspend End Block Item: 15 of 16 ~ Ma rk -<:J I> £!1?' ~~~ QIO: 2786 ,. • ..L Prev i-ous Next LabfJ lu es Notes Calculat o r • • • ~ • Blood 2 vessel 3 Insulin secretion by pancreatic ~ cells lnsuUn-dependent glucose uplilke 4 5 FA17 p 322.2 6 Signaling pathway of Steroid hormones arc lipophilic and therefore 7 Cytoplasm steroid hormones must circulate bound to specific binding / Nucleus 8 globulins. which t their solubility. 9 Bindong lO enhancer· - In men, t sex hormone-binding globnl in like element on DNA ~ Gene 10 (SHBG) lo,,ers free testosterone Pre-mRNA ( H.,...._... ----· mRNA 11 -- gynecomastia. TransformatJo n of In women, l SHBG raises free testosterone receptor to expose ONA­ .. 12 bindong domaon mRNA -- hirsutism. t 13 Bmdong to receptor ... OCPs, pregnancy -- t SIIBG. Prot eon 14 located 1n nucleus or on cytoplasm ... Response 15 t • 16 H Hormone

FA17 p 322.1 Signaling pathways of endocrine hormones cAMP FSH, LH, ACTH, T SI I, CRI I, hCG, ADI I FL\TChAMP ( r receptor), ~iSH , PTH. calcitonin. G HRH. a s 8 Lock Suspend End Block Item: 16 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 3843 ..L a r Previous Next Lab~lu es Notes Calculat o r

1 • A 34-year-old woman complains of a bulge on her neck (shown in the Image) that has developed over the past few months. The patient also 2 complains of heat intolerance and weight loss. Physical examination also reveals exophthalmos. Her thyroid-stimulating hormone level is 0.1 IJU/ml. 3 4 5 6 7 8 9 10

11 12 13 14 15 • 16

Which medication can be used to treat the cardiovascular abnormality associated with this condition?

: A. Atenolol

B. Atropine a s 8 Lock Suspend End Block Image courtesy of Wikimedia Commons 11 12 Which medication can be used to treat the cardiovascular abnormality associated with this condition? 13 : 14 A. Atenolol 15 B. Atropine • 16 c. Isosorbide dinitrate

D. Mirtazapine

E. Norepinephrine

a s 8 Lock Suspend End Block Item: 16 of 16 ~ 1 • M k -<:J 1>- Jil ~· !:';-~ QIO: 3843 ..L a r Previous Next Lab~lu es Notes Calculat or • 1 Th e c o rrect an sw er i s A. 840/o ch ose this. 2 Based on the clinical presentation and physical findings, this patient most likely has hyperthyroidism. Graves disease is the most common cause of hyperthyroidism. Patients produce IgG autoantibodies against the thyroid-stimulating hormone receptor, resulting in excess thyroid hormone production. 3 Through feedback inhibition, the excess thyroid hormone reduces levels of thyroid-stimulating hormone. Excess thyroid hormone causes overstlmulatlon of Class II antiarrhythmlcs 4 the sympathetic nervous system and enhanced metabolism by affected tissues. This leads to arrhythmias and tachycardia. (13- blockers such as atenolol) are drugs of choice for the treatment of tachycardia and arrhythmias. 5 Graves' d;sease Atenolol Thyroid-stimulating hormone Hyperthyroidism Sympathetic nervous system Thyroid hormone Autoantibody AntiarrhythmiC agent Thy1 uod 6 Cardiac a1 (t 1moa Tachycardia Enzyme inhibitor Metabolism Immunoglobulin G Hormone Nervous system Receptor (biochemistry) 7 B i s not correct. 5% chose this. Atropine Is a muscarinic antagonist that is used to treat bradycardia by acting on cardiac M2 receptors. Atropine side effects include mydriasis and 8 cycloplegia, decreased lung secretions, bradycardia, and decreased gut motility. Note that increased levels of thyroid hormone lead to tachycardia, not 9 bradycardia. Mydriasis Atropine Cycloplegia Bradycardia Muscarinic antagonist Tachycardia 7hyroid hormone Receptor antagonist Muscarinic acetylcholine receptor Peristalsis 10 Thyroid Hormone Adverse drug reaction Receptor (biochemistry) Side effect Lung Gastrointestinal tract

11 C is n ot correct. 4 % chose this. 12 Isosorblde dinitrate causes vasodilation by the release of nitric oxide. It Is used clinically in the treatment of angina. Common side effects Include headache, nausea, and lightheadness. 13 Isosorbide dinitrate Nitric oxide Vasodilation Angina pectoris Headache Nausea Isosorbide 14 D is not co rrect. 50fo chose this.

15 Mlrtazaplne Is an o2 -selective a-blocker used in the treatment of depression. Side effects are fairly nonspecific, including dry mouth, constipation, weight gain, and drowsiness. 16 Mirtazapine Constipation Somnolence Xerostomia Major depressive disorder Depression (mood) Weight gain Adverse drug reaction Side effect

E is n ot co rrect. 20/o ch ose this.

Norepinephrine is a catecholamine with high o 1 activity that is used to treat hypotension. Thyroid hormone causes hypertension, not hypotension. Other side effects include tachycardia, sweating, vomiting, chest pain, and local vasoconstriction/ tissue necrosis (if used as an injectable). Catecholamine Norepinephrine Hypotension Tachycardia Thyroid hormone Hypertension Chest pain Vomiting Thyroid Hormone Perspiration Necrosis Adverse drug reaction Side effect

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1 E is not correct. 2 % chose this. Norepinephrine is a catecholamine with high a activity that is used to treat hypotension. Thyroid hormone causes hypertension, not hypotension. Other 2 1 side effects include tachycardia, sweating, vomiting, chest pain, and local vasoconstriction/tissue necrosis (if used as an injectable). 3 Catecholamine Norepinephrine Hypotension Tachycardia Thyroid hormone Hypertension Chest pain Vomiting Thyroid Hormone Perspiration Necrosis 4 Adverse drug reaction Side effect 5 6 Bottom Line: 7 Excessive thyroid hormone secretion can affect the cardiovascular system through overstimulation of the sympathetic nervous system, leading to arrhythmias, tachycardia, hypertension, and increased cardiac contractility. 8 Sympathetic nervous system Thyroid hormone Tachycardia Circulatory system Hypertension Thyroid Hormone Nervous system Cardiac arrhythmia Contractility Cardiovascular system Secretion 9 10

11 I iii I ;fi 1!1 I•J for year:l 2017 .. 12 FI RST AI D FACTS 13 14 FA17 p 329.1 Hyperthyroidism 15 Graves disease Most common cause of hyperthyroidism. Thyroid-stimulating immunoglobulin (lgC; type ll 16 hypersensitiv ity) stimulates TSH receptors on thyroid (hyperthyroidism, diffuse goiter) and dermal fibroblasts (pretibial myxedema). Infiltration of rctroorbital space by acti,·atcd T-cells - t cytokincs (cg, T F-a, IFN-y) - t fibroblast secretion of hydrophilic GAGs - t osmotic muscle swelling, muscle inAammation, and adipocyte count - exophthalmos r.J. Often presents during stress (eg, pregnancy). Associated with HLA-DR3 and HLA-88. Ta ll , crowded foll icular epithel ial cells; scalloped colloid ll]. 6 s 0 lock Suspend End Block 7 8 FA17 p 237.1 9

10 P,.blockers Acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebi,·olol, pindolol, propranolol, I imolol. 11 APPLICATION ACTIONS NOTES/EXAMPLES 12 Angina pectoris ! heart rate and contractility, resulting in I 0 2 13 consumption 14 Myocardial infarction l mortality 15 Supraventricular I AV conduction velocity (class II letop rolol, esmolol 16 tachycardia antiarrhythmic) Hypertension ! cardiac output, I renin secret ion (due to ~ 1 -rece pto r blockade on JGA cells) Heart failure I mortality (bisoprolol, carvedilol, metoprolol) Glaucoma I production of aqueous humor Timolol

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