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Flashcards in Endocrine - Physiology Deck (20):
1

Insulin

  • Synthesis
  • Source

  • Synthesis
    • Preproinsulin (synthesized in RER)
      • -->Ž cleavage of “presignal”
      • -->Ž proinsulin (stored in secretory granules)
      • -->Ž cleavage of proinsulin Ž
      • --> exocytosis of insulin and C-peptide equally.
    • Insulin and C-peptide are increased in insulinoma, whereas exogenous insulin lacks C-peptide.
  • Source
    • Released from pancreatic β cells.

2

Insulin (308)

  • Function
    • Binds...
    • Anabolic effects of insulin:
    • Insulin...
    • Insulin-dependent glucose transporters:
    • Insulin-independent transporters:
    • Brain...

  • Function
    • Binds insulin receptors (tyrosine kinase activity [1]), inducing glucose uptake (carrier-mediated transport) in insulin-dependent tissue [2] and gene transcription.
    • Anabolic effects of insulin:
      • Increased glucose transport in skeletal muscle and adipose tissue
      • Increased glycogen synthesis and storage
      • Increased triglyceride synthesis
      • Increased Na+ retention (kidneys)
      • Increased protein synthesis (muscles, proteins)
      • Increased cellular uptake of K+ and amino acids
      • Decreased glucagon release
    • Insulin moves glucose into cells.
      • Unlike glucose, insulin does not cross placenta.
    • Insulin-dependent glucose transporters:
      • GLUT-4: adipose tissue, skeletal muscle
    • Insulin-independent transporters:
      • GLUT-1: RBCs, brain, cornea
      • GLUT-5 (fructose): spermatocytes, GI tract
      • GLUT-2 (bidirectional): β islet cells, liver, kidney, small intestine
      • BRICK L (insulin-independent glucose uptake): Brain, RBCs, Intestine, Cornea, Kidney, Liver.
    • Brain utilizes glucose for metabolism normally and ketone bodies during starvation.
      • RBCs always utilize glucose because they lack mitochondria for aerobic metabolism.

3

Insulin (308)

  • Regulation
    • Glucose (general)
    • GH and β2-agonists
    • Glucose (mechanism)

  • Regulation
    • Glucose is major regulator of insulin release.
    • GH (causes insulin resistance --> increased insulin release) and β2-agonists -->Ž increased insulin.
    • Glucose enters β cells [3]Ž
      • --> increased ATP generated from glucose metabolism [4] closes K+ channels [5] and depolarizes β cell membrane [6]
      • --> opens voltage-gated Ca2+ channels, resulting in Ca2+ influx [7] and stimulating insulin exocytosis [8].

4

Glucagon

  • Source
  • Function
  • Regulation

  • Source
    • Made by α cells of pancreas.
  • Function
    • Catabolic effects of glucagon:
      • ƒƒGlycogenolysis, gluconeogenesis
      • Lipolysis and ketone production
  • Regulation
    • Secreted in response to hypoglycemia.
    • Inhibited by insulin, hyperglycemia, and somatostatin.

5

Hypothalamic-pituitary hormones

  • For each
    • Function 
    • Clinical notes 
  • CRH
  • Dopamine
  • GnRH
  • Prolactin
  • Somatostatin
  • TRH

  • CRH 
    • Function: increases ACTH, MSH, β-endorphin 
    • Clinical notes: Decreased in chronic exogenous steroid use
  • Dopamine 
    • Function: decreases prolactin
    • Clinical notes: Dopamine antagonists (e.g., antipsychotics) can cause galactorrhea
  • GnRH 
    • Function: increases FSH, LH
    • Clinical notes: Regulated by prolactin
      • Tonic GnRH suppresses HPA axis
      • Pulsatile GnRH leads to puberty, fertility
  • Prolactin 
    • Function: decreases GnRH
    • Clinical notes: Pituitary prolactinoma -->Ž amenorrhea, osteoporosis
  • Somatostatin 
    • Function: decreases GH, TSH
    • Clinical notes: Analogs used to treat acromegaly
  • TRH 
    • Function: increases TSH, prolactin
    • Clinical notes: N/A

6

Prolactin

  • Source
  • Function
  • Regulation

  • Source
    • Secreted mainly by anterior pituitary.
  • Function
    • Stimulates milk production in breast
    • Inhibits ovulation in females and spermatogenesis in males by inhibiting GnRH synthesis and release.
    • Excessive amounts of prolactin associated with decreased libido.
  • Regulation
    • Prolactin secretion from anterior pituitary is tonically inhibited by dopamine from hypothalamus.
      • Prolactin in turn inhibits its own secretion by increasing dopamine synthesis and secretion from hypothalamus.
      • TRH increases prolactin secretion.
    • Dopamine agonists (bromocriptine) inhibit prolactin secretion and can be used in treatment of prolactinoma.
    • Dopamine antagonists (most antipsychotics) and estrogens (OCPs, pregnancy) stimulate prolactin secretion.

7

Growth hormone (somatotropin)

  • Source
  • Function
  • Regulation

  • Source
    • Secreted mainly by anterior pituitary.
  • Function
    • Stimulates linear growth and muscle mass through IGF-1/somatomedin secretion.
    • Increases insulin resistance (diabetogenic).
  • Regulation
    • Released in pulses in response to growth hormone–releasing hormone (GHRH).
      • Secretion increases during exercise and sleep.
      • Secretion inhibited by glucose and somatostatin.
    • Excess secretion of GH (e.g., pituitary adenoma) may cause acromegaly (adults) or gigantism (children).

8

Antidiuretic hormone

  • Source
  • Function
  • Regulation

  • Source
    • Synthesized in hypothalamus (supraoptic nuclei), released by posterior pituitary.
  • Function
    • Regulates serum osmolarity (V2-receptors) and blood pressure (V1-receptors).
      • Primary function is serum osmolarity regulation (ADH decreases serum osmolarity, increases urine osmolarity) via regulation of aquaporin channel transcription in principal cells of renal collecting duct.
    • ADH level is decreased in central diabetes insipidus (DI), normal or increased in nephrogenic DI and 1° polydipsia.
    • Nephrogenic DI can be caused by mutation in V2-receptor.
    • Desmopressin (ADH analog) = treatment for central DI.
  • Regulation
    • Osmoreceptors in hypothalamus (1°)
    • Hypovolemia (2°).

9

Adrenal steroids and congenital adrenal hyperplasias (312)

  • 17α-hydroxylase
    • Minearlocorticoids (increased/decreased)
    • Cortisol (increased/decreased)
    • Sex hormones (increased/decreased)
    • Labs
    • Presentation

  • 17α-hydroxylasea   
    • Minearlocorticoids: increased
    • Cortisol: decreased
    • Sex hormones: decreased
    • Labs
      • Hypertension
      • Hypokalemia
      • Decreased DHT
    • Presentation
      • XY: pseudo-hermaphroditism (ambiguous genitalia, undescended testes)
      • XX: lack secondary sexual development

10

Adrenal steroids and congenital adrenal hyperplasias (312)

  • 21-hydroxylase
    • Minearlocorticoids (increased/decreased)
    • Cortisol (increased/decreased)
    • Sex hormones (increased/decreased)
    • Labs
    • Presentation

  • 21-hydroxylasea   
    • Minearlocorticoids: decreased
    • Cortisol: decreased
    • Sex hormones: increased
    • Labs
      • Hypotension
      • Hyperkalemia
      • Increased renin activity
      • Increased 17-hydroxy-progesterone
    • Presentation
      • Most common
      • Presents in infancy (salt wasting) or childhood (precocious puberty)
      • XX: virilization

11

Adrenal steroids and congenital adrenal hyperplasias (312)

  • 11β-hydroxylase
    • Minearlocorticoids (increased/decreased)
    • Cortisol (increased/decreased)
    • Sex hormones (increased/decreased)
    • Labs
    • Presentation
  • All congenital adrenal enzyme deficiencies are characterized by...

  • 11β-hydroxylasea 
    • Minearlocorticoids:
      • Decreased aldosterone
      • Increased 11-deoxycorticosterone (results in increased BP)
    • Cortisol: decreased
    • Sex hormones: increased
    • Labs
      • Hypertension (low-renin)
    • Presentation
      • XX: virilization
  • All congenital adrenal enzyme deficiencies are characterized by an enlargement of both adrenal glands due to increased ACTH stimulation (due to decreased cortisol).

12

Cortisol

  • Source
  • Function
  • Regulation

  • Source
    • Adrenal zona fasciculata.
    • Bound to corticosteroid-binding globulin.
  • Function
    •  Cortisol is a BIG FIB.
      • Increased Blood pressure (upregulates α1-receptors on arterioles Ž--> increased sensitivity to norepinephrine and epinephrine)
      • Increased Insulin resistance (diabetogenic)
      • Increased Gluconeogenesis, lipolysis, and proteolysis
      • Decreased Fibroblast activity (causes striae)
      • Decreased Inflammatory and Immune responses:
        • Inhibits production of leukotrienes and prostaglandins
        • Inhibits leukocyte adhesion -->Ž neutrophilia
        • Blocks histamine release from mast cells
        • Reduces eosinophils
        • Blocks IL-2 production
      • Decreased Bone formation (decreased osteoblast activity)
    • Exogenous corticosteroids can cause reactivation of TB and candidiasis (blocked IL-2 production).
  • Regulation
    • CRH (hypothalamus) stimulates ACTH release (pituitary), causing cortisol production in adrenal zona fasciculata.
    • Excess cortisol decreases CRH, ACTH, and cortisol secretion.
    • Chronic stress induces prolonged secretion.

13

PTH (314)

  • Source
  • Function
    • PTH
    • PTH-related peptide
  • Regulation

  • Source
    • Chief cells of parathyroid.
  • Function
    • PTH = Phosphate Trashing Hormone.
      • Increased bone resorption of Ca2+ and PO43-.
      • Increased kidney reabsorption of Ca2+ in distal convoluted tubule.
      • Decreased reabsorption of PO43- in proximal convoluted tubule.
      • Increased 1,25-(OH)2 D3 (calcitriol) production by stimulating kidney 1α-hydroxylase.
      • PTH increases serum Ca2+, decreases serum (PO43-), increases urine (PO43-).
      • Increased production of macrophage colony-stimulating factor and RANK-L (receptor activator of NF-κB ligand).
        • RANK-L binds RANK on osteoblasts -->Ž osteoclast stimulation and increased Ca2+.
    • PTH-related peptide (PTHrP) functions like PTH and is commonly increased in malignancies (e.g., paraneoplastic syndrome).
  • Regulation
    • Decreased serum Ca2+ Ž--> increased PTH secretion.
    • Decreased serum Mg2+ -->Ž increased PTH secretion.
    • Really decreased serum Mg2+ -->Ž decreased PTH secretion.
    • Common causes of decreased Mg2+ include diarrhea, aminoglycosides, diuretics, and alcohol abuse

14

Calcium homeostasis

  • Plasma Ca2+ exists in three forms:
  • Increase in pH -->

  • Plasma Ca2+ exists in three forms:
    • Ionized (~45%)
    • Bound to albumin (~40%)
    • Bound to anions (~15%)
  • Increase in pH
    • -->Ž increased affinity of albumin (negative charge) to bind Ca2+
    • --> clinical manifestations of hypocalcemia (cramps, pain, paresthesias, carpopedal spasm).

15

Vitamin D (cholecalciferol)

  • Source
  • Function
  • Regulation
  • Deficiency causes...
  • 24,25-(OH)2 D3
  • PTH vs. 1,25-(OH)2

  • Source
    • D3 from sun exposure in skin.
    • D2 ingested from plants.
    • Both converted to 25-OH in liver and to 1,25-(OH)2 (active form) in kidney.
  • Function
    • Increased absorption of dietary Ca2+ and PO43-
    • Increased bone resorption -->Ž increased Ca2+ and PO43-
  • Regulation
    • Increased PTH, decreased [Ca2+], decreased PO43- cause increased 1,25-(OH)2 production.
    • 1,25-(OH)2 feedback inhibits its own production.
  • Deficiency causes rickets in kids and osteomalacia in adults.
    • Caused by malabsorption, decreased sunlight, poor diet, chronic kidney failure.
  • 24,25-(OH)2 D3 is an inactive form of vitamin D.
  • PTH vs. 1,25-(OH)2
    • PTH leads to increased Ca2+ reabsorption and decreased PO43- reabsorption in the kidney
    • 1,25-(OH)2 leads to increased absorption of both Ca2+ and PO43- in the gut.

16

Calcitonin

  • Source
  • Function
  • Regulation

  • Source
    • Parafollicular cells (C cells) of thyroid.
  • Function
    • Decreases bone resorption of Ca2+.
    • Calcitonin opposes actions of PTH.
      • Not important in normal Ca2+ homeostasis.
    • Calcitonin tones down Ca2+ levels.
  • Regulation
    • Increased serum Ca2+ causes calcitonin secretion.

17

Signaling pathways of these endocrine hormones

  • cAMP
  • cGMP
  • IP3
  • Steroid receptor
  • Intrinsic tyrosine kinase
  • Receptor-associated tyrosine kinase

  • cAMP
    • FLAT ChAMP GCG
    • FSH, LH, ACTH, TSH, CRH, hCG, ADH (V2-receptor), MSH, PTH, GHRH, Calcitonin, Glucagon
  • cGMP
    • Think vasodilators
    • ANP, NO (EDRF)
  • IP3
    • GOAT HAG
    • GnRH, Oxytocin, ADH (V1-receptor), TRH, Histamine (H1-receptor), Angiotensin II, Gastrin
  • Steroid receptor
    • VETTT CAP
    • Vitamin D, Estrogen, Testosterone, T3/TCortisol, Aldosterone, Progesterone
  • Intrinsic tyrosine kinase
    • Think growth factors
    • Insulin, IGF-1, FGF, PDGF, EGF
      • MAP kinase pathway
  • Receptor-associated tyrosine kinase
    • PIG, think acidophiles and cytokines
    • Prolactin, Immunomodulators (e.g., cytokines IL-2, IL-6, IL-8, IFN), GH
      • JAK/STAT pathway

18

Signaling pathway of steroid hormones

  • Steroid hormones
  • Men vs. women
  • OCPs, pregnancy

  • Steroid hormones are lipophilic and therefore must circulate bound to specific binding globulins, which increase their solubility.
  • Men vs. women
    • In men, increased sex hormone–binding globulin (SHBG) lowers free testosterone -->Ž gynecomastia.
    • In women, decreased SHBG raises free testosterone --> hirsutism.
  • OCPs, pregnancy increases SHBG (free estrogen levels remain unchanged).

19

Thyroid hormones (T3/T4) (316)

  • Definition
  • Source
  • Function

  • Definition
    • Iodine-containing hormones that control the body’s metabolic rate.
  • Source
    • Follicles of thyroid.
    • Most T3 formed in target tissues.
  • Function ("4 B's")
    • Brain maturation
      • CNS maturation
    • Bone growth
      • Bone growth (synergism w/ GH)
    • β-adrenergic effects
      • Increased β1 receptors in heart = increased CO, HR, SV, contractility
    • Basal metabolic rate increased
      • ​Increased basal metabolic rate via increased Na+/K+-ATPase activity = increased O2 consumption, RR, body temperature
      • Increased glycogenolysis, gluconeogenesis, lipolysis

20

Thyroid hormones (T3/T4) (316)

  • Regulation
    • TRH
    • Wolff-Chaikoff effect
    • Thyroxine-binding globulin (TBG)
    • T4 vs. T3
    • Peroxidase
    • Propylthiouracil vs. methimazole 
      • Propylthiouracil
      • Methimazole

  • Regulation
    • TRH (hypothalamus) stimulates TSH (pituitary), which stimulates follicular cells.
      • Negative feedback by free T3, T4 to anterior pituitary decreases sensitivity to TRH.
      • Thyroid-stimulating immunoglobulins (TSIs), like TSH, stimulate follicular cells (e.g., Graves disease).
    • Wolff-Chaikoff effect
      • Excess iodine temporarily inhibits thyroid peroxidase --> decreased iodine organification Ž--> decreased T3/T4 production.
    • Thyroxine-binding globulin (TBG) binds most T3/T4 in blood
      • Only free hormone is active.
      • Decreased TBG in hepatic failure
      • Increased TBG in pregnancy or OCP use (estrogen increases TBG).
    • T4 vs. T3
      • T4 is major thyroid product; converted to T3 in peripheral tissue by 5'-deiodinase.
      • T3 binds receptors with greater affinity than T4.
    • Peroxidase is enzyme responsible for oxidation and organification of iodide as well as coupling of monoiodotyrosine (MIT) and diiodotyrosine (DIT).
    • Propylthiouracil vs. methimazole
      • Propylthiouracil inhibits both peroxidase and 5'-deiodinase.
      • Methimazole inhibits peroxidase only.

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