Flashcards in Medical Physiology Block 7 Week 2 Deck (79):
Describe the location of the thyroid gland.
located in the anterior neck, lying like small bow ties across the front of the trachea (left and right lobes and a small connecting branch known as the isthmus)
How are thyroid hormones made? Where are they stored?
Thyroid hormones are made by iodinating tyrosine residues on thyroglobulin and are stored as part of thyroglobulin molecules in thyroid follicles
What is the structure of T3?
two iodines on inner ring and single iodine on outer benzyl ring
How do follicular cells of the thyroid obtain iodine?
iodide anion is absorbed by gastrointestinal tract; A specialized sodium/iodide cotransporter (NIS) is located at the basolateral membrane of the thyroid follicular cell (secondary active transport; TSH-dependent)
What happens when iodide leaves the follicular cell for the colloid lumen?
Iodide leaves the follicular cell and enters the lumen of the follicle across the apical membrane (maybe through pendrin anion exchanger); Thyroid peroxidase, on the luminal surface of secretory vesicle oxidizes iodide to iodine
iodination of thyroglobulin (simultaneously secreted by the follicular cell) in the follicular lumen; conjugation of iodinated tyrosines to form T4 and T3 linked to thyroglobulin (internal rearrangement); fluid-phase endocytosis of iodinated thyroglobulin into the follicular cells from the thyroid colloid; proteolysis of the iodinated thyroglobulin in the lumen of the lysoendosome; secretion of T4 and T3 into the circulation
How is thyroid hormone transported in the blood?
more than 99% bound to thyroid-binding globulin, albumin, transthyretin in the circulation (produced by the liver)
T/F: most of the thyroid hormone secreted by follicular cells is T3?
What conditions can change the concentration of thyroid-binding globulin? Does the concentration of free thyroid hormone in the circulation change in pathologic conditions?
Pregnancy, oral estrogen therapy, hepatitis, and chronic heroin abuse can all elevate the amount of TBG; steroid hormone and nephrotic syndrome decrease levels of TBG; No
Do target tissues modify the thyroid hormones?
Yes; A 5'/3'-monodeiodinase (cytoplasmic) removes iodine from the outer benzyl ring (yields T3; type 1: high concentrations in the liver, kidneys, and thyroid; type 2: pituitary, CNS, and placenta), whereas a 5/3-monodeiodinase removes iodine from the inner benzyl ring (yields Rt3)
Why is T3 more active than T4?
T4 is bound more tightly to plasma proteins; T3 and T4 are present at similar concentrations in the cytoplasm of target cells; TR has 10 fold greater affinity for T3
Describe the thyroid hormone receptor.
Receptors are bound to chromatin (heterodimer of TR and RXR)
What are the actions of thyroid hormone on target tissues?
increase basal metabolic rate by stimulating futile cycles of catabolism/anabolism (heat production or oxygen consumption): hepatic gluconeogensis (antagonist increase in insulin signaling), increased muscle proteolysis (some protein synthesis), increased lipolysis (some lipogenesis); increased sodium/potassium pump activity (accompanying ion leak prevents electrolyte imbalance); thermogenin (UCP) in brown fat produces heat; increased sensitivity to beta adrenergic signaling; (regulates myosin heavy chain)
What happens in instances of thyroid hormone deficiency during development?
cretinism: profound mental retardation, short stature, delay in motor development, coarse hair, and protuberant abdomen; Development of hypothyroidism at any time before fusion of the epiphyses of the long bones leads to growth retardation or arrest
Does exogenous thyroid hormone affect brain development?
No; unless this treatment is begun days after birth
Describe in detail the TRH-TSH-thyroid hormone axis.
TRH binds to a GPCR (Gq; raises intracellular calcium; some activation of PLA; may stimulate secretion of prolactin); TSH binds to receptors on the basolateral membrane of thyroid follicular cells (Gs)
Describe the structure of TSH.
glycoprotein (alpha chain is identical to other trophic glycoproteins produced by the anterior pituitary; beta chain is unique to TSH)
Describe negative feedback mechanisms associated with thyroid hormone.
5'/3'-monodeiodinase type 2-dependent (or requires plasma T3)
direct: inhibits the synthesis of the alpha and beta TSH genes (T3 response element in promoter); indirect: decreases number of TRH receptors
Does T3 cross the placenta?
Describe the synthesis of insulin.
gene on short arm of chromosome 11; transcribed as preproinsulin (cleaved to proinsulin in the lumen of the ER); excision of c peptide occurs in secretory granules (alpha and beta chain linked by disulfide bonds; associates with zinc); most of the secreted insulin is extracted by the liver (c peptide gets excreted in urine)
What are secretagogues for insulin?
glucagon, glucose, arginine and leucine amino acids, small keto acids, and hexoses (fructose)
How does glucose trigger insulin secretion from beta cells?
Glucose enters the Langerhan cells through GLUT2 transporter; glucose is metabolized (glucokinase is rate limiting step); closure of ATP-dependent potassium channel results in membrane depolarization; activates voltage-gated calcium channels; calcium influx followed by calcium induced calcium release from ER; exocytosis of insulin
What signaling pathways modulate insulin secretion?
CCK and acetylcholine through Gq g alpha protein; beta adrenergic, alpha adrenergic, glucagon, and somatostain through Gi/Gs g alpha protein
Does experimentally raising the extracellular potassium concentration increase insulin secretion?
What primes beta cells in the pancreas to secrete insulin?
acetylcholine from the vagus nerve during cephalic phase and incretins (GLP-1 and GIP)
Does beta adrenergic stimulation increase insulin secretion? alpha?
yes (mostly through epinephrine); no (mostly through norepinephrine)
What is the rationale for insulin signaling to be silenced during exercise?
Suppression of insulin secretion during exercise may serve to prevent excessive glucose uptake by muscle, which if it were to exceed the ability of the liver to produce glucose, would lead to severe hypoglycemia, compromise the brain, and abruptly end any exercise.
Describe the insulin receptor.
Where does insulin bind?
receptor tyrosine kinase; heterotetramer (two extracellular alpha chains and two membrane-spanning beta chains; two chains joined by disulfide bonds; synthesized as a single polypeptide that is later cleaved)
cysteine residues on alpha chain
What are downstream signaling molecules of the insulin receptor?
insulin receptor substrates (IRS molecules) and SH2 family proteins (Src domain)
PI3K phosphorylates a membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP 2 ) to form PIP 3 (leads to major changes in glucose and protein metabolism): Both phosphorylated SHC and activated GRB2 trigger Ras signaling (MEK and MAPK)
phosphorylates glycogen synthase; recruits GLUT4; suppresses FOXO1 transcription to inhibit gluconeogenesis (metformin)
Can insulin stimulate the IGF-1 receptor?
Yes (at high concentrations)
What happens to the insulin receptor in cases of hyperglycemia?
hyperglycemia decreases receptor synthesis and increases receptor degradation (decreases sensitivity or insulin resistance);
In cells from the type 2 diabetic, a maximum response to insulin is reached, but only at a much higher insulin concentration
What is the effect of insulin on the liver?
glycogen synthesis, glycolysis, lipogenesis, and protein synthesis
What is the effect of insulin on muscle?
increases glucose uptake by recruiting GLUT4 transporter; promotes glycogen synthesis through activation of glycogen synthase; promotes glycolysis and subsequent carbohydrate oxidation through activation of hexokinase, phosphofructokinase, and pyruvate dehydrogenase); also promotes protein synthesis
What is the effect of insulin on adipocytes?
increases glucose uptake by recruiting GLUT4 transporter; promotes glycolysis and formation of alpha-glycerol phosphate; promotes fatty acid synthesis; inhibits hormone-sensitive lipase and increases synthesis of lipoprotein lipase (exported to endothelial cell)
What is the major target tissue of glucagon? What is the major secretagogue?
liver; amino acids (glucose inhibits secretion)
Describe synthesis of glucagon.
chromosome 2; preproglucagon cleaved to proglucagon in RER; cleaved by proteases in alpha cells to active form (along with several biologically active byproducts)
Describe the glucagon receptor. What are downstream effector molecules and what is the result of this pathway?
Gs alpha protein (phosphorylates key enzymes);
peptide inhibitor 1, phosphorylase kinase (glycogen phosphorylase a), and PPARgamma;
inhibits glycogen synthase (activating glycogen phosphorylase and G6Pase); promotes gluconeogensis (reduces activity of glucokinase, phosphofructokinase, and pyruvate kinase; increases transcription of PEPCK, FBPase, and G6Pase); oxidation of fatty acids (inhibits activity of acetyl coA carboxylase indirectly promoting CAT1 activity)
Describe the structure of somatostatin.
14 and 28- amino acid peptide; biological activity reside in c-terminal 14 amino acids
How is iodine excreted from the body? Is thyroid hormone excreted?
first gets glucoronoated and then excreted by the kidney
bound thyroid hormone is not readily excreted
Describe the daily profile of TSH release.
sequence of peaks
Describe the effects of TSH.
iodide trapping (activity of NIS); stimulates iodination of thyroglobulin; stimulates conjugation, endocytosis, and proteolysis; stimulates secretion; acts as a growth factor to increase cell number and cell size (as well as stimulates follicle formation)
glucose oxidation and NADPH generation (DNA, RNA, protein and phospholipid synthesis)
What are intermediate products of iodinated thyroglobulin?
MIT and DIT (recirculate from secretory vesicles to the luminal space)
rapidly deiodinated (provides twice as much iodide for hormone synthesis as the iodide pump)
What amino acid is thyroid hormone derived from?
What happens to metabolism of thyroid hormone with caloric restriction or severe stress?
inhibition of type 1 deiodinase (kidney, liver, thyroid)
net effect is decline in metabolic rate
What are the metabolic effects of thyroid hormone?
skeletal muscle growth (co-associated with GH); maturation of the CNS (myelination, axonal density, and dendritic branching); increased activity of sympathetic nervous system; thermogenesis (sweaty palms)
Which organs do not increase oxidative metabolism through thyroid hormone signaling?
brain, spleen, testes
accelerated metabolism (warm skin), tremor, increased sweating, increased pulse pressure, pre-hypertensive state, increased production of binding proteins for sexual hormones (weight loss; women may be present with amenorrhea)
mental retardation, decreased metabolism (cold skin), altered cardiac function, myxedema, and amenorrhea (female reproductive syndrome)
decreased amplitude of ECG due to pericaridal effusion; goiter; moon facies
How does pendrin deficiency present on perchlorate test?
a pendrin deficiency presents as a steep drop in iodide intake as the iodide builds up in the follicular cytosol and is transported back into the blood
What is the effect of propylthiouracil on thyroid hormone? fluoride?
Propylthiouracil blocks iodination of thyroglobulin
Fluoride affects the normal deiodination of T4 (reaction favors production of reverse T3)
Is thyroid cancer more common in men or women? older or younger population?
younger women (hereditary transmission; not necessarily neoplastic)
What does the presentation of high TSH and low T4 suggest?
primary hypothyroidism (check antibodies; may be Hashimoto thyroiditis)
What does the presentation of low/normal TSH and low T4 suggest?
secondary hypothyrodism (test be administering TSH or TRH)
Describe glucose metabolism following a carbohydrate meal.
Following primarily a carbohydrate meal, glucose not converted into glycogen in the liver is converted to glycogen and protein in muscle and converted to triglycerides in adipose tissue
What is the concentration of glucose required by the central nervous system?
Which metabolic pathways are activated during fasting?
glycogenolysis and gluconeogensis (hepatic)
Is plasma glucagon concentration higher in the fed or fasting state?
Is glucagon receptor expressed on skeletal muscle?
Describe GLUT2 transporter
allows inflow and outflow of glucose; insulin independent; expressed on liver and pancreatic beta cells
Does insulin affect amino acid metabolism?
yes; stimulates absorption of amino acids by muscle
What increases insulin secretion?
Glucose, proteins, ketoacids, free fatty acids, potassium, calcium, glucagon, GLP-1, GIP, secretin, CCK, vagal activity (acetylcholine), beta adrenergic activity, and sulfonylureas
What decreases insulin secretion?
Fasting, exercise, somatostatin, galanin, IL-1, alpha-adrenergic activity, and prostaglandin E2
Is insulin present in the fasting state?
How does PKA affect calcium channels? What tissue is this relevant for?
PKA phosphorylates and actives L-type calcium channels (similar mechanism occurs in cardiac muscle)
promotes transcription and translation of insulin
Does glucagon decrease the concentration of circulating amino acid?
No; amino acids absorbed through the gut are used for gluconeogenesis
Low circulating insulin induces protein breakdown in the muscle
What happens to pancreatic beta cells following loss of insulin?
atrophy (insulin is a trophic factor)
What are causes of obesity?
type of diet (high fat);
basal metabolism (Increased UCP results in increased energy expenditure (less storage of fat as the oxidative molecules are used to generate heat instead));
types of hormones, cytokines, and adipokines (leptin regulates hunger; ghrelin stimulates food intake; CCK inhibits food intake; Peptide YY inhibits food intake; activation of NPY increases food intake)
quantity of sleep (Increased sleep duration increases leptin signaling and decreases ghrelin signaling)
microbiota: Losing healthy microbiota decreases body fat storage (accompanied by lower leptin, insulin, and glucose levels)
Is ghrelin signaling decreased by gastric bypass? weight loss by reducing calories?
Is not having fat advantageous?
No; insulin resistance
UCP-1 short circuits the proton circuit and oxidative energy is dissipated as heat instead of ATP production
Genetics is a factor in determining the basal level of UCP transcription and the response to stress such as increased fat diet
Describe the Randle hypothesis.
What prevents this phenomenon?
availability of free fatty acids for oxidation by muscles and other tissues may lead to impairment of carbohydrate oxidation and lead to glucose intolerance as is seen in obesity and obese diabetics
During fasting, the glycerol 3-phosphate comes from a modified gluconeogenesis pathway called glyceroneogenesis; increased PEPCK
What is the difference between brown adipose tissue and white adipose tissue?
Brown adipose tissue has many mitochondria (thermogenesis)
BAT found in subscapular region
shared developmental pathways
Describe the function of each adipokine.
Leptin can signal to the brain to regulate food intake and can impact fatty acid oxidation in muscle
adiponectin activates AMP kinase (increased fatty acid oxidation), decreases gluconeogenesis, may upregulate GLUT4 translocation
resistin deficiency increases body weight, body fat, decreases energy expenditure, but paradoxically improves glucose sensitivity
How adipokines are altered by obesity?
decreased adiponectin; increased leptin and resistin; increased circulating free fatty acids, TNF-alpha, and IL-6
What is the effect of leptin on muscle?
Leptin causes the phosphorylation of AMP kinase, which in turn phosphorylates ACC, inactivating it; Leptin thus inhibits malonyl coA synthesis, leading to greater mitochondrial import and consumption of fatty acids (beta oxidation)
Does TSH stimulate iodide secretion into the colloid?
Where is the major fraction of T3 in the body?
in the nonthyroid tissues
What substances does the pancreatic beta cells secrete?
insulin, proinsulin, c-peptide, and amylin
Does insulin affect the intestinal absorption?