ASCI 442 Unit 2 Notes

Thyroid, Parathyroid, Melanocortins, Pancreas

TRH

thyrotropin releasing hormone

from the hypothalamus

7TM Gs or Gq 

TSH

thyrotropin stimulating protein

from the anterior pituitary

7TM Gs

thyromegaly

enlarged thyroid, increased TSH, decreased T3 and T4

thyroid gland/hormone effects

cellular differentiation and development

metabolic pathways

synthesis and release of TSH

stored in secretory granules

carbohydrate added in golgi

release regulated by H

lesions in median eminence block release

stimulation of preoptic area causes release

estrogen stimulates release

SST and T3/T4 inhibit

TSH, LH, FSH, and hCG have same alpha subunit and distinct beta subunit

secondary responses of TSH

increase cellular uptake of iodine

synthesize thyroglobulin, iodotyrosine, iodothyrosines

proteolysis of thyroglobulin

thyroid gland

TSH receptors - estrogen stimulates synthesis of the receptor, T3 and T4 inhibit receptor synthesis

function unit → follicle → secretory cells

C cells - parafollicular cells secrete calcitonin

calcium homeostasis

Goiter

enlarged thyroid, case for iodized salt

T3 and T4 made from

2 tyrosine (from thyroglobulin)

3 or 4 iodine

thyroglobulin 

allows for storage of hormones for up to 2 months

tyrosine coupling

Na+/I- symporter brings iodine into cell

Na+/K+ ATPase pump maintains Na+ gradient (out→in)

iodine must be at higher ocidative state for coupling, oxidized by thyroid peroxidase (PTO) H2O2 system, glucose regulation for NADPH production

endocytosis upon TSH → clipped off thyroglobulin → free T3/T4 secreted into the blood

excess iodine

iodoaldehydes with in the thyroid

Wolff-Chaikoff effect

impairs TPO leading to decreased T3 and T4 transient (1-2 d)

T3/T4 transport

serum levels: T4 70x > T3

half life: T4 - 7d; T3 - 1d

99% bound to proteins in circulation 

• thyroxine binding globulin

• albumen (lower affinity)

diffuse through membranes

free hormone carrient into cell via carrier proteins (MCT8)

nuclear receptor → ligand modulated transcription factor

T3 receptor in liver and kidney

binding highly correlated with synthesis of GH (synergistic effects)

Thyroid hormone regulation of differentiation and growth

brain, cartilage, lungs, regulation of GH and PRL

metabolism: O2 consumption, mineral balance, CHO/lipid/protein metabolism

cardiovascular - heart rate and output

hepatic synthesis of vitamin A

increased intestinal glucose absorption

hypothyroidism

deficiency of synthesis and secretion of thyroid hormones

cause

• absence of thyroid gland

• pathological destruction of thyroid gland

• insufficient secretion of thyroid hormones - elevated TSH

compensatory goiter: weakness, dry/coarse skin, lethargy, edema, cold, infertility, constipation, weight gain, impaired memory

Hashimoto’s Thyroiditis

autoimmune attack of the thyroid gland

increased TSH

10x more common in women

Hyperthyroidism

toxic goiter (Grave’s disease): autoimmune attack of thyroid gland, enlarged eyes

increased basal metabolic rate, cardiac output, temp, food intake, GI activity, diarrhea → weight loss

T3 and T4 biosynthesis

iodine transport

oxidation → Tyr

coupling

storage (colloid 2 mo)

endocytosis (induced by TSH binging to 7TM Gs) 

lysis

released into circulation

mechanism of action of T3 receptor

nuclear receptor

binds to TRE sequence of DNA

homo- or hetero-dimer

different forms of TR expressed through development

Thyroid hormone receptors

TRa1 - binds T3, DNA binding, heterodimer formation

TRa2 - does not bind T3, DNA binding, weak heterodimer formation

TRB1 - binds T3, DNA binding, heterodimer formation

TRB2 - binds T3, DNA binding, heterodimer formation

NO T3 = co-repressor (CoR) inhibits transcription

T3 binding = activation of transcription

Grave’s disease

fatigue, restlessness, tachycardia, weight loss despite eating, GI issues, increased temp

TSH low, thyroid enlarged

autoimmune - antibodies stimulate TSH receptor

hyperthyroidism

treat with antagonist for TSH receptor or T3 receptor

Calcium importance

muscle contraction, neurotransmission, cell signaling, skeletal support, coagulation enzyme and hormone regulation, exocytosis (secretion of hormones), mitosis

Ca and P

two most abundant elements

Ca transport

Ca typically bound

sequestered in mitochondria and ER

movement across membranes via channels and ATPase pumps

Calcium binding proteins

Troponin C - striated muscle

Parvalbumin - muscle

S-100 protein - nervous system, melanocytes

Vitamin D-dependent CaBP - cartilage, bone, teeth

Vitamin K-dependent CaBP - osteoblasts

Calmodulin - ubiquitous binding protein in all animals and plants

Ca regulated by

parathyroid - releases PTH in low Ca levels

kidney - regulates excretion of Ca and vitamin D

bone - bone mineralization, major source of Ca

PTH axis

parathyroid Ca receptor (CaSR)

7TMGPCR (Gi)

activation of PLC system through binding of Ca to CaSR to inhibit transcription of gene for PTH

low/no Ca → inhibition removed and PTH genes transcribes

parathyroid hormone (PTH)

produced and secreted by parathyroid gland

synthesized in pre-pro form → 84 aa

regulated by changes in [Ca] 

decreased Ca → increased PTH synthesis/secretion

secretion - fusion of secretory granule and exocytosis

parathyroid hormone related protein (PTHrP)

similar structure to PTH

works in similar manner, back up, in multiple tissues, 7TMGPCR

PTH mechanism to increase Ca

increased PTH → osteoblasts → produce RANKL → activate osteoclasts → breakdown bone

calcitonin

thyroid C-cells produce

inhibit action of osteoclasts and pre osteoblasts→osteoclasts

small effect compared to PTH

RANKL binding

estradiol and OPG (binding protein) - bind RANK L

estradiol protects bone by making OPG

PTH-R 

7TMGPCR (Gs & Gq) 

cause production of RANKL by osteoblasts, make pre osteoclasts from precursor cell

PTH action

direct in bone and kidney

bone - osteoblasts → RANKL → maturation of osteoclasts

kidney - formation of avtive vitamin D, increase Ca reabsorption, increased PO4 excretion

indirect: SI via vitamin D → increases Ca absorption

Bone cells

osteoblasts - build up bone

osteoclasts - break down bone

PTH on kidneys

cAMP

Ca reabsorption in distal tubules

increased PO4 excretion - proximal tubule, don’t want PO4 to increase with Ca

increased activity of a1-hydroxylase to form active vitamin D (1,25(OH)2D3)

Calcitonin

Gs

secreted by thyroid C-cells/parafollicular cells

protein with extreme PTM

regulation of secretion

• slight increase in Ca → increase in calcitonin secretion

• gastrin, secretin, cholecystokinin and glucagon stimulate release (anticipatory)

  • SST inhibits calcitonin

calcitonin in bone

inhibits resorption of Ca by osteoclasts

may not affect bone formation but protects bone mass

calcitonin in renal cortex

renal tubules have receptors

increase urinary excretion of Ca, PO4, Na, K

actions of vitamin D

increased Ca reabsorbtion in gut

bone formation and resorption

Ca reabsorption in kidney

intestine: increase permeability of SI to Ca

bone: mobilization of Ca

kidney: increased reabsorption of P and possibly Ca

muscle: increased muscle tone and contraction through Ca flux

DBP - binding protein

cholecalciferol → hydroxylated in liver and kidney → calcitriol (active)

melanocortin origins

cleaved from POMC

prohormone convertase

PC 3/1, PC2

melanocortins

ACTH, alpha MSH, beta MSH, gamma MSH

protein hormones

melanotrophs, intermediate pituitary in color changing species and brain in mammals

PC1/3

endopeptidase found in anterior pituitary corticotrophs

in golgi of cells and packaged in pro-hormone form into endocytotic vesicles with prohormone

POMC cleaved into ACTH, beta LPH and other peptides - also found in different parts of hypothalamic nuclei that produce alpha MSH

PC2

endopeptidase found in brain and pancreatic islet cells

in the brain, ACTH is further cleaved to alpha MSH and CLIP, and beta LPH is digested into gamma LPH and beta endorphin

carboxypeptidase E (CPE)

cleaves carboxyl end of protein

melanocortin receptors

5 receptors, 7TMGPCR (Gs) (some Gi some Gq)

MC1R, MC2R, MC3R, MC4R, MC5R

always need ACTH but a,b,y, MSH are interchangeable for most part because MC2 only binds ACTH

MC1R

a=B=ACTH>y

agouti - antagonist

pigmentation, anti inflammatory

MC2R

binds ACTH only

Agouti - antagonist

glucocorticoid production, stress-induced lipolyis

MC3R

a=B=ACTH=y

AgRP - antagonist

energy homeostasis, anti inflammatory, pro-inflammatory cytokine release

MC4R

a=B=ACTH>y

AgRP, agouti - antagonist

body weight regulation, pain processing, grooming, sexual behavior, penile erections

MC5R

a=B=ACTH>y

agouti - antagonist

natriuresis, sebum secretion, preputial lipogenesis

functions of genes in POMC prepro-polypeptide

mutations in POMC gene affect coat color and cause obesity

a-MSH binds to MC1R to act on skin and MC4R to regulate obesity

• agouti overexpression antagonizes aMSH in skin → yellow coat

• AgRP overexpression antagonizes aMSH in H → obese phenotype

aMSH regulates skin pigmentation - chameleons via reflection of light off light/dark background on retina (dark increases aMSH release from IP)

aMSH affects melanocytes to alter skin color/pigmentation

receptor downregulation

signal attenuation: B arestin → receptor engulfed in vesicle → ribosome phosphatase removes ligand → receptor to lysosome or back to plasma membrane (determined by protein on c-terminal)

MC2R actions

in adrenal gland, binds ACTH and stimulates zones of cortex

• zona fasciculata - glucocorticoids

• zona glomerulosa - mineralocorticoids

also in adipocytes and mediates lipolytic effects of ACTH

MC4R actions

regulation of feed intake/appetite → suppresses appetite

KO mice results in obesity with human adolescents that have the mutation, they also have obesity in adolescence

hyperinsulinemia, diabetes (adult onset)

MC5R actions

closely homologous with MC4R, but mainly in peripheral tissues

KO mice - wetter in swin trial → less hair lipid production, water repulsion, thermal regulation

may be involved in release of pheromones

regulates aldosterone secretion

regulation of POMC

food restriction and weight loss - decreased POMC

increased feed intake - increased POMC

insulin and leptin - increased POMC

increased ACTH, a-MSH, B-MSH, y-MSH - decreased POMC

discovery of insulin

1921 - Banting and McLeod Nobel Prize

experiment in dogs - removing pancreas

purified insulin from bovine pancreas and transplanted into 14 yo boy'

insulin

protein hormone, synthesized as preproinsulin, varies across species

necessary for glucose homeostasis

stimulates glucose uptake by cells, stimulates glucose → glycogen in liver

pancreas

exocrine function aids in digestion (digestive enzymes)

endocrine function in islets of langerhans 

alpha cells, beta cells, delta cells, F cells

alpha cells (A cell)

20% of pancreatic cells

alcohol insoluble (large red) granules

located at periphery of islet

secrete glucagon

beta cell (B cell)

75% of pancreatic cells - most numerous cell type

alcohol soluble (brownish) granules

secrete insulin

delta cells (D cell)

pancreatic cell type fewest in number 

cytoplasm stains blue

secrete SST

F cells

secrete pancreatic polypeptide (PP)

proinsulin → insulin

cleaved by prohormone converting enzymes

biosynthesis of insulin

synthesized in B cell

preproinsulin synthesized in rER

pre sequence cleaved and disulfide bridges added → pro-insulin

proinsulin converting enzymes synthesized in ribosomes

proinsulin and converting enzymes enclosed in vesicles → cis Golgi → trans Golgi

clathrin coated vesicles pinch off and are rich in proinsulin

acidification (pH 6.5→5.5) of the vesicle induces activation of proinsulin converting enzymes

proteolysis of proinsulin and C-peptide

vesicles lose clathrin coat and mature into secretory granules rich in insulin

stored in cytoplasm until stimulated to undergo exocytosis by actions of glucose

biosynthesis of insulin (condensed)

B cells (rER) → prepro in vesicle with converting enzymes → cis/trans Golgi → proinsulin in clathrin coated vesicles → pH 6.5 to 5.5 → converting enzymes cleave proinsulin and vesicle loses clathrin coating → secretory granules stored in cytoplasm

control of insulin secretion

anabolic hormone, energy storage

stimulated for release by elevated blood levels of glucose, fatty acids, or amino acids

anticipatory signals - GI tract motility and stimulation by parasympathetic nerves

• activation of insulin by acetyl choline

  • presence of carbohydrate in intestine causes release of gastric inhibitory peptide which is an insulin secretagogue 

regulation of insulin secretion

intracellular regulators of insulin secretion are induced by metabolic products in B-cells

• calcium, cyclic nucleotides and products of phospholipids

metabolism of glc, FA, and some AA within the B-cell results in closure of ATP-sensitive K+ channels

• leads to depolarization of the cell and a consequent influx of Ca++ through voltage-sensitive channels

• calcium then induces the secretion of insulin

insulin receptor

receptor tyrosine kinase

2 glycoprotein subunits (heterodimer, 2 alpha + 2 beta)

insulin binds to alpha and signals through beta

cascade of phosphorylation and dephosphorylation (Ser & Thr)

2nd: IRS1 (docking protein) (phosphorylated by receptor)

events following insulin receptor binding

insulin internalized and degraded

receptors not degraded - recycled to membrane

actions on cells: increase rate of glucose uptake

seconds: binds receptor Tyr-Kinase activity

minutes: hexose transport, altered enzyme activity, gene regulation, receptor internalization and down regulation

hours: induction of DNA, RNA, protein, and lipid synthesis, cell growth, downregulate insulin receptor… long acting growth promoting through IGF-1 receptor

mechanism of insulin action

anabolic hormone: converts building blocks to “storage forms”

• glycogen, proteins, triglycerides

affects metabolism by altering substrate flow

• insulin stimulates the uptake of glucose within cells (recruitment of GLUT 4 transporters → increased rate of uptake)

• elevated levels of glucose-6-phosphate allosterically activates glycogen synthesis

• blocks and reverse effects of other hormones

  • activates phosphatases (de-phosphorylate)

  • reverses phosphorylation of proteins by cAMP-induced protein kinases

other regulators of insulin

hormones and neurotransmitters causing increase in insulin

gastrin, secretin, CCK, GIP

catecholamines inhibit secretion of insulin

ketoacidosis

severe deficiency of insulin

conversion of FFA to ketones for energy (liver) rather than using glc for energy

lowers blood pH

glucagon

29aa, linear peptide

produced by a-cells

elevate blood glucose levels

catabolic - antagonizes insulin - stimulates liver glycogenolysis

aided by epinephrine (EP)

EP and glucagon act by increasing cAMP (7TMGs)

Cortisol plays a complementary role (stimulates gluconeogenesis in liver)

GLP-1 and GLP-2

act like glucagon

GLP-1

• decreased glucagon

• increased insulin 

• increased somatostatin

• decreased gastric emptying

• increased sensation of satiety

• decreased appetite

GLP-2 (less known)

• increased blood flow

• increased mucosal growth

• decreased apoptosis

• increased nutrient transport

• decreased gastric motility

  • decreased intestinal permeability 

regulation of blood glucose

insulin (B-cells in response to low insulin) decrease blood glucose

glucagon (a-cells in response to low blood glucose) increase blood glucose

after a meal blood glucose rise above normal (80-90ng/100ml)

release insulin → bind receptors (increase glc transporters) → glc remove from blood and stored in muscle as glycogen → inhibits gluconeogenesis in liver

if blood glucose falls below 80ng/100ml

a cell’s release glucagon → degradation of glycogen and release of glucose into the blood

glucagon on liver

inactivates glycogen synthetase and activates phosphorylase a, which leads to an activation of glycogenolysis

increases activity of glucose-6-phosphate

enhances synthesis of glucose from pyruvate and lactate as well as amino acids, especially arginine and alanine → activates gluconeogenesis

glucagon on muscle

no response

glucagon on adipose

in large doses can stimulate lipolysis, under normal circumstances there is no effect

glucagon on pancreas

stimulates insulin secretion, particularly after intestinal absorption of amino acids

glucagon on brain

no response

insulin on liver

sufficient

• no effect on glucose uptake

• stimulates biosynthesis of hexokinase IV and activates glycogen synthetase

• promotes glycolysis and formation of ATP

deficient

• uptake of FFA and conversion to ketones

insulin on muscle

sufficient

• stimulation of glucose uptake

• stimulates biosynthesis of hexokinase II and pyruvate kinase

• stimulates glycolysis and formation of ATP

• increases muscle glycogen levels and creatine phosphate

deficient

• impaired blood glucose

insulin on adipose

sufficient

• stimulation of glucose uptake

• enhances glycolysis which makes available glycerol phosphate which enhances triglyceride synthesis

• inhibits lipase activity

deficient

• decreases triglyceride synthesis due to a lack of glycerol phosphate

• stimulation of lipolysis and release of FFA into the bloodstream

insulin on the brain

no direct actions of insulin

brain is dependent of blood glucose

osteoporosis

lack of estrogenm

metastatic bone disease

primary cancer that has metastasized to bone

Symptoms of Vitamin D deficiency

secondary hyperparathyroidism

osteopenia (bone loss)

fatigue, muscle and bone pain, muscle cramps and weakness, mood changes

symptoms of POMC deficiency 

early onset obesity → insatiable hunger

red hair, pale skin

hypoglycemia

adrenal insufficiency

treatment for POMC deficiency

Setmalenotide - MC4R, MC3R, and MC1R agonist, SQ injection

Glucocorticoid substitution - oral, not ACTH because it is a protein which would be more likely to elicit an immune reaction, since glucocorticoids are steroids they can diffuse through membranes

symptoms of GLP-1 medication

activates receptors on vagus nerves which slow peristaltic waves in the stomach → delayed gastric emptying

stimulates insulin secretion and decreases glucagon secretion

medications for Type II Diabetes

regulate blood glucose levels, lifestyle and weight management

metformin

GLP-1 agonis

orexigenic center

feeding and eating

AgRP, NPY

anorexigenic center

satiety

a-MSH, CART