Endocrine Exam 410B Instruction 4-5
3 forms of calcium in plasma
1. Free ionized calcium ( Ca2 + ) , 45 % free ( in plasma ) 2. Protein - bound calcium 3. Calcium complexed with citrate or oxalate
Vitamin D is a vitamin , Can be obtained from the diet
1. Vitamin D₂ - vegetables 2. Vitamin D3 - the liver of fishes like cod and halibut , eggs , fortified milk and bread
calbindin effect
1.Buffer cytosolic Ca² + to keep favorable Ca² + -gradient 2.Allows cell to absorb large amounts of Ca² + , while keeping free cytosolic [ Ca2 + ] low
Hypercalcemia of Malignancy (2)
1.Local osteolytic hypercalcemia 2.Humoral Hypercalcemia of Malignancy
Vitamin D intoxication
1.vit D synthesis by lymphomas or Vit D overdose 2. - 100,000 Units / day is required to produce hypercalcemia
Parathyroid Glands Location
4 pea shaped glands on surface of thyroid gland( posterior side)
Other regulators of insulin release :
Amino acids Neural factors ( acetylcholine ... ) iii.ß - adrenergic receptors iv.a - adrenergic receptors v.Exercise Feeding
The parathyroid gland is ______________, not _________________ related to the thyroid gland .
Anatomically, not functionally
How vitamin D enhances Ca² + absorption via transcellular pathway in duodenum
Ca2 + enters cell via Ca² + channels Ca² + binds to several binding proteins , particularly calbindin Ca² + is transported across basolateral membrane by Ca² + pump : Na - Ca exchanger
Vitamin D deficiency rickets
Chikdhoodmbone disorder- low mineralization of bones- vit D disorder Several years of very low dietary intake is required before deficiency develops
Parathyroid Glands
Composed of chief cells that synthesize and secrete parathyroid hormone ( PTH )
PTH fragments: N - terminal
Contains all biological activity and Rapidly hydrolyzed
What is major source of calcium
Dairy products(diet)
Glucose is transported into ß - cells via
GLUT2 transporters
__________stimulates insulin release from B - cells .
Glucose
Parathyroid - independent Hypercalcemia (2)
Hypercalcemia of Malignancy and Vitamin D intoxication
Calcitonin __________ bone resorption
Imhibits
Insulin synthesized as a pre - prohormone
In trans - Golgi , proteases cleave C peptide to form insulin ( A , B ) . Insulin ( B , A ) is the A - peptide linked to the B - peptide by bisulfide bonds Insulin ( A , B ) , proinsulin ( B , C , A ) , and C peptide are packaged into secretory vesicles .
Two ways vitamin D increases calcification of bone
Indirect: increased absorption of Ca² + in intestine and kidney Direct: mobilize Ca² + out of bone 2.promote development of osteoclasts from precursor cells 3.stimulate osteoblasts to produce alkaline phosphatase collagenase , plasminogen activator
PO4 3- and 1 , 25- ( OH ) ₂D _______ 1a - hydroxylase
Inhibit
PTH ________ synthesis and secretion of OPG from osteoblasts
Inhibits
C peptide is a good measure of insulin secretion because
Insulin removed by liver, C peptide is not
PTH fragments: C - terminal
Long half life and Complicates measurements of PTH release .
Familial Hypercalcemic Hypocalciuria ( FHH )
Mild hypercalcemia caused by loss of function mutations of the Ca² + sensing receptor ( CASR )
Will Vitamin D stimulate phosphorylation of the NaPi ?
NO
3 types of bone cells
Osteoblasts, Osteocytes, Osteoclasts
Bone Resorption by the Osteoclast
Osteoclasts move along surface of bone and secrete acids into lacuna that provide optimal conditions for the action of lysosomal proteases to dissolve bone
Actions of Vitamin D on Bone
Overall effect of Vitamin D is to increase calcification of bone .
Calcium inhibits VitD by inhibiting ___
PTH
How PTH inhibits PO4³- reabsorption mainly in proximal tubules
PTH causes NaPi cotransporters to be sequestered within endocytic vesicles , delivered to lysosomes where they undergo proteolysis
Process of bone remodeling by osteoclasts and osteoblasts
PTH stimulates osteoblasts to secrete RANK ligand and Macrophage colony stimulating factor ( M - CSF ) RANK stimulate osteoclast differentiation and osteoclast activity M - CSF induces stem cells to differentiate into osteoclast precursors , mononuclear osteoclasts , and mature multinucleated osteoclasts .
How PTH stimulates Ca² + reabsorption in the distal tubules
PTH stimulates the insertion and opening of the apical Ca² + channel, Ca² + binds calbindin, Ca² + is transported out of the cell by a Na / Ca exchanger
Hypercalcemia types
Parathyroid - dependent , Primary Hyperparathyroidism ( parathyroid adenoma Excess PTH - is most often due to parathyroid adenomas 75 80 % Familial Hypercalcemic Hypocalciuria ( FHH ) .
major organ governing calcium homeostasis
Parathyroid gland
primary regulator of PTH secretion
Plasma Ca² + is the primary regulator ( inhibits ) Plasma Ca² + activates a calcium - sensing receptor ( CaSR ) in the membrane of chief cells in parathyroid gland . CaSR is a GPCR -- > Gaq -- > PLC -- > IP3 -- > Ca² +
Synthesis of Insulin Proinsulin
Preprohormone/ coded for by a single gene on human chromosome 11/ stimulated when ß cells of the pancreatic islet are exposed to glucose
PTH Receptor
Receptor binds the PTH 1R receptor most abundant on kidney ( proximal and distal convoluted tubules ) and bone ( osteoblasts )
Other hormones affect bone
Sex steroid and Glucocorticoids
Parathyroid Hormone - Related Peptide ( PTHRP )
Similar actions as PTH , same receptor . Made in Lactating breast Squamous cell tumors of the lung , head , and neck ; renal and bladder carcinomas ; adenocarcinomas ; and lymphomas
Role of Vitamin D.
Stimulate Ca² + absorption from the intestine, Stimulate Ca² + absorption from the kidney, Regulate bone resorption and formation, Repress transcription of PTH
PTH ___________ the activity of la - hydroxylase .
Stimulates
RANK ligand _________ bone resorption
Stimulates
Hypercalcemia
Symptoms : confusion , polydypsia ( increased thirst ) , polyuria ( increased urination ) , constipation , nausea , vomiting demineralization Formation of kidney stones
How Sex steroid hormones effect bone
Testosterone and estradiol maintain bone mass .
glycogen synthesis
The process of making glycogen
NaPi function :
Transports sodium with phosphate molecules
Binding of ________ inhibits transcription of the PTH gene .
Vitamin - D / RXR
2.Humoral Hypercalcemia of Malignancy
a.tumors that secrete PTHrP b.usually only very advanced malignancies produce hypercalcemia
Hypercalcemia of Malignancy 1.Local osteolytic hypercalcemia
a.when malignancy invades bone , produces cytokines that stimulate osteoclasts to break down bone releasing calcium
How does insulin affect glycolysis?
activate pyruvate kinase and glucokinase to promote Glycolysis
Osteocytes
are derived from osteoblasts , transfer mineral from the interior to growth surfaces
gain of function mutations in CASR result in
autosomal dominant hypocalcemia ( OMIM )
Calcitriol ( 1,25- ( OH ) ₂D3 )
biologically active form of VitD .
Most calcium is located in
bone
What is the net effect of Continuous PTH secretion
bone resorption
PTH stimulates both bone ___________ and bone ____________
bone resorption and bone formation
What do you parafollicular cells(C cells) in the thyroid gland secrete
calcitonin
PTH storage and circulation
cleaved into 2 fragments N - terminal and C - terminal
Glycolysis
conversion of glucose to pyruvate ( can be used in citric acid cycle to produce energy in the form of ATP )
PTH stimulates osteoblasts _________ and osteoclasts __________
directly and indirectly
Actions of Vitamin D in the small intestine and kidney : calcium absorption
does not regulate passive pathway of Ca² + absorption ( paracellular ) enhances Ca² + absorption via transcellular pathway in duodenum stimulates transcription of Ca² + channels , Ca 2+ pumps , ATPase and Ca2 + binding proteins
PTH 1 Receptor ( PTH1R ) cell signaling
exhibits dual intracellular signaling ( Gas Gaq )
Gluconeogenesis
formation of glucose from the breakdown of pyruvate
mutation causes severe hypercalcemia
homozygous mutation
la - hydroxylase
hydroxylates Vitamin D2 smd D3 in the liver and kidney to make active forms
PTH Receptor cell signaling
ii.PTHIR exhibits dual intracellular signaling 1.Gas -- > AC -- > CAMP -- > PKA ( primary signaling pathway ) 2.Gaq -- > PLC -- > IP₂ / DAG -- > PKC increase plasma
mild hypercalcemia elevated
ii.heterozygous mutation ( autosomal dominant )
Net effects of PTH signaling cascades are to
increase plasma Ca² + ] and decrease plasma [ phosphate ]
Insulin promotes glycogen synthesis by
increasing activity of glycogen synthase and inhibits glycogenolysis by decreasing activity of glycogen phosphorylase
GLUT2 transporters are insulin
independent
v.Exercise
inhibi insulin releas
iv.a - adrenergic receptors
inhibit insulin releas
Intracellular Ca2 + __________ PTH synthesis and secretion
inhibits
Calcitonin effect
inhibits bone resorption/Minimal contribution to calcium regulation Important in fish for dealing with high [ Ca² + ] in sea water important in uterus for implantation of the conceptus
Glycogen phosphorylase is dephosphorylated due to
insulin signaling
Glycogen synthase is inactive dephosphorylated due to
insulin signaling
OPG ( osteoprotegerin ) =
member TNF receptor family/ secreted by osteoblasts and blocks binding of RANKL to RANK
C peptide
no known biological activity Secreted with insulin
heterozygous mutation ( autosomal dominant ) levels
normal PTH levels , but elevated serum Ca² + levels , reduced urine Ca² + levels
Vitamin D Receptor ( VDR )
nuclear receptor which heterodimerizes with the retinoic acid receptor/ binds D3 with much higher affinity than D2
Which bone cell type has PTH receptor
osteoblasts
Calcitonin
peptide hormone / Produced by parafollicular cells ( C cell ) of the thyroid gland in response to elevated [ Ca² + ] .
Parathyroid hormone
peptide hormone/ synthesized as a pre - prohormone/ circulates as free hormone
glycogenolysis
process of breaking glycogen down into glucose
Osteoblasts
promote bone formation .
How Glucocorticoids affect bone
promote bone resorption
Osteoclasts
promote bone resorption located on growth surfaces of bone
Oxyphil cells
release PTHrP (PTH-like factor)
Osteoclasts resorb bone which does what?
releasing Ca2 + and phosphate
Tumors producing PTHRP will result in..
severe hypercalcemia
Vitamin D
steroid hormone/ Can be synthesized from 7 - dehydrocholesterol in the skin - requires UV radiation ( Vitamin D3 )
iii.ß - adrenergic receptors
stimulate insulin releas
Effects of PTH on the Kidney
stimulates Ca² + reabsorption in the distal tubules exchanger, inhibits PO4³- reabsorption mainly in proximal tubules, activate a - hydroxylase to produce the active form of Vitamin D ( VitD )
Feeding
stimulates insulin release before ingestion
Actions of Vitamin D in the Small Intestine and Kidney : phosphate absorption
stimulates phosphate absorption Stimulates transcription of Na / phosphate ( NaPi ) cotransporter This is the rate - limiting step for delivery of phosphate into the circulation
RANKL is a member of the
tumor necrosis family