Endo 3 Flashcards
what is Ca2+ important for?
- membrane stability
- neuronal transmission (depolarization threshold)
- bone structure/ muscle function
- blood coagulation
- hormone secretion
what is phosphate important for?
- cellular energy (ATP)
- nucleic acid backbone
- intracellular signaling pathways (activation/deactivation of enzymes)
- bone structure
what is worse- hypocalcemia or hypophosphatemia?
hypocalcemia- muscle tetany- depolarization threshold is lowered, becomes easier to depolarize membrane with less calcium in extracellular space
what often causes hyperphosphatemia?
a “crush” injury of soft tissue which releases phosphate (10x more phosphate than Ca2+ in soft tissue)
describe the Ca2+ and Pi in plasma
Ca2+ - 10 mg/dl- 50% ionized, 45% albumin-bound, 5% complexed (albumin levels can give idea of Ca2+)
Pi- 4 mg/dl- 84% ionized, 10% bound
2 main regulators of Ca2+ and what they target
- Parathyroid hormone (PTH)- bone, kidney
2. Vitamin D - bone, kidney, gut
where is most of Ca2+ stored in body?
99% in bone- is exchangeable pool
how many parathyroid glands and where do you have them? main cell and what do they do? second type of cell?
4, on top of the thyroid gland
- chief cell- synthesize PTH (parathyroid hormone)
- oxyphil cell
what is PTHrP ?
Parathyroid related peptide ; mimics action of PTH in bone and kidney (binds receptor just as well, despite dissimilar structure) ; has no role at all for Ca2+ regulation under normal conditions; produced by a lot of tumors
which part of PTH is active? what has the longest half life?
N-terminal; C-terminal (not indicative of real PTH In blood)
what are the two parathyroid receptors?
PTH 1R- bone and kidney- GPCR (what also binds PTHrP, un-cleaved peptide)
PTH 2R- doesn’t bind PTHrP, binds active form
net effect of PTH
increase plasma Ca2+ levels, decrease phosphorus
key characteristics of osteoblasts
- have PTH receptors
- important for mineralization of bone; will extrude Ca2+/Pi from interior of bone (stored in hydroxyapeptite crystals vesicles inside osteoblasts); promote mineralization (hardening of bone)
- derived from mesenchymal stem cells
osteoclasts
- derived from HSCs, make precursors, not mature/active until mononucleated cells come together to form a multi-nucleated cell
- do NOT express PTH receptors AT ALL
- all PTH actions are happening indirectly through osteoblasts
- important for breaking down bone
osteocytes
- bone matrix
- terminally differentiated from osteoblasts
- communicate with osteoblasts to shuttle ca2+ back and forth
steps of PTH action
1) PTH stimulates osteoblasts to release M-CSF
2) M-CSF acts on its two targets- HSCs to make more osteoclast precursors, and stimulates osteoblasts to secrete RANK-L
3) RANK-L binds to RANK on osteoclast precursors, activating them to mature status
4) mature osteoclasts secrete hydrolytic enzymes which dissolves bone mineral and hydrolyzes bone matrix - releasing Ca2+ and Pi to systemic circulation
5) osteoblasts export Ca2+ and Pi into the extracellular space for bone mineralization - important for plasma homeostasis
what binds up RANK-L to keep it from activating RANK on osteoclast precursors? what inhibits/activates it?
OPG
inhibited by cortisol
activated by estrogen
what are the actions of PTH on the thick ascending limb of the kidney?
1) stimulates CYP1alpha to encode 1 alpha hydroxylase which converts 25-OH-vit D to its active from (1,25-(OH)2-vit D
2) stimulates Ca2+ channel insertion into apical membrane of distal tubule
what is the relationship between serum calcium and serum PTH?
low Ca2+, high PTH
three places that have the calcium sensing receptor
1) chief cells of parathyroid gland
2) kidney tubules
3) C-cells that secrete calcitonin in thyroid
what two actions does ca2+ on CaSr in the parathyroid gland have?
1) inhibits transcription of PTH
2) breaks down PTH already made
what two actions does Vit D in the parathyroid gland have?
binds nuclear receptor (VDR) to
1) inhibit the synthesis of PTH
2) stimulate the transcription of CaSR
calciferol, cholecalciferol, calcidiol, calcitriol
- calciferol- all types of vitamin D
- cholechalciferol- vitamin D3- specifically from animal tissues/human skin; low affinity to receptors
- calcidiol- 25-hydroxy-cholecalciferol (affinity for receptor is lower)
- calcitriol- 1, 25-dihydroxy-vitamin D (activated by 1 alpha hydroxylase (activated by PTH))
3 targets of vitamin D
bone, gut, kidney
what does vit D do in bone
bone- osteoblasts and osteoclasts have VDRs; primary role is bone mineralization; VIT D breaking down old bone at expense of making new bone
what does vit D do in gut
- increases transcellular Ca2+ absorption in duodenum by
stimulating synthesis of Ca2+ channels and calbindin (controls free ionized Ca2+ levels inside cell) - stimulates Pi reabsorption from small intestine
what does vit D do in bone
bone- osteoblasts and osteoclasts have VDRs; primary role is bone mineralization (none= rickets); VIT D breaking down old bone at expense of making new bone
what is osteoporosis?
- reduced bone density caused by glucocorticoid therapy, menopause, genetic, low Ca2+
what is hyperparathyroidism?
- over activation of parathyroid gland due to hyperplasia/cancer/kidney failure (reduced vitamin D)
- causes hyper-calcemia amd kidney stones
what does hypoparathyroidism cause?
- hypocalcemic tetany
- Chvostek sign- twitching of facial muscles in response to tapping the facial nerve
what is rickets?
get unmineralized bone (soft bone) b/c you don’t have enough vitamin D, causes bowing of the legs (called osteomalacia in adults)
- get widened epiphyseal plates
what is pseudohypoparathyrodism?
- defect in G-protein associated with PTHR
- have low calcium, high PTH, high phosphate
- also affects TSH, LH, FSH
parameters that change with PTH infusion
1) plasma Ca2+ rises
2) plasma Pi falls
3) tubular reabsorption of phosphate falls (TPR)
4) urinary hydroxyproline increases (enhanced bone resorption)
T/F Remove c-cells (calcitonin secreting cells in thyroid), you affect calcium levels in blood
false, but does inhibit osteoclast reabsorption
Is the pancreas a part of an endocrine axis? What makes up the endocrine pancreas?
- NOT part of axis
- 3 major cell types clutered into groups- islets of langerhans- that don’t secrete into pancreatic duct
3 major cell types of endocrine pancreas
beta cells- 75%- synthesize and secrete insulin (“beta cell mass”)
alpha cells- 25%- synthesize and secrete glucagon
delta cells- 5%- synthesize and secrete somatostatin
major and minor pancreatic hormones
insulin- anabolic hormone
glucagon- catabolic hormone- get glucose back into blood
somatostatin
amylin (same vesicle as insulin)
pancreatic polypeptide
ghrelin
arrangement of alpha and beta cells in humans
alpha cells- glucagon- on outer edges, line capillaries
beta cells- insulin- in the middle (“the core”)
describe how blood flow in pancreas alters hormone secretion
- arteriole feeds center of islet where the beta cells out, blood flows out
- beta cells making insulin which will directly impact glucagon on outside (glucagon has no direct action on beta cell to inhibit insulin)
describe the insulin gene; which part is insulin?
- signal- B chain- C chain- A chain*
- insulin is A and B peptide folded together
- without cleavage of C chain, insulin cannot bind receptor
- C peptide secreted with insulin, is good indicator of pancreatic function (is pancreas able to secrete insulin?)
Steps for insulin release from pancreatic beta cell
1) glucose outside beta cell transported in by GLUT2
2) glucose phosphorylated by glucokinase, g6p metabolism generates ATP
3) increased ATP closes K+ channels (SUR subunit), K+ stays in cell
4) cell depolarizes, opening voltage gated Ca2+ channel
5) vesicles exocytose
What other pathways potentiate insulin release?
1) AAs & FAs can give more ATP to close K+ channel
2) GLP-1 receptor uses PKA pathway to potentiate Ca2+
3) catecholamines inhibit GLP pathway via alpha-adrenergic receptors
how in what pattern is inulin released? how is impacted by type 2 diabetes?
- biphasic release
- first phase- an immediate spike (insulin docked and ready to go)
- second phase- glucose still being elevated as you digest food (stored & synthesized)
type 2 diabetes - bunted first phase, no second phase
whats special about insulin receptors?
- are tyrosine kinases, have intrinsic catalytic activity
- insulin binds to alpha subunit
- beta subunit is autophosphorylated & recruits IRSs (insulin receptor substrates)
two responses of muscle cells to insulin
1) PI3K pathway (PIP/PKB/small G protein)- inserts glut4 into membrane, mediates insulins metabolic effects
2) MAPK pathway mediates mitogenic (growth) effects
what is the only GLUT that is insulin dependent and which tissues is it found in?
GLUT4
muscle/fat
which GLUT is important for regulating insulin release? where else is it found?
GLUT 2
pancreatic beta cells, liver, intestines, kidney
what is the only GLUT that is insulin dependent and which tissues is it found in?
GLUT4
muscle/fat
where most of glucose goes/what causes hyperglycemia
which GLUT is important for regulating insulin release? where else is it found?
GLUT 2
pancreatic beta cells, liver, intestines, kidney
net outcome of insulin on three targets
- liver- promotes synthesis of TAGs and glycogen
- muscle- promotes synthesis of TAGs, glycogen and proteins (inhibits protein breakdown, increases AA/GH uptake)
- adipose tissue- promotes TAG production, glycolysis release FFAs from chylomicrons, inhibits lipolysis
products from glucagon gene
- tissue specific enzymatic activity
- cleaved in pancreas- glucagon
- cleaved in intestines- incretins (GLP1 & 2) (high carbs & fat); GRPP inactivates glucagon
what stimulate glucagon?
catecholamines, amino acids - both act directly in alpha cells
main targets of glucagon
mobilizes energy in liver and adipose tissue
T/F Insulin promotes ketogenesis
FALSE- Insulin INHIBITS ketogenesis
* ketoacidosis is rare in type 2 diabetics
T/F Glucagon directly inhibits beta cells and insulin directly inhibits alpha cells
FALSE- Catecholamines inhibit beta cells, insulin inhibits alpha cells
T/F Insulin and glucagon target the same enzymes
true- by phosphorylating phosphatase or kinase domains
what is somatostatin made by and stimulated by? inhibited by? what does it inhibit?
- delta cells of pancreas; stimulated by high fat/high carb
- inhibited by insulin (blood flow) BUT also inhibits insulin release (w/ TUMOR)
what does amylin do?
- released with insulin, synergistic role
- makes amyloid deposits (vessels, heart, pancreas)
what does ghrelin do?
- made in stomach, responds to mechanical stimulus of lack of food (says you’re hungry); low ghrelin, high obesity
- made in epsilon cells
- inhibits insulin release by opening K+ channels
counter-regulatory hormones of insulin
- immediate: glucagon, catecholamines
- delayed response: growth hormone, cortisol
where is renin produced and what does it do?
- produced in JG cells of afferent arterioles
- cleaves angiotensinogen to angiotensin I
where is erythropoietin produced and what does it do?
EPO made in kidney; stimulates proerythroblasts and differentiation of RBCs (increases number of red blood cells)
major side effect of raising hematocrit too quickly
hypertension, leading to encephalopathy & seizures
where are ANP and BNP released from and in response to? what do they do generally?
ANP- atrial myocytes- blood volume
BNP- ventricular myocytes- mechanical stretch
- both are potent vasodilators, increase excretion of sodium/water; lower blood pressure
out of ANP and BNP, which is the more useful diagnostic tool? what can it rule out?
BNP- longer half life, normal levels rule out heart failure
what are 3 more specific actions of ANP and BNP? what are the 4 target organs?
- decrease vascular smooth muscle tone
- decrease PVR
- increase capillary permeability, increasing hematocrit
- target organs:
kidney, adrenal cortex, blood vessels, heart
4 pathways targeted by decreased ECV
- JGA secretes renin
- sympathetic division of ANS
- posterior pituitary secretes ADH
- atrial myocytes secrete ANP
what is an endocrine disrupter?
chemicals that may interfere with the body’s endocrine system and produce adverse developmental, reproductive, neurological, and immune effects in both humans and wildlife
two examples of endocrine disruptors?
- PCB- competes with thyroid hormone binding globulin, results in goiters
- DES/BPA- synthetic estrogen, increases cervical and vaginal cancers
what happens during early starvation?
80% energy from released fatty acids, breakdown of liver glycogens, and break down of proteins (300g/day)
describe the metabolic switch
- after a prolonged fast, brain starts using ketone bodies instead of glucose
- free AAs from the breakdown of protein activate GH, which is trying to conserve lean body mass, get less protein breakdown (20 g/day)
- only occurs with no intake at all, is very important
4 criteria for metabolic syndrome (syndrome x)
- visceral obesity (waist size)
- insulin resistance (fasting glucose)
- dyslipidemia (high TAGs/HDL)
- hypertension
primary hormone produced by adipose tissue; what does it do?
leptin
(increased fat cells, increased leptin)
- inhibits appetite and food intake during the fed state
what transcription factor is important for TAG synthesis? what is it activated by?
Sterol- regulatory binding protein 1C (SREBP-1C)
- promotes TAG synthesis
- activated by lipids & insulin
what is a nuclear steroid receptor that regulates TAG storage and adipocyte differentiation? what is its clinical use?
PPARgamma
- regulates TAG storage
- was targeted by TZD to treat insulin resistant type II diabetes by making more fat cells
what are the hypothalamic hormone regulators of appetite, regulated by leptin?
(leptin stimulation= decreased food intake)
stimulators (inhibited by leptin): neuropeptide Y, AGRP
inhibitors (activated by leptin)- alphaMSH (from POMC), CART
what happens with leptin deficiency?
leptin normally decreases food intake, by removing it, mice eat themselves to death
what is insulin resistance and what does it cause?
insulin not efficiently transported into cells; have high plasma glucose and high circulating insulin, which down regulates insulin receptors; over time, pancreas reduces insulin output; beta cells can get depleted and cause switch from type 2 to type 1 diabetes
in obesity, what responses are exaggerated following an increase in plasma glucose?
increased insulin, increased c-peptide
what three measures are used to diagnose diabetes mellitus type 2?
- elevated HbA1C > 6.5% (glucose increases glycosylated RBCs, measures average over long period of time)
- fasting blood glucose > 126 mg/dl
- oral glucose tolerance test > 200 mg/dl
3 key symptoms of diabetes mellitus type 2
- polyphagia- excessive hunger
- polyuria- excess glucose in urine (causing H20 and sodium loss) increases plasma osmolarity
- polydipsia- excessive thirst
what does metformin do?
- inhabits hepatic gluconeogenesis
- increases insulin receptor activity (makes more sensitive to insulin)
what characterizes type 1 diabetes?
autoimmune destruction of beta cells, development of ketoacidosis (no insulin)
describe diabetic ketoacidosis
- no insulin + increased counterregulatory hormones
- increased FFA release
- metabolism of ketones increases blood acidity
- dehydration + acidosis results in diabetic coma
what are some counterregulatory hormones to insulin?
GH, cortisol, glucagon, catecholamines
3 things diabetes metabolism causes
decreased cellular glucose uptake
increased protein catabolism
increased lipolysis
what causes diabetic coma?
dehydration, increased plasma osmolarity
3 important genes for islet cell development
- PDX1- islet neogenesis/beta cell proliferation
- TCF72- beta cell proliferation
- neurogenin 3- all endocrine cell development
type 2 diabetes risk factors
- impaired beta cell proliferation during childhood (malnutrition, mother)
- propensity for insulin resistance (high calories, low exercise)
describe insulin secretion & beta cell mass during T2DM progression
- initially both increase during the impaired fasting glucose stage, then decrease during early stages of T2DM
what does an incretin mimetic do?
e.g. GLP1 agnoist
restores the 1st phase of insulin secretion and improves the second
T/F beta cell replication continues through adulthood
false- occurs during embryonic development, continues through adolescence, then stops
most genes identified in the GWAS studies affect
beta cells (development, proliferation, survival, function)
