Leff Flashcards
(99 cards)
1
Q
What is the primary function of insulin?
A
increased plasma glucose stimulates beta cells to produce insulin;
insulin functions to: 1. stop the liver from making glucose 2. cause the body to take up glucose (skeletal muscle/adipose)
-Anabolic hormone (signals storage of energy)
2
Q
What is the primary function of glucagon?
A
released from alpha cells in response to decreased blood glucose; primarily targets the liver to cause it to produce glucose and release it into circulation
3
Q
What are the primary theories behind type II diabetes?
A
- too many fat stores in the body challenges the limits of safely storing fat; fat leaks out to be stored in tissues that don’t normally store fat (ie: liver and muscle) leading to insulin resistance
- TNF and otther inflammatory cytokines, are released from adipocytes and act on tissues in the body, resulting in insulin resistance
4
Q
Describe the nutrient metabolism after a meal
A
under the influence of insulin;
Stimulates the skeletal muscle and adipocytes to take up insulin (GLUT 4); brain and liver do NOT require insulin to take up glucose;
glucose production in the liver is decreased and storage is increased
5
Q
Describe nutrient metabolism during fasting
A
under the influence of glucago;
causes the breakdown of glycogen in the liver (short fast); eventually causes gluconeogenesis in the liver (gets progressively more important in longer fasts as glycogen stores are used up)
6
Q
Describe the composition of the pancreas (ie: cells, blood flow, endocrine/exocrine)
A
Mostly an EXOCRINE organ (digestive enzymes); 1.2% is an endocrine organ (islets of langerhaans)
ISLETS: alpha cells (10-15%); mainly in the periphery, produce glucagon beta cells (80%): mainly in the center of the islet; produce insulin gamma cells (5-10%) mainly in the periphery; produce somatostatin
Blood flows: from the CENTER to the PERIPHERY; thus alpha cells are exposed to insulin, but beta cells are not exposed to glucagon
7
Q
Describe how Insulin is synthesized and processed
A
Beta cells in islets sense glucose levels and synthesize insulin accordingly (it is stored in vesicles/secretory granules)
Gene for insulin is transcribed to give pre-pro-insulin (signal peptide + C peptide + mature insulin)
signal peptide = cleaved to give proinsulin in the ER
C protein = cleaved from pro-insulin in the GOLGI to get the active insulin peptide
C protein and mature insulin are released together; C protein is not degraded as fast as insulin and is thus a good marker of insulin in the blood
8
Q
Describe the insulin receptor
A
TYROSINE KINASE RECEPTOR;
tetramer (2 alpha, 2 beta domains) that dimerizes upon ligand (insulin) binding;
the alpha domain = ligand binding
beta domain = transmembrane and cytoplasmic portion
cystein rich domain (on alpha) binds insulin
9
Q
Describe the insulin signal cascade
A
insulin binds (to alpha part of ) receptor; dimerizes, causes autophosphorylation of cytoplasmic domain of receptor which induces a conformational change to activate the tyrosine kinase which gets phosphorylated and then acts as a phosphorylator; (docking site for signalling proteins)
10
Q
What are IRS proteins?
A
Central Docking System;
phosphorylated by insulin receptor on multiple sites that serve as binding for signaling molecules;
activates PKB, which phosphorylates and INACTIVATES GSK-3 (which normally inactivates glycogen synthase) therefore GSK -3 is inactive and so glycogen synthase is ACTIVE and causes glycogen synthesis and storage
11
Q
Describe the MAPK pathway
A
MAPK activates another kinase that phosphorylates and activates a protein phosphatase, which dephosphorylates and activates Gycogen Synthase, causing glycogen synthesis and storage
12
Q
Describe the effect of insulin on GLUT4 expression
A
PKB also activates a series of proteins that leads to the expression of GLUT4 on the cell surface
Mechanism similar to AQP2 expression
13
Q
Describe the effect of insulin on HEPATOCYTES
A
stimulates glycogen synthesis and inhibits gluconeogenesis:
1. Inhibits PEPCK:
PEP CK = catalyzes the committed step of gluconeogenesis; insulin receptor binds insulin, activates IRS2 which activates PKB(AKT) which phosphorylates Foxo, a transcription factor needed for the transcription of PEP CK gene; as a result phosphorylation, Foxo leaves nucleus and trascription of PEP CK goes down (OCCURS FAST!!)
- Inhibits glucose - 6 phosphatase (keeps glucose phosphorylateds as GDP so it cannot leave the cell)
14
Q
Describe the effect of Insulin on Myocytes:
A
- Insulin promotes the uptake of glucose into the cell (GLUT4 expression)
Either stored as glycogen or used for energy (glycolysis)
Note: ¾ or more of the glucose after a meal goes to skeletal muscle under normal conditions; in diabetes this process is defective (not as much glucose can be taken up by muscle)
- Insulin also increases the uptake of AA and synthesis of protein (minor role)
15
Q
Describe the effect of Insulin on Adipocytes:
A
1.Action similar to in skeletal muscle (GLUT4 expression)
Difference: most of the glucose undergoes glycolysis; some is used for energy but most of it is converted to glycerol and acetate for TAG synthesis and storage of fat
- Inhibits Hormone Sensitive Lipase: (catabolic)
Normally active during fasting for TAG break down - Activates Lipoprotein Lipase: (anabolic)
Secreted from the cell and resides in vessel wall
Liberates free FA from VLDL and chylomicron which are then take up into the adipocytes
16
Q
What are the stimulators of Insulin Secretion:
A
Nutrients: Glucose, Amino acids,Ketone bodies
Hormones: Incretins (produced in gut), Glucagon* (because it stimulates glucose release which then
goes to stimulate insulin), Growth hormone
Neurotransmitters: ACh (PS) or BETA SS ADRENERGIC
Drugs: cholinergic drugs, sulfonylureas, cAMP
Electrolytic: increase in calcium, sodium, postassium
17
Q
What are the Inhibitors of Insulin Secretion
A
Hormones: Somatostatin
Neurotransmitters: Epi, NE (SS; ALPHA ADRENERGIC) ;
Drugs: atropine (cholinergic (ACh) blocker)
Electrolytic: Mg2+
18
Q
Describe the bi-phasic insulin RELEASE
A
Phase I : insulin release is due to vesicles that are close to the plasma membrane (very rapid response; 2-5 minutes
Phase II: (delayed response) due to vesicles that are further away from the plasma membrane
An early symptom of type II diabetes is the loss of PHASE I (EARLY) insulin secretion
19
Q
Describe the regulation of secretion by the beta cells
A
Glucose from circulation enters beta cell via GLUT 2 channel and is used for glycolysis, increasing the energy charge charge (ATP:ADP or NADH:NAD+ ratios) of the cell ** GLUT 2 lets the inside of the B-cell see the same [glucose] as theoutside of the B-cell which is linked to plasma [glucose]
The increase in energy charge causes closure of a ATP sensitive K+ channel that normally maintains membrane potential; closure causes the cell to depolarize (because K+ builds up inside the cell ) and Vm to increase;
then the voltage gated Ca2+ channel is opened, causing Ca2+ to enter the cell (**this is all localized to one area of the cell) ; the Ca2+ influx also induces Ca2+ release from the ER leading the docking and fusion of secretory granules, resulting in the release of insulin
20
Q
What are sulfonylureas?
A
drugs used in early stages of diabetes that inhibit the K+ channel, which allows for small canges in ATP levels to stimulate insulin release (cell is better at releasing insulin in response to glucose)
21
Q
What are the three phases of insulin secretion?
A
- Cephalic
release of insulin that precedes food ingestion (due to sight/pscyhe/smell of food)
stimulated by the PS (PARASYMPATHETIC)/ACh
not a huge amount of insulin is released, but it primes the body to respond faster after food intake - Early Postprandial .
immediately after food is ingested, but before the nutrients reach the blood stream;
Insulin release is stimulated by gut-derived incretetin hormones, GLP1 (glucagon like peptide-1) and GIP; effects overlap with phase 3 - Postprandial
AFTER meal-derived nutrients reach the blood stream;
Insulin released due to elevated blood glucose and amino acid levels (sensed IN circulation)
22
Q
Describe the neural regulation of insulin secretion
A
- Parasympathetic: stimulates insulin secretion
- mediated by ventral-lateral hypothalamus via vagus nerve and release of ACh
- mediates the CEPHALIC PHASE of insulin secretion - Sympathetic: INHIBITS insulin secretion
- mediated by ALPHA adrenergic signalling (epi/NE) **BETA adrenergic has opposite effect
- important in regulating insulin secretion during exercise (want to turn off insulin so that you expend energy on catabolism not anabolism)
23
Q
Describe the regulation of insulin secretion by gut hormones
A
= incretins
gut produces GIP and GLP, which are incretins that stimulate insulin release BEFORE blood glucose levels change (secreted by intestinal L-cells)
if you give glucose ORALLY: causes a LARGE INSULIN SPIKE
if you give glucose IV (bypasses the gut): there will only be a small release of insulin
therefore conclusion: something (GIP and GLP-1) enhance the effect of blood glucose
24
Q
Describe the effect of GLP-1 on early postprandial insulin secretion
A
After a meal, (before the blood glucose levels change) gut secretes GLP-1 into circulation, which causes:
- insulin secretion–> causing increased glucose disposal in adipose tissue and muscle (leading to decreased plasma glucose)
- decreased glucagon section –> decreased hepatic glucose output (gluconeogen) leading to decreased plasma glucose
25
Describe the paracrine feedback of the islets of langerhans
Glucagon = stimulates insulin secretion (even though the alpha cells are located in the periphery of the islet and blood flows from central to periphery)
insulin = inhibits glucagon secretion (enhances counter regulatory effects)
somatostatin = inhibits both insulin and glucagon secretion
Insulin: activates beta cells and inhibits alpha cells
Glucagon: activates alpha cells which activates beta cells and delta cells
Somatostatin: inhibits alpha cells and beta cells
26
Describe the structure and processing of glucagon
= derived from a larger precursor protein called "proglucagon" which also gives rise to other hormones;
undergoes different processing in pancreatic alpha cells compared to intestinal L cells:
pancrease: cleaved into GRPP, glucagon, and roglucagon fragment
Lcells = cleaved into glicentin, GLP-1 and GLP-2 (incretins) and IP-2 (unknown function)
27
Describe the regulation of glucagon secretion:
Nutrients: glucose, fatty acids = inhibit; amino acids = stimulate release
Neuronal signals: SS (via alpha2 or Beta1 adrenergic receptors and PS both stimulate)
Hormones: GLP-1 inhibits release, cortisol stimulates
28
what tissues does glucagon primarily act on? insulin?
glucagon = liver mainly (stim glycogenolysis and gluconeogenesis)
insulin = liver, muscle, adipose (stim glycogenosis and glycolysis)
29
What is the effect of protein rich meals on glucagon/insulin/metabolism?
stimulates both insulin and glucagon; results in VERY LITTLE CHANGE IN BLOOD GLUCOSE!
because there is no real storage form of amino acids in the body (because skel muscle has a \fixed rate of protein cat/anabolism) and as a result most is converted to glucose, some is used for protein synthesis but not a lot is needed;
glucagon effects = dominant in the liver to stim gluconeogen (aa used as substrates to make glucose, and glucose tops off glycogen stores in the liver and then the rest is released into circulation)
insulin effects = dominant in periphery, where it stimulates uptake of excess glucose into muscle and adipocytes
30
What is the effect of glucagon on hepatocytes?
downstream effect = synthesis of glucose (gluconeogen/glycogenolysis) and release of glucose into circulation
1. Activates PEP CK (catalyzes rate limiting step in gluconeogen)
glucagon binds receptor to activate PKA pathway, PKA phosphorylates CREB which causes:
a). stimulation of transcription of TFs that stimulate PEP CK transcription
b). stimulates transcription of PEPCK itself
2. Activates glucose -6 phosphatase
promotes dephosphorylation of glucose and release from the cell
31
Describe the metabolic stages that occurs in type II diabetes
Normal: does not take a lot of insulin to bring glucose levels back to normal
Insulin resistance: takes more insulin to achieve the same level of glucose tolerance (but glucose tolerance is not yet impaired; no clinical manifestations, you are able to reduce the blood glucose after elevated insulin)
Glucose intolerance: not able to maintain glucose tolerance regardless of increase in insulin release (early stage of diabetes, you are still able to treat it, but blood glucose is elevated regardless of the large increase in insulin secretion)
Diabetes: failure of the endocrine pancreas results in uncontrollable blood glucose levels because of total lack of insulin
32
Explain the progession of type II diabetes
initially, although a person is becoming more insulin resistant, they can maintain normal blood glucose by compensatory increase in insulin release; however eventually the endocrine pancreas fails as insulin resistance continues to increase and glucose levels skyrocket due to lack of insulin
33
Describe the incretin based diabetes therapies
inject GLP-1 mimetics to increase insulin concentration;
or DPP4 usually breaks down GLP-1, so inhibit DPP4 to cause prolongation of GLP-1 half life
34
Describe the structure of growth hormone
```
2 forms (resulting from differential splicing producing 2 different mRNAs)
20 kDa (176 aa) and 22 kDa (191 aa; primary hormone)
differ by 14 aa; no clear understanding why
```
35
What does the growth hormone (GH) gene encode?
GH is a part of a gene cluster of closely related genes on Chromosome 17;
encodes for:
1. Human GH (191aa)
other stuff: relating to fetal growth and placenta function:
2. pvGH (191 aa; 93% homologous to GH); regulators of fetal growth (hGH doesnt); has same affinity for GH receptor as hGH
3.Human CS1 and CS2 (191 aa each, 84% homologous to GH)
= human chorionic somtomammotropin; relevant only in embryonic development (produced by placenta)
4. Human PRL (199 aa; 16% homologous)
36
Describe how GH is synthesized
gene is differentially spliced, resulting in the pre-22 kDA or pre-20 kDA growth hormone mRNA (in the nucleus);
-mRNA enters the RER where it is transcribed to the pre-prohormone and then it is transported to the golgi for processing into prohormone;
eventually, active hormone is stored in secretory granules in the somatotrophic cells of the ANTERIOR PITUITARY, awaiting signal (GHRH) for release
37
How is GH production episodic?
higher GH levels exist at night during NON-REM SLEEP; (occurs more earlier in the night; = slow wave/deep sleep);
in treatment, therapeutic GH is administered at night when endogenous GH is normally produced
during the day it is still pulsatile, but the amplitude of secretion is no where near as high as it is at night (still pulsatile, just higher amp/more secreted)
38
What are some of the factors increase GH production?
1. Fasting (hypoglycemia, low circulating free FAs.. ie: daily fasting at night, not starvation)
2. High protein diet (elevated circulating amino acids, especially arginine; if there is available material for growth then there is an increase in GH)
3. Exercise
4. Deep sleep (later stages of non-REM)
39
What factor(s) decrease GH production?
stress/anxiety: short term stress causes an increase in epi/NE and actually causes an increase in GH, but chronic stress = release of glucocorticoids which suppresses downstream GH effects causing inhibition of growth (not due to a decrease in GH production)
40
What are the direct (acute) effect of GH
mainly anti-insulin effects (short term);
- decreased glucose uptake in muscle
- increased lipolysis in fat
- increased gluconeogenesis in liver
- insulin resistance in muscle, fat, and liver
41
How does GH promote growth?
GH ITSELF DOES NOT HAVE GROWTH PROMOTING ACTIVITY!! indirect effects mediated by IGF-1 cause increased growth!
IGF-1 = produced in liver when stimulated by GH and causes CHRONIC (indirect) effects of GH (all related to growth)
- increased DNA, RNA, and protein synthesis
- increased cell size and number
- increased organ size
- increased organ function
- increased linear growth (has a direct effect on osteoblasts, causing bone building process to be favored)
42
Describe the GH signalling pathway
1. GH binds to extracellular JAK/STAT receptor (on two different sites on two different receptors)
2. Receptor dimerizes
3. autophosphorylation of both: receptor
4. Phosphorylation of JAK (cytoplasmic) associated with the receptor = JAK activated
5. STAT proteins phosphorylated (tyrosines)
6. Phosphorylated STATs move to the nucleus and act as transcription factors and modulate gene expression (increases the expression of IGF-1 (priamary target) and IGFBPs (secondary target; causes increase in half life) )
43
Define the structure of IGF-1/Somatomedin
IGF-1 = highly homologous to insulin (in lower animals, one hormone carries out activities of IGF-1 and insulin); "C peptide" in IGF-1 is shorter and NOT cleaved out of IDF-1 gene product (as it is in insulin)
IGF-2 = homologous to IGF-2; function not totally known (maybe specific periods of growth)
44
Describe the IGF-1 Receptor and IGF-2 Receptor:
IGF-1: since the hormones are so similar, the receptor/signalling cascade for IGF-1/insulin = super similar (tyrosine kinase); also at very high concentrations of insulin ( ie: type II diabetes//hyperinsulinemia) insulin can bind IGF-1 receptor causing undesirable effects
IGF-2 receptor = Mannose-6-phosphate receptor
Does not induce cell signaling inside the cell
IGF-2 can also bind the IGF-1 receptor in some circumstances
IGF 1 receptro: can be activated by IGF-1, IGF-2, and insulin
IGF2 receptor = no affinity for IGF-1; has no signaling component
45
What is the role of IGF-1 and growth?
most rapid growth occurs in early childhoodm but it is NOT mediated by IGF-1 (not sure what exactly mediates this growth, might be IGF-2)
IGF-1 = primarily mediates pubertal growth (levels increase during childhood and peak at puberty)
46
What regulates GH secretion?
Cells in the arcuate nucleus secrete GHRH which STIMULATES GH release; causes fusion and release of GH by somatotrophs--- GHRH binds GHRH receptors (Gs coupled) which activate adenylate cyclase, increasing cAMP and PKA, causing Ca2+ influx
circadian rhythm monitors GHRH production (increased GH at night!)
Cells in the periventricular region release somatostatin which INHIBIT GH release; somatostatin binds to receptor that (Gi coupled) which inactivates adenylate cyclase, decreasing cAMP and PKA thus preventing Ca2+ influx into cell and preventing docing and fusion of GH vesicles
47
Describe the feedback mechanism associated with GH and IGF-1
GH Feedback:
feeds back to inhibit somatotrophs in anterior pituitary and therefore inhibits GH release; GH is removed rapidly from circulation
IGF-1 Feedback:
1. Feeds back to inhibit somatotrophs in anterior pituitary, therefore inhibiting GH release
2. Feeds back to inhibit GHRH secretion fro arcuate nucleus
3. Feeds back to stimulate somatostatin release (inhibit GH release)
IGF-1 has a longer half life in circulation than GH
48
Other than GH/IGF-1 what are some other hormones that affect body growth?
1. thyroid hormone
2. sex steroids
3. glucocorticoids
4. insulin
5. tissue-and cell specific growth factors that promote growth (have hormone life effects) =
- nerve growth factor (NGF)
- fibroblast growth factor (FGF)
- angiogenesis factor
- vascular endothelial growth factor (VEGF; repairs vascular endothelium)
- epidermal growth factor
- hepatocyte growth factor (HGF)
49
What does GH excess cause? what is it caused by?
caused by: tumor of somatotrophs in anterior pituitary (or tumor of arcuate nucleus causing excess GHRH to constantly stimulate GH)
Causes: hyperglycemia, insulin resistance (because GH causes anti-insulin/pro-glucagon effects), reduced body fat/increased lean body mass,
acromegaly in adults (epiphyseal plates have been fused but the excess GH occurs in adulthood, do not get increased linear body growth, but do get bone density growth and enlarged features);
giantism in kids (epiphyseal plates do not close; followed by acromegaly later in life)
50
What does GH deficiency cause?
short stature, hypoglycemia, increased body fat, reduced lean body mass (muscle mass)
Laron dwarfism: mutation in the receptor for GH (therefore cannot induce production of IGF-1)
51
what is the role of leptin compared to GH? How was the leptin gene discovered?
```
GH = regulation of LINEAR growth
leptin = regulation of body mass
```
discovery:
2 genes; when defective cause obesity; Ob gene and Db gene
2 mice fused together so that they exchange small amount of circulatory system (ie: soluble blood factors)
1. Ob defective mouse attached to normal mouse:
Ob defect mouse became slender, normal mouse remained normal; therefore the Ob mouse must have a defective hormone that normally reduces body weight (because it became slender after being to receive the normal mouse's hormone)
2. Db defective mouse attached to normal mouse;
Db mouse remained fat, normal mouse became anorexic; therefore Db mouse must have a defective receptor (non-diffusible component) for the normal hormone that reduces body weight because it remained fate even after receiving hormone from the normal mouse; it must also have functioning hormone since the normal mouse became anorexic (received extra weight reducing hormone from the DB mouse)
52
What are the physiological effects of Leptin?
- Leptin affects appetite (reduce appetite)
- does NOT affect metabolic processes (receptors for leptin are found in the CNS)
- giving leptin to Ob mouse (with defective hormone) = decreased food intake dramatically
- giving leptin to the Db mouse (with the defective receptor) had no effect on food intake)
53
What is the hormonal regulation of appetite?
-leptin is secreted at ALL TIMES from ALL adipose tissues in the body (receptor is in the CNS); amount of leptin produced is proportional to the amount of body fat a person has
leptin is only secreted by adipose tissue (because that is the only place where the gene is expressed)
Receptor for leptin are located in the arcuate nucleus of the hypothalamus on 2 populations of neurons:
1. Anorexogenic neurons (POMC/CART; DECREASE appetite)
2. orexigenic neurons (AGRP/NPY; INCREASE appetite)
Leptin stimulates ANOREXIGENiC neurons and INHIBITS OREXIGENIC neurons
Other hormones playing a role = ghrelin (stim appetite) and CCK released from gut
54
How can Leptin be used clinically?
Leptin is only effective at decreasing appetite and body weight in people that have a defect in the leptin gene (very rare);
Obese individuals actually have more leptin than normal sized individuals; thought is that there is hyperleptinemia leading to leptin resistance in a similar fashion to hyperinsulinemia causing insulin resistance in diabetes
**therefore leptin fails as a therapeutic weight loss drug
55
How is calcium distributed and balanced in the body?
calcium = high extracellular; low intracellular; most of calcium is found within bone
1. diet: take in ~ 1g Ca2+/day; majority of this leaves in feces (the rest is removed in urine)
2. Kidney: filters ~10g Ca2+/day; most is reabsorbed
3. Bone formation/resorption: lots of activity daily, but no net change in bone density as a result; pathology occurs when there is an imbalance
In normal healthy person: net calcium excreted = next calcium absorbed through GI
56
How is phosphate distributed and balanced in the body?
basically the same regulation as Ca2+ (diet, kidney, bone) except that is not as tightly regulated and more variation occurs in its concentration on a minute to minute basis in circulation
57
What is the relationship between Ca2+ and phosphate?
- both required for bone mineralization: Hydroxyapatite crystals are composed of both ions (Ca(PO4)(OH))
- reciprocal regulation of circulating levels (kidney: PTH causes increased Ca2+ reabsorption but decreased Phosphate reabsorption)
- differntial effects on PTH production: elevated circulating Ca2+ suppresses PTH production, elevated phosphates stimulates PTH production
58
Describe the structure of bone. What art is more/less active?
organized into osteons;
outer compact bone is less active that trabecular bone in terms of bone deposition/resorption
-the canaliculi are involved in sensing stress and transmitting that information to more active parts of the bone to modify resorption and deposition of bone
59
How is bone density maintained
normally: balance between osteoblasts/osteoclasts;
1. osteoblasts:
= promote bone deposition (prefer to deposit bone at sites where osteoclasts were just active)
-*** DIRECTLY stimulated by PTH and vitamin D to form new bone by depositing Ca2+ and phosphate:
Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANK ligand (L); osteoclasts have RANKL receptor which if stimulated, causes osteoclastic activity (increased bone resorption) .
vit D also stimulates differentiation of stem cells into osteoclast precursors to form osteoclast
osteoblasts also produce IL-6 (interleukin/cytokine) which stimulates osteoclast activity
2. Osteoclast
= Multinucleated cells that promote bone resorption (seal off a portion of the cell and alter the
environment of sealed off region)
* Osteoblast precursors stimulated to differentiate by vitamin D
60
Describe the mechanism behind osteoclast signaling
IL-6/RANK ligand (from osteoblast after binding PTH) bind to receptors on osteoclasts to stimulate bone resorption
Osteoprotegrin (from osteoblast): blocks RANKL/RANKR binding
Calcitonin: inhibits osteoclast activity (receptor is coupled to a Gs protein.. activates PKA to inhibit bone resorption)
61
What is the general function and structure of PTH?
Parathyroid hormone; senses circulating levels of Ca2+ and causes the release of Ca2+ in response to decreaseing levels (PTH = INCREASE PLASMA CALCIUM)
Structure:
synthesized from a larger molecule (pre-pro-PTH)
-enters ER and is secreted as PTH is 84 aa long (just cleave signaling sequence) PROHORMONE
cleaved again in GOLGI to generate the active hormone PTH whic is released into the cytoplasm and is secreted in response to high Ca2+
* N-terminus = functional end
* *Teriparatide = drug that mimics the N-terminal of PTH and used as a treatment of osteoporosis
62
Describe the way in which PTH is secreted
Ca2+ sensing receptor on the surface of parathyroid chief cell binds Ca2+ (senses levels in blood)
If Ca2+ levels increase:
Receptor binds Ca2+, activates Gq mechanism of cell signaling-->activates PLC-->PIP2-->IP3+DAG
o IP3 -->release of Ca2+ from the ER and increase intracellular levels of Ca2+
o This increase in Ca2+ INHIBITS vesicle docking and fusion, and PTH is no longer released**(PTH
synthesis is also inhibited)
o DAG activates PKC and contributes to the same pathway and PREVENT vesicle fusion with cell
membrane
63
What are factors that stimulate/inhibit PTH release?
Stimulate = BETA adrenergic signaling, intracellular cAMP, GI hormones, glucocorticoids, growth hornomes
Inhibit = ALPHA adrenergic signaling, increased plasma calcium
64
What are the actions of PTH?
to maintain circulating calcium levels (increases calcium levels when they are low)
DIRECT EFFECTS:
bone: increase Ca2+ resorption
Kidney: increase kidney tubule ca2+ reabsorption//decrease kidney tubule phosphate reabsorption
increase enzyme for conversion of 25(OH)D3 to 1,25(OH)2D3 (active vitamin D)
INDIRECT EFFECTS
gut: increase intestinal Ca2+ reabsorption from dietary sources
Bone: increase bone resorption
Kidney: INCREASE calcium reabsoprtion in tubules
65
How is vitamin D related to PTH?
25-(OH)-D3 -->1,25-(OH)2-D3 (Active form) in kidney; this step is stimulated by PTH
66
What are the effects of Vitamin D (on calcium)?
1. increase Ca2+ & PO4 absorption in the Gut:
2. acts synergistically w/ PTH to increase Ca2+ reabsorption in kidney
3. Directly acts to mobilize Ca2+ out of bone
Thus overall effect of Ca2+ is to increase bone mineralization
67
How does Vitamin D regulate calcium absorption in the gut?
Vitamin D acts like a steroid hormone (lipid soluble) so it can pass the plasma membrane, and enter nucleus and alters transcription of genes, resulting in the production of proteins required for the transport of Ca2+ out of the gut
Proteins synthesized include:
1. Ca 2+ channel (bring Ca2+ into intestinal cells from lumen)
2. Calbindin (Ca2+ binding protein that helps create a favorable Ca2+ gradient allowing more Ca2+
to enter from lumen)
3. Ca2+ transporter (ATP dependent) to move it to the ISF (exchanger with H+)
4. Ca2+/Na+ transporter (exchanger) (not ATP dependent)
68
How is phosphate absorption regulated?
Alters gene transcription resulting in synthesis of proteins associated with transport of phosphate out
of the lumen and into the ISF (one transporter on each side of the intestinal cell)
69
What are some of the other hormones (Not PTH/vit D/phosphates) that affect calcium metabolism?
1. Calcitonin: inhibits osteoclasts (slows bone resorption); complicated actions
2. Sex Steroids (testosterone and estrogen): promotes bone deposition----Decrease in estrogen in menopause often causes osteoporosis in women
3. Glucocorticoids: promote bone resorption
4. PTH-related peptide (PTHrP): mimics PTH; synthesized as a prohormone that is post-translationally cleaved by covertases (each peptide has its own receptor!); works in a paracrine/autocrine manner to regulate SMC, transepithelial calcium transport, and organ growth/development
70
Describe the synthesis, structure, and regulation, adn actions of calcitonin
Produced by the parafollicular cells (C-Cells) of the thyroid gland; initially it is synth as a pre-pro-peptide (procalcitonin) that is cleaved into shorter active homrone;
32 aa
stimulated by elevated plasma calcium levels; GI hormones (gastrin, CCK, glucagon)
suppressed by hypocalcemia
actions:
inhibits bone resorption (by inhibiting osteoclast activity);
decreases plasma [Ca2+]
decreases gastrin secretion
increases renal excretion of ions: Na, KPO4, Cl
**not involved in min to min regulation of calcium, but rather to prevetn major excurisions of plasma calcium
acts through a G-coupled Gs receptor that mediates its cellular effects through cAMP signals
71
How does blood flow in the adrenal glands? what is the significance of this?
flow from cortex to the medulla, so that the cells of the medullar are exposed to the hormones produced in the cortex;
72
What hormones are released from the adrenal cortex? what are their functions?
releases the cortical steroids in response to hormonal stimulation; derived from MESODERM
All are steroid hormones and derived from cholesterol, so they all have similar ring structure, just different side chains; they each have their own nucleoreceptor but some degree of crosstalk can occur b/n hormone/receptor binding
1. Zona glomerulosa = mineralcorticoid (aldosterone) for maintaining Na+/H2O balance
2. Zona Fasiculata = glucocorticoids (cortisol): for regulating Carb and protein metabolism
3. Zona Reticularis = androgen secretion (DHEA and androstenedione): for establishing and maintaining secondary sex characteristics
All are steroid hormones and derived from cholesterol, so they all have similar ring structure, just different side chains; they each have their own nucleoreceptor but some degree of crosstalk can occur b/n hormone/receptor binding
73
What hormones are released from the adrenal medulla? what are their functions?
Catecholamines in response to NEURAL stimulation; derived from NEURAL CREST cells;
epinephrine/NE: cell surface receptor packaged into vesicles
74
How are the adrenal steroids synthesized?
NO STORAGE VEHICLE FOR STEROID HORMONES (unlike peptide hormones which are stored in vesicles); thus regulation of hormone secretion is done by controlling hormone synthesis (once they are synthesized, they act);
**enzyme location dictates the location of hormone production!
Cholesterol --> Pregnenalone via Side Chain Cleavage Enzyme (conversion occurs in mitochondria)
21-alpha hydroxylase: required for synthesis of glucocorticoids and mineralcorticoids; it converts progesterone to 11-deoxycorticosterone in SER; also converts 17-alpha-hydroxyprogesterone to 11-deoxycortisol in SER; it is most commonly inherited defect in adrenal gland enzyme function (results in reduced cortisol/aldosterone and elevated androgen )
Aldosterone Synthase = required to synthesize aldosterone from cortisol in mitochondria; FOUND ONLY IN GLOMERULOSA CELLS!!
17 alpha -hydroxylase is NOT present in the glomerulosa therefore allows for cortisol production to occur only in fasiculata zone
75
Describe the Hypothalamic-Pituitary-Adrenal Axis
Hypothalamic PV nucleus is stimulated by various signals: circadian rhythm, physical/emotional/biochemical stress;
signals cause PV to release CRH into the portal system and travel to the anterior pituitary to act on corticotrophs to stimulate ACTH production and release;
CRH binds to CRH receptor (Gs coupled) which activates AC, increasing cAMP and PKA, causing Ca2+ influx ad vesicle fusion/docking;
ACTH binds to melanocortin-2 receptors on adrenal cortex to cause cortisol release (Gs protein coupled; AC; cAMP; PKA; to activate expression of genes that encode for enzymes required to make the desired hormones (they are steroid, so in order for them to be released they are synthesize unlike peptide hormones ie: ACTH which are already in vesicle and need Ca2+ to stimulate their release)
76
Describe the feedback involved with the Hypothalamic-Pituitary-Adrenal Axis
1. short loop = ACTH acting on PV of hypothalamus to inhibit CRH release
2. Long loop = Cortisol acting on PV of hypothalamus to inhibit CRH release
Cortisol also (and is the only adrenal hormone that does) acts on anterior pituitary to inhibit corticotrophs from synthesizing and releasing ACTH
77
What is ACTH derived from? explain further..
POMC = ACTH precursor molecule; But if ACTH is very high (as in Addison's disease), POMC can be differentially cleaved to form gamma-MSH and Beta-endorphin (so increased ACTH = increased pigmentation)
78
What is the function of nuclear receptor?
they bind steroid hormones and are ligand activated transcription factors.
They have a specificity for both ligand (hormone it binds) and the DNA itself (where it binds to act as TF); they bind the ligand in cytoplasm, dimerize with another NR/hormone complex, and then enter the nucleus via nuclear pores
79
How does ACTH stimulate adrenal cortex hormone release? (mechanism of action)
ACTH binds to its Gs protein coupled receptor, activating AC; cAMP; and increasing PKA;
downstream signaling results in:
-activation of the enzyme CEH (Cholesterol ester hydrolase) which cleaves cholesterol (from LDL) from ester storage form to free cholesterol
the primary source of cholesterol in the adrenal gland is LDL; so ACTH release causes INCREASED LDL receptor amount; when LDL binds, cholesterol enters the cell and is stored as cholesterol esters; ACTH (PKA pathway) then stimulates CEH to release cholesterol for further modifications
-stimulation of the side chain cleavage enzyme allowing cholesterol --> pregnenalone; thus the cotical steroids can be synthesized; not all of the cells of the body see the SAME concentration of steroid hormone because they are lipid soluble and don't rely on an extracellular receptor to get into a cell like peptide hormones do;
THUS: MAIN THINGS STIMULATED FROM ACTH PKA PATHWAY:
1. increased LDL receptors
2. Increased Cholesterol Ester Hydrolase (CEH) enzyme
3. Increased Side-Chain Cleavage enzyme (SSC)
4. Increased amounts of key enzymes involved in steroid hormone biosynthesis
80
Describe the rhythmic secretion of ACTH and Cortisol
Regulated by light/dark cycles of circadian rhythm (therefore, blind people do not have the same pattern of release);
More ACTH is secreted in the MORNING, resulting in higher levels of CORTISOL JUST AFTER WAKING (there is also a spike of ACTH and cortisol later in the day)
Note:
1. ACTH is released in a highly episodic/pulsatile fashion which dictates the amount of cortisol released (an increase in ACTH precedes any cortisol increase)
2. cortisol = less spikey because it takes a while for ACTH to influence cortisole
3. Big cortisol spike after waking (due to changes in blood flow and changes in gut flow)
81
How does cortisol effect metabolism?
overal = INCREASE BLOOD GLUCOSE LEVELS (maintain blood glucose for brain during times of stress)
- stimulates gluconeogenesis
- stimulates protein break down (mobilizes aa for gluconeogenesis in liver)
- stimulates appetite
- stimulates lipolysis in some areas, lipogenesis in other (redistribution of fat stores)
ALSO: long term exposure to cortisol results in insulin resistance (decreased uptake of glucose into fat and skeletal muscles)
*** note: anytime you do lipolysis, the acetyl coA does not go back to make free glucose, rather lipolysis occurs in order to provide energy for gluconeogenesis of glycerol and proteins and lactate
82
What is the relationship between cortisol and insulin?
chronic cortisol exposure causes increased insulin resistance (decreased glucose uptake in fat and muscles); high cortisol levels present similarly to diabetes mellitus
83
What is the relationship between cortisol and the inflammatory responses?
cortisol causes suppression of the inflammatory response; cortisol is involve in all aspects of inflammation (inhibits)!!
thus it is used therapeutically as an anti-inflammatory substance by inhibiting multiple steps; prostaglanding synthesis is inhibited by cortisol
84
What are the global effects of cortisol?
1. increased bone resorption
2. Decreased connective tissue
3. Anti-inflammatory
4. Maintains CO, increase CV tone, decreases endothelial permeability
5. Maturation of fetus
6. Increases GFR
7. modulates emotional tone and wakefulness
8. maintains muscle function, chronical effects --> decreased muscle mass
85
How do nuclear receptors work? (for a lipid hormone) How are they effected by cortisol?
hormone binds IN THE CELL; binding activates homodimers and the hormone/receptor complex enters nuclear envelope through a nuclear pore; and then binds to the DNA to increase transcription of target genes;
Cortisol causes increased PEP CK transcription (to increase gluconeogenesis)
overall the nuclear receptor mechanism takes longer than peptide/PKA response (other cell cell surface receptors)
86
How is aldosterone secretion stimulated?
1. ACTH release (not as important as it is for cortisol release)
2. Angtiontensin II release (in response to low blood volume or low blood pressure)
3. High plasma K+ concentrations
**because aldosterone causes increased Na+ reabsorption and increased K+ secretion
87
What does aldosterone do to the kidney?
causes decreased Na+ and water excretion; increased K+ excretion; thus resulting in overall increase in blood volume and pressure;
also effects the salivary gland and secretory tissues etc.
88
What is the role of 11BHSD2 in corticosteroid activity?
generally, hardly any aldosterone in circulation under normal circumstances, but always a lot of cortisol present;
at physiological levels, cortisol can bind to the mineralcorticoid receptors and active it (ie: under stress) wouln't really want this to happen because then you would have constant high blood pressure
SO: 11BHSD2 is present in the kidney and other tissues that minceralcorticoids respond to (ie: colon, sweat glands, salivary gland, placenta) and converts cortisol to its INACTIVE for of cortisone, preventing it from binding the mineralcorticoid receptor;
this ensure that the receptor only responds to changes in ALDOSTERONE levels NOT changes in cortisol levels
**a different enzyme can take cortisone to cortisol, and the two enzymes that go between the two states of active/inactive cortisol are in different concentrations based on the tissue function (ie: whether you want cortisol or mineralcorticoids to be more responsive)
89
What is the function of adrenal androgens?
secondary sex characteristics but really they are not a major hormone source (mainly testosterone/estrogen)
- Come into play in pathological states where you have no ability to synthesize cortisol
o Lose negative feedback control of ACTH production, resulting in increased ACTH and production of these hormones
- PCOS is an example of a disorder in which there is an increase in adrenal androgen secretion
90
What stimulates the adrenal medulla to release its hormones?
preganglionic sympathetics
91
How are catecholamines synthesized?
Adrenal medulla = only place in the body where epinephrine is made and put into circulation;
synthesized in chromaffin cells:
L-tyrosine --> L-DOPA (**formation stimulated by SS and ACTH ) --> Dopamine (in CYTOSOL)
Dopamine enters the chromaffin granule --> NE, which leaves the chromaffin granules
NE --> epi in cytosol and then epi is transported back into chromaffin granule where both epi and NE are packaged into secretory vesicles and secreted in response to SS input
******* NE PRODUCTION IS CONTROLLED BY SS AND ACTH (EPI = ALSO CORTISOL)
NE SECRETION = CONTROLLED BY SS PREGANG USING ACH (basically chromaffin cell = post-gang neuron)
** Dopamine --> NE = in granule
DOPA --> Dopamine and NE--> epi = in cytosol
92
How is the adrenal medulla and a sympathetic ganglion similar/different?
adrenal gland = analgous to symp ganglion (both stim by ACh)
but ganglion = for local response, and adrenal gland = for catecholamines in circulation (not local) and targe for all of the body;
any epi found in the body = from the adrenal gland; most NE found in the body = from adrenal gland, some from smyp gang
93
How does insulin induced hypoglycemia effect catecholamine production?
rapid decrease in blood glucose via insulin cause and increase in ACTH which stimulates catecholamine production super FAST (EPI > NE) , but causes a SLOW response from cortisol
94
What is the effect of catecholamines on metabolism?
similar to glucocorticoids (free up glucose), but just more rapid (because it doesn't involve TF)
Emergency response to keep blood glucose levels elevated;
stimulates the release of glucose from the liver (liver has catecholamine receptors and so it responds directly to the increase in catecholamines by stimulating gluconeogenesis from lactate and glycogenolysis)
stimulates lipolysis in adipose tissue (stronger than by cortisol)
stimulates glucagon release from the pancreas (further simulates gluconeogenesis)
weakly inhibits insulin release from pancreas
** technically, it both stimulates insulin release via BETA receptor and inhibits insulin release via ALPHA receptor; but in the case of the pancreateic beta cell, inhibition dominates;
increased release of glucose in the form of lactate from skeletal muscle;
CV effects = increased heart rate, cardiac contractility, cardiac conduction velocity
95
What are the specific action of catecholamines on adreneric receptors:
1. Alpha 1: PLC pathway= smooth muscle contraction
2. Alpha 2: PKA pathway = inhibition of transmitter release, smooth muscle contraction (in the gut)
3. Beta: PKA pathway = heart muscle contraction, smooth muscle RELAXATION, glycogenolysis
If the response is on TF then it causes phosphorylation of CREB gene
In general, alpha = vasocontriction (in gut)
and beta = vasodilation (in muscles).. just think where do you want to get the blood to go during catecholamine stimulation;
also generally Beta respond more to EPI > NE and alpha respond more to NE > EPI
96
How are the catecholamines degraded?
EPI and NE = short lived molecules in circulation (half lives = minutes) so their effect is transient and hard to get a blood sample to measure the levels of it. but you CAN measure their degradation products like vanillymandelic acid (VMA) which can be measure in the uring to give informaiton about catecholaamine levels
97
What is Cushings syndrome? what are its symptoms/causes?
= primary hyperadrenocortism;
due to an OVERproduction of cortisol (due to a tumor somewhere in the HPA axis) or due to a chronic administration of glucocorticoid as drug treatment;
causes: redistribution of fat (less in arms and legs, more visceral fat, large fat pads and moon face);
osteoporosis due to bone resorption;
damaged collagen CT leading to: striations, thin skin, bruisability, red cheeks
increased blood pressure due to effect of higher vascular tone (low K+ high Na+ due to simulation of aldosterone if it is an ACTH problem)
Type II diabetes
98
What is addisons disease? what are some of the symptoms?
caused by auto-immune destruction of adrenal cortex leading low levels of cortisol, so there is no feedback onto the anterior pituitary/hypothalamus to stop secreting ACTH; so excess ACTH causes abnormal processing of POMC leading to MSH production leading to hyper pigmentation;
since tehre are no glucocorticoids/mineralcorticoids, serious issues regulating: metabolism, blood pressure, and volume;
can be treated with hormone replacement
99
what is phenochromocytoma?
ectopic tumor of the adrenal medulla that causes continuous overproduction of adrenal catecholamines and exaggerated response to normal stimuli (increased stress response, sweating etc.)
