Ch 74-79 Endocrinology Flashcards
1
Q
What hormones does the hypothalamus produce? Which one is an amine?
A
TRH, CRH, GHRH, GHIH/somatostatin, GnRH, PIF
PIF is an amine. The rest are peptides
2
Q
What hormones does the anterior pituitary produce? What is their chemical structure?
A
Growth hormone, TSH, ACTH, Prolactin, FSH, LH. They are all peptides
3
Q
What hormones does the posterior pituitary produce?
A
ADH/vasopressin, Oxytocin. Both are peptides
4
Q
What hormones does the thyroid produce?
A
Thyroxine and triiodothyronine, calcitonin. T4 and T3 are amines
5
Q
What hormones does the adrenal cortex produce?
A
Cortisol and aldosterone. Both are steroids
6
Q
What hormones does the kidney produce?
A
Renin (peptide), 1,25-Dihydroxycholecalciferol (steroid), Erythropoietin (peptide)
7
Q
What hormones does the small intestine produce?
A
Secretin and cholecystokinin (CCK). Both peptides
8
Q
How are peptide vs steroid vs amine hormones “stored”
A
Peptides/proteins are stored in bio-active form in secretory vesicles within cells.
Steroids aren’t really stored, they are prepped as large stores of cholesterol ethers in cytoplasm vacuoles that are mobilized to make steroids, which diffuse across cell membranes once made
Amines/thyroid hormones are synthesized and stored in the thyroid and incorporated into thyroglobulin, which is stored. Secretion occurs when the amine splits off and hormone is released. In blood, it’s mostly bound to plasma proteins
9
Q
What are the ways in which hormones can interact with a receptor and cause intracellular signaling?
A
- Ion channel-linked receptors
- G Protein-linked hormone receptors
- Enzyme-linked hormone receptors
- Intracellular hormone receptors and gene activation
10
Q
How are g protein coupled receptors activated? Inactivated?
A
Hormone activates receptor, which activates the inactive alpha, beta, and gamma G protein complex when GDP swaps out for GTP. GTP is bound to alpha subunit, which dissociates from the rest and interacts with membrane-bound target enzymes to initiate intracellular signals.
Inactivation: when hormone is removed and alpha subunit converts its GTP to GDP
11
Q
How are enzyme linked receptors activated?
A
Hormone binds to the extracellular part and causes phosphorylation/activation of the intracellular JAK2. A signal transducer is phosphorylated and then STAT transcription proteins activate, and the target proteins are synthesized.
Another option, cAMP route:
hormone binds transmembrane receptor, which becomes activated adenylyl cyclase, that catalyzes cAMP (or cGMP) formation, which acts as a second messenger to cause effect
12
Q
How do intracellular hormone receptors lead to gene activation?
A
Lipophilic hormone diffuses into cell and binds a receptor in the cytoplasm or nucleus. The hormone-receptor complex binds to a promoter on the DNA to activate or inhibit gene transcription and mRNA and protein synthesis
12
Q
What are the three most common second messenger systems for intracellular hormone functions?
A
- Adenylyl cyclase-cAMP second messenger system
- Calcium ions and calmodulin
- Products of membrane phospholipid breakdown
12
Q
How does the calcium-calmodulin second messenger system work?
A
Calcium enters a cell and binds with one of the 4 binding sites on calmodulin. When 3-4 sites are filled, calmodulin changes shape to initiate activation or inhibition of protein kinases. Example is activation of myosin light chain kinase, which causes smooth muscle contraction.
Troponin C of skeletal muscle is similar to this
13
Q
Briefly, what is the action of growth hormone?
A
From somatotropes. Stimulates body growth, secretion of IGF-1, stimulates lipolysis, inhibits actions of insulin on CHO and lipid metabolism
13
Q
Briefly, what is the action of ACTH?
A
From corticotropes.
Stimulates production of glucocorticoids and androgens by the adrenal cortex, maintains the sie of zona fasciculata and zona reticularis of the cortex
14
Q
Briefly, what is the action of TSH?
A
From thyrotropes.
It stimulates the production of thyroid hormones by follicular cells and maintains their size
15
Q
Briefly, what is the action of prolactin?
A
From Lactotropes and mammotropes
Stimulates milk production and secretion
16
Q
Where are hormones of the posterior pituitary produced?
A
From large magnocellar neurons in the supraoptic and periventricular nuclei of the hypothalamus. Hormones are transported in the axoplasm to the ppg
17
Q
How is secretion by the anterior pituitary gland controlled?
A
Hypothalamic releasing or inhibiting hormones secreted by the hypothalamus are transported to the apg by the hypothalamic-hypophysial portal vessels.
18
Q
What are the specific functions/effects of growth hormone?
A
- Growth in almost all body tissues: more cell mitosis and size
- Increased rate of protein synthesis by enhancing transport into cells and increasing RNA translation, and decreased protein catabolism by mobilizing large amounts of free fatty acids to supply body energy
- Increased fatty acid mobilization by enhancing conversion into acetyl-CoA and its utilization for energy
- Decreased rate of glucose utilization by decreasing uptake by tissues, increased hepatic gluconeogenesis, and increasing insulin secretion because of attenuated ability by insulin to cause glucose utilization.
- Stimulates bone and cartilage growth by increasing protein deposition, increasing the rate of chondrocyte and osteocyte reproduction, and converting chondrocytes into osteogenic cells to increase deposition. It also strongly stimulates osteoclasts. *** GH also causes the liver to form somatomedins/insulin-like growth factors that increase all aspects of bone growth. Somatomedin C also greatly prolongs the effective action of GH
19
Q
What stimuli increase growth hormone secretion?
A
Hypoglycemia, decreased blood free fatty acids, increased blood amino acids, starvation/fasting, protein deficiency, trauma/stress, exercise, testosterone or estrogen, deep sleep, GHRH, Ghrelin
20
Q
What inhibits growth hormone release?
A
hyperglycemia, increased blood FFAs, aging, obesity, somatostatin, exogenous GH, somatomedins
21
Q
How is growth hormone release regulated by the ant pituitary and hypothalamus?
A
Hypothalamus: the ventromedial nucleus, which is sensitive to blood glucose conc, causes secretion of GHRH. Other areas control somatostatin. GHRH attaches to outer membrane receptors on cells in the APG and activate adenylyl cyclase to increase intracellular cAMP, which increases Ca++ ion transport into the cell and causes vesicle fusion and release. Long-term, it increases transcription to make more GH.
22
Where are oxytocin and ADH produced, and how are they secreted?
Oxytocin is formed primarily in the paraventricular nuclei and ADH is formed primarily in the supraoptic nuclei. Nerve impulses traveling down these fibers causes hormone release from the secretory granules in the nerve endings via exocytosis, and then are absorbed into the nearby capillaries. The hormones are secreted in combo with their carrier proteins, "neurophysins" and separate once in the blood
23
What is the function of ADH?
ADH combines with membrane receptors to activate adenylyl cyclase and cause cAMP to form inside the cell, leading to phosphorylation of special vesicles which fuse to the apical cell membranes and create more aquaporins.
This happens at the collecting ducts and tubules, allowing greater water reabsorption and concentration of the urine. It takes 5-10 minutes. Without ADH, more water is lost and the urine becomes dilute
24
How is ADH regulated?
When extracellular fluid near the hypothalamus is too concentrated, fluid is pulled by osmosis from the osmoreceptor cells and decreases its size -> ADH secretion. When EC fluid is too dilute, water moves into the cell and decreases signal for ADH release.
Concentrated body fluids stimulate the supraoptic nuclei and dilute body fluids inhibit
ALSO, if blood volume decreases 15-25%, the atrial stretch receptors are unexcited due to underfilling and greatly increase ADH secretion, and decreased stretch of he carotid, aortic, and pulmonary baroreceptors stimulates ADH secretion. Stretch of these lumens excites the receptors and inhibits ADH release
25
What are the functions of oxytocin?
Stimulates uterine contractions and milk letdown. How? Cervical stretch increases release, and nursing on the teat stimulates sensory nerves that excite neurons in the periventricular and supraoptic nuclei to cause release of oxytocin, which then causes myoepithelial cells to contract and cause both milk letdown and ejection
26
How is iodide utilized in the thyroid gland?
Iodide is needed to synthesize thyroid hormones. Idodides are transported from the blood by a sodium-iodide symporter (one I for every 2 Na), with a sodium gradient created by a Na/K ATPase.
Iodide is then trapped inside the cell, and the rate at which this happens is influenced by TSH conc.
Iodide is transported out of the cells by a Cl/I counter-transporter called Pendrin.
27
How are the thyroid hormones formed?
1. Iodide ions are oxidized via peroxidase
2. Iodine now binds to thyroglobulin (organification) via thyroid peroxidase enzyme
3. Iodination occurs until the major product Thyroxin (T4) is formed. **T3 is an earlier form
28
How is thyroid hormone stored?
In the form of thyroglobulin molecules within the follicles of the gland, enough to last several months
29
How is thyroxine and T3 released from the thyroid gland?
1. Apical surface of the thyroid cells send pseudopod extensions to wrap around portions of colloid (pinocytic vesicles)
2. Lysosomes immediately fuse with vesicles
3. Proteases from the lysosomes digest thyroglobulin and release T4 and T3
4. T4 and T3 diffuse through the base of the thyroid cell and into capillaries
30
Which form of thyroid hormone is used by the tissues?
Mostly Triiodothyronine, because even though mostly thyroxine is released, it gets slowly deiodinated to form T3
31
How are T4 and T3 delivered to tissues?
They bind with plasma proteins synthesized by the liver: thyroxine-binding globulin and a little thyroxine-binding prealbumin and albumin. They have high affinity for these proteins and so are very slowly released to tissue cells. When entering tissue cells, they bind again with intracellular proteins and have a long latent period; max cellular activity takes days. Most of the thyroid hormone that binds receptors is T3 (1 iodide removed), which has high affinity for receptors
32
What are the two main destinations/functions for thyroid hormone in the cell?
1. Bind to (mostly) retinoid x receptors at thyroid hormone response elements on/near DNA strands to activate DNA transcription and production of new proteins/enzymes
2. Nongenomic functions include regulating ion channels and oxidative phosphorylation, or activation of intracellular signaling pathways.
33
How do thyroid hormones influence cellular activity?
**increase metabolic activities of most body tissues, increased protein synthesis and catabolism
1. Increased size, # , surface area, and activity of mitochondria
2. Increases active transport of ions through the cell membrane (increased Na/K ATPas activity and leakier cell membrane)
34
What are the overall effects of thyroid hormone on the bodily systems?
1. Increased fat and CHO metabolism
2. Decreased concentrations of cholesterol, phospholipids, and triglycerides in the plasma and increased free fatty acids (reverse if hypothyroid). Due to increased cholesterol secretion in the bile and loss in feces
3. Increased requirement for vitamins
4. Increased basal metabolic rate
5. Decreased body weight
6. Increased blood flow and cardiac output via vasodilation and compensatory increase in cardiac output
7. Increased heart rate (direct effect)
8. Increased strength of cardiac contractions
9. Normal mean arterial pressure but increased systolic pressure
10 . Increased RR due to greater O2 utilization
11. Increased GI motility and digestive juice secretion
12. Increased nervousness/anxiety
13. Vigorous skel muscle reaction , but eventual weakening
14. Fine muscle tremors
15. Inability to sleep if hyperthyroid, or somnolence if hypothyroid
16. Increased need for insulin and parathyroid hormone, increased ACTH production
17. Hypothyroidism decreases libido
35
What effects does TSH have on thyroid secretion?
**1. Increased thyroglobulin proteolysis. MOST important early effect, occurs in 30 minutes
2. Increased iodide pump activity
3. Increased iodination of tyrosine
4. Increased sie and secretory activity of thyroid cells
5. Increased number of thyroid cells and change from cuboidal to columnar
36
How does TSH initiate effects on cells of the thyroid gland?
TSH binds to specific receptors of the basal membrane, which activates adenylyl cyclase, which increases intracellular cAMP, which is a second messenger to activate protein kinase, which causes phosphorylation throughout the cells, immediately increasing secretion of thyroid hormones and prolonged gland growth
37
How is release of TSH regulated?
The hypothalamus secretes TRH from nerve endings in the median eminence. TRH is transported to the aPG by portal blood flow. It binds to TRH receptors in the apg membrane.
This activates the phospholipase second messenger system inside pituitary cells to produce lots of phospholipase C, then second messengers such as calcium and diacyl glycerol, and TSH is released.
When thyroid hormone secretion rises to 1.75x normal, TSH secretion falls to ~zero
38
How does environmental temperature influence TRH release?
Exposure to cold increases TRH secretion
39
What are the layers of the adrenal cortex, and what is produced in each?
1. Zona glomerulosa: aldosterone. Just under the capsule. Controlled by angiotensin II and potassium conc in the EC fluid
2. Zona fasciculata: middle, widest. Cortisol and corticosterone, and a little adrenal androgens/estrogens. Controlled by ACTH
3. Zona reticularis: Deep layer. Secretes adrenal androgens and androstenedione, and some estrogens and cortisol.
40
What is the rate-limiting step in adrenal steroid production?
Cleavage of intracellular cholesterol by the enzyme cholesterol desmolase, to form pregnenolone
41
List the mineralocorticoids produced by the adrenals, indicating the most and least potent
1. Deoxycorticosterone (least potent)
2. Corticosterone
3. Cortisol
4. Cortisone
5. Aldosterone (very potent, 90% of all mineralocorticoid activity)
42
List the six common glucocorticoids, synthetic and endogenous, in increasing order of potency
1. Corticosterone
2. Cortisone
3. Cortisol (has weak mineralocorticoid activity too)
4. Prednisone (synthetic, 4x potency of cortisol)
5. Methylprednisone (synth, 5x potency of cortisol)
6. Dexamethasone (synth, 30x potency of cortisol)
43
What are the elimination half-lives of cortisol and aldosterone, respectively? What explains the length of their half lives?
Cortisol: t1/2 60-90 minutes because 90-95% of it is bound in the plasma to cortisol-binding globulin or transcortin (and albumin, slightly)
Aldosterone: t1/2 is 20 minutes because only 60-40% binds to plasma proteins
44
How are the adrenocortical hormones metabolized and excreted?
Degraded in the liver and conjugated to glucuronic acid and sulfates (less so). 25% of the conjugates are excreted in bile --> feces. The rest are soluble in the plasma, unbound to proteins, and are excreted into urine after renal filtration
45
How do aldosterone and cortisol respectively contribute to total body mineralocorticoid production?
-Aldosterone = 90% of mineralocorticoid activity of adrenal secretions
-Cortisol = significant amount because its greater plasma concentration makes up for its reduced mincort activity. But it binds with high affinity to mincort receptors, including those in the kidney with an enzyme that converts them to cortisone (less affinity).
------the renal enzyme responsible is 11beta hydroxysteroid dehydrogenase type 2
46
What is/are the effects of aldosterone on renal tubular management of electrolytes?
It increases renal tubular (principal cells of collecting tubules esp) reabsorption of sodium and secretion of potassium. .
The net effect is to increase the total quantity of Na+ in the ECF while decreasing K+.
47
What is the effect(s) of aldosterone on ECF volume and arterial pressure? What is meant by "aldosterone escape"?
Only transient Na+ chnages occur because Na+ reabsorption by the kidneys leads to osmotic absorption of nearly equivalent H2O amounts, and small increases in ECF Na+ stimulate thirst and increase water intake.
Aldosterone escape:
When aldosterone increases the ECF volume for > 1-2 days, arterial pressure increases kidney excretion of salt and water via pressure natriuresis and diuresis
48
How does aldosterone influence potassium levels?
Excess aldosterone: causes K+ loss into the urine AND stimulates K+ transport into cells (out of ECF). HYPOKALEMIA = severe muscle weakness via prevention of normal action potentials
Inadequate aldosterone: causes toxic K+ levels in the ECF, leading to cardiotoxicity via arrhythmia development and weakened heart contractions, then heart failure
49
How does aldosterone influence body pH?
Aldosterone causes secretion of hydrogen ions in exchange for sodium into he intercalated cells of the cortical collecting tubules. Result is metabolic alkalosis
50
What is the effect of aldosterone on the sweat and salivary glands and in the intestines?
Increases Na+ reabsorption and K+ secretion by the salivary and sweat glands. It causes Na+ absorption by the colon
51
What cellular events take place in response to aldosterone in the tubular epithelial cells
1. Diffuses across the plasma membrane of principal cells of the collecting tubules
2. In the cytoplasm, binds to specific mineralocorticoid receptor protein
3. Aldosterone-receptor complex diffuses into the nucleus to induce DNA to form mRNA for proteins to....
4. Travel to cytoplasm and induce production of enzymes and membrane transport proteins for Na, K, and H
a. Na/K adenosine triphosphatase for Na/K exchange at the renal tubular cell basolateral membranes
b. Epithelial sodium channels in the luminal membrane of same cells
52
Briefly, how is aldosterone secretion by the zona glomerulosa cells controlled?
***1. Increased ECF [K+] greatly increases secretion
***2. Increased angiotensin II in the ECF greatly increases secretion
3. Increased [Na+] in the ECF slightly decreases secretion
4. ACTH is necessary but has little effect on rate of secretion
53
How does cortisol stimulate gluconeogenesis?
1. Increases the enzymes required to convert amino acids into glucose in the liver cells by upregulating transcription of said enzymes
2. Causes mobilization of amino acids from the extrahepatic tissues, especially skeletal muscle
...also causes increased hepatic glycogen storage so epinephrine and glucagon can easily mobilize it
54
How can glucocorticoids contribute to insulin sensitivity?
High levels of glucocorticoids reduce tissue sensitivity to insulin, especially skeletal muscle and adipose
55
What are the effects of cortisol on protein metabolism?
1. Reduction of cellular protein stores (less synthesis, increased catabolism). This affects muscle and lymphoid immunity tissue
2. Increased liver and plasma proteins despite reduction elsewhere
3. Increased blood amino acids, diminished transport of amino acids into extrahepatic cells, and enhanced transport into hepatic cells
-Cortisol mobilizes amino acids from the nonhepatic tissues
56
Specifically, how does cortisol influence handling of protein by the liver?
1. Increased rate of deamination of aa's by the liver
2. Increased protein synth in the liver
3. Increased formation of plasma proteins by the liver
4. Enhanced gluconeogenesis
57
What are the effects of cortisol on fat metabolism?
1. Promotes fatty acid mobilization from adipose. Seemingly direct effect to enhance FA oxidation in cells
2. Diminished transport of glucose into fat cells
3. Shifts metabolic systems to use fatty acids, not glucose, for energy (takes hours to develop)
58
In what ways does cortisol prevent the development of inflammation?
1. Cortisol stabilizes the lysosomal membrane
2. Cortisol decreases the permeability of the capillaries
3. Cortisol decreases migration of wbc's into the inflamed area, and phagocytosis of the damaged cells via decreased formation of prostaglandins and leukotrienes
4. Cortisol suppresses the immune system, reducing lymphocyte (esp T lymphocytes) markedly
5. Cortisol attenuates fever by reducing release of interleukin-1 from wbc's
59
What other effects does cortisol have on the immune response and inflammatory events?
1. Causes resolution of inflammation
2. Blocks the inflammatory response to allergic reactions
3. Decreases numbers of eosinophils and lymphocytes in the blood
4. Increases production of red blood cells
60
BRIEFLY, how does cortisol enact changes at a cellular level?
Diffuses into cells and binds with cytoplasmic receptor, and the hormone receptor complex interacts with glucocorticoid response elements to induce or repress gene transcription
61
How is cortisol release by the adrenal gland controlled?
ACTH secretion from the aph almost entirely controls cortisol release. ACTH also stimulates release of adrenal androgens.
ACTH release is controlled by hypothalamic release of corticotropin-releasing factor (CRF) secreted into the capillaries of the hypophyseal portal system in the median eminence of the hypothalamus
CRF-producing neurons have their cell bodies in the paraventricular nucleus of the hypothalamus
62
What is/are the principal effects of ACTH on the adrenocortical cells?
What is the rate limiting step?
It activates adenylyl cyclase in the cell membrane, which induces formation of cAMP and this activates intracellular enzymes needed to cause formation of adrenocortical hormones
Rate limiting step: activation of the enzyme Protein Kinase A, which causes the initial conversion of cholesterol to pregnenolone
63
What is the inhibitory effect of cortisol on the hypothalamus and APG?
Direct negative feedback control on both the apg and the hypothalamus
64
How does circadian rhythm influence cortisol levels?
CRF, ACTH, and cortisol are high in the early morning and low in late evening
65
Which other hormones are secreted simultaneously with ACTH?
POMC (proopiomelanocortin), a precursor of ACTH
MSH (melanocyte stimulating hormone)
Beta lipotropin
Beta endorphin
Bonus: the pars intermedia secretes a LOT of MSH, which is independently controlled by the hypothalamus in response to light exposure
66
What do the cell types of the pancreas produce, respectively?
Acini: digestive juices
Islets of langerhans:
-Beta cell: Insulin and amylin
-Alpha cell: glucagon
-Delta cell: Somatostatin
67
Briefly, how is insulin synthesized?
Preproinsulin -> proinsulin -> package insulin and connecting peptide C together
68
How does insulin enact its effect on target cells?
1. Insulin binds to alpha subunits of a membrane receptor protein and the beta units are phosphorylated (enzyme-linked receptor)
2. Local tyrosine kinase activates, phosphorylating other enzymes
3. Glucose uptake increases (except not in the brain)
4. Cell membrane becomes more permeable to amino acids, K+, and phosphate ions, and they are transported INTO the cell
69
How does insulin promote muscle glucose uptake and metabolism?
-If the muscles aren't exercising after a meal, insulin will cause muscle cells to store glucose as glycogen
70
How does insulin promote the uptake, storage, and use of glucose in the liver
1. Insulin inactivates liver phosphorylase to prevent glycogen breakdown
2. Insulin causes enhanced uptake of glucose from the blood by hepatic cells by increasing activity of glucokinase
3. Insulin increases activities of enzymes promoting glycogen synthesis (glycogen synthase)
Net effect = increased glycogen in liver
71
HOw is glucose released from the liver between meals?
1. Blood glucose falls, so insulin secretion falls
2. Lack of insulin = stops glycogen synthesis and prevents uptake
3. Phosphorylase activates = split glycogen into glucose phosphate
4. Glucose phosphatase is activated and splits phosphate radical from the glucose
72
How does insulin promote the conversion of excess glucose into fatty acids and inhibit gluconeogenesis in the liver?
Excess glucose = converted into fatty acids, which are packaged tightly as triglycerides in VLDL's and transported to adipose. Insulin inhibits gluconeogenesis by decreasing quantities and activity of liver enzymes needed for the process
73
Why does insulin not affect brain glucose usage?
Because most of the brain's cells are permeable to glucose and can use it without insulin
74
How does insulin promote fat synthesis and storage?
1. Insulin increases glucose transport to the liver cells. After glycogen synthesis stops, glucose is split until Acetyl co A forms
2. When excess glucose is used for energy, there is excess citrate and isocitrate ions formed, which activate acetyl-CoA carboxylase for fatty acid synthesis
3. Most fatty acids are synthesized within the liver to form triglycerides, then released into the blood as lipoproteins. Insulin activates lipoprotein lipase in adipose capillary walls and that splits TRIGs into fatty acids
75
What is the role of insulin to cause fat storage within adipose?
1. Insulin inhibits hormone-sensitive lipase, inhibiting release of fatty acids from the adipose into blood
2. Insulin promotes glucose transport through the cell membrane into fat cells, and large amounts of alpha glycerol phosphate is formed, which supplies glycerol to form TRIGs as the storage form of fat
76
How does insulin deficiency influence the use of fat for energy
1. Insulin absence leads to activation of hormone-sensitive lipase, causing hydrolysis of stored triglycerides and release into the blood
2. Insulin deficiency increases plasma cortisol levels and phospholipid concentrations
77
How can insulin deficiency lead to ketosis and acidosis?
Excess usage of fat during insulin lack can cause ketosis and acidosis because excess acetoacetic acid is formed in the liver BECAUSE the carnitine transport mechanism for transporting fatty acids is increasingly activated. THe excess acetyl-CoA is condensed to form acetoacetic acid that is released
BUT lack of insulin depresses tissue ability to use acetoacetic acid and concentrations can rise until causing acidosis
Some of the acetoacetic acid is converted to BHB, and their presence creates ketosis in large enough quantities
78
How does insulin promote protein synthesis and storage?
1. Insulin stimulates transport of many amino acids into the cells by increasing uptake
2. Insulin increases the translation of mRNA to form new proteins
3. Over time, insulin increases the rate of transcription of selected DNA genetic sequences
4. Insulin inhibits catabolism of proteins
5. In the liver, insulin depresses rate of gluconeogenesis
79
How is insulin secreted within a pancreatic beta cell ?
1. GLUT 2 glucose transporters allow glucose influx into the cell
2. Once intracellular, glucose is phosphorylated to glucose-6-phosphate by glucokinase (rate limiting step)
3. Glucose-6-phosphate is oxidized to form ATP
4. ATP inhibits the ATP-sensitive K+ channels of the cell
5. K+ channels close and the cell depolarizes
6. Voltage gated Ca2+ channels open, and the calcium influx causes insulin-containing vesicles to dock to the cell membrane and release insulin via exocytosis
80
How does increased blood glucose affect insulin levels?
1. After an acute BG elevation, preformed insulin is released from islet cells and insulin spikes immediately
2. Insulin then decreases halfway back
3. At 15 minutes, insulin secretion rises again to reach a new plateau in 2-3 hours as new insulin forms and enzymes are activated
81
How is insulin secretion stopped?
When blood glucose falls back to fasting level, insulin secretion rapidly stops
82
What other factors can influence insulin secretion?
1. Amino acids, esp arginine and lysine, which potentiate the glucose stimulus for insulin secretion
2. GI hormones cause a moderate insulin increase in anticipation of a meal
3. Glucagon, GH, cortisol, progesterone, and estrogen
83
What are the effects of glucagon on glucose metabolism?
1. Glycogenolysis
2. Increased gluconeogenesis in the liver
84
How does glucagon cause increased blood glucose?
1. Glucagon activates adenylyl cyclase in the hepatic cell
2. Cycline adenosine monophosphate forms
3. Activates protein kinase regulator protein
4. Activates protein kinase
5. Activates phosphorylase b kinase
6. Converts phosphorylase b into phosphorylase a
7. Glycogen gets degraded into glucose-1-phosphate
8. This is phosphorylated and glucose is released
85
What is the other significant effects of glucagon?
1Activates adipose cell lipase to make more fatty acids available for energy and inhibits storage of triglycerides in the liver
2. Enhances heart strength
3. Increases blood flow in tissues (**kidneys)
4. Inhibits gastric acid secretion
5. Increases bile secretion
86
How is glucagon secretion regulated?
1. Decreased blood glucose to hypoglycemic levels increases plasma concentration of glucagon
2. Increased blood amino acids stimulate glucagon
3. Exercise stimulates glucagon
4. Somatostatin inhibits glucagon (and insulin)
87
Briefly, what are the effects of somatostatin on the GI tract and blood sugar regulation?
1. Acts locally in the pancreas to depress insulin and glucagon secretion
2. Decreases stomach, duodenum, and gallbladder motility
3. Decreases absorption and secretion in the GI tract
88
Briefly: How is calcium absorbed? How is it excreted?
-Vit D promotes intestinal absorption
-90% of daily intake is excreted in feces and 10% into urine
-At the kidneys, reabsorption occurs at the loop of Henle, early distal tubules, and proximal tubules. A little bit is reabsorbed in the late distal tubules and early collecting ducts
89
Briefly, how is phosphate absorbed and excreted?
Absorption: from the GIT, excreted in the urine
Excretion is via overflow mechanism: all is reabsorbed and none is lost until it rises above 1 mmol/L, then it's directly proportional to the increase
90
What is the function of pyrophosphate?
An inhibitor to prevent precipitation of hydroxyapatite crystals in normal tissues except bone despite supersaturation
91
What are the 'hormonal' effects of Vitamin D on calcium absorption?
Vit D can increase formation of calbindin, which is a calcium-binding protein in intestinal epithelial cells at the brush border, working to transport calcium into the cell cytoplasm. Ca then moves through the cell by facilitated diffusion and remains for weeks in the cell after the 1,25-dihydroxycholecalciferol is gone
Vit D also influences formation of calcium-stimualted ATPas in the rush border and an alkaline phosphatase in epithelial cells
92
Summarize the effects of Vitamin D on phosphate absorption
1. Enhances phosphate flux through the GIT
2. Increases phosphate reabsorption by the epithelial cells of the renal tubules (weak)
93
In summary, what are the actions of vitamin D?
1. Promotes intestinal calcium absorption
2. Decreases renal calcium and phosphate excretion
3. Promotes phosphate absorption by the intestines
4. In excess, causes bone absorption
5. In small amounts, causes bone calcification
94
Where is PTH produced and which cells secrete it?
In the parathyroid gland, mainly in the chief cells
95
VERY briefly, how does PTH alter calcium and phosphate levels?
Ca rises and Phos falls because although PTH causes increased absorption of both from the bone and decreases calcium loss from the kidneys, but renal phosphate excretion increases
96
What is the fast phase of calcium absorption from bone?
-Removal of bone salts in the vicinity of the osteocytes within the bone and in the vicinity of the osteoblasts along the bone surface.
-Osteoblasts form an osteocytic membrane system that pumps calcium ions from the bone fluid into the extracellular fluid to create a low calcium concentration in fluid around the bone to draw out Ca from the bone itself by osteolysis.
-PTH facilitates this by binding to the osteoblasts and osteocytes' receptors, and binds to the calcium pump to cause rapid removal of calcium phosphate salts from the amorphous bone crystals near the cells and increases calcium permeability of the bone fluid side of the osteocytic membrane. The calcium pump on the other side transfers said calcium to the ECF
97
How does PTH activate osteoclasts to cause the slow phase of bone absorption?
-Activated osteocytes/blasts send signals to osteoclasts
-Secondary messenger Osteoprotegerin ligand activates receptors on the preosteoclast cells and matures them
-Already-formed osteoclasts are activated to resorb bone rapidly
-New osteoclasts form and continue as long as PTH is high
98
What is the effect of PTH on the kidneys?
1. Reduced proximal tubular reabsorption of phosphate ions
2. Increases renal tubular reabsorption of calcium in the late distal tubules, the collecting tubules, and early collecting ducts especially
3. Increased rate of reabsorption of magnesium ions and H+
4. Decreased absorption of Na+, K+, and amino acid ions
99
What is the effect of PTH at the intestines?
-Via vit D probably.
Remember! A big part of the effect of PTH at all its targets owes to how PTH increases intracellular cAMP in osteocytes, osteoclasts, and other targets, leading to formation of 1,25-dihydroxycholecalciferol in the kidneys ...increasing GI absorption
100
How does the body's Ca++ ion concentration control PTH secretion?
-Conditions such as excess dietary calcium, increased dietary VitD, and bone absorption for other reasons leads to decreased PT gland activity
-Changes in ECF [Ca] are detected by calcium sensing receptor in PT cell membranes. This G-protein coupled receptor is stimulated by Ca++ to activate phospholipase C and increase intracellular inositol, 1,4,5-triphosphate and diacylglycerol formation.
These stimulate release of intracellular Ca and decreases PTH secretion.
101
Where is calcitonin produced and what is its function?
1. Produced from the parafollicular cells/C cells of the thyroid gland
2. Mostly effective in young/baby animals
3. Increased extracellular fluid calcium stimulates release
1. Immediate effect is to decrease osteoclast absorptive activity
2. Longterm effect is to decrease the formation of new osteoclasts
Easily overridden by PTH if Ca falls, in adult animals
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