1
Q
Pancreatic: Islets of Langerhans
Alpha cells
A
glucagon
2
Q
Pancreatic: Islets of Langerhans
Beta Cells
A
insulin
3
Q
Pancreatic: Islets of Langerhans
Delta
A
somatostatin
4
Q
Pancreatic: Islets of Langerhans
F cells
A
pancreatic polypeptide
5
Q
insuline synthesis
A
proinsulin = insulin + C-peptide
6
Q
Major stimuli for insulin secretion?
A
Increase plasma glucose concentration Increase amino acids Increase in GI hormones (GIP) Increase in parasympathetic activity Decrease in sympathetic activity Increase glucogon Growth Hormone and Cortisol
7
Q
Major stimuli for glucagon secretion?
A
Decrease plasma glucose concentration
Increase plasma amino acids
Decrease in glucose
8
Q
Insulin
A
T1/2 = 5 min
Degradation: 80% in liver and kidney
-rest in other tissues
-insulinase (protease?)
may act when insulin receptor is internalized
possile site of drugs to prolong insulin life and make limited last longer
Go to liver
Acts on MUSCLE, LIVER, ADIPOSE TISSUE (most other tissues too)
9
Q
Glucagon
A
T1/2 = 5-10 min
Degradation: most occurs in liver, peripheral conc. of Gg are low
Go to liver
Acts on LIVER
10
Q
Insulin stimulates glucose uptake in?
A
- muscle
- adipose tissue
11
Q
Insulin does NOT stimulate glucose uptake in?
A
- brian (except hypothalamus)
- intestinal muscosa
- red blood cells
- kidney tubules
12
Q
Hepatic actions of glucagon
A
- Increase glycognelolysis
- Increase amino acid uptake
- Increase gluconeogenesis
- Increase ketoneogenesis
13
Q
Enzymes altered by Glucagon
A
- increase phosphorylase activity
- decrease glycogen synthetase activity
14
Q
Glucaagon and catecholamines need prior action of ? to function optimally in the liver.
A
cortisol
15
Q
Speed of Insulin Action
A
Fast for glucose uptake
Slower for synthesis of enzymes (hours)
16
Q
Potency of Insulin
A
Most potent
17
Q
Anabolic aspect of Insulin
A
- Major storage hormone
- promotes synthesis of 3 main nutrient storage forms: protein, carbohydrate (glycogen), fat (triglyceride)
18
Q
Anti-Catabolic aspect of Insulin
A
- decrease protein degradation
- decrease (stop) glycogenolysis
- decrease gluconeogenesis
- decrease (stop) lipolysis
19
Q
Islets in Pancreas
A
- scattered throughout
- only 2% of mass
- mostly in tail
- beta cells in center, occupy 60-85%
20
Q
Hormone Synthesis of Insulin
A
1) translation, transolcation
2) folding, oxidation & signal peptide cleavage
3) ER export, Golgi transportation, vesicle packaging
4) protease cleavage liberates C-peptide
5) carboxypeptidase E produces mature insulin
* measure C Peptide to get B-cell function*
21
Q
Speed/Duration of action of Glucagon?
A
fast
-promotes glucose release from liver to maintain normal plasma glucose conc.
22
Q
Dual action of Insulin?
A
- stimulates building up
- inhibits breaking down of nutrient stores
23
Q
Action of Insulin on Muscle?
A
- increase glucose uptake
- increase amino acid uptake
- increase ribosomal PROTEIN synthesis
- increase synthesis of lipoprotein lipase
- DECREASE protein breakdown
- DECREASE release of amino acids
24
Q
Action of Insulin on Adipose Tissue?
A
- increase glucose uptake
- increase fatty acid synthesis from glucose
- increase alpha-glycerol phosphate synthesis
- increase synthesis of LPL
- SUPER increase TaG synthesis from FA and glycerol phosphate
- DECREASE lipolysis (decrease activity of “hormone-sensitive lipase”)
25
Action of Insulin on Liver?
- Decrease release of glucose
- Increase lipid synthesis (TAG)
- Increase protein synthesis
- Decrease ketogenesis
26
What hormones down regulate sensitivity of target cells to insulin?
- growth hormone
| - cortisol
27
Mechanical Strength of Bone
-pulling work muscles and tendons
28
Biomechanical: Bone
scaffolding and support
| -gravity protecting
29
Calcium Homeostasis: Bone
- 99% of body calcium
| - bone resorption and bone formation are coupled or bone disorders osteoporosis, Paget's disease
30
Bone Repairs Itself
- remodeling - development
| - bone is depot for mineral binding proteins and growth factors
31
Bone Growth and Remodeling
- can repair with production of matrix just like previous matrix
- ex: fracture repair, forms callus to and repaired bone is as strong as previously
- bone is a tissue that continuously remodels, can respond to stress
- cycle of bone formation & resorption depends on cells of bone: osteoblast, osteocyte, osteoclast
- bone contains vascular tissue and nerves
- devitalized, demineralized bone contains growth and differentiation factors that will stimulate bone growth in ectopic sites even under skin
32
Osteoblasts
- specific transcription factors for osteoblast differentiation are made in response to developmental regulators called BMPs are members of the TGF-beta superfamily
- differentiated osteoblasts make osteoid a collagenous matrix containing bone-specific proteins
- if become entrapped in matrix are osteocytes that can communicate with each other and with osetoblasts through cell processes in canaliculi
- demand for calcium stimulates bone resorption to release Ca2+ from mineralized matrix
- bone acts like a bank for deposits and withdrawals of calcium
33
Osteoclast
- multinucleated giant cells formed by differentiation and fusion of monocytes
- differentiation involves cell-cell interaction with osteoblasts through a RANK-RANKL interaction
- resorb bone matrix, releasing calcium and degrading the proteins of osteoid
- resorb a region of bone matrix sealed off below the cell body by releasing acid and proteases into the sealed off space
34
Bone remodeled because?
- in response to demands for calcium and to mechanical stresses that demand enhanced or reduced bone mass
- Ca2+ demands involve the Ca homeostatic mechanisms and endocrine hormones like parathyroid hormone which enhances calcium release and calcitonin which opposes the release of ca
- Vit. D3 and calcitriol are essential for calcium absorption and bone mineralization
- rickets (children), osteomalacia (adults)
35
Endochondral Bone Formation
- bone forms on a cartilage scaffold in the process of endochondral bone formation, the cartilage becomes calcified and then is replaced by bone matrix and a vascular bed at the growing ends of bone
- components of cartilage like type II collagen and aggregan are replaced by bone specific proteins like osteocalcin, ostoepontin, bone sialoprotien and a highly crosslinked type I collagen (bone collagen crosslinks are a commonly used marker for clinical bone turnover measurement. Rich in crosslinks derived from HYL)
36
Osteoporosis
-1 in 4-5 postmenopausal women
-113,00 women and 34,000 men/year suffer broken hip
-"pediatric disease with geriatric outcome" early buildup of bone mass in prepuberty and early adulthood is protective
-diet Ca2+, vit D sunlight, fortified foods, protein sufficiency, other factors VIT K
-exercise builds and maintains better bone mass
-genetic factors (caucasians/asians)
-common in postmenopausal women
Not clear if increases bone resorption or decreases in bone formation are primary cause
37
Physiological Importance of Calcium
- bone growth/remodeling
- excitation-secretion (exocytosis) coupling
- excitation-contraction coupling
- action potentials
- cofactor for enzymes (blood clotting proteases)
- second messenger in cells
38
Calcium in Blood: the #'s
- normal total in blood = 10mg/dl
- range 8.5-10.5mg/dl
- only 55-60% free Ca2+
- hypo is < 8.5mg/dl
- hyper is > 10.5mg/dl
39
What does hypocalcemia cause?
-nervous system excitement
below 50% from normal, peripheral nerve fibers become so excitable that they begin to spontaneously discharge impluses that pass to peripheral skeletal muscles to elicit tetanic muscle contraction
-tetany (carpopedal spasm in hand)
40
What happens with ingested Calcium?
- most eliminated in feces
- kidneys can excrete large amounts by reducing tubular reabsorption
- deposti/resorption from bone
- in extracellular fluid
41
PTH
Parathyroid hormone
- secreted by chief cells of parathyroid gland as polypeptide containing 84 aa's
- increases calcium and decreases phosphate upon infusion
- PTH receptors are on osteoblasts
42
Calcitonin
-hormone produced by the C cells of the thyroid gland as a polypeptide containing 32 aa's
43
How does bone exchange with it's surroundings?
- it's immersed in saturated aqueous solution of Ca2+ and PO4-
- this Ca2+ pool is separated from the ECF by osteocytic membrane formed by osteocytes and osteoblasts, but it readily exchanges with the ECF via the osteocytes and osteoblasts
44
PTH action on bone fluid?
- 1) lowers plasma PO4- by decreasing renal PO4 reabsorption, which causes the product of [Ca] and [PO4] to be less then the solubility product
2) increases Ca permeability and Ca2+ pump activity of the osteocytic membrane (allow bone salts to move from the bone fluid to the ECF)
3) slowly increases the formation & activity of osteoclasts, which resorb bone, thereby releasing Ca
- PTH receptors are on osteoblasts
45
PTH action on Osteoclasts>
1) slowly increases the formation & activity of osteoclasts, which resorb bone, thereby releasing Ca
2) binds to PTHR1 receptor in osteoblasts & stimulates the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) expression on the cell surface
- RANKL binds to RANK (cell surface protein on osteoclast precursors)
- binding activates osteoclast gene transcription and the differentiation into a mature osteoclast, resulting in bone resorption at the ruffled membrane
46
Osteoprotegerin
- soluble protein secreted by osteoblasts, prevents binding of RANKL to RANK, thereby inhibiting osteoclastic bone resorption
- PTH decreases osteoprotegerin production
- Estrogen stimulates it
47
Intermittent Low-Dose PTH does?
- increases bone formation
- act through PTH receptor to enhance proliferation and differentiation of osteoblasts
- also decreases apoptosis of osteoblasts, thus resulting in increased bone formation
48
Renal Ca2+ Reabsorption
-55% filterable
-60% reabsorbed in proximal tubule
-20% Loop of Henle
-10-15% distal tubule (increased PTH)
-5% in collecting duct
1% excreted ( decrease PTH/increase Na/protein diet)
49
Effect of Ca2+ on PTH and Calcitonin
-small change of few % points can cause 100% change in PTH
50
What senses changes in ECF Ca2+ concentrations?
-G protein-coupled receptor on the parathyroid chief cells
51
Main peripheral actions of PTH?
| -increased PTH in response to decreased ECF Ca
1) increases calcium reabsorption and decreases phosphate reabsorption by renal tubules, leading to decreased excretion of calcium and increased excretion of phosphate
2) stimulates bone resorption by the renal tubules, leading to decreased excretion of calcium and increased excretion of phosphate
3) needed for conversion to active vit D which increases Ca absorption by intestines
- CaSR, calcium-sensing receptor
52
Main Peripheral Actions of Calcitonin
1) Opposite of PTH
2) lowers plasma Ca and phosphate concentration predominantly through:
- reducing bone resorption through inhibiting osteoclast activity
- inhibiting renal tubular cell reabsorption or Ca allowing it to be excreted in the urine
3) inhibits phosphate reabsorption by the kidney tubules
4) Calcitonin protects against Ca loss from the skeleton during periods of Ca mobilization, such as during pregnancy and lactation, also active in children
5) can be used pharmacologically to treat osteoporosis
53
Vitamine D Peripheral Actions
- increased bone resorption
- increased Ca absorption (in intestines), increase plasma Ca conc.
- increase Ca reabsorption in kidney
- decrease PTH synthesis
54
Vitamine D Metabolism
-occurs in kidneys
cholecalciferol to active form 25(OH)VitD
1) provit D in skin is converted to cholecalciferol by UV light
2) Cholecalciferol and Ergocalciferol are transported to liver - first step of bioactivation which is hydroxylation at C-25 to 25-hydroxy-vitD (major circulating form)
3) 2nd hydroxylation step at C-1 occurs in the kidney and results in the hormonally active 1,25(OH)2 mediated by 1alpha-hydroxylase (which is stimulated by PTH and inhibited by Ca and Vit D)
4) decreased activity of 1alpha-hydroxylase favors C-24 hydroxylation and formation of the less active 24,25 (OH)2D
55
Vitamine D Actions at Target Organs
1) increases bone resorption
2) increases Ca absorption from the intestine (MAJOR EFFECT)
3) increases renal Ca reabsorption
4) decreases production of PTH by parathyroid gland
* ****OVERALL TO INCREASE PLASMA Ca*****
56
Effect of Plasma Ca on Plasma Vit D?
-slight decrease in Ca conc. below normal causes increased Vit D formation which leads to increased absorption of Ca from intestine
57
Relationship between Ca and Phosphate?
- Phosphorus is commonly found in pentavalent form in combination with oxygen (PO4)
- chemical equilibrium b/w Ca and phosphate
- bone is complex precipitate of Ca and phosphate (hydroxyapatite), which is laid down in the protein osteoid matrix
- the product of Ca and P concentrations determines if it is laid down (precipitated from solution) or resorbed from bone (go into solution)
58
Product of Ca and P
if product is > solubility product = bone deposition
-increase in extracellular fluid (ECF) concentration of either Ca or phosphate increases bone mineralization (an increase in plasma phosphate would increase the product of their conc., promote precipitation, and lower free Ca in the ECF
if product is < solubility product = bone resorption
-decrease in ECF conc. of either Ca or phosphate promotes the resorption of these sals from bone
59
Physiological Importance of Phosphate
```
-form: high energy compounds
second messangers
-component of: DNA/RNA
Phospholipid Membranes
Bone
-Phosphorylation of enzymes
-Intracellular anion
```
60
Phosphate # in blood
Normal: 4mg/dl
Range: 3-4.5
Approx. 55% free
-levels of P are usually higher in children b/c bone growth is still actively occurring (normal: 4.5-6.5)
61
Distribution of Body Phosphate
85% bone
intracellular 14%
free is 55%
62
Excretion of Phosphate
-urinary
-then fecal
Intake matches excretion
63
Fibroblast Growth Factor
| FGF23
- protein produced in bone
- structurally a member of FGF protein family but has little relation to fibroblasts
- FGF23 is secreted into the circulation potentially in response to increased levels of phosphate, vit D, & PTH
- acts in kidney to decrease the expression of Na-P co-transporters Npt2a and Npt2c and decrease production of Vid D resulting in hypophosphatemia
- might reduce PTH messenger RNA and protein in a feedback loop (Pi)
64
Renal Phosphate Reabsorption
90% filterable
- 85% reabsorbed in proximal tubule (inc. vit D, dec. PTH, FGF23)
- 5-10% in distal tubule
- 5-10% collecting duct
0. 2-20% (increase PTH, FGF23, increase by increase filtered P)
Endocrinology
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