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BHS 116.2 – Physiology
Notetaker: Vivien Yip
Date: 1/9/2012, 1st hour
Page1
Test 2 Material
Lectures 7- 12
Reading assignment on diabetes
Clicker Q
Which of the following does not require a plasma protein carrier for transport in the blood?
- Epinephrine
- Because it is Water soluble and also Tyrosine derived
Recap of last lecture on calcium
- Parathyroid hormone (PTH) maintains calcium levels in the body
- Labile pool: acute PTH
- Chronic effect: break down bone and stimulate osteoclasts
- Vitamin D3, produced in the skin that is activated by sunlight or through diet
o Help GI tract absorb calcium in the blood
- Addison Disease
o Hypoaldosteronism, hypocortisolism
o Hypoadrenalism
o Decreasing aldosterone levels
o Start decreased cortisol levels as disease progresses
o Autoimmune attack on adrenal cortex
o Affects both aldosterone and cortisol
- Cushiong disease
o Hypercortisolism, Elevated cortisol levels
o Stimulate blood levels of glucose, fatty acids and amino acids
o Permissive effect on sympathetic nervous system (like thyroid hormone)
o Enhances effects of sympathetic nervous system
o Can act like aldosterone at high enough levels and can stimulate sodium and water
resabsorption from the kidneys
Primary and Secondary hyperparathyroidism
- Disease of thyroid gland
- Usually tumour
BHS 116.2 – Physiology
Notetaker: Vivien Yip
-
Date: 1/9/2012, 1st hour
Page2
Primary: disease of thyroid gland, start off with normal calcium levels, excess PTH end up with
hypercalcemia
Secondary: caused by other diseases that result in low levels of calcium, start out with
hypocalcemia (from other disease, usually Vit D deficiency or renal disease)With chronic
hypocalcemia, get elevated PTH secretion to counteract hypocalcemia, get back to normal levels
– no hypercalcemia
Lecture 11 Regulation of Insulin and Glucagon
Describe the structure of the pancreas, as well as the cell types and the hormones they produce.
Pancrease secrete both insulin and glucagon
Structure of the pancrease
- Both endocrine and exocrine cells
- Acini (exocrine cells)
o Secrete digestive juices into the duodenum
- Islets of Langerhans (endocrine cells) *focus on for now
o Secrete insulin and glucagon into blood
o 1-2 million
o 3 cells that make the Islets: alpha, beta, sigma cells
- α Cells
o constitute 25% of cells
o secrete glucagon
- β Cells
o constitute 60% of cells and lie in the middle of the islet
o secrete insulin (major) and amylin (minor)
o Primary cell type
- δ Cells
o Constitute 10% of cells
o Secrete somatostatin (also released from hypothalamus and inhibits growth hormone)
Describe how insulin is synthesized and how it acts on the cell
- Receptor effects
- Cell effects
Insulin Synthesis
- Insulin is a peptide hormone
- Insulin preprohormone is cleaved in the
ER to proinsulin
o Composed of 2 peptides (A and B
chain) joined by 2 disulfide bonds
and a connecting peptide
- Connecting peptide is non functional
o Needs to be removed, just
connects the 2 chains together
- Proinsulin is further cleaved in the golgi to
insulin
- Insulin is a dimer of A chain and B chain
and connected via disulphide bonds
- Stored in beta cells until it needs to be released
BHS 116.2 – Physiology
Notetaker: Vivien Yip
Date: 1/9/2012, 1st hour
Page3
Insulin degradation
- Peptide hormone doesn’t require carrier in the blood, water soluble
- Very short half life of 5-6 minutes before it is degraded
- Act on target cells much quicker than that, therefore it does what it needs to and does not linger
around for long periods of time
- Liver does a lot of the degrading via enzyme insulinase
Insulin receptor
- Peptide hormone requires a surface receptor on
plasma membrane of target cells
- Insulin receptor made up of 4 different subunits
o 2 alpha
o 2 beta
- Held together via disulphide bonds
- Alpha will be extracellular domains
- Beta will be transmembrane domainds (span cell
membrane)
o Partially intracellular and extracellular
- Once insulin binds to the receptor on the
extracellular side,it activates the receptor and
receptor autophosphorylates itself
- Receptor becomes an active receptor tyrosine
kinase
- Cytoplasmic domain of beta subunits
autophosphorylates
- The receptor acts as an enzyme, a number of
phosphorylation reactions that occur inside the cell
Phosphorylated receptor results in:
- Increased permeability to glucose
- Most cells are not permeability to glucose without presence of insulin
- Glucose transporter is inserted into the plasma membrane
o A stock of glucose transporters inside the cell (pre-existing)
- Once enzyme portion of cell is activated, those transporters become inserted into plasma
membrane
- Allow glucose to freely diffuse inside the cell via facilitated diffusion
o Transporter is called GLUT 4
- GLUT 4 is insulin dependent glucose transporter
- Resting muscle
o Main cell type where GLUT 4 is inserted
o Adipose tissue another big target
o Most tissues use this type of mediated transport for glucose
- Exception: neurons and liver
o Do not have GLUT 4 transporters
o Do not require insulin to uptake glucose
o Can take up glucose at any time
Effects due to phosphorylation
- Increased permeability to amino acids, K+ and phosphate ions
- Increased protein synthesis, fat synthesis and glycogen synthesis
BHS 116.2 – Physiology
Notetaker: Vivien Yip
-
Date: 1/9/2012, 1st hour
Page4
Insulin is the STORAGE hormone
Fats, protein, glycogen is stored inside their target cells
Additionally get translation and transcription reactions in the cell (occurs slower)
Describe the effects of insulin on carbohydrate metabolism in the various cell/organ types
- Muscle, adipose, liver, brain
Insulin effects on carbohydrate metabolism
- Promote glucose uptake
metabolism and storage
- Look at resting skeletal muscle,
insulin increases glucose uptake up
to 15 fold when insulin is present
- As glucose levels go up, insulin is
secreted and level of glucose uptake
increases
- Skeletal muscle during exercise
does not require insulin for glucose
uptake
- Exercise stimulates GLUT 4
transport to membranes
- One of the major treatments for
diabetes is increasing exercise: do not require insulin to take up glucose
- Muscle cells will utilize glucose differently
o Resting muscle tissue and insulin will uptake the glucose and store it (not active does not
require metabolism)
o Exercising muscle will break glucose down into ATP for contraction
In Liver Cells
- GLUT 2, is insulin independent, can always take up glucose
- BUT, Insulin increases glucose metabolism and glycogen synthesis
o Helps with metabolism and storage of glucose
- Absence of insulin, liver will uptake the glucose but will not necessarily metabolize it to glycogen
o Insulin is required to increase the metabolism and storage of glycogen
- 1st reaction: inactivates liver phosphorylase
o This enzyme cleaves glycogen into glucose
o Prevents glycogen from becoming glucose
o Do not want to make glucose, want to store it
- 2nd reaction: Insulin Activates glucokinase
o Phosphorylates glucose and prevents it from leaving liver cell
- 3rd reaction: Insulin activates glycogen synthase
o Phosphorylate the glucose and store it for when it is needed
- If we have a lot of glucose (after eating a meal)
o Liver can only make so much and store so much glycogen, liver will make fatty acids out
of the excess
o Glucose is converted into fatty acids
o Package fatty acid as triglycerides then LDL particles and sent to adipose tissue for
storage
o Excess glucose eventually is stored as fat
- Insulin will inhibit glucogneogenesis
 Inhibits liver from converting amino acids into glucose
 Decreasing amino acid uptake (specific to liver)
BHS 116.2 – Physiology
Notetaker: Vivien Yip
Date: 1/9/2012, 1st hour
Page5
In brain/neurons
- Insulin has no effect
- Always has to take up glucose
- Glucose is the only energy source
- BBB has GLUT 1 (another insulin independent transport mechanism)
- Neurons themselves have GLUT 3 (also insulin independent glucose transporter)
In adipose cells
- Cells do require insulin to uptake glucose
- Have GLUT 4 transporters
- Glucose gets converted to glycerol, backbone of triglycerides
- Start out with glycerol molecule, tag on 3 fatty acids to get triglyceride
- Insulin promotes fat synthesis and storage
o Recall back to liver, liver has all glycogen it can make, makes fatty acids, packages into
LDL particles, LDL gets to adipose tissue, fatty acids can be taken up
o Insulin increases utilization of glucose for energy, thus sparing fats
o Insulin increases the production of fatty acids by the liver
 Enhances triglyceride synthesis
Describe the effects of insulin on fat and protein metabolism
Insulin effects on fat metabolism
- Insulin activates lipoprotein lipase (LPL)
- LPL cleaves triglycerides off LDL particle
- Breaks down the triglycerides into individual fatty acids
- Fatty acids that are taken up by adipose tissue
- Bind to the glycerol
- Stored as triglyceride
- Insulin Inhibits lipolysis
o Fat break down in adipose tissue
o Insulin is storage hormone, therefore does not want to break things down
Insulin effects on protein metabolism
- Promotes protein synthesis and storage
- Stimulate amino acid uptake
o Similar to growth hormone
- Increase transcription and translation
- Inhibit protein break down
- In liver, decrease gluconeogenesis
- No need for circulating amino acids to be converted to glucose
- As long as glucose is around, don’t need to break down lipid or protein for energy source
Summary of Insulin effects on major tissue targets
Adipose tissue
Liver
- Increase glucose uptake
- Decrease
- Increase lipogenesis
gluconeogenesis
- Decrease lipolysis
- Increase glycogen
synthesis
- Increase lipogenesis
Genesis: make
Lysis: break
Skeletal and cardiac muslce
- Increase glucose uptake
- Increase glycogen
synthesis
- Increase protein
synthesis
BHS 116.2 – Physiology
Notetaker: Vivien Yip
Date: 1/9/2012, 1st hour
Page6
Insulin acts synergistically w/ growth
hormone to promote growth
- Normal 50 days of growth, then
take out pancreas and pituitary
o No growth hormone, no
insulin produced
o Flat lined with growth
- If we add growth hormone
o get slight rise in growth
- Take growth hormone out
o flat line
- Add insulin
o get slow rise in growth
- Take out insulin
o flat lines
-
When we add both GH and insulin
o huge spike in growth
o Both hormones are promoting protein synthesis
Describe the regulation of insulin secretion
Regulation of insulin secretion
- Increased blood glucose levels stimulate insulin secretion
- Normal: 80-100 mg/dl
- When glucose go above these levels, get quick spike in blood levels of insulin
- Very immediate response
- Beta cells (vesicles are filled with insulin) ready to release the insulin that is stored
o Don’t need time for synthesis
- After release, there is a moderate decline in glucose levels
Excitation secretion coupling
- Beta cells in pancreas are insulin
independent for their glucose uptake
o GLUT2 transporters
- Beta cells get phosphorylated and
oxidized
o ATP is going to act on ATP
sensitive K+ channel causing it
to close
o K+ cannot leave cell
- Keeps more positive charges inside cell
 depolarize beta cell
- Depolarization causes voltage sensitive
-
calcium channel to open
o Calcium enters cell
o Causes fusing of vesicles with membrane to release insulin
o Change in depolarization causes calcium to come in
o Calcium causes vesicles to fuse
Reason why we get huge spike
BHS 116.2 – Physiology
Notetaker: Vivien Yip
-
Date: 1/9/2012, 1st hour
Page7
As insulin degrades, get decrease in insulin
Second more stable rise in insulin as glucose levels stay elevated, due to glucose synthesis
Once process is active, beta cells will constantly be releasing insulin into the blood
Keep fairly stable level in insulin over extended period of time
Regulation of insulin secretion
- 20 fold increase in insulin by the time the plasma glucose concentration is 400mg/dl
o After this, tends to level off
o Cells can’t keep up with churning out more than 20 fold normal levels
- How to shut off insulin release?
- As insulin acts on target tissues
- Target tissues will be taking glucose up and decreasing plasma levels of glucose
- Once levels get back to normal range (80-100mg/dl), will shut down insulin secretion
- Feedback mechanism
- Elevated levels of glucose, trigger insulin release, once glucose comes back to normal, insulin
shuts off
Amino acid levels
- As it rises, help potentiate the glucose stimulus for insulin secretion
- Glucose will stimulate even more insulin release
- Most potent are arginine and
lysine
- Can double the effect of glucose
alone
GI hormones
- Can be released before food is
even in the stomach
- Once food in stomach, more GI
hormones released
- Anticipatory release of insulin
- Once food is digested and
glucose is produced and
absorbed from the intestines
- There will be some insulin
already present in the blood for
cells to uptake immediately
- Gastrin, secretin, incretin
BHS 116.2 – Physiology
Notetaker: Vivien Yip
Date: 1/9/2012, 1st hour
Page8
Summary regulation of insulin secretion
- Increase blood glucose levels stimulate insulin release (main control)
o GI hormones also stimulate
o Increased amino acid levels in blood
o Parasympathetic stimulates
- Sympathetic inhibits insulin release
o Glucose will be present in the blood and the organ systems most needed during
fight/flight is brain, skeletal muscle and neurons
- Main effects of glucose: decrease blood glucose (stored by target tissue), decrease blood fatty
acids
Describe the effects of and regulation of glucagon and somatostatin
Glucagon
- Large polypeptide
- Released by islets (α Cells)
- Released when glucose is too low
- Stimulate glucose production and release into the blood
- As blood levels decrease, glucagon levels go up
- Opposite of insulin
Metabolic effects of glucagon
- Induces breakdown of liver glycogen
- End result is glucose
- Glucagon binds receptor and activates adenylyl cyclase system
- Results in production of phosphorylase a
- Phosphorylase a degrades glycogen into glucose 1 phosphate
- After many enzymatic reactions, cause release of glucose into the blood
- Cascade amplification system, allows a lot of glucose to be released
- Stable 4 hour of glucagon infusion can deplete a liver of glycogen
Effects of Glucagon on Carbohydrate metabolism
- Induce gluconeogenesis in liver
- Start converting amino acids into glucose
- Only utilizing its own protein
- Will not work on muscle tissue (like cortisol does)
- Increases the blood glucose conetration
Effects of glucagon on Lipid metabolism
- Glucagon will increase bloody fatty acid concentration
- Need alternative energy source, because glucose levels is low
- Break down fatty acids for energy
- Atkins mechanism
o Low carb diet
o Still going to get fat break down because glucagon will break down fat
o And get conversion of glycogen into glucose
o Amino acid into glucose
o Sustain glucose levels for tissues
BHS 116.2 – Physiology
Notetaker: Vivien Yip
Date: 1/9/2012, 1st hour
Page9
Regulation of glucagon secretion
- As blood levels of glucose begin to rise to normal levels, glucagon secretion is inhibited
o Opposite effects as on insulin
- Increased amino acid levels will stimulate glucagon secretion
o also increases for insulin
o glucagon promotes the rapid conversion of amino acids into glucose in the liver
- Exercise increases blood glucagon levels
- High protein/low carb diet effect (atkins) to maintain plasma glucose levels
o Don’t have glucose to stimulate insulin release, but high amino acid levels will stimulate
glucagon
o Glucagon will convert the amino acids into glucose
o Will have necessary glucose for metabolism
o Glucagon also stimulates fatty acid break down  fat loss
- Amino acids potentiates effects of glucose on insulin secretion
o High amounts of amino acid does not directly cause insulin secretion
- Glucagon can be released just by high amino acid levels
Complementary Interactions of Insulin and Glucagon
- High blood glucose
o Stimulate insulin release (β cells)
o Inhibit glucagon release (α cells)
- Low blood glucose
o Stimulate glucagon release (α cells)
o Inhibit insulin release (β cells)
Metabolic switch b/w carbohydrate and lipid metabolism
- Carbohydrate is main energy source
- Insulin is the only hormone that promotes glucose as energy source
- Many of the other hormones promote fats as metabolic energy source:
o GH released during hypoglycemia
o Cortisol released during stress
o EPI, released during stress and exercise
o Glucagon induced during hypoglycemia
- These hormones are secreted when we want to spare glucose for brain and exercising skeletal
muscle and promote fat utilization
Sherwood table 19-6 Summary chart of hormones
Insulin and cortisol are completely opposite effects on blood glucose and fatty acids
Insulin: uptake and storage, decrease blood levels
Other hormones: promote break down and release of glucose and fat into the blood
BHS 116.2 – Physiology
Notetaker: Vivien Yip
Date: 1/9/2012, 1st hour
Page10
Metabolic Effects of Somatostatin
- Small polypeptide hormone (secreted by δ cells)
- Short half life of 3 minutes
- Decrease motility of GI tract
- Prevent break down and movement of food in GI
- Decrease absorption and secretion of GI
- Prevent GI tract from absorbing nutrients into blood
- Primarily inhibit both glucagon and insulin secretion
- Somatostatin lets nutrients to assimilate in blood before we get insulin and glucagon to act on the
tissue
Regulation of somatostatin
- Stimulated by factors related to the ingestion of food
o Increased by:
 Blood glucose levels
 Amino acid levels
 Blood fatty acid levels
 GI hormone levels
Clicker Q
Which cell in the pancreas secrete insulin?
- Beta cells