Insulin, Glucagon, Diabetes Flashcards
what two important hormones do the islets secrete
glucagon and insulin
what 2 cells make up the physiological anatomy of the pancreas and which cells make up most of it
acini and islets of langerhans
acini make up most of the pancreas
what do the acini cells secrete
secrete digestive juices into small intestines (duodenum)
describe islets (4)
small,
1-2 million in a pancreas,
located around capillaries,
discovered by paul langerhans in 1869
what are the 3 major types of cells (% dominance) of the islets and what do they secrete
-alpha cells: 25% secrete glucagon
-beta cells: 60% secret insulin
-delta cells: 10% secrete somatostatin (GH-inhibiting H) secreted within islets not into circulation
what does the somatostatin do in the islets and in ant pituitary
islets: regulate alpha and beta cells
ant pituitary: controls somatotopes
describe how the 3 H antagonize each other and why are they not produced at same time
-insulin inh glucagon secretion
-glucagon inh insulin secretion
-somatostatin inh insulin and glucagon secretion
to maintain homeostasis of blood glucose
describe chemistry of insulin (2)
small prot
composed of 2< aa connected with 2 disulphide bonds
why are the disulphide bonds important for insulin
because when they are broken, insulin looses its functional activity
steps of insulin synthesis in beta cells
1- insulin RNA attaches to ER to form a precursor insulin preH (kept as reservoir for future insulin use, not ready to be used by body)
2- preH cleaved in the ER to form proinsulin
3- further cleaved in Golgi apparatus to form insulin
4- insulin is packed into secretory granules
5-secreted into blood when glucose levels are high
4-
what happens to the rest of the proinsulin when the A chain and B chain are cleaved off
it gets degraded in the secretory granule and becomes waste
describe pharmokinetics of insulin (4)
- plasma half life is only 5-6 min
- bc of half life, insulin function can be turned off fast if glucose levels go back to normal
-total clearance is 10-15 min
-mainly cleared in the liver which assumes that its not being synthesized and secreted
what can happen if insulin is continually secreted
can overcome clearance rate and stay elevated for long time and is problematic in diabetes
what are the 2 parts of the insulin receptors
one part will react with only insulin and the other part will transmit a signal inside the cell
can insulin cross the cell mem on its own
no it needs a receptor at the surface
describe an insulin receptor
-protein w 4 subunits (subunit= piece of prot that needs to form w other subunits to become functional)
- 2 alpha subunits that lie outside cell mem
- 2 beta subunits that cross cell meme into cytoplasm
steps of insulin receptor actions
1- beta chains of insulin receptor changes shape once insulin binds to alpha cells (phosphorylation)
2- insulin signalling
3- vesicle moves and starts to fuse w plasma mem
4-glucose channels are now imbedded in plasma mem
5- gradient created by muscle’s need to drives glucose into cell
6-after 5-6 min, insulin isn’t required anymore so it detaches from alpha chains
7- beta chains change shape again to go back to og state
8-vesicle and glucose channels return to normal place
t/f insulin can only act for 5-6 min
false it can act for longer if a larger meal filled with carbs is ingested
t/f glucose is very lipophilic and hydrophobic and so it can’t enter the cell w/o receptor prot channels
false its lipophobic and hydrophilic
what is the most important function of insulin
regulating blood glucose (effect on carbohydrates metabolism)
what happens minutes after eating a meal or consuming nutrients (carbs)
insulin rises
promotion of glucose uptake by tissues especially muscle
allows storage of glucose in the liver as glycogen
what represents the first big peak after a meal and the second large constant peak
first peak: insulin released from beta cells
second peak: proinsulin is being converted to insulin so takes longer bc of complex carbs being processed, absorbed and digested
why is glucose phosphorylated
bc G-6-P can’t escape the liver once its phosphorylated
bc extra E from P bond helps it turn into glycogen
what is the most important effect of insulin
cause glucose to be absrobed by the liver
how does insulin cause glucose to be absorbed by the liver
-insulin enhances glucose phosphorylation by glucokinase
-once phosphorylated, G-6-P can’t escape liver and is transformed into glycogen
what effect does insulin have on glucokinase
it stimulates glucokinase in liver
enhances glucose phosphorylation
enhances glucose uptkae from blood by liver cells
what effects does insulin have on glycogen synthase
it activates glycogen synthase which promotes glycogen synthesis (polymerization of glucose)
what effects does insulin have on glucose phosphatase
it inactivates glucose phosphatase which reduces the splitting of P from the phosphorylated glucose which then reduces the release of free glucose back into the blood
what effects does insulin have on glycogen (liver) phosphorylase
it inactivates the glycogen phosphorylase which prevents the breakdown of glycogen into glucose in the liver
what happens if there is still an excess of glucose after insulin has add its effects and glucose has reached the tissues
some tissues can store the extra glucose as glycogen (m. for ex)
what happens 2 hours after a meal to the blood glucose
it falls to baselin levels after 2 hours and then it drops below baselin which is due to the effects of insulin
what can happen after the drop below baseline of glucose 2 hours after a meal
insulin secretion from the beta cells is decreased
what effects occur after insulin disappears
-in liver, glycogen phosphorylase is activated causing glycogen to split into G-P, which stops the synthesis of glycogen and prevents glucose uptake from blood
-glucose phosphorylase is activated causing P to split from glucose and allowing free glucose to diffuse back into the blood
what happens to the m. at rest (no recent meal) when the glucose required by m. is minimal
-m. mem is only slighlty permeable to glucose (no food intake so no insulin present)
-insulin isn’t absolutely required
-energy mainly depends on fatty acids
what happens to the m. at rest soon after a meal has been eaten
-glucose concentration in the blood is higher
-insulin release is stimulated in islets (binds to receptors)
-glucose uptake into m. cells is enhanced by up to 15 fold
-m. can use glucose for E
-or extra glucose is stored as glycogen in m.
what are the glucose needs met by when a muscle is being used for ex: mod or heavy exercise
-insulin promotes glucose uptake, assuming a meal was eaten recently
-increased blood flow promotes glucose uptake regardless of insulin (only m. can do this w/o insulin present)
-metabolic activity of the working m. promotes glucose uptake regardless of insulin
does glucose need to be phosphorylated to be trapped in m.
no
a ___ m. might require ___ to get glucose. however, when a m. is being ____, it can obtain ____ without ____.
resting, insulin
used, glucose, insulin
t/f if a moving m. experiences insulin, it will take up the same amount of glucose as without insulin
false it will take up even more glucose
where is insulin not required for glucose uptake and why
brain, spinal cord and peripheral n.
bc they are essential for life and the body is willing to sacrifice other parts like m. to keep glucose levels steady
what condition can lead to glucose coma
severe hypoglycemia that induces a coma that is due to significant decline in brain activity due to relative lack of glucose
what does insulin do in lipid metabolism
reduces fat utilization for E and promotes the synthesis of new ffa in the liver which are then transported to adipose tissue
describe path of insulin in lipid metabolism
1- fa are synthesized in liver
2- become tgr in liver
3- tgr released from liver cells to blood in the lipoproteins
4- insulin activates lipoprot lipase in cap walls of adipose tissue
5- lipase splits the tgr into fa again to be absorbed into adipose cells
6-fa in the cells are converted back into tgr for storage
paths of insulin for promotion of fat storage in adipose cell
1-insulin promotes glucose uptake into adipocyte
2- glucose forms large amount of alpha-glycerol-P which combines w fa to form tgr to be stored in adipose cell
1-insulin inhibits the action of H-sensitive lipase (which normally turns tgr into ffa)
2-this inhibits the hydrolysis of tgr stored in adipocyte
3- this inhibits the release of fa from adipose cells into blood
what happens to H-sensitive lipase in the absence of insulin
1- H-S-L becomes strongly activated
2- hydrolysis of stored tgr
3- large amount of fa and glycerol are released into blood
4- increase of ffa in blood for energy utilization
what do excess ffa in the plasma promote
conversion of fa into phospholipids and cholesterol in the liver
what is cause by the absence of insulin in lipid metabolsim (whats released, what happens to concentration and what can happen if chronic
- phospholipids, cholesterol and excess tgr are released into the bloood in the lipoprot
-cause concentration increase of the 3 sub to 300% during brief period of insulin lack
-if chronic, will lead to rapid development of artherosclerosis (complex inflammation and damage to blood vessels)
what happens if fat is constantly used for energy (consequences)
- increased ffa trnasported into mito in liver cell which causes oxidation of fa in mitochondria which causes extreme released amounts of AcOA which is condensed to form acetoacetic acid to be released into blood and transported to peripheral cells
-lack of insulin drecreases use of acetoacetic acids in peripheral cells for E and if excess concentration of acetoacetic acids in blood, blood ph will drop and sever acidosis may occur
-acetoacetic acids are also converted into beta hydroxybutyric acid and acetone. the presence of large amount of this and acetoacetic acid in body fluids is ketosis which can cause severe acidosis and ketosis and coma and death
what is the role of insulin in switching btw carb and fat metabolism
-in healthy person use of fat for E is good but should never reach pt of causing acidosis or ketosis bc insulin will turn on again after next meal
- insulin promotes use of carbs for E and reduces use of fats
-lack of insulin causes the reversed utilization dfor E
-blood glucose concentration controls the switching mechanism: low glucose which supresses insulin which increase use of fat for E and supresses use of glucose
-when glucose concentration is high it stimulates insulin secretion and increases glucose utilization for E
what H does insulin work with to make the m. grow and build
growth H and thyroid H
when does insulin loose its anabolic effect on proteins
when its low
how does insulin decrease the release rate of aa from cells (especially m. cells)
1- insulin promotes aa uptake in the m. cells
2- insulin stimulates the DNA transcription (in cell nucleus) and ribosomes (in cytoplasm) to form new proteins
3- insulin inhibits proteolysis (catabolism of prot)
4- insulin decrease the release rate of aa from cells
how does insulin make more aa available for prot synthesis
1- insulin suppresses gluconeogenesis (form glucose from aa) by inactivating the enzyme for gng
2- more aa are availbale
what can lead to a accelerated rate of growth in babies
combined influence of GH and insulin
effects of lack of insulin on prot metabolism
-prot catabolism increases & prot synthesis stops
-aa increase dramatically in blood
-gluconeogenesis can now occur in liver to create new glucose
what can happen due to insulin being chronically absent or dysfunctional
classic diabetes condition of accelerated prot loss w resulting decrease in lean body mass
who discovered insulin
Frederick banting and J.J.R Macleod
who discovered the structure of insulin
Frederick Sanger
who discovered the development of crystallography
Dorothy Crowfoot Hodgkin
who discovered the development of the radioimmunoassay for insulin
Rosalyn Sussman Yalow
who discovered the islets
Paul Langerhans
who discovered that when removing the pancreas on a healthy dog urine became sweet
Oscar Minkowski
who did a major breakthrough by selling large qty for treatment of diabetes
Eli Lilly
a rapid increase in blood glucose leads to what kind of insulin response
biphasic
if blood glucose concentration is increased to 2 or 3 times above normal level, insulin secretion increases in what 2 stages
- first 3-5 min insulin increases almost 10 folds then it decreases halfway back bc the increase transport of glucose into liver, m. and other cells
-at about 15 min, insulin secretion rises a second time and reaches to a new plateau which is approximately 20 times normal level in 2 to 3 hours.
what sub have similar affects on promoting insulin secretion (aa)
lysine and arginine
aa cause a small increase in insulin secretion without thw rise of what
blood glucose
what happens if aa and glucose both rise in blood
insulin secretion is strongly promoted it even double.
what sub are synergistic in relation to insulin
aa and glucose bc they do more than just the sum of their individual effects
Metabolic Effects of Insulin
what secretes glucagon and when
alpha cells of islets in pancreas, when blood glucose concentration falls
what effect does glucagon have on glucose
powerful hyperglycemic effect that can elevate blood glucose by 25% in 20 min with only 1ug/kg of glucagon
how does glucagon have such a strong effect on glucose
and what do both actions serve to do
it increases the breakdown of liver glycogen into glucose (glycogenolysis)
it increases gluconeogenesis in the liver
they both serve to maintain or elevate blood glucose levels
how does glucagon increase glycogenolysis
1-glucagon activates liver cell meme and promotes degradation of glycogen into G-1-P
2-G-1-P is dephosphorylated
3-glucose is released from liver cells into blood
how does glucagon increase gluconeogenesis in the liver
glucagon activates enzymes for promoting aa uptake by liver cells and activates enzymes for conversion of aa to glucose by gluconeogenesis
what effects does glucagon have on lipid metabolism
-glucagon increases hormone sensitive lipase activity (turns tgr into ffa and glycerol) in adipose cells by increasing fa availability to energy sys
-glucagon inhibits tgr storage in the liver
-it opposes the effects of insulin on carbohydrate and fat metabolism
what regulates glucagon
-low blood concentration (most potent factor)
-effect of blood glucose on glucagon secretion is exactly opposite to insulin secretion
-increase aa (alanine and arginine) stimulates glucagon secretion and promotes conversion of aa to glucose (might do the same for insulin)
what is somatostatin
GHIH produced and secreted by delta cells of islets and is the same H that is involved in the pituitary control but here it controls insulin and glucagon secretion
how does somatostatin depress insulin and glucagon secretion
it decreases the use of the absorbed nutrients by tissues and prevents rapid exhaustion of food making food available over a longer period of time
steps of how glucagon and insulin work together to regulate blood glucose
1- person eats meal
2- glucose rises
3-insulin secretion
4-insulin rises
5- glucose drops over time
6-glucagon is secreted and rises
7-glucose rise to normal levels
what kind of sys is the glucagon and insulin sys
important feedback control sys for maintaining a normal blood glucose concentration
how does the liver act as a blood glucose buffer sys
when blood glucose rises too high after a meal:
-increase of insulin secretion which increases glucose storage in the liver as glycogen and then glucose decreases towards normal
when blood glucose falls btw meals:
-stimulates secretion of glucagon and glucose is then released from liver back into blood
when does the glucagon mechanism become very valuable
starvation, excessive utilization of glucose during exercise, excess cortisol (increase prot into aa which increases gluconeogenesis) and other stressful situations
what happens in order to release glucose in hypoglycemia
low blood glucose on hypothalamus stimulates the SNS which causes secretion of epinephrine from adrenal medulla which causes release of glucose from liver to protect against hypoglycemia
how does the body protect itself in severe and prolonged hypoglycemia
GH and cortisol are secreted to decrease glucose utilization by most cells of the body to help for returning blood glucose concentrations back to normal
why is good blood glucose concentration regulation important
-bc glucose is the best nutrient for brain, retina, and germinal epithelium of the gonads (need it for E)
-bc if rise too high, since glucose exerts large amount of osmotic pressure in extracellular fluid would lead to considerable cellular dehydration
-too high blood glucose causes glucose loss in urine that causes osmotic diuresis by kidneys which can deplete the body of its fluids and electrolytes
what can happen ifchronic osmotic diuresis
affects BP and hypertension
what are the metabolic effects of glucagon
describe type I diabetes
-secretion of insulin from beta islet cells is significantly diminished
-due to autoimmune disease destroying islet cells
-requires insulin injections to regulate blood glucose and to maintain blood glucose to near normal levels
describe type II diabetes
-normal or high insulin levels associated w high blood glucose levels
-insulin receptor may be deficient or absent on target cell (obesity decreases insulin receptors)
-receptors may not bind to insulin properly
describe gestational diabetes
elevated blood glucose levels during pregnancy only
has high incidence of type II diabetes for the mother later in life
what effects of insulin lack can be attributed to pathological features of diabetes mellitus
-decreased mobilization of glucose by body cell
-increased mobilization of fats from fat storage and deposition of cholesterol in arterial walls (atherosclerosis)
-decrease protein storage in tissues of the body
what are the signs and symptoms of diabetes
-glucosuria: glucose spill over into urine when glucose concentration rise above threshold
-polyuria: increase of urine production results in whole body dehydration (osmotic diuresis) also brings on a strong thirst to drink water (polydipsia)
-energy use depends almost entirely on fat which causes increased acidosis and ketosis
what are the treatments for diabetes
-life style changes such as diet and mod exercise (strenuous exercise requires a doctors clearance)
-type II or gestational : variety of drugs to promote good glycemic control and if not well treated can require insulin injections
-type I: insulin injections
why is moderate exercise like walking extremely effective?
bc the moving muscles absorb glucose which lowers the blood glucose and has a lasting effect
