Pancreas Flashcards
Pancreas
nTissue
uAcini
___ glands that secrete __ ___
uIslets of Langerhans
FSecrete___ into the blood
Pancreas: Endo and exocrine gland
Acinar cells secrete digestive enzymes and bicarb but we are going to focus on the endocrine portion of the gland
Pancreas
nTissue
uAcini
Fexocrine glands that secrete digestive juices
uIslets of Langerhans
FSecrete hormones into the blood
Pancreas: Endo and exocrine gland
Acinar cells secrete digestive enzymes and bicarb but we are going to focus on the endocrine portion of the gland
Pancreas
nAlpha cells
___ (20%)
nBeta cells
___(70%)
nDelta cells
___ (10%)
nF cells
___ ____
Somatostatin: Inhibitory
Pancreas
nAlpha cells
uGlucagon (20%)
nBeta cells
uInsulin (70%)
nDelta cells
uSomatostatin (10%)
nF cells
uPancreatic polypeptide
Somatostatin: Inhibitory
This shows the blood supply for the pancreas
The blood supply moves from the___ to ___
Interior: Most of the ___ cells
When insulin released from beta cells blood caries the insulin to the outside
Ouside is where you find most of the ___ cells
When insulin comes from the inside, it will shut down the production of ____ by alpha cells.
___ also has impact on glucagon secretion. (inhibitor)
This shows the blood supply for the pancreas
The blood supply moves from the interior to the exterior
Interior: Most of the Beta cells
When insulin released from beta cells blood caries the insulin to the outside
Ouside is where you find most of the alpha cells
When insulin comes from the inside, it will shut down the production of glucagon by alpha cells.
Glucose also has impact on glucagon secretion. (inhibitor)
Insulin
nHistory:
uDiscovered in 1921 by Banting and Best
nChemistry
uSynthesized by the ___ cells of the pancreas from ____ (single chain of 110 amino acid).
uThe 24-amino acid N-terminal of preproinsulin is ___ to form proinsulin, after___ through the membrane of the rough endoplasmic reticulum (RER).
nHistory:
uDiscovered in 1921 by Banting and Best
nChemistry
uSynthesized by the B cells of the pancreas from preproinsulin (single chain of 110 amino acid).
uThe 24-amino acid N-terminal of preproinsulin is cleaved to form proinsulin, after translocation through the membrane of the rough endoplasmic reticulum (RER).
Endogenous Synthesis of insulin
This is the mRNA from insulin gene
There is a signal sequence and the A, C, and B domains
mRNA gets tlating
As it moves thru ER, the __ ___ gets cleaved
With the signal sequence its _____
Once its cleaved you get _____
Form pro insulin
This has A and B chain connected by a C peptide
Further processing occurs in golgi
In trans golg __ ___ iis cleaved by prohormone convertase
Once its cleaved you have packaging of mature ___ with ___ ___ in a vesicle
Vesicle also has ___ which is important for insulin stabilization and fcn
For every mole of insulin, you have a mol of C peptide. C peptide doesn’t have much biological fcn
__ ___ can be used to ___ how much insulin is in the body
Same molar ratio
This is the mRNA from insulin gene
There is a signal sequence and the A, C, and B domains
mRNA gets tlating
As it moves thru ER, the Signal sequence gets cleaved
With the signal sequence its preproinsulin
Once its cleaved you get pro insulin
Form pro insulin
This has A and B chain connected by a C peptide
Further processing occurs in golgi
In trans golgi, C peptide iis cleaved by prohormone convertase
Once its cleaved you have packaging of mature insulin with C peptide in a vesicle
Vesicle also has Zn which is important for insulin stabilization and fcn
For every mole of insulin, you have a mol of C peptide. C peptide doesn’t have much biological fcn
C peptide can be used to asses how much insulin is in the body
Same molar ratio
Human proinsulin and its conversion to insulin.
This is insulin
A chain has ___ chain disulfide bond
Connected to B chain by ___ chain disulfide bond
___ is the aa that forms disulfide bonds
Human proinsulin and its conversion to insulin.
This is insulin
A chain has intra chain disulfide bond
Connected to B chain by INTER chain disulfide bond
Cysteine is the aa that forms disulfide bonds
Insulin
nRegulation of insulin secretion
uTightly regulated to allow ___ conc. of glucose in both fasting and fed state
uSecretion of insulin promoted by
___
__ __
__ __
__ __
___ __ ___
___ ___ ___ ___, VIP, gastrin, secretin, cholecystokinin, enteroglucagon
β2-AR and vagal nerve stimulation release
Brain depends on glucose for E so glucose has to available. If not, you go into a coma.
Glucose is primary stimulant for insulin release
___ stimulate the production of insulin
Insulin’s major fcn is to store nutrients
GIP and GLP. These two are___
Incretins stimulate ____ production by the Beta cells
Symp NS can stimulate (thru __ recep) or inhibit (thru ___ recep) insulin secretion
Insulin
nRegulation of insulin secretion
uTightly regulated to allow stable conc. of glucose in both fasting and fed state
uSecretion of insulin promoted by
F glucose
F amino acids,
Ffatty acids,
Fketone bodies,
FGIP (gastric inhibitory polypeptide), (incretins)
F GLP-1 (glucagon-like intestinal peptide 1), VIP, gastrin, secretin, cholecystokinin, enteroglucagon
β2-AR and vagal nerve stimulation release
Brain depends on glucose for E so glucose has to available. If not, you go into a coma.
Glucose is primary stimulant for insulin release
Nutrients stimulate the production of insulin
Insulin’s major fcn is to store nutrients
GIP and GLP. These two are incretins.
Incretins stimulate insulin production by the Beta cells
Symp NS can stimulate (thru B recep) or inhibit (thru alpha recep) insulin secretion
Glucose [] vs time
If glucose given orally
As glucose gets absorbed in the intestine, glucose level rises
As glucose level rises you have __ ___ in insulin
If same amount of glucose was given by IV
Way ___ insulin is released
The difference is bc of those molecules we talked about. GLP and GIP
They are released from the intestines go to the __ ___ and stimulate ___ insulin release
Even though glucose is the main stimulant, GLP and GIP contribute too.
You see that difference here
Type I: Diabetic Patient in B
Baseline for glucose is much ___ here than a normal patient
__ ___ insulin release because the beta cell has been ___
If after 2 hrs. glucose levels are above 200 mg/dL you are a diabetic
C:
Person receives glucose. Response is a rapid ___e in insulin.
The insulin that is release, this is insulin that was ___ within the Beta cells
Second phase of release is more sustained (this is ___ and ___ ___ d insulin) This will remain high until glucose level falls
Glucose [] vs time
If glucose given orally
As glucose gets absorbed in the intestine, glucose level rises
As glucose level rises you have massive increase in insulin
If same amount of glucose was given by IV
Way less insulin is released
The difference is bc of those molecules we talked about. GLP and GIP
They are released from the intestines go to the Beta cells and stimulate more insulin release
Even though glucose is the main stimulant, GLP and GIP contribute too.
You see that difference here
Type I: Diabetic Patient in B
Baseline for glucose is much higher here than a normal patient
Hardly any insulin release because the beta cell has been destroyed
If after 2 hrs. glucose levels are above 200 mg/dL you are a diabetic
C:
Person receives glucose. Response is a rapid increase in insulin.
The insulin that is release, this is insulin that was preformed within the Beta cells
Second phase of release is more sustained (this is preformed and newly formed insulin) This will remain high until glucose level falls
Insulin
uRegulation of insulin
FAny condition that ___ the ____nervous system (e.g. severe burns, hypoxia, hypothermia, surgery) ____the secretion of insulin via activation of ___
uGlucose is the ___stimulus for insulin release and require___ nto the β-cells (via ___) and ___.
u
____ acts as the glucose sensor
uRegulation of insulin
FAny condition that activates the autonomic nervous system (e.g. severe burns, hypoxia, hypothermia, surgery) suppress the secretion of insulin via activation of α2-AR.
uGlucose is the principal stimulus for insulin release and requires entry into the β-cells (via GLUT2) and metabolism.
u
uGlucokinase acts as the glucose sensor
Regulation of Insulin Release
How does glucose stimulate insulin release?
Glucose has to be ___ by the Beta cell before it can cause release.
Glucose will pass thru a glucose transporter.
GLUT 2: ___
GLUT4: ____
Glucose is metabolized by ___
Glucose forms___
ATP binds __ channels
K channel ___
Membrane potential ___ ( ____ )
___ channels in membrane are voltage gated
Ca channels ___
Ca moves___ cell ___ its gradient
The increase in Ca triggers ___ of vesicles to release insulin
Sulfaurida drugs can bind to K channel and ___ it just like ___
Diabetic take this drug, ___ released
How does glucose stimulate insulin release?
Glucose has to be metabolized by the Beta cell before it can cause release.
Glucose will pass thru a glucose transporter.
GLUT 2: pancreas
GLUT4: muscle, adipose tissue
Glucose is metabolized by Glycolysis.
Glucose forms ATP
ATP binds K channels
K channel closes
Membrane potential rises..Depolarized
Ca channels in membrane are voltage gated
Ca channels open
Ca moves into cell along its gradient
The increase in Ca triggers exocytosis of vesicles to release insulin
Sulfaurida drugs can bind to K channel and close it just like ATP
Diabetic take this drug, insulin released
Molecular Mechanism of Insulin Action
Insulin is also required for____
How does it regulate growth and metabolism?
It has 2 different signaling cascades that allow it to do that
Metabolic Effect:
Insulin Receptor
A chain is seen extracellularly
B chain is transcellular
B chain has Tyrosine kinase activity
Insulin binds to its receptor
Conf change
Activation of B chain
B chain phosphorylates A
A phosphorylates B
Once you have P group on receptor, the P groups act as binding sites for other proteins. (____, 1/2/3/4)
In turn these recruit other proteins like PI3 kinase, Protein dependent kinase and ____ (Protein Kinase B)
Akt: PKB: When Akt activated, it signals to___ ___ normally found in the cell to move into the membrane to let glucose into the cell
If you disrupt this, lot of glucose in blood but it __ __ ___ the cell
Growth Effect
P group attracts ____, Ras, MEK and __ ___
MAP kinase can phosphorylate __ ___ that lead to gene expression and growth regulation
Insulin is also required for growth
How does it regulate growth and metabolism?
It has 2 different signaling cascades that allow it to do that
Metabolic Effect:
Insulin Receptor
A chain is seen extracellularly
B chain is transcellular
B chain has Tyrosine kinase activity
Insulin binds to its receptor
Conf change
Activation of B chain
B chain phosphorylates A
A phosphorylates B
Once you have P group on receptor, the P groups act as binding sites for other proteins. (IRS, 1/2/3/4)
In turn these recruit other proteins like PI3 kinase, Protein dependent kinase and AKT (Protein Kinase B)
Akt: PKB: When Akt activated, it signals to glucose transporters normally found in the cell to move into the membrane to let glucose into the cell
If you disrupt this, lot of glucose in blood but it can’t get into the cell
Growth Effect
P group attracts Grb2, Ras, MEK and Map Kinase
MAP kinase can phosphorylate tx factors that lead to gene expression and growth regulation
Molecular Mechanism of Insulin Resistance
Obesity is driving the epidemic of Type II diabetes
How are they related?
Obestity…Excess of ___ or ___
Mitochondria cannot deal with the oxidation of all the fa.
Excess___ and ____ (byproducts of fa oxidation)
Excess of these ___ the mitochondria
These fa byprod are activators of ___ __ ___
Normally the___ proteins are phosphorylated on __ residues
But they also have a phosphorylation site for ___
Excess of these DAG and fatty acyl coA activate more than normal activation of these ___kinases
These phosphorylate IRS Serine residue
This __ ___phosphorylation
Now it doesn’t work
Insulin cant send the signal to __ ___ to get into the cell
Signal gets interrupted
Serine phosphorylation also marks these IRS proteins for ___
Less IRS, less ability to signal to the glucose transporters, less glucose taken up-à __ ___ (Type _ diabetes)
Obesity is driving the epidemic of Type II diabetes
How are they related?
Obestity…Excess of Fa or their byproducts
Mitochondria cannot deal with the oxidation of all the fa.
Excess DAG and fatty acyl coA (byproducts of fa oxidation)
Excess of these leave the mitochondria
These fa byprod are activators of serine Thr kinases
Normally the IRS proteins are phosphorylated on Y residues
But they also have a phosphorylation site for serine
Excess of these DAG and fatty acyl coA activate more than normal activation of these Serine kinases
These phosphorylate IRS Serine residue
This Blocks Y phosphorylation
Now it doesn’t work
Insulin cant send the signal to GLUT transporters to get into the cell
Signal gets interrupted
Serine phosphorylation also marks these IRS proteins for degradation
Less IRS, less ability to signal to the glucose transporters, less glucose taken up-à insulin resistance (Type 2 diabetes)
Insulin Pharmacology
nClinical uses of insulin
uPatients with type I diabetes
uGestational diabetes not controlled by ___t alone
uEmergency treatment (___.) of ____ diabetic emergencies (e.g. diabetic ketoacidosis)
uEmergency treatment of ___: ___is given with glucose to ____ extracellular K+ by directing it into cells.
uMany type ___ diabetic patients ultimately require insulin treatment
People with gestational diabetes, not controlled by diet. Need to be given insulin
People with diabetic ketoacidosis have to be given __ __ ____
Insulin can also help get K ___ cells
If there are high levels of K in the blood, insulin is given along with glucose to get K into cells
Insulin has action on the __ __ ___ that takes K into cells
Many type 2 diabetics require insulin when the oral agents no longer work
Insulin Pharmacology
nClinical uses of insulin
uPatients with type I diabetes
uGestational diabetes not controlled by diet alone
uEmergency treatment (i.v.) of hyperglycemic diabetic emergencies (e.g. diabetic ketoacidosis)
uEmergency treatment of hyperkalemia: insulin is given with glucose to lower extracellular K+ by directing it into cells.
uMany type 2 diabetic patients ultimately require insulin treatment
People with gestational diabetes, not controlled by diet. Need to be given insulin
People with diabetic ketoacidosis have to be given fast acting insulin
Insulin can also help get K into cells
If there are high levels of K in the blood, insulin is given along with glucose to get K into cells
Insulin has action on the Na/K pump that takes K into cells
Many type 2 diabetics require insulin when the oral agents no longer work
Effect of Insulin on Liver
nPromotes ___ of glucose as glycogen and conversion of glucose to ____
nPromote __ ___
transcription of ___
__ ___
___ ____
__ __ ___
nPromotes storage of glucose as glycogen and conversion of glucose to triglycerides
nPromote glycogen synthesis
u transcription of glucokinase
uglycogen synthase
u¯glycogen phosphorylase
u¯glucose-6-phosphatase
Effect of Insulin on Liver
nPromote___ and carbohydrate oxidation
u activity of ___
u___
u__ ___
uPromote metabolism via __ ___ shunt
u __ ___
uInhibit ___
u
nPromote glycolysis and carbohydrate oxidation
u activity of glucokinase
uphosphofructokinase
uPyruvate kinase
uPromote metabolism via hexose monophosphate shunt
u pyruvate dehydrogenase
uInhibit gluconeogenesis
u
Effect of Insulin on Liver
nPromote __ ___ of fat by __ __ ____ and __ __ ___
nPromote ___ ___ and inhibit ___ ___
nPromote synthesis and storage of fat by acetyl CoA carboxylase and fatty acid synthase
nPromote protein synthesis and inhibit protein breakdown
Metabolic Effects of Insulin on Liver
Insulin has 4 major actions in the liver:
Stimuate __ ___ in the liver
Store aa as protesins
__ __e as glycogen
Gà G6P by glucokinase. Insulin stimulates that enzyme
Insulin also stimulates glycogen synthase so more glycogen gets produced.
Stimulates ___
Stimulates certain critical enzymes. PFK and Pyruvate Kinase
Stimulate conversion of ___ ___ to ___
Excess glucose stored as fat.
Stimulates enzyme Aceryl coA carboxylase which takes Acetyl CoAàmalonyl coA
Malonyl coA inhibits movement of fa to mitochondria for oxidation and allows it to be converted to triglycerides
Metabolic Effects of Insulin on Liver
Insulin has 4 major actions in the liver:
Stimuate protein synthesis in the liver
Store aa as protesins
Stores glucose as glycogen
Gà G6P by glucokinase. Insulin stimulates that enzyme
Insulin also stimulates glycogen synthase so more glycogen gets produced.
Stimulates glycolysis
Stimulates certain critical enzymes. PFK and Pyruvate Kinase
Stimulate conversion of Acetyl coA into TAG
Excess glucose stored as fat.
Stimulates enzyme Aceryl coA carboxylase which takes Acetyl CoAàmalonyl coA
Malonyl coA inhibits movement of fa to mitochondria for oxidation and allows it to be converted to triglycerides
Insulin Action in Muscle
nPromotes ___ of glucose and its storage as ___
u ___ transporter to plasma and glucose ___
u transcription of ___ and activate __ ___
uPromote ___ and carbohydrate oxidation
uPromote ___ synthesis and ¯ protein breakdown
nPromotes uptake of glucose and its storage as glycogen
u Glut4 transporter to plasma and glucose uptake
u transcription of hexokinase and activate glycogen synthase
uPromote glycolysis and carbohydrate oxidation
uPromote protein synthesis and ¯ protein breakdown
Metabolic Effects of Insulin on Muscle
4 actions in muscle too!
1) Stimulates movement of __ ___ into the membrane so you can have more glucose coming into the cell. We didn’t see that in the liver bc transport of glucose into the liver is not insulin dependent.
2) Store Glucose as ____Stimulate glycogen synthase
3) Stimulate ___
4) Stimulate usage of__ as ___
4 actions in muscle too!
1) Stimulates movement of GLUT transporters into the membrane so you can have more glucose coming into the cell. We didn’t see that in the liver bc transport of glucose into the liver is not insulin dependent.
2) Store Glucose as Glycogen. Stimulate glycogen synthase
3) Stimulate glycolysis.
4) Stimulate usage of ketones as fuel
Insulin Action in Adipocytes
nPromote uptake of glucose and its conversion to___ for storage
u ____ transporter to plasma and glucose uptake
uPromote ___ and formation of____
uPromote esterification of ____
uWith free fatty acids to form___e for storage
uPromote ___s of lipoprotein lipase
u
nPromote uptake of glucose and its conversion to triglyceride for storage
u Glut4 transporter to plasma and glucose uptake
uPromote glycolysis and formation of α-glycerophosphate
uPromote esterification of α-glycerophosphate
uWith free fatty acids to form triglyceride for storage
uPromote synthesis of lipoprotein lipase
u
Insulin Action in Adipocytes
1) Stimulates__ ___ ____s into the membrane to let more glucose in
2) Stimulate breakdown of glucose by ____.. Difference here. Product of glycoylsis is __ __ ___e. It goes from PEP and then insulin stimulates the conversion to AGP. This can then be combined with fa to make triglycerides
1) Where does fa come from? Diet
1) Insulin stimulates production of__ _____e. Made within adipose but exported to endothellial cells where it sits on surface of endothelial cell waiting for chylomicrons, fat containing molecules coming from the liver. When it gets there LPL breaks that into __. Fa then go back into the adipocytes where it combines with AGP to from __
3) Inhbit breakdown of Triglycerides
1) Stimulates movement of transporters into the membrane to let more glucose in
2) Stimulate breakdown of glucose by glycolysis. Difference here. Product of glycoylsis is alpha-glycerol-phosphate. It goes from PEP and then insulin stimulates the conversion to AGP. This can then be combined with fa to make triglycerides
1) Where does fa come from? Diet
1) Insulin stimulates production of lipoprotein lipase. Made within adipose but exported to endothellial cells where it sits on surface of endothelial cell waiting for chylomicrons, fat containing molecules coming from the liver. When it gets there LPL breaks that into fa. Fa then go back into the adipocytes where it combines with AGP to from TG
3) Inhbit breakdown of Triglycerides
Insulin
nAdverse Effects
uMost common is _____ (sweating, hunger, paresthesias, palpitations, tremor, anxiety) ____symptoms occur first followed by loss of concentration, confusion, weakness, drowsiness, blurred vision, loss of consciousness (n_____ symptoms)
uWeight ___
___ (due to insulin’s ____ action)
____ (due to ___ actions of high local concentrations of insulin.
u
If you have patient sweating while the AC is on, it could be that they are hypoglycemic.
Don’t leave hypoglycemic patient alone.
Ask someone to stay with the patient
Weight gain because stores nutrients
Insulin
nAdverse Effects
uMost common is hypoglycemia (sweating, hunger, paresthesias, palpitations, tremor, anxiety) autonomic symptoms occur first followed by loss of concentration, confusion, weakness, drowsiness, blurred vision, loss of consciousness (neuroglycopenic symptoms)
uWeight gain
uEdema (due to insulin’s antinatriuretic action)
ulipohypertrophy (due to lipogenic actions of high local concentrations of insulin.
u
If you have patient sweating while the AC is on, it could be that they are hypoglycemic.
Don’t leave hypoglycemic patient alone.
Ask someone to stay with the patient
Weight gain because stores nutrients
Treatment of Hypoglycemia
nAdminister __ ___ sugars such as fruit juice, soda, table sugar by mouth who are able to ___
__ ___ of ___ if patient is unable to swallow
__ ___ if in hospital setting
n
If patient is unconcious or cant open mouth, give IM injection of glucagon.
In hospital setting you can give IV glucose but…
You usually don’t have IV glucose in a dental office!!
Give glucagon if they cant open their mouth
Treatment of Hypoglycemia
nAdminister readily absorbable sugars such as fruit juice, soda, table sugar by mouth who are able to swallow.
nI.M. injection of glucagon if patient is unable to swallow
nIV glucose if in hospital setting
n
If patient is unconcious or cant open mouth, give IM injection of glucagon.
In hospital setting you can give IV glucose but…
You usually don’t have IV glucose in a dental office!!
Give glucagon if they cant open their mouth
Nutritional State and Regulation of Blood Glucose
GH Cortisol Glucagon EP
Blood Glucose
FA
AA
MP
MP: Muscle protein
All four of these oppose action of insulin.
But when nutrients are available (we eat), insulin is king during that period. The other 4 have very little effect
Nutritional State and Regulation of Blood Glucose
GH Cortisol Glucagon EP
Blood Glucose ↑ ↑ ↑ ↑
FA ↑ ↑ ↑ ↑
AA ↓ ↑ N N
MP ↑ ↓ N N
MP: Muscle protein
All four of these oppose action of insulin.
But when nutrients are available (we eat), insulin is king during that period. The other 4 have very little effect
Somatostatin
Somatostatin
uProduced by__ cells of the stomach and duodenum; hypothalamus, and d cells of the pancreas
uAct on pancreas to ___ _____secretion
Pancreatic Polypeptide
uProduced by ___ cells of pancreas
uInhibit ___ ____secretion and __ __ ___
n
Somatostatin: Inhibit insulin and glucagon secretion and exocrine secretion
Somatostatin
nSomatostatin
uProduced by D cells of the stomach and duodenum; hypothalamus, and d cells of the pancreas
uAct on pancreas to ¯ endocrine/exocrine secretion
nPancreatic Polypeptide
uProduced by F cells of pancreas
uInhibit pancreatic enzyme secretion and gall bladder contraction
n
Somatostatin: Inhibit insulin and glucagon secretion and exocrine secretion
Glucagon
nChemistry
u Proglucagon-derived peptides are encoded by ___le mammalian proglucagon ___
u
uProglucagon is cleaved by __ ____ (PC) in a__ ___c manner to yield ___ hormones
u
uIn the ___ cells of the pancreas proglucagon is cleaved to yield a 29 amino acid peptide called ___
u
uGlucagon is cleaved just before secretion. Glucagon and ___ ____ are present in a ____ relationship in the islets.
Works with insulin to maintain blood glucose levels
Insulin and glucagon form a regulatory couple and oppose each other in actions
Glucagon
nChemistry
u Proglucagon-derived peptides are encoded by a single mammalian proglucagon gene.
u
uProglucagon is cleaved by prohormone convertase (PC) in a tissue specific manner to yield different hormones
u
uIn the alpha cells of the pancreas proglucagon is cleaved to yield a 29 amino acid peptide called glucagon.
u
uGlucagon is cleaved just before secretion. Glucagon and pancreatic polypeptide are present in a reciprocal relationship in the islets.
Works with insulin to maintain blood glucose levels
Insulin and glucagon form a regulatory couple and oppose each other in actions
Processing of Glucagon
Glucagon formed from this peptide
In the alpha cell, glucagon is cleaved to be ____
In the ____, it is cleaved differently. You don’t get glucagon but you get ____
Glucagon formed from this peptide
In the alpha cell, glucagon is cleaved to be glucagon
In the intestine, it is cleaved differently. You don’t get glucagon but you get GLP1
Factors affecting glucagon secretion
nGlucagon and insulin form a ____ couple. Glucagon is ___glycemic: it acts on liver and adipose tissue to ____ blood glucose and fatty acid concentrations.
n
uHypoglycemia( [glucose] < 50 mg/dL)____ glucagon secretion.
uHyperglycemia ( [glucose] > 200 mg/dL) ____ glucagon secretion.
u↑ fatty acid ____ insulin secretion and ___ glucagon secretion
u↑ Amino acids stimulate the release of_______
u
u Exercise, glucocorticoids, gastrin, arginine, alanine, gastrin, VIP, GIP Cholecystokinin (CCK), ____ glucagon release, while fatty acids, secretin, somatostatin, ____ glucagon release.
uStress ___ glucagon secretion via the ___c nervous system
u
n
Hypoglycemia: Stimulates Glucagon Secretion
Hyperglycemia: That is when insulin is king
High protein diet favors secretion of ____
High carb diet favors secretion of ___
Mixed meal, get secretion of both
Need both glucagon and insulin
If you have high protein diet and secrete only insulin. It will take all carb and move it into cell bc most of diet is protein
If too much carb goes into the cell what will you get? Hypoglycemia
So to prevent hypoglycemia you need to secrete glucagon
Factors affecting glucagon secretion
nGlucagon and insulin form a regulatory couple. Glucagon is hyperglycemic: it acts on liver and adipose tissue to raise blood glucose and fatty acid concentrations.
n
uHypoglycemia( [glucose] < 50 mg/dL) stimulates glucagon secretion.
uHyperglycemia ( [glucose] > 200 mg/dL) suppresses glucagon secretion.
u↑ fatty acid stimulate insulin secretion and ↓ glucagon secretion
u↑ Amino acids stimulate the release of both insulin and glucagon. (E)
u
u Exercise, glucocorticoids, gastrin, arginine, alanine, gastrin, VIP, GIP Cholecystokinin (CCK), stimulate glucagon release, while fatty acids, secretin, somatostatin, inhibit glucagon release.
uStress stimulate glucagon secretion via the sympathetic nervous system
u
n
Hypoglycemia
Stimulates Glucagon Secretion
Hyperglycemia: That is when insulin is king
High protein diet favors secretion of glucagon
High carb diet favors secretion of insulin
Mixed meal, get secretion of both
Need both glucagon and insulin
If you have high protein diet and secrete only insulin. It will take all carb and move it into cell bc most of diet is protein
If too much carb goes into the cell what will you get? Hypoglycemia
So to prevent hypoglycemia you need to secrete glucagon
Factors affecting glucagon secretion
Control of Glucagon Secretion
Increase Glucagon Secretion Decrease Glucagon
Secretion
Amino acids fatty acids
Exercise Secretin
Glucocorticoids Somatostatin
Gastrin
Arginine
Alanine
Vasoactive intestinal peptide (VIP)
Gastrin intestinal peptide (GIP)
Cholecystokinin (CCK)
Factors affecting glucagon secretion
Control of Glucagon Secretion
Increase Glucagon Secretion Decrease Glucagon
Secretion
Amino acids fatty acids
Exercise Secretin
Glucocorticoids Somatostatin
Gastrin
Arginine
Alanine
Vasoactive intestinal peptide (VIP)
Gastrin intestinal peptide (GIP)
Cholecystokinin (CCK)
Factors affecting glucagon secretion
uDuring mixed meals, both ___ and ___ are secreted.
n
n High protein diets favor ___ and ___comes from glycogenolysis and gluconeogenesis.
u High carbohydrate diets favor____ secretion.
uDuring mixed meals, both glucagon and insulin are secreted.
n
n High protein diets favor glucagon and glucose comes from glycogenolysis and gluconeogenesis.
u High carbohydrate diets favor insulin secretion.
Factors affecting glucagon secretion
nGlucose
uThe __-cells are more sensitive to glucose than __-cells. The glucose effect on α-cells is ___ and___of its ability to stimulate __ ___. However, insulin can modulate the effectiveness of ___on the ___-cells. It potentiates the____ effect of glucose.
Hypoglycemia not only ____ the inhibition on ____ secretion, but it also activates the ____ which results in the stimulation of both ___ and ___ nerve endings terminating in the islets of Langerhans.
n
n
nActivation of Parasymp and sympathetic cause ___ of glucagon
Factors affecting glucagon secretion
nGlucose
uThe α-cells are more sensitive to glucose than β-cells. The glucose effect on α-cells is direct and independent of its ability to stimulate insulin secretion. However, insulin can modulate the effectiveness of glucose on the α-cells. It potentiates the suppressive effect of glucose.
uHypoglycemia not only removes the inhibition on glucagon secretion, but it also activates the CNS which results in the stimulation of both parasympathetic and sympathetic nerve endings terminating in the islets of Langerhans.
n
n
nActivation of Parasymp and sympathetic cause release of glucagon
Factors affecting glucagon secretion
nNervous System
uα-cells secrete glucagon in response to both parasympathetic and sympathetic stimulation
uIn addition, the __ ___ responds to hypoglycemia by secreting ____e, which ____ glucagon secretion, ___ insulin secretion, and ____ glucagon action on the ___
uCatecholamines serve in __ ___ regulation of blood glucose
nNervous System
uα-cells secrete glucagon in response to both parasympathetic and sympathetic stimulation
uIn addition, the adrenal medulla responds to hypoglycemia by secreting epinephrine, which potentiates glucagon secretion, inhibits insulin secretion, and reinforces glucagon action on the hepatocyte
uCatecholamines serve in short term regulation of blood glucose
Physiologic Effects of Glucagon
nActivates __ ___ and initiate a phosphorylation-amplification cascade.
__ ___e is activated, leading to glycogen____ and glucose ___
__ ___ is inactivated; thus glycogen synthesis is diminished
Activates adenylate cyclase which causes activation glycogen phosphorylasea
Physiologic Effects of Glucagon
nActivates adenylate cyclase and initiate a phosphorylation-amplification cascade.
nGlycogen phosphorylase is activated, leading to glycogen breakdown and glucose release.
nGlycogen synthase is inactivated; thus glycogen synthesis is diminished
Activates adenylate cyclase which causes activation glycogen phosphorylasea
Physiologic Effects of Glucagon
___ __ ____ is activated, releasing ___ ___from triacylglycerol
nFatty acids are metabolized by ____ and ____released into the circulation
nGlucose and ketones are___ for peripheral tissue
Glucagon also activates hormone sensitive lipase
Ketones can be used as fuel for muscle and heart leaving glucose for the brain
Physiologic Effects of Glucagon
nHormone sensitive lipase is activated, releasing fatty acids from triacylglycerol
nFatty acids are metabolized by ketogenesis and ketones released into the circulation
nGlucose and ketones are fuel for peripheral tissue
Glucagon also activates hormone sensitive lipase
Ketones can be used as fuel for muscle and heart leaving glucose for the brain
Effects of Glucagon on Liver
Activates adenylate cylase
That leads to the conversion of glycogen to glucose by activating glycogen phsophorylase
Effects of Glucagon on Liver
Activates adenylate cylase
That leads to the conversion of glycogen to glucose by activating glycogen phsophorylase
Glucagon stimulates the __ ____ cycle
nMuscle proteins are __ ___ to amino acids
nThe amino acids are ____ to yield __ ___s, which enter the __ __ ___
___ and ____ are produced and released into the blood stream
nLiver uses __ ___ ___ for ____. The nitrogen from glutamine and alanine are released as___
The net result is conversion of___ ___ into blood ____
Glucagon stimulates the breakdown of muscle proteins
Muscle proteins are then deaminated and then placed in gluconeogenesis to form glucose
Glucagon stimulates the glucose-alanine cycle
nMuscle proteins are broken down to amino acids
nThe amino acids are transaminated to yield keto acids, which enter the citric acid cycle
nAlanine and glutamine are produced and released into the blood stream
nLiver uses alanine carbon skeleton for gluconeogenesis. The nitrogen from glutamine and alanine are released as urea.
The net result is conversion of muscle protein into blood glucose
Glucagon stimulates the breakdown of muscle proteins
Muscle proteins are then deaminated and then placed in gluconeogenesis to form glucose
Bone Physiology
nVitamin D and PTH___ osteo____ to secrete ___ ___ ____factor (M-CSF) that cause osteo___ precursors to ____e and produce ____
uOsteoclasts attach to bone by using ____s on its surface to bind to____ in bone matrix
uOsteoclasts secrete ____ and ____e across its ruffled border to dissolve bone mineral and the acid proteases hydrolyze matrix protein.
uOsteoclasts move ___ from pit to allow ___ to come in
nVitamin D and PTH stimulate osteoblast to secrete macrophage colony –stimulating factor (M-CSF) that cause osteoclasts precursors to proliferate and produce osteoclasts
uOsteoclasts attach to bone by using integrins on its surface to bind to vitronectin in bone matrix
uOsteoclasts secrete acid and protease across its ruffled border to dissolve bone mineral and the acid proteases hydrolyze matrix protein.
uOsteoclasts move away from pit to allow osteoblasts to come in
This is osteoclasts and osteoclast has binding sites for calcitonin.
Calcitonin binds and inhibits osteoclast action
RANK bind to receptors and activate
Osteoclast has integrins on its surface that binds to vitronectin on the bone and that seals off surface on both sides
Releases acid
Acid breaks down mineral component of bone
Lysosomal enzymes break down protein component of bone
This is osteoclasts and osteoclast has binding sites for calcitonin.
Calcitonin binds and inhibits osteoclast action
RANK bind to receptors and activate
Osteoclast has integrins on its surface that binds to vitronectin on the bone and that seals off surface on both sides
Releases acid
Acid breaks down mineral component of bone
Lysosomal enzymes break down protein component of bone
Parathyroid Hormone (PTH)
nPlasma____ regulates synthesis and secretion of PTH
___ cells of PTH glands synthesize and release PTH
uMajor regulator of PTH is plasma Ca2+ and__ ___, both ___ synthesis or release of PTH
u↑ plasma _____ stimulates PTH release
u____ Ca2+ stimulates PTH release and synthesis and ___ Ca2+ inhibits release
uUnlike other systems a ____ in [Ca2+]i inhibit PTH secretion
u
u
u
Purpose: ____ blood Ca levels
How does it do that?
Stimulates syn of__ ___ and that causes uptake of Ca from intestines
PTH itself can cause reabsorption of Ca from the kidneys
Parathyroid Hormone (PTH)
nPlasma Ca2+ regulates synthesis and secretion of PTH
uChief cells of PTH glands synthesize and release PTH
uMajor regulator of PTH is plasma Ca2+ and vitamin D, both ↓ synthesis or release of PTH
u↑ plasma phosphorus stimulates PTH release
uLow Ca2+ stimulates PTH release and synthesis and high Ca2+ inhibits release
uUnlike other systems a rise in [Ca2+]i inhibit PTH secretion
u
u
u
Purpose: Raise blood Ca levels
How does it do that?
Stimulates syn of Vit D and that causes uptake of Ca from intestines
PTH itself can cause reabsorption of Ca from the kidneys
Actions of PTH
nActions
uPTH acts in kidney to ____ Ca2+ from the Thick Ascending Limb (TAL) and Distal Convoluted Tubule (DCT) and ____ plasma [Ca2+]
uPTH inhibits ____ reabsorption in Proximal Tubule (PT) and Distal Tubule (DT) by using___ and ___ to remove Na-PO4 _____ (NaPi) from the apical membranes to the cytosol.
uPTH is the most____ regulator of renal Ca2+ ___ and PO43- ___n.
nActions
uPTH acts in kidney to reabsorb Ca2+ from the Thick Ascending Limb (TAL) and Distal Convoluted Tubule (DCT) and ↑ plasma [Ca2+]
uPTH inhibits PO43- reabsorption in Proximal Tubule (PT) and Distal Tubule (DT) by using PKC and PKA to remove Na-PO4 cotransporters (NaPi) from the apical membranes to the cytosol.
uPTH is the most important regulator of renal Ca2+ reabsorption and PO43- excretion.
PTH stimulates the final step of 1,25-Dihydroxyvitamin D
nPTH stimulate the ___-hydroxylation of ___-hydroxyvitamin D in the ____ of PT
u____ dihydroxyvitamin D is the most biologically active form of vitamin D.
FVitamin D then enhance renal Ca2+____
FEnhance absorption of Ca2+ by the __ ___
FModulate movement of ___ and___- in and out of ___
nPTH stimulate the 1-hydroxylation of 25-hydroxyvitamin D in the mitochondria of PT
u1,25 dihydroxyvitamin D is the most biologically active form of vitamin D.
FVitamin D then enhance renal Ca2+ reabsorption
FEnhance absorption of Ca2+ by the small intestines
FModulate movement of Ca2+ and PO43- in and out of bone.
PTH Promotes Both Bone Resorption and Bone Synthesis
nBone resorption
___ increases of PTH cause bone resorption
uOsteo___ have receptors for PTH
uOsteo____ have no PTH receptors
uPTH and vitamin D stimulate osteo___ to release___which stimulate existing osteo___ to ___ bone
____ increases in plasma PTH have bone forming effects
uPTH activates ___ channels in osteo___ which pass Ca to osteo___ to form bone
PTH and Vit D stimulate osteoblasts to release cytokines which stimulate osteoclasts
Ca is released when bone is broken down
PTH Promotes Both Bone Resorption and Bone Synthesis
nBone resorption
uPersistent increase of PTH cause bone resorption
uOsteoblasts have receptors for PTH
uOsteoclasts have no PTH receptors
uPTH and vitamin D stimulate osteoblasts to release IL-6 which stimulate existing osteoclasts to resorb bone
uIntermittent increases in plasma PTH have bone forming effects
uPTH activates Ca channels in osteocytes which pass Ca to osteoblasts to form bone
PTH and Vit D stimulate osteoblasts to release cytokines which stimulate osteoclasts
Ca is released when bone is broken down
Vitamin D
nDeficiency of vitamin D causes ____
u___calcemia and skeletal deformities
uDietary replacement of vitamin __ corrects the disorder so add to milk, bread etc.
uVitamin D__ can be made from ___dehydrocholesterol if ___ light is absorbed. Can also be obtained from cod or halibut liver, eggs
uVitamin D___ is obtained only from the diet, mainly from vegetables.
uFat soluble vitamin so need __ ___ for ___ absorption
nDeficiency of vitamin D causes rickets
uHypocalcemia and skeletal deformities
uDietary replacement of vitamin D corrects the disorder so add to milk, bread etc.
uVitamin D3 can be made from 7-dehydrocholesterol if UV light is absorbed. Can also be obtained from cod or halibut liver, eggs
uVitamin D2 is obtained only from the diet, mainly from vegetables.
uFat soluble vitamin so need bile acids for intestinal absorption
In presence of UV light 7-dehydrocholesterolà D3
This is not active form of vitamin
This D3 has to be ____ twice
1) ___
2) __
One in the kidney is the one that ___ ___ so you have active D
Reabsorb Ca from intestines and kidney
In presence of UV light 7-dehydrocholesterolà D3
This is not active form of vitamin
This D3 has to be hydroxylated twice
1) Liver
2) Kidney
One in the kidney is the one that PTH stimulates so you have active D
Reabsorb Ca from intestines and kidney
Vitamin D
Promote Bone Mineralization
nVitamin D Act on The __ ___ and____ to ↑[Ca2+] and Promote Bone____
nVitamin D regulates__ ___
nVitamin D Act on The Small Intestines and Kidney to ↑[Ca2+] and Promote Bone Mineralization
nVitamin D regulates cell growth
Actions of Vitamin D
____Ca2+ uptake in small intestines
uVitamin D through ____c effects ↑ the synthesis of _____ Ca2+ ___, pumps and Ca2+ binding ____s in the duodenum
uPTH increases ____l Ca2+ uptake ____ly by ↑ the renal formation of ____________
uVitamin D stimulate PO43- ____ by ↑ the synthesis of the NaPi cotransporter that takes phosphate ___ intestinal mucosal cells
nIncrease Ca2+ uptake in small intestines
uVitamin D through genomic effects ↑ the synthesis of epithelial Ca2+ channels, pumps and Ca2+ binding proteins in the duodenum
uPTH increases intestinal Ca2+ uptake indirectly by ↑ the renal formation of 1,25-dihydroxyvitamin D
uVitamin D stimulate PO43- absorption by ↑ the synthesis of the NaPi cotransporter that takes phosphate into intestinal mucosal cells
Actions of Vitamin D
nKidney
uVit. D acts synergistically with PTH to enhance Ca2+ _____ in the DCT
uVit. D promotes PO43-_____
u1,25-dihydroxyvitamin D directly inhibits the___ ____ of vitamin D
nKidney
uVit. D acts synergistically with PTH to enhance Ca2+ reabsorption in the DCT
uVit. D promotes PO43- reabsorption
u1,25-dihydroxyvitamin D directly inhibits the 1-hydroxylation of vitamin D
Actions of Vitamin D
nBone
uVitamin D effects on bone are complex, the direct effect is to____ ____+ from bone, while the indirect effect is to ___ bone ____.
uOverall effect is net bone____ since the ____ effects overshadow the ___ effects.
uBy ↑ the _____ of Ca2+ and PO43- from the _____ and by ↑ the reabsorption of Ca2+ and PO43- from the ____, __ ___↑ plasma levels of [Ca2+] and [PO43-] which favors ____
nBone
uVitamin D effects on bone are complex, the direct effect is to mobilize Ca2+ from bone, while the indirect effect is to ↑ bone mineralization
uOverall effect is net bone mineralization since the indirect effects overshadow the direct effects.
uBy ↑ the absorption of Ca2+ and PO43- from the intestines and by ↑ the reabsorption of Ca2+ and PO43- from the kidney, vit. D ↑ plasma levels of [Ca2+] and [PO43-] which favors mineralization
Rickets and Osteomalacia
nRickets
uCaused by deficiency of vitamin D in children
uBone has abnormal amount of___ ___ leading to diminished bone rigidity and a____of the long bones of the leg
nOsteomalacia
uCaused by a deficiency of vitamin D in adults
uSimilar to bone in rickets but no____. Bone is ___and prone to fracture
nRickets
uCaused by deficiency of vitamin D in children
uBone has abnormal amount of unmineralized osteoid leading to diminished bone rigidity and a bowing of the long bones of the leg
nOsteomalacia
uCaused by a deficiency of vitamin D in adults
uSimilar to bone in rickets but no bowing. Bone is weak and prone to fracture
Calcitonin
nMade by the clear or __ ___ of the ____
u↑ extracellular [Ca2+] cause ____ of calcitonin
uCalcitonin binds to its receptor on ____ to activate___ pathway and ___ the resorptive activity of the osteo___ and ____ the rate of bone turnover.
uInhibit osteo___ osteolysis and so taken together the overall action is ___calcemic
nMade by the clear or C cells of the thyroid
u↑ extracellular [Ca2+] cause release of calcitonin
uCalcitonin binds to its receptor on osteoclasts to activate cAMP pathway and inhibit the resorptive activity of the osteoclast and slows the rate of bone turnover.
uInhibit osteocytic osteolysis and so taken together the overall action is hypocalcemic
