Pancreas Flashcards
(50 cards)
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
