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Flashcards in Pancreas Deck (50):
1

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

2

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

3

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)

4

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). 

5

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

6

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

7

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 

8

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

9

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 

10

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

11

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

12

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)

13

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

14

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

15

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

16

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

17

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

18

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

19

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

20

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

21

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

22

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

23

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

24

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 

25

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

26

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

27

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

28

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

29

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)

30

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.
 

31

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

32

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

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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

34

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

35

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

36

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

37

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

38

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

39

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

40

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. 

41

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.

42

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

43

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

44

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

45

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

46

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

47

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

48

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

49

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

50

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