endo] pancreas. for the class

8/14/2019 ENDO] Pancreas. for the Class

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Kristienne O. Apostol, M.D.

ENDOCRINE PANCREAS


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organized into acini

produce digestive

enzymes secretedinto duodenumPeptidasesLipases

AmylasesNucleases

Physiologic Anatomy of thePancreas

EXOcrineEXOcrine


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Organized into Isletsof Langerhans

Produce hormonessecreted into thehepatic portalvein

InsulinGlucagon Somatostatin

Pancreatic polypeptide

ENDOcrineENDOcrine

Physiologic Anatomy of thePancreas


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Form about 2% of the pancreas

Comprised of 1-2 million Islets

More plentiful in the tail than inthe body and head

Physiologic Anatomy of the

Endocrine Pancreas


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Physiologic Anatomy of the

Endocrine PancreasTypes of cells in theTypes of cells in theIslets:Islets:1.Alpha cells (A cells)

25% ; glucagon-secreting2.Beta cells (B cells)

60% ; insulin-secreting

3.Delta cells (D cells)10% ; somatostatin-

secreting

4.Pancreatic polypeptidecells (PP or F cells)5%

ISLET:ISLET: a functionala functional

syncytiumsyncytiumAlpha, beta anddelta cells forma paracrinecontrol system


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INSULINProduct of Beta cells


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Coordinates use of fuels by tissues byfavoring ANAANAbolism

Promotes storage when metabolic

fuels are in abundance (hormone ofenergy storage)synthesis of glycogen, TAG and

protein when carbohydrates,

fatty acids and amino acids are inexcess

Most important regulator of glucose

homeostasis

FUNCTION of Insulin


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Stimulated by plasma glucoseglucose>3.9mmol/L (70mg/dL)

Enhance protein translation andprocessing

Also stimulated by amino acids (esp.arginine)

Insulin BIOSYNTHESIS


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C-peptide:

connectingpeptide thatremains aftercleavage ofproinsulin toinsulin

Essential toproper insulinfolding

Produced inamountsequimolartoinsulin

Longer plasmahalf-life than



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Primary stimuliPrimary stimuliCarbohydrates

Amino acids

Fatty acids and Keto acids

Secondary stimuliSecondary stimuli

Gastrointestinal hormonesParasympathetic stimulation

Glucagon

Insulin SECRETION


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monosaccharides that can be metabolized(e.g. hexose, triose) are more potentstimuli than those that cannot (e.g.mannose)

PRINCIPAL STIMULUS: GLUCOSEGLUCOSE

Stimulation of Insulin Secretion by...

Carbohydrates


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Carbohydrates

-R a te lim itin g ste p-n in su lin d e p e n d e n t


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Action ofGLUCOSE on insulinsecretion is biphasicInitial response: release of

preformed insulinProlonged response: release of

newly synthesized insulin


Carbohydrates


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Amino acidsAmino acidsArgininelysine

Leucine ...Fatty acidsFatty acids

Short- and long-chain

Keto acidsKeto acidsAcetoacetate3-

hydroxybutyrat

e


Amino, Fatty and Keto Acids A lso g e n e ra te A T Pw h e n m e ta b o lize d

-A T P clo se s A T Pse n sitiv e K +...ch a n n e ls

nsul nxo tos s

S tro n g ly p o te n tia teg lu co se stim u lu s


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Gastrin

Secretin

CCK

Gastricinhibitorypeptide


Gastrointestinal Hormones R e le a se d a fte r ap erson e ats a m ea l

C a u se a n ticip a to ry

in cre a se in in su lin In cre a se C a +2 influx

-through voltage gatedCa +2 channels

Also stronglypotentiate glucose andamino acid stimulus


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Islets are innervated by branchesof the right vagus nerve

Causes insulin release only whenglucose levels are elevated


Parasympathetics


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Parasympathetics

Ch +M4

receptorPLC+

PIP2

IP3 DAGCa+2 from endoplasmicreticulum into

cytoplasm Insulinexocytosis


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Glucagon

lucagon+

receptor

Adenylyl

cyclase+

ATP

cAMP. .IncreaseintracellularCa+2

Insulinexocytosis


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Insulin half-life: 5-6 minutesAllows for rapid changes in its

circulating levels and effects

Degraded by insulinase50% in liver before entering

systemic circulation

Insulin DEGRADATION


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Pulsatile release of insulinSmall secretory outbursts every 10

mins

Greater amplitude oscillations every 80-150 mins

Major stimuli of insulin secretion (mealintake) induce large bursts of insulin

secretionRapid four to five-fold increase (2-3 mins)Followed by decrease halfway down (5-

10 mins)

then a greater continuing increase (2-3

Insulin SECRETORY PROFILE


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InhibitorsInhibitorsStarvation (hypoglycemia)Sympathetic stimulation

Stress, traumaExerciseLargely overrides the influence of the

plasma glucose concentration in

emergency situationssomatostatin

Insulin SECRETION


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Inhibition of Insulin Secretion by...

Sympathetics

22 adrenergicadrenergic

Inhibits adenylyl

cyclase ...INHIBITS insulin

secretion


Activates adenylyl

cyclase ...STIMULATES insulin

secretion

E T E F F E C TE T E F F E C T : inhibitionof insulinsecretion


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Mechanism #2

Mechanism #3

Mechanism #1

In su lin MECHANISMOF ACTION


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LiverLiverIncreaseglycogenesis Activate of glycogen

synthase

Decreaseglycogenolysis Inactivate glycogen

phosphorylase

EFFECTS of Insulin on...

CARBOHYDRATE METABOLISM

In cre a se g lyco lysis In cre a se am o u n t o f

,g lu co kin a sep h o sp h o fru cto kin a se

, pyruvate kinase

D e cre a seg lu con e o g e n e sis

in d ire ctly

Promotes storage and use of glucose in,especially in the liver adipose tissue and

muscles


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MusclesMuscles

Increase glycogenesis

Decrease

glycogenolysisIncrease glycolysis

INCREASE GLUCOSEUPTAKE

Increase glycolysis

INCREASE GLUCOSE

UPTAKE

Adipose TissueAdipose Tissue




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Muscles &Muscles &Adipose TissueAdipose Tissue



Increase glucoseuptake


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n glucose uptake and. . .nsulin

-Main insulin DE :pendent glucose transporterGLUT4

,Adipose tissue skeletal and cardiac muscles -Major insulin IN :dependent tissues

, , ,Nerve cells RBCs liver epithelial cells of, ,the kidney and intestine cornea lens of the

eyes

Physiologicsignificance?

Clinicalsignificance?


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Promotes fat synthesis and storage in theliver and adipose tissue


FAT METABOLISM

L i v e ri v e r Increase fatty acid synthesis Activate acetyl CoA carboxylase

Increase TAG synthesis

( )Increase glycerol precursor glucose Increase fatty acids substrates by increasingamount of lipoprotein lipase


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FAT METABOLISM

Adipose TissueAdipose TissueIncrease fatty acid synthesis

Increase TAG synthesisDECREASE LIPOLYSIS

Inactivate hormone-sensitive lipase


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Promotesprotein synthesis andstorage


PROTEIN METABOLISM

S tim u la te tra n sp o rt o f a m in o a cid s in toce lls

In cre a se m R N A tra n sla tio n In cre a se ra te o f D N A tra n scrip tio n

In h ib it p ro te o lysis In cre a se a m in o a cid su b stra te s b y

su p p re ssin g g lu co n e o g e n e sis


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On POTASSIUM BALANCEOn POTASSIUM BALANCEStimulates movement of extracellular K+

into insulin-sensitive cell (muscle andhepatic tissue)Stimulate Na+-K+ ATPase pump

Other Insulin EFFECTS


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Rapid (seconds)Increased transport of glucose, amino acids,

and K+ into insulin-sensitive cells

Intermediate (minutes)

Increase protein synthesisDecrease protein degradationIncrease glycolysis and glycogenesisDecrease of glycogenolysis

Long-term effectsPromotion of cell growth

EFFECTS of Insulin


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GLUCAGONProduct of Alpha cells


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Coordinates use of fuels by tissues byfavoring CATACATAbolism

Mobilizes energy stores (hormone ofenergy release)

Opposes many of the actions ofinsulin

FUNCTION of Glucagon


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StimuliStimuliStarvation (hypoglycemia)Amino acidsGastrointestinal hormones (CCK,

gastrin)Cortisol

Sympathetic stimulation

Glucagon SECRETION


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Stimulation of Glucagon Secretion by...

Sympathetics


Inhibits adenylyl

cyclase ...INHIBITS glucagon

secretion


Activates adenylyl

cyclase ...STIMULATES

glucagon secretion

T E F F E C TE F F E C T : stimulation of glucagon secreti


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secreted with...Stress, traumaExercise

Largely overrides the influence of theplasma glucose concentration inemergency situations

Stimulation of Glucagon Secretion by...

Sympathetics


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InhibitorsInhibitorsGlucoseFree fatty acids, keto acidsInsulinSomatostatin

Glucagon SECRETION


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Mechanism#2

- alter gene expression

Mechanism #1- direct de- or activation of enzymes by phosph

GlucagonMECHANISM OF

ACTION


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On FAT METABOLISM...On FAT METABOLISM...Decrease fatty acid synthesis

Inactivate acetyl CoA carboxylase

Increase lipolysis (TAG degradation)Activate hormone-sensitive lipase in

adipocytes

Increase ketogenesis indirectly

Increased fatty acids from increased lipolysisoverwhelm oxidative capacity of the liver

Other Glucagon EFFECTS

INSULIN and GLUCAGON:


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Major controlling factor:Major controlling factor: plasma glucoseplasma glucoseconcentrationconcentration

INSULIN and GLUCAGON:Major Regulators of FuelMetabolism

Pre fe rs F ATfor energy

PrefersA R B O H Y D R A T E S

for energy


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SomatostatinProduct of Delta cells


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SECRETIONSECRETION: practically stimulated byall related to food ingestionblood glucoseamino acidsfatty acidsseveral GI hormones

Somatostatin


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EFFECTSEFFECTS: inhibitoryDepress secretion of insulin, glucagon*

and even PP

Decrease motility of the stomach,duodenum and gallbladderDecrease digestive enzyme secretion

and absorption in the GIT

FUNCTIONFUNCTION: Extend the period of time overwhich food nutrients are assimilated intothe bloodPrevent rapid exhaustion of food

Somatostatin


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Pancreatic PolypeptideProduct of PP cells


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SECRETION:SECRETION:Stimulated by cholinergics, fasting,

exercise and acute hypoglycemia

Inhibited by somatostatin and glucoseEFFECTSEFFECTS:

Inhibit secretion of insulin andsomatostatin

Inhibits trypsinogen and bicarbonatesecretion (affects exocrine pancreas)

FUNCTIONFUNCTION:

Slow down digestive process

Pancreatic Polypeptide


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slet as a functional. . .yncytium


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Other Hormones affecting

Fuel MetabolismThe Counterregulatory Hormones


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1.Islets of Langerhans

2.Hypothalamically-mediated system Activate sympathetic nervous

system Release ACTH and growth

hormone by the anteriorpituitary

wo systems activated byhypoglycemia :

The Counterregulatory


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The CounterregulatoryHormones

1.Glucagon

2.Catecholamines

3.Cortisol4.Growth

hormone

Counter the effects of insulin onCounter the effects of insulin onglucose useglucose use


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EFFECTS:EFFECTS:Promotes mobilization of stored carbohydrates

Suppresses mobilization of stored fatsInhibits insulin secretionDecrease insulin-dependent peripheral

glucose utilization

The Counterregulatory Hormones

CATECHOLAMINES

,To g e th e r w ith g lu ca g o n co m p rise th e-m o st im p o rta n t a cu te sh o rt te rm

g lu co re g u la to ry m e ch a n ism s


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EFFECTS:EFFECTS:Promotes gluconeogenesis

Promotes mobilization of amino acids

Promotes mobilization of stored fats

Promote fat utilizationDecrease insulin-dependent peripheral glucose

utilization


CORTISOL

-P la y a ro le in lo n g te rm re g u la tio n o fg lu co se m e ta b o lism

A lte rs g e n e e xp re ssio n


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Play a role in long-term regulationof glucose metabolism

Alter gene expression

:F F E C T S :F F E C T S Promote fat utilization Decrease peripheral glucose

utilization


GROWTH HORMONE


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MENTAL EXERCISEDiabetes Mellitus


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P A T H O L O G YA T H O L O G YAbsolute or relativeinsulin deficiency

coupled with someglucagon excess

Proteinmetabolism?

Carbohydratemetabolism?

Fatmetabolism?

Diabetes Mellitus


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END.

endo] pancreas. for the class

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