[KULIAH 9] Sintesis Dan Sekresi Indokrin PankreasKul

8/19/2019 [KULIAH 9] Sintesis Dan Sekresi Indokrin PankreasKul

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PANCREAS GLAND

Suyasning HI


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DEFINITIONZAT KIMIA YANG DIHASILKAN DALAM CAIRAN TUBUH OLEH

SEL ATAU KELOMPOK SEL YANG MENIMBULKAN EFEK

PENGATURAN FISIOLGIS PADA SEL-SEL TUBUH

The role

Is a control system of INTEGRAtiON

S. SARAF

ORGAN

S.ENDROKRIN


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DEFINITION

• Ligand

• Receptor

• Effector

• First –second messenger


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DEFINITION

• Ligand: any small molecules that

binds specifically to a receptor site

• Agonist—antagonist

• Ex.: hormone, drugs, etc.


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DEFINITION

• Effector : a molecules in the cellmembranes---continue signal from

hormone or ligand.• Trans membrane molecules/enzyme

or ion channel

• Adelynate cyclase . Ca 2+ channel ,phospholipase C


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Second messenger

• Be maintained at low concentration in the resting cell

• Be produced only in response toactivation of specific

receptors

• Be produced in proportion to the size of extracellular

signal

• Produced a cellular response in proportion to the

change in concentration of the second messenger

• Be degraded rapidly to ensure traniency in signalling

pathways

• cAMP, cGMP, PI, Ca ion, protein kinase


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Development of the receptor

concept• Cells posses specific receptors for

hormones derived from pharmacologic

studies on the action of toxin and drugs

• Sutherland and other researchers: second

messenger of hormone concept; hormone

is the first messenger


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JENIS HORMON BERDASARKAN

LETAK TARGET ORGAN• H. LOKAL (TARGET ORGAN : LOKAL)

– ASETHYLKHOLIN

– SEKRETIN,PANKREOZIMIN

– GASTRIN

• H. GENERAL (TARGET ORGAN : JAUH)

– GH

– THYROID

– INSULIN/GLUKAGON

– H STEROID


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Hormones and their receptorsHormone Class of

hormoneLocation

Amine(epinephrine)

Water-soluble Cell surface

Amine (thyroidhormone)

Lipid soluble Intracellular

Peptide/protein Water soluble Cell surface

Steroids andVitamin D

Lipid Soluble Intracellular


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MEKANISME KERJA HORMON

• DALAM MENJALANKAN FUNGSINYA HORMON

BEKERJA DENGAN BEBERAPA CARA :

– MERUBAH REAKSI KIMIA

– MERUBAH AKTIVITAS ENZIM

– MERUBAH PERMIABILITAS MEMBRAN SEL

– MEMACU SINTESIS PROTEIN

– KONTRAKSI DAN RELAKSASI OTOT

– MERANGSANG SEKRESI


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H. Peptide


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Gbr.reseptor

hormon peptida


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Kerja h. steroid


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MEKANISME KERJA HORMON

(PROTEIN )HORMON

ATP

3’5 cAMP

•ENZIM

•PERMIABILITAS

MEMB. SEL

•KONTRAKSI-

RELAKSASI•SINTESIS PROTEIN

•SEKRESI

RESEPTOR


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MEKANISME KERJA HORMON STEROID

SINTESIS

PROTEIN

(SEL TARGET)

FS. SEL • H. STEROID

•HS ~ PRS (SITOPLASMA) HS-PS HS-PS KEDALAM NUKLEUS

• SEPANJANG PERJALANAN DALAM

NUKLEUS, PS

PROTEIN BM

SINTESIS mRNA SITOPLASMA

SINTESIS DALAM RIBOSOM


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Learning objectives

• Glucose homeostasis

• The synthesis and secretion of

insulin and glucagon


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ATP

Glucose CO2 + H2O

ins

NEFA

Glucose Glycerol Triglyceride

ins ins

Glycogen

ins cats

Glucose G-6-P ins

CO2

Glycolysis Pyruvate Lactate

Glucose

glcg glcg

ins cats cats ins

cort

Gluconeogenesis Glycogen

LactateGlycerol Amino Acids

glcg(+)

(+) (+)

(+)(-)

Liver

(+) (+)

(+)

Skeletal muscle

Adipose tissue

Glucose

Central nervous system

NIMGU

NIMGU

NIMGU

GLUT-4

GLUT-4

ins

ins (+)

(+)

(+)

GUT

Carbohydrate

(+) (+)

F ig. Overview of carbohydrate metabolism William and Pickup. Handbook of Diabetes, 2000


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Cell types of Islets of Langerhans

Type of cell Location Function

Beta

Alpha

Central islet

Outer rim

Secrete insulin

Secrete glucagon

Delta

Pancreatic

polypeptide

Intermixed Secrete

somatostatinSecrete

pancreatic

polypeptide


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Stimulus for

secretionMajor

action

Overall

effect of

blood levels

Insulin(tyrokinase

receptor)

Glucagon

Increased B Gluc

I amino acids

I fatty acidGlucagon

GIP

GH

Cortisol

D B glucose

I amino acids

CCK

Norepinephrine,

epinephrine, ACH

Increases glu

uptake into cells

and glucagon

formation

D glycogenolysis

I protein syntesis

I fat depo and D

lipolysis

I uptake K

I glycogenolysis and

gluconeogenesis

I lipolysis and keto

production

Dec glucagon

D

D

D

Hypokalemia

I

I

I


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Cause increased glucagon Cause decreased glucagonsecretion

•

D glucose•I amino acids

•CCK (alert alpha cells to

protein meal)

• Norepinephrine,

epinephrine

•Ach

•

I blood glucose•Insulin

•Somatostatin

•Fatty acids, ketones

Regulation of glucagon secretion


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Hormonal control of glucose homeostasis

Effect Insulin Glucagon Epine-

phrine

Growth

Hormone

Cortisol

Glucose uptake

Glucose product ion

Glycogenolysis

Gluconeogenesis


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Glucose

glcg glcg

ins cats cats ins

cort

Gluconeogenesis Glycogen

LactateGlycerol Amino Acids

glcg

(+)

(+) (+)

(+)(-)

Glucose

~50 g of glucose stored as glycogen

Glycogen breakdown: glucagon,

epinephrine, GH, cortisol

After ~40 hours of fasting – glycogen

largely depleted and

gluconeogenesis becomes

predominant of hepatic glucose

release

Carbon precursor: glycerol, lactate,

amino acidIn health, after overnight fast liver

release glucose at ~2 mg/kg/min =

rate glucose uptake

Hepatic glucose release


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Glucose transport pathways

• Facilitative glucose carriers (GLUTs)

– Class I : high-affinity binding proteins GLUT1,

GLUT3, GLUT4, and lower-affinity

transporter GLUT2

– Class I I : GLUT5, GLUT7, GLUT9, and GLUT11 or

myoinositol transporter (HMIT1) have a

very low affinity for glucose and

preferentially transport fructose

– Class I I I : GLUT6, GLUT8, GLUT10, GLUT12

• Sodium-glucose cotransporters (SGLTs)

Glucose, hydrophilic nature, can not penetrate lipid

bilayer; specific

transporterproteins are required for facilitated diffusion

into cells


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Glucokinase

Glucose G-6-P ATP

ins

NEFA

Glucose Glycerol Triglyceride

ins ins

Glycogen

ins cats

Glucose G-6-P ins

CO2

Glycolysis Pyruvate Lactate

(+) (+)

(+)

Skeletal muscle

Adipose tissue

Glu-

cose

Beta cell pancreas

NIMGU

NIMGU

NIMGU

GLUT-4

GLUT-4

ins

ins (+)

(+)

(+)

(+) (+)

Glucose uptake

Insulin-sensitive tissue

Insulin-independent tissue

GLUT-2


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STRUCTURE OF MEMBRANE

RECEPTORS• 4 common motifs:

Seven transmembrane G protein-

coupled receptor Receptor-type ion channel

Single transmembrane receptors thatposses intrinsic enzyme activity

Transmembrane receptors that interactwith other cellular protein with enzymeactivity


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INSULIN RECEPTOR STRUCTURE

• Transmembrane glycoprotein complex

• WM, 400 kDa

•

Two 135 kDa a-subunits and two 95 kDa b-subunit

• Linked by disulphide bonds to form a

heterotetramer

•

The a-subunits enterily extracelullar • The b-subunit has an extracellular domain, a

transmembrane domain and an intracellular

domain


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I nsul in biosynthesis and processing

Insulin C peptide

Prohormone convertase 3 Prohormone convertase 2

Split (32-33)

proinsulin

Split (65-66)

proinsulin

Des (31,32)proinsulin Des (64,65)proinsulin

Carboxypeptidase

Proinsulin

The insulin hexamer with

each of the six molecules

coloured differently


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INSULIN SECRETION


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Insulin secretion profiles in Type 2

diabetic patients and healthy people

I n

s u l i n s e c r e t i o n ( p m o l / m i n )

800

6a

m Time

10am 2p

m

6p

m

10pm 2a

m

6am

700

600

500

400

300

200

100

Healthy

peopleType 2 diabetic

patients


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Fig. Insulin signaling pathway that regulate

glucose metabolism in muscle cells and adipocytes

(Shepherd and Kahn, 1999 )


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INSULIN ACTIONIN LIVER


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INSULIN ACTIONIN MUSCLE AND ADIPOCYTE


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INSULIN RECEPTOR FUNCTIONS

a-subunits• Binds insulin in N-terminal one-third

• Repress tyr kinase activity intrinsic to b-subunit

b-subunitsAutophosphorylates six tyr residues

• Juxtamembrane domain (tyr 960): intracellular substrates

phosphorylation, internalization

• Regulatory domain (tyr 1146, 1150, 1151): enhances activity

of receptor towards exogenous substrates

• C-terminal region (tyr 1316, 1322): mediates mitogenic

action of insulin?


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Fig. Structural domain

of insulin receptor

Maratos-Flier et al. 1998


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Insulin

G

GG G

(-)

(+)

GGG

GGG

GGG

CO2 H2O

Fasting-state

Glucose

Fig. In the fasting state, glucose enters the circulation from the liver and taken up

predominantly by non-insulin-sensitive tissues (such as the brain). Relatively little glucose is

taken up by insulin-sensitive tissues such as muscle. The blood glucose is maintained by the

actions of insulin to restrain hepatic glucose release to match the rate of glucose uptake


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Insulin

G

GG G

(-)

(+)

GGG

GGG

GGG

CO2 H2O

Fed-state

Glucose

Fig. Fed state- following meal ingestion, glucose enters the circulation from both the meal

and the liver. In health, in response to the resulting increment in blood glucose, there is a

prompt increase in insulin secretion. As a consquence, hepatic glucose release is suppressed

and glucose uptake b insulin-sensitive tissues such as skeletal muscle is rapidly increased


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INSULIN SIGNALING

Signaling substrate of insulin receptor: three levels

1. Level I: proximal substrates (IRS, SHC) directly

interact with them

2. Level II: downstream intermediates (MAPKinases, Akt)

3. Level III: final biological responses

Level I and II molecules function primarily at plasma

membrane or in cytosolMany of Level III molecules are transported into

nucleus


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Fig. Insulin receptor signaling pathway


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GLUCOSE TRANSPORTERS

Two distinct molecular families of cellular

transporters of glucose

1. Sodium-linked glucose transporters, restricted to

intestine and kidney

2. Facilitated diffusion down glucose-concentration

gradient (GLUT 1 7)

GLUT 4 is the main insulin-responsive glucose transporter

and is located primarily in muscle cells and

adipocytes.

GLUT 4: 90 sequestered intracellularly in absence of

insulin or other stimuli such as exercise


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Fig. Insulin signaling pathway that regulate

glucose metabolism in muscle cells and adipocytes

(Shepherd and Kahn, 1999 )


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Fig. Mechanism involved in the translocation

of GLUT 4 in muscle cells and adipocyte(Shepherd and Kahn, 1999)


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KELAINAN SEKRESI INSULIN

• KADAR DAN KERJA INSULIN :• KADAR ABSOLUT : DM TIPE I (IDDM)

• KADAR + KEMAMPUAN KERJA : DM TIPE II

(NIDDM)

INSULIN RESISTEN

• HORMON INSULIN : HIPOGLIKEMI


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Plasma glucose is maintained during exercise by

• increasing liver glycogen mobilization, using more

plasma FFA, increasing gluconeogenesis, and

decreasing glucose uptake by tissues.

The decrease in plasma insulin and the increase inplasma E, NE, GH, glucagon, and cortisol during

exercise control

These mechanisms to maintain the glucose

concentration.


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CELLULAR MECHANISM OF

INSULIN RESISTANCE


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RECEPTOR REGULATION

•Homologous vs. heterologous

regulation•Down- and up-regulation ~

number of receptors

•

Receptor and postreceptorsignaling


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LIFE CYCLE OF THE HORMONE-

RECEPTOR COMPLEX

Biosynthesis and turnover of membrane receptor

Fig. A general model for the life cycle of the hormone receptor


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Fig. Insulin-

receptor inter-

nalization inclathrin-coated

pits


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INSULIN RESISTNACE PLAYS A MAJOR

ROLE IN TYPE 2 DM DEVELOPMENT

1. The presence of insulin resistance 10-20

years before the onset of the disease

2. Cross sectional studies demonstrating that

isnulin resistance is a consistent finding in

patients with Type 2 DM

3. Prospective studies demonstrating that

isnulin resistance is the best predictor of

whether or not an individual will later

become diabetic

Shulman GI, J Clin Invest 106, 2000


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ROLE OF INSULIN SIGNALING

SYSTEMS IN INSULIN RESISTANCE

• Obesity and Type 2 DM

• Postbinding defect > its receptor

• Mutations IR gene: rare and no play animportant role in the pathophysiologyof typical Type 2 DM or obesity

• IR is downregulated in obesity, nodecrease its activity in liver and muscleof Type 2 DM patient -> Type 2 DM:primarily a postreceptor


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1. Glucose metabolism and

Glycogen synthesis2. Glucose transporters


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Insulin Release

• In a 24 hour period, 50% of the insulin

secreted is basal and 50% is stimulated.

• The main stimulator is glucose.

• Amino acids also stimulate insulin release,

especially lysine, arginine and leucine. This

effect is augmented by glucose.


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Control of Insulin secretion

• Insulin secretion is also increased by intestinal

polypeptide hormones

• GLP-1 (glucagon like peptide) [exendin-4]

• Glucose-dependent insulinotropic peptide

(GIP)

• Cholecystokinin

•And by pancreatic glucagon.

• Insulin secretion is decreased by pancreatic

somatostatin.


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Control of Insulin secretion

• Insulin secretion is also increased by

growth hormone (acromegaly)

• glucocorticoids (Cushings’)

• prolactin (lactation)

• placental lactogen (pregnancy)

• sex steroids


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GLUT 4 and INSULIN RESISTANCE

GLUT Mmutation

•Polymorphism in GLUT 4 gene very rare in patients

with Type 2 DM, and same prevalence with normal

subjjects

Tissue specific alterations

•Obese, IGT, Type 2 DM: reduced GLUT 4 in adipocytes,

not in skeletal muscle

Translocation defects

•

Trafficing, docking and fusion

Defects in signaling pathway

• FFA, glucose toxicity, TNF-a


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Ser/Thr phosphorylation of IRS

protein and insulin resistance

Signaling

IRS Insulin IRS IRS Negative

P-Tyr P-Ser/Thr feedback control(physiological)

P-Ser/Thr IRS Insulin

Elevating agent P-Ser/Thr resistance

(TNF) (pathological)

Activators of P-Ser/Thr: PKC, cAMP dependent protein kinase


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TNF-a as an inducer of insulin

resistance

• TNF-a expression is increased inabdominal fat and muscle tissue of

obese individual• Causes IR are direct or indirect?

• Directly: increase Ser phosphorylationof IRS1 and IRS2

• Inderectly: stimulated leptin dancorrelated with FFA -> IR


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The role of PPARg in insulin action and

insulin resistance

• PPARg

regulating gene- adipogenesis IR

•PPARg activation (TZD) -> adipocyte differentiation and

induced gene expression involved in insulin action (aP2,

PEPCK, acylCoA synthase, and LPL)

•PPAR

g

activation inhibits leptin gene expression

•TNFa inhibits PPARg gene expression

•Fat tissue > liver and muscle - > increase insulin

sensitivity indirectly via TNFa , leptin, FFA

•PPARg activation (TZD) -> induced LPL -> increase TG

uptake to fat -> reduced FFA -> reduced IR

• Enhanced GLUT4 gene expression

PPAR=peroxisome proliferator-activated receptor

TZD=thiazolidinediones


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Summary of insulin secretion• ↑ blood glucose

• ↓

• ↑ insulin

•

↓• ↑ transport of glucose into cells,↓ gluconeogenesis, ↓ glycogenolysis

• ↓

• ↓ blood glucose

• ↓

• ↓ insulin


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THE ROLE OF INSULIN

Metabolic Effects of Insulin

• main effect is to promote storage of

nutrients

• paracrine effects

• carbohydrate metabolism

•lipid metabolism

• protein metabolism and growth


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[KULIAH 9] Sintesis Dan Sekresi Indokrin PankreasKul

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