[os 202c] 20120102 pancreatic islet physiology (insulin)

8/13/2019 [OS 202C] 20120102 Pancreatic Islet Physiology (Insulin)

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I.THE PANCREASTWO TYPES OF PANCREATIC TISSUES

Exocrine Tissueo Found in pancreatic acinio Secretes pancreatic enzymes & bicarbonates for

digestion

Endocrine Tissueo Found in the Islets of Langerhans, scattered among

the pancreatic acini

o Releases pancreatic hormonesTable 1. Four Major Types of Cells found in the Islets

Beta () cells (most numerous)

- 60%of the total cell type

- Located in the centerof the islets

- Secreteinsulin-1 in 10 becomes diabetic every year

Delta () cells


- located peripheral to alpha

cells- Secrete somatostatin

Alpha () cells


- Located in the peripheryof the

Islets

- Secrete glucagon

PP cells

-located peripheral to alpha

cells

-Secrete pancreatic

polypeptide

Figure 1.Four Major Cell Types Found in the islet

The arterial system supplies the center of the islet firstbefore supplying the periphery

Berne: If islets are disaggregated experimentally and theindividual cells dispersed, these cells spontaneously reaggregateinto islets if the cells are brought back together again in culture.

Berne: Gap junctions exist between neighboring islet cells andpermit the flow of molecules (that exert possible paracrine

effects) and electrical currents between them.

Insulin produced in the cells influences the secretion ofthe other islet cells in the periphery paracrine effects of

insulin on the outer islet cell types

INSULIN

Is the primary anabolic hormone responsible for maintaining theupper limit of blood glucose levels, done by:

o Promoting glucose uptake and utilization by muscle andadipose tissue

oIncreasing glycogen storage in the liver and muscleoReducing hepatic glucose output

Promotes protein synthesis from amino acids and inhibits proteindegradation in peripheral tissues

Promotes triglyceride synthesis in the liver and adipose tissue andrepresses lipolysis of adipose triglyceride stores

Regulates metabolic homeostasis through effect on satiety(Source: Berne & Levy)

AA..IINNSSUULLIINNSSTTRRUUCCTTUURREE

Figure 2. Structure of Human Proinsulin

Human proinsulin is composed of three parts:o chain - 21 amino acids containing an intrachain

disulfide ring

o chain 30 amino acids; the and the subunits areconnected by two disulfide bridges

oC chainknown as the connecting peptide or C peptide;it connects the and the subunits

The mature insulin hormone consists only of the and chains connected by 2 disulfide links and the third disulfide

bridge in the subunit

Upon insulin release, C peptide is also released

Figure 3. (Pre)proinsulin and insulin molecules

OUTLINE

I. The PancreasII. Insulin

A. Insulin StructureB. Insulin GeneC. Insulin SynthesisD. Insulin SecretionE. Insulin-Nutrient

Feedback

F. In Vivo RelationshipBetween Plasma

Glucose and Insulin

Secretion

G. Biphasic Response toGlucose

H. Stimulants & Inhibitors ofInsulin Secretion

I. Actions of InsulinJ. Effects of Insulin

III.GlucagonA. Glucagon SynthesisB. Regulation of Secretion

IV.SomatostatinA. Somatostatin SynthesisB. Regulation of Secretion

IIII..IINNSSUULLIINN

OS 202C: Endocrine SystemPANCREATIC ISLETS PHYSIOLOGY

Jan 2, 2012

Dr. Cynthia Halili-Manabat


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Preproinsulin contains 4 sequential peptides: N-terminalsignal peptide, chain of insulin, C peptide and chain of

insulin

BB..IINNSSUULLIINNGGEENNEE Composed of 4 exons and 2 introns Directs synthesis of preproinsulin Translation of mature mRNA initiates synthesis in the

ribosomes

Order of synthesis of polypeptide chain: N-terminalsignal peptide, B chain, C chain, A chain

A long polypeptide is formed, allowing it to fold onitself (by disulfide bonds); sequences not needed are

cleaved

CC..IINNSSUULLIINNSSYYNNTTHHEESSIISS

Figure 4. Synthesis of Insulin

Step 1: Insulin gene codes for preproinsulin Step 2: Mature mRNA initiates synthesis of N-terminal signal

peptide (S) in the ribosomes, followed by B,C and A chain

Step 3: The signal is degraded during the course ofcompletion of the proinsulin molecule

Step 4: The latter is folded into a conformation that permitsdisulfide linkages between the A and B chains to form

Step 5: within the Golgi and secretory granules, convertingenzymes cleave off the C chain (C peptide), completing the

synthesis of insulin*

Step 6: insulin molecules are concentrated in the electron-dense core of the granule, whereas C peptides are in the

peripheral halo of the granule

DD..IINNSSUULLIINNSSEECCRREETTIIOONNNotes: Please refer to Figure 5: Insulin Secretion in the appendix. The

step numbers refer to the numbers in the diagram. The premise in the

following sequence is that there is already preformed insulin waiting for

release.

Glucose, more specifically increase in glucose levels, is themost important stimulus for insulin secretion.

oStep 1: Entry of glucose facilitated by GLUT2transportersGLUT2 transportersare concentrated in the microvilli of the

canaliculi between cells

facilitates diffusion of glucose into the cell helps maintain the glucose conc. in the cell at a level that is

essentially equal to that of the interstitial fluid

takes up glucose freelyoStep 2: Glucose undergoes glycolysis; reacts with

glucokinase

Glucokinase is the fundamental glucose sensor that controlsthe subsequent cell response

Has Km for glucose of 5 mM, which is in the physiologicalrange

Phosphorylation of glucose by glucokinase is the first andrate-limiting step in islet glucose use

oStep 3 (and 4): Increase in ATP levels due to glycolysis,leading to increased ATP/ADP ratioBerne: subsequent rate of insulin secretion parallels that of

glucose oxidation)

oStep 5: Closure of ATP-sensitive K+ channelsefflux ofK+ from cell suppressed K accumulates

depolarization in cell cytoplasm

oStep 6: Depolarization of cell cytoplasm opens Ca

++

channels which results in Increased intracellular Ca

++

concentration

oStep 7: Increased intracellular Ca++ concentrationactivates mechanism for secretory granule movement

along the microtubules (the microtubules contract)

secretory granules fuse with cell membrane

exocytosis of insulin

There are other mechanisms of insulin production:oStep 8: Glucagon (and GLP1, -adrenergic)binds to Gsadenyl cyclase Secondary rise in cAMP levels (thru

G-protein linked receptors) stimulates insulin release

by cAMP-dependent protein kinase A mediate

insulin-releasing effects

o-adrenergic receptor stimulation decreasecAMPdecrease insulin secretionoSomatostatin binds to Gi decreases cAMP levels

decreases insulin release

oStep 9: Parasympathetic innervation (vagal stimulationof cells) acetylcholine binds to Gq(note that in

the figure it is Gs; however, Gq is the one that forms

the link in the phosphoinositide signaling system [Voet &

Voet, Biochemistry 3rd

ed.]) phospholipase C IP3

and DAG IP3 increases Ca2+

and DAG stimulates

Special Notes (from 2015 trans)

*Cleavage is done as proinsulin is packaged into granules by Golgi

Apparatus (cleaved here); the enzymes that cleave C-peptide are

proconvertase-1 and carboxypeptidase-H; resultant insulin

molecule, along with C peptide, is retained in the granules and

released by exocytosis in 1:1 ratio

Insulin becomes associated with zinc as the secretory granules

mature; zinc insulin crystals form the dense central core of the

granule, whereas C peptide is present in the clear space between the

granule membrane and core

NOTE: Molar ratio of C-peptide to insulin is 1:1, thus amount of C-

peptide approximates the amount of ENDOGENOUS insulin in the

blood

Measured used to differentiate type I diabetes mellitusversus type II: zero or very low C peptide suggests type I

DM (meaning zero production/total lack of endogenous

insulin)

bodys intrinsic production of insulin cannot be measuredby taking insulin levels in type I DM patients because the

treatment is exogenousinsulin


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protein kinase C increase in calcium and protein

kinase C mediates insulin-releasing effects

oInflux of ketoacids, fatty acids and amino acids resultingin increase intracellular ATP (upper left of diagram)

oSulfonylureas (eg 2nd generation drugs: glibenclamide,glicazide, glimepiride) binds to receptors (SUR) that

forms one component of the K+

channels closes K+

channels causes cytoplasmic depolarization

increase insulin production (right of diagram)

EE..IINNSSUULLIINN--NNUUTTRRIIEENNTTFFEEEEDDBBAACCKK

Figure 6. Feedback Relationship of Insulin and Nutrients

Insulin secretion is governed by a feedback relationship withexogenous nutrient supply

When substrate supply is abundant insulin is secreted inresponse insulin stimulates use of incoming nutrients and

simultaneously inhibits the mobilization of analogous

endogenous substrates

When nutrient supply is low or absent insulin secretion isdampenedmobilization of endogenous fuels is enhanced

FF..IINNVVIIVVOORREELLAATTIIOONNSSHHIIPPBBEETTWWEEEENNPPLLAASSMMAA

GGLLUUCCOOSSEEAANNDDIINNSSUULLIINNSSEECCRREETTIIOONN

Figure 7. Relationship of serum glucose to insulin response

The relationship between plasma insulin and plasma glucoseis sigmoidal.

Virtually no insulin is secreted below a plasma glucosethreshold of about 50 mg/dl

oAt no time, however, will you have insulin at 0 because itmodulates ketogenesis.

oIf insulin is still secreted, hypoglycemia will occur,decreasing available glucose to the braincoma

A half-maximal insulin secretory response occurs at a plasmaglucose level of about 150 mg/dl (normal fasting blood

glucose level: 70-100 mg/dl).

A maximal insulin response occurs at a level of about 300mg/dl.

oExogenous insulin is required for the uptake of excessglucose.

oIn chronically high glucose levels, the maximal responseoccurs until such a time a point of exhaustion is reached

by the pancreatic islet cells, resulting to a decline of

insulin production.

GG..BBIIPPHHAASSIICCRREESSPPOONNSSEETTOOGGLLUUCCOOSSEE

Figure 8. Plasma glucose and insulin responses over time with

a glucose infusion

Phase 1oInitial rapid riseoSurge of insulin due to the release of preformed insulin

stored in the secretory granules in the cells

oLost in diabetic patientsoGoes down after 5-10 minutesoThe part of the graph that follows phase 1, wherein a

steep decrease in insulin level is observed, is due to the

depletion of insulin stored in secretory granules.

Phase 2oContinuous and gradual rise then plateau due to newly-

synthesized insulin from the cells

HH..SSTTIIMMUULLAANNTTSS&&IINNHHIIBBIITTOORRSSOOFFIINNSSUULLIINNSSEECCRREETTIIOONN

Figure 9. Stimulation and inhibition of insulin production and

release

cells

insulin


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Table 2: Stimulants & Inhibitors of Insulin Secretion

Stimulants Inhibitors

Glucose Somatostatin

-inhibits both

insulin and

glucagons

Amino acids (most

potent are arginine

and lysine)

-adrenergic

stimulators

Intestinal hormones

(GLP-1 and GLP-2) -

Anticipates rise in

insulin secretion

-adrenergic

blockers

Ketoacids

-Has minimal effect on

insulin secretion only

when levels of ketone

bodies decrease

-Maintain basal insulin

secretion

Diazoxide

-Keeps K+

channels open

-No depolarization

-No rise in Ca+2

-No insulin

secretion

Acetylcholine Thiazide diuretics- acts on Na-Cl

channel

Glucagon

cAMP

Table 3: Stimulants and Inhibitors of Beta Cells

Stimulants Inhibitors

Direct stimulantsstimulate beta cells

to produce more

insulinoGlucose-

primary

oFatty acidsoAcetylcholineoGlucagonsoAmino acidsoKetonesoGI hormones

**FA and ketones: lower

effect; only permissive

effect since they are

present in state of

starvation; Ach: vagal

stimulation

o Somatostatin (generallyinhibitory in

endocrinology)

o Epinephrineo Norepinephrine (has a

larger effect than

epinephrine)

Indirect stimulantsincrease beta cell

production of insulin

due to the primary

effect of the

hormones of raising

blood glucose levels

oGrowthhormone

oCortisolJ. EFFECTS OF INSULIN

J. EFFECTS OF INSULIN


INSULIN

II..AACCTTIIOONNSSOOFFIINNSSUULLIINNNotes: Please refer to Figure 10: Actions of Insulin in the appendix.

Primarily anabolic Transport of insulin through the capillary wall- rate-

limiting step

Insulin receptoroin the cell membrane since insulin is a peptide hormoneo2 subunits (extracellular)Bind insulin731 amino acids each

o2 subunits (intracellular)Coupling domain; Have tyrosine kinase domainsIntrinsic enzyme activityHas 194 extracellular residues and 23 amino acid

transmembrane anchor each

oSubunits are bound by disulfide linkages Binding of insulin to the insulin receptor causes activation of

the tyrosine kinase domain

The hormone-receptor complex is subsequently internalizedby endocytosis; the hormone is degraded; and the receptor

is either degraded, stored or recycled back to the plasma

membrane.

Tyrosine kinase phosphorylates Insulin Receptor Substrate(IRS)

Phosphorylated IRS activates PI-3 kinase, whichphosphorylates PI-3 phosphates

PI-3 phosphates cause the translocation and binding of theGLUT-4 transporters from the intracellular pool to the

plasma membrane

Insulin promotes cellular uptake of amino acids, K+, PO4-,and Mg2+

Insulin also affects RNA transcription (mitogenic signals) byacting on Insulin Response Elements (IREs)

Insulin also regulates the action of metabolic enzymesinvolved in glycogenesis, glycolysis, and lipogenesis

Note: Please refer to Figure 11: Levels of Insulin Function in the

appendix.

Levels of insulin actionoLevel 1up to the level of IRSoLevel 2up to the level of kinasesoLevel 3final effects in cell

J. EFF J. EFFECTS OF INSULIN


J. EFFECTS OF INSULINJ. EFFECTS OF INSULIN




ECTS OF INSU INSULIN

LIN


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JJ..EEFFFFEECCTTSSOOFFIINNSSUULLIINNNote: Please refer to Figure 12: Effects of Insulin in the appendix.

Insulin has mostly anabolic effects on cells Glucose metabolism

o(-) Glucose productiono(-) Plasma glucoseo(+) Glucose oxidationo(+) Storage of glucose as glycogeno(+) glucose transport

Protein uptakeo(-) Plasma amino acids and ketoacidso(+) Protein synthesis

Lipid synthesiso(-) Glucose from livero(-) Mobilization and oxidation of fatty acidso(-) Plasma free fatty acids and glycerolo(+) Uptake in insulin-sensitive tissueso(+) Storage

Growth and gene expression Ion transport Effects on specific tissues

oMuscle(+) Glucose and amino acid uptake(-) Protein breakdownoAdipose tissue(-) Lipolysis and ketogenesis(+) Triglyceride uptakeoLiver(-) Gluconeogenesis and glycogenolysisDecreases the levels or activities of the committed

gluconeogenic enzymes (pyruvate carboxylase,

phosphoenolpyruvate carboxykinase and fructose-1,6-

bisphosphatase)

Inhibits oxidation of fatty acids (Guyton)(+) Glycogenesis and glycolysisPromotes synthesis fatty acids

INSULIN

INSULIN

INSULIN

INSULIN

INSULIN

INSULIN

INSULIN

INSULIN

INSULIN

INSULIN

IIIIII..GGLLUUCCAAGGOONN Increases blood sugar, making energy more availableo Has the opposite effect as insulino Catabolic

Notes: How Glucagon WorksGlucagon binds to glucagon receptor activates G proteins

activates the enzyme adenylate cyclase adenylate

cyclase manufactures cAMP activates cAMP-dependent

enzyme protein kinase A protein kinase A

phosphorylates an enzyme, whihch either stimulates or

inhibitsthe enzyme

Effects inside the liver:o Increases rate of glycogenesis by changing the

intracellular cAMP levels using the G protein mechanism

to activate glycogen phosphorylase via the protein kinase

A path

o Increases hepatic gluconeogenesisby stimulating fructose2, 6-bisphosphatase

o Decreases glycogenesis by deactivating glycogen synthase This step prevents the glucose-1-phosphate released in

glycogenolysis from undergoing resynthesis to glycogen

o Decreases glycolysisby deactivating phosphofructokinaseand pyruvate kinase

o Increases ketogenesis and decreases cholesterolsynthesis, directing free fatty acids away from triglyceride

synthesis and towards -oxidation by inactivating acetly-

CoA carboxylase (which is the enzyme for the rate-limiting

step)

Just to be clear: it's the phosphorylation caused by protein

kinase A that activates the enzymes glycogen phosphorylase

and fructose 2,6-bisphosphatase AND deactivates the

enzymes glycogen synthase, phosphofructokinase, and so on.

Effects outside the livero Increases lypolysis and delivery of free fatty acids to the

liver (by activating adipose tissue lipase)

o Inhibits renal tubular sodium resorption, causingnatriuresis

o Slightly increases cardiac outputo May play a role in regulating the appetite by acting on the

CNS

AA..GGLLUUCCAAGGOONNSSYYNNTTHHEESSIISS Preproglucagon to proglucagon Different processing of the precursors yields different

productso -cells of pancreatic islets: glucagon with GRPP and major

proglucagon fragment

o intestinal L-cells: GLP-1 (glucagon-like peptide-1): stimulates insulin

synthesis and secretion, increases insulin sensitivity,

increases mass of -cells and decreases glucagon

secretion

GLP-2 (glucagon-like peptide 2) Glicentin: stimulation of insulin secretion (though this

effect can be ascribed to glucagon)

In the islets, glucose and insulin inhibit glycogen synthesis byrepressing transcription of the glucagon gene

The direction of the blood flow in the islets (insulin-rich core-cells mantle -cells) facilitates inhibitionIV. Somatostatin

IV. SomatostatinINSULIN


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From 2014 Trans: Baby Scott Ong

1) The primary neuroendocrine inhibitor of prolactin secretion is

dopamine.

2) GH stimulates the liver to produce somatomedin.

3) ACTH stimulates the adrenal gland to secrete cortisol,

aldosterone and androgen.

4) TSH is structurally homologous to LH, FSH and HCG.5) The hormone that decreases plasma glucose is insulin.

6) Hormone that increases plasma glucose levels are glucagon,

cortisol and epinephrine.

7) Hormones that increase following blood loss are arginine

vasopressin or ADH, aldosterone and cortisol.

8) One biological effect of glucagon is stimulation of

gluconeogenesis.

9) A parent with an aldosterone producing adenoma

(hyperaldosteronism) may present with hypokalemia.

10) A patient with hypercortisolemia may present with

hyperglycemia, hypertension and visceral obesity.

BB..RREEGGUULLAATTIIOONNOOFFSSEECCRREETTIIOONN Primarily secreted in regards to glucose deficiency in order to

return the circulating glucose to normal levels

Main target: liver Action: promote glycogenolysis and gluconeogenesis Secretion stimulated by (+):o Low plasma glucose: stimulation of secretion is greater

when insulin is low or absent

o Increased plasma amino acids (especially arginine andalanine): stimulation of secretion is greater when insulin is

low or absent and less when insulin is high

To protect from hypoglycemia after consuming an all-protein meal

Increase in amino acids increases the amount ofsubstrate for gluconeogenesis

o Fastingo Exerciseo Neural mechanisms (vagal stimulation, acetylcholine

release, sympathetic nervous system)

o Stressing factors (infections, burns, major surgery, etc.)o catecholamines: epinephrine and norepinephrineo Vasoactive intestinal peptide (VIP)o Cholecystokinin (CCK)

Secretion inhibited by (-):o Hyperglycemia (though not to the same degree as

hypoglycemia)

o Somatostatino Insulin (via GABA)o Increased ketones and free fatty acids in the bloodo Increased urea production

Overall: insulin vs. cortisol, GH, glucagon, epinephrine andnorepinephrine

How come the blood sugar level is maintained and notlowered after an all-protein meal?

o Absorption of AA Increase in blood AA increasedinsulin secretion decreased plasma glucose

o However, glucagon is also secreted, increasing livergluconeogenesis by using the available AA

Note: Please refer to Figure 13 in Appendix for Glucagon Effects on

Carbohydrate and Fat Metabolism

IV. Somatostatin

IIVV..SSOOMMAATTOOSSTTAATTIINN Primary function: extension of the period of time during

which nutrients are assimilated

Specific functions:o Inhibits both insulin and glucagon secretiono Decreases assimilation rate of all nutrients in the GI tract

by inhibiting:

Motilityin the stomach, duodenum and gall bladder Secretionof HCl, pepsin, gastrin, secretin, and intestinal

juices

Exocrinefunctionof the pancreaso Inhibits gastrin, CCK, secretin, motilin, VIP, gastric

inhibitory polypeptide (GIP), enteroglucagon, thyrotropin-

releasing hormone (TRH) and GH

o Inhibits release of pancreatic hormones: insulin andglucagon

o Decreases rate of gastric emptying and reducescontraction of smooth muscles and blood flow within the

intestine

INote: Please refer to Figure 14 in Appendix for Somatostatin role in

Paracrine Interaction in Pancreatic Islets

Somatostatin

IV. Somatostatin

V. Somatostatin

AA..SSOOMMAATTOOSSTTAATTIINNSSYYNNTTHHEESSIISS Synthesized by the:o D cells of the stomach, duodenum/jejunum and

ileum/colon

o cells of the pancreatic isletso Hypothalamus

Exocytosis is stimulated by cAMP Two types:o

SS 14 (14-amino acid): produced by pancreatic cells;via neurocrine/paracrine secretion directly inhibit

insulin and glucagon responses to meals

o SS 28 (28-amino acid): produced by intestinal cells;released after ingestion of fat; can reach islets via

bloodstream, thereby functioning as a true hormone

RREEGGUULLAATTIIOONNOOFFSSEECCRREETTIIOONN Stimulated by (+):o Glucoseo Amino acidso Free fatty acidso GI hormoneso Glucagono -adrenergic neurotransmitterso Cholinergic neurotransmitters

Inhibited by (-):o Insulino -adrenergic neurotransmitters

Jay-V: Happy New Year 2016! Ang saya ng OS202C, in 3 days

lang, endocrinologist ka na! Chos. Cheers to my co-transers,

windang lang na malaman mong transer ka pala right after ng

lecture. To the person I love the most, hindi mo to mababasa.

Ahahaha. Looking forward for a terrific year with you batch! :D

Niko: I don't have anything to say so please enjoy this smiley

instead. :D

Pam: Brilliant first half day back!


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Figure 5. Insulin Secretion

Figure 10. Actions of Insulin


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Figure 11. Levels of Insulin Action

Figure 12. Effects of Insulin


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Figure 13.Glucagon Effects on Carbohydrate and Fat Metabolism

Figure 14.Paracrine Interaction of Pancreatic Islets


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From 2013:

Table 4. Summary of Metabolic Hormones Controlling the Overall Flow of Fuels

Liver Muscle Adipose Tissue

Insulin + glycogen synthesis + glycolysis - glycogenolysis - gluconeogenesis - ketogenesis

+ glucose uptake + amino acid uptake - proteolysis

+ glucose uptake + free fatty acid uptake - lipolysis

Glucagon + glycogenolysis + gluconeogenesis + ketogenesis

minimal action minimal action

Cortisol + glycogenolysis + gluconeogenesis -amino acid uptake +proteolysis

- insulin action + lipolysis - insulin action

Growth Hormone + gluconeogenesis + IGFS/IGFBP + amino acid uptake - glucose uptake + lipolysis - glucose uptake

Epinephrine + glycogenolysis + gluconeogenesis +ketogenesis

+ glycogenolysis - insulin action + lipolysis - insulin action

Thyroid Hormone +gluconeogenesis + proteolysis + lipolysis

[os 202c] 20120102 pancreatic islet physiology (insulin)

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