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Pancreatic HormonesPancreatic Hormones

สุวัฒณีสุวัฒณี คุปติวุฒิคุปติวุฒิ

ตึกจุฑาธุชตึกจุฑาธุช หองหอง 111111

Pancreatic hormonesInsulinGlucagon

Describe the fundamental physiological mechanisms controlling of the secretion of insulin and glucagon into the blood stream.Understand the effects of insulin and glucagonon glucose, fatty acid, and amino acid metabolism in the various body tissues.

AimsAims

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Islet of langerhans:Insulin, Glucagon

Exocrine gland: enzymes

Anatomy and histological of Anatomy and histological of pancreaspancreas

Islet of Islet of LangerhansLangerhansA, α 20-30 % Glucagon

B, β 60-80% Insulin

D, σ ∼8% SomatostatinB cellsB cells

A cellsA cellsD cellsD cells

Parasympathetic fibersParasympathetic fibers

Sympathetic fibersSympathetic fibers

F ∼2% Pancreatic polypeptide

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Chain A: 21 aa

Chain B: 30 aa

Disulfide bridge

Insulin Peptide hormone

MW ∼6000

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Insulin processing

Insulin C peptide

Rough ER

Vesicle

Golgi

Processingin vesicles

Insulin secretion

Cleavage of proinsulin

Insulin : C peptide1:1

Insulin : C peptide1:1

PreproinsulinPreproinsulin

ProinsulinProinsulin

Hemoglobin A1C (HbA1C)Hemoglobin A1C (HbA1C)• Glycosylated hemoglobin Glucose

Hemoglobin

HbA1C

Clinical Application

• HbA1C lives for 8-12 wks

• Normal value for HbA1C = 3.5-5.5 mM

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ControlledControlled diabetesdiabetes,,notnot muchmuch glucoseglucose,,notnot muchmuch glycosylatedglycosylatedhaemoglobinhaemoglobin

Uncontrolled diabetes,more glucose,much more glycosylatedhaemoglobin

Factor affecting insulin Factor affecting insulin secretionsecretion

β cells

Insulin

• Diabetogenic H• Parasympathetic•• DiabetogenicDiabetogenic HH•• ParasympatheticParasympathetic

• Sympathetic• Insulin• Somatostatin

•• SympatheticSympathetic•• InsulinInsulin•• SomatostatinSomatostatin

++

-

•• Glucose Glucose ••Amino acidsAmino acids•• GI hormonesGI hormones

Mixed mealMixed meal

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Normal blood glucose ∼100 mg/dl (3-5 mM)Basal plasma insulin concentration ∼ 10 microU/mlNormal blood glucose ∼100 mg/dl (3-5 mM)Basal plasma insulin concentration ∼ 10 microU/ml

Meals

Insulin

Glucose

1 st phase

2 nd phase

Glucose

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GlucoseGlucose--induced induced insulin insulin

secretionsecretion

G

ATP

Ca2+

Ca2+

Ca2+

Insulin secretionInsulin secretion

Non ATPNon ATPdependentdependent

ATPATPdependentdependent

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GLP-1

M2 receptor GRP40NEFA

Insulin secretionInsulin secretion

Incretins: GLP-1, GIP

Incretin effect

B-cells

Insulin secretion

www.incretininfo.co.kr/.../incretin_diagram1.jpg

+ Glucose

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Insulin transportInsulin transportInsulin (peptide hormone)

Dissolve in blood plasma

Half life of insulin is less than 10 minutes

Insulin Action on Cells: Insulin Action on Cells: Dominates in Fed State MetabolismDominates in Fed State Metabolism

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Insulin signaling

Glucose transport

Protein synthesis

Lipid synthesis

glycogensynthesis

Growth and Gene expression

Insulin

Insulin receptor

α−subunit

β−subunit

containing tyrosine kinase

Insulin actionsMetabolic effect

CarbohydrateCarbohydrate• Facilitates glucose transport into muscle,

adipose and many other tissues but not brain

• Stimulates glycogen production (glycogen synthesis)

and inhibits glycogen breakdown (glycogenolysis) in

liver and skeletal muscle

Glucose Glucose uptakeuptake

Glucose Glucose usageusage GlycolysisGlycolysis

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• inhibits glucose synthesis (gluconeogenesis) in liver

ProteinProtein

• Facilitates amino acids into muscle and other

tissues

• Stimulates protein synthesis and inhibits protein

breakdown

Insulin actions

LipidLipid

• Promotes formation of fatty acids and glycerol

from glucose

• Facilitates free fatty acids into cells ( lipoprotein

lipase)

• Promotes synthesis of triglyceride and inhibits

their breakdown ( hormone sensitive lipase)

Insulin actions

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GrowthGrowth

• Promotes growth of the fetus

• Promotes postnatal growth by inhibiting protein

degradation

• Needed for promotion of IGFs

Insulin actions

Insulin actionsInsulin actions

CHOCHOGlycogen synthesisGlycogen synthesis

GlycogenolysisGlycogenolysisGluconeogenesisGluconeogenesisHepatic glucose Hepatic glucose productionproduction

ProteinProtein

Amino acid uptake &Amino acid uptake &protein synthesisprotein synthesis

Amino acid output &Amino acid output &amino acid oxidationamino acid oxidation

LipidLipid

TriglycerideTriglyceridesynthesissynthesis

LipolysisLipolysis

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Insulin deficit Diabetes Mellitus

Absolute: Insulin dependent diabetes Absolute: Insulin dependent diabetes mellitus (IDDM)/ Type I mellitus (IDDM)/ Type I ∼∼ 55--10%10%

Relative: Non insulin dependent diabetes Relative: Non insulin dependent diabetes mellitus (NIDDM)/ Type II mellitus (NIDDM)/ Type II ∼∼ 9090--95%95%

Defect in insulin secretionDefect in insulin secretionInsulin resistanceInsulin resistance

ReceptorReceptorPostreceptorPostreceptor

••A casual plasma glucose level (taken at any A casual plasma glucose level (taken at any time of day) of 200 mg/time of day) of 200 mg/dLdL or greater when or greater when the symptoms of diabetes are present.the symptoms of diabetes are present.

••A fasting plasma glucose value of 126 mg/A fasting plasma glucose value of 126 mg/dLdLor greater. or greater.

••An OGTT value in the blood of 200 mg/An OGTT value in the blood of 200 mg/dLdLor greater measured at the 2or greater measured at the 2--hour interval.hour interval.

Diagnosis Diabetes MillitusDiagnosis Diabetes Diagnosis Diabetes MillitusMillitusADA: American Diabetes AssociationADA: American Diabetes Association

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Insulin deficiencyInsulin deficiency

Glucose uptakeGlucose uptake GlycogenolysisGlycogenolysis

GluconeogenesisGluconeogenesis

ChangeChangein bloodin blood Plasma glucosePlasma glucose

(hyperglycemia)(hyperglycemia)

ChangeChangein urinein urine Glucose in urineGlucose in urine

((glycosuriaglycosuria))

Osmotic Osmotic diuresisdiuresis

Frequency of urinationFrequency of urination((polyureapolyurea))Sign andSign and

symptomssymptoms Dehydration, ThirstDehydration, Thirst((polydipsiapolydipsia))

Food consumptionFood consumption((polyphagiapolyphagia))

Protein breakdownProtein breakdown

Weight lossWeight loss

Insulin deficiencyInsulin deficiency

LipolysisLipolysis

ChangeChangein bloodin blood

ChangeChangein urinein urine

Plasma lipid used as fuelPlasma lipid used as fuel

KetosisKetosis

KetonesKetones in the urinein the urine((ketonureaketonurea))

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Signs and symptoms of diabetes mellitus

Hyperglycemia Glucosuria(Osmotic diuresis)

Hyperlipidemia Ketonemia

Protein wasting Weight loss

Insulin excessInsulin excessOver dose insulinInsulinoma

HypoglycemiaNeuroglycopenia

HungerDizzinessComa

Cathecolamine: anxiety, sweating, tachycardia

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GlucagonGlucagon

29 amino acids identical to 29 amino acids identical to enteroglucagonenteroglucagon

GlucagonGlucagon act by binding to its act by binding to its receptor receptor andandactivated G protein which cause an increaseactivated G protein which cause an increasein in cAMPcAMP. . GlucagonGlucagon has the effect of increasing blood has the effect of increasing blood glucose levels (glucose levels (opposite effect of insulinopposite effect of insulin))

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EnteroglucagonEnteroglucagon

Factor affecting Factor affecting glucagonglucagonsecretionsecretion

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GlucagonGlucagon actionsactions

• Stimulates breakdown of glycogen stored in the

Liver and inhibits glycogen synthesis

• Stimulates gluconeogenesis in the liver

Metabolic effect

CarbohydrateCarbohydrate

• Stimulates amino acids uptake in the liver

ProteinProtein

• Stimulates protein breakdown and inhibits protein

synthesis

GlucagonGlucagon actionsactions

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• Stimulates lipolysis in fat and liver

• Stimulates ketone formation in the liver

LipidLipid

GlucagonGlucagon actionsactions

GlucagonGlucagon actionsactions

CHOGlycogen synthesis

Glycogenolysis

GluconeogenesisHepatic glucose production

Lipid

Lipolysis

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Insulin & Insulin & GlucagonGlucagon Regulate Regulate MetabolismMetabolism

Fed stateFed state insulininsulin dominatesdominates

Insulin & Insulin & GlucagonGlucagon Regulate Regulate MetabolismMetabolism

Fast stateFast state glucagonglucagon dominatesdominates

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High blood High blood glucoseglucose

Insulin released by Insulin released by B cells of pancreasB cells of pancreas

Fat cells take in Fat cells take in glucose from bloodglucose from blood

Low blood Low blood glucoseglucose

GlucagonGlucagon released by released by A cells of pancreas A cells of pancreas

Liver releases Glucose Liver releases Glucose into bloodinto blood

Achieve Normal blood Achieve Normal blood Glucose levelsGlucose levels

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Insulin and Insulin and glucagonglucagon cause the cause the tight control of blood glucose tight control of blood glucose concentrationconcentration

CatecholaminesCorticosteroidsGrowth H

CounterCounterregulatoryregulatoryhormonehormone

GlucagonGlucagon excess and deficit are excess and deficit are rarerare

Glucagon excess: cancer of alpha cells (glucagonomas)

There is no report of glucagondeficit.

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SomatostatinSomatostatinSomatotrophin-release inhibiting factor (SRIF)Also found in nerve terminals and other tissues.Somatostatin is a local inhibitor of insulin and glucagon secretion.Also function as a neurotransmitter/ neuromodulator in the control of moteractivity and cognitive functions.

Pancreatic polypeptide (PP)Pancreatic polypeptide (PP)36 amino acidsSecretion of PP is mainly under autonomic control.PP is released following feeding or during hypoglycaemiaRole of PP is still not understood.