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Pancreatic HormonesPancreatic Hormones
สุวัฒณีสุวัฒณี คุปติวุฒิคุปติวุฒิ หองหอง 216216โทรโทร:: 75787578
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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
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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
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Factor affecting insulin Factor affecting insulin secretionsecretion
β cells
Insulin
• Diabetogenic H• Parasympathetic•• DiabetogenicDiabetogenic HH•• ParasympatheticParasympathetic
• Sympathetic• Insulin• Somatostatin
•• SympatheticSympathetic•• InsulinInsulin•• SomatostatinSomatostatin
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-
•• 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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iii
i
i
Tolbutamide
K+
Ca++
[Ca++]
−ΔV
[ATP]/[ADP]
Glucose G-6-PGKGlucose Pyruvate
Mitochondria
Acetyl Co A
TCA
Electron transport chain
ATP
Glut 2
Glucose-stimulated insulin secretion mechanism
Hk
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Insulin secretionInsulin secretion
Non ATPNon ATPdependentdependent
ATPATPdependentdependent
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Insulin transportInsulin transportInsulin (peptide hormone)
Dissolve in blood plasma
Half life of insulin is less than 10 minutes
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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 receptorα−subunit
β−subunit
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Insulin actions
Metabolic 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
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• inhibits glucose synthesis (gluconeogenesis) in liver
Insulin actions
ProteinProtein
• Facilitates amino acids into muscle and other
tissues
• Stimulates protein synthesis and inhibits protein
breakdown
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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)
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Insulin actions
GrowthGrowth
• Promotes growth of the fetus
• Promotes postnatal growth by inhibiting protein
degradation
• Needed for promotion of IGFs
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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 secretion
Insulin resistanceInsulin resistanceReceptorReceptorPostreceptorPostreceptor
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••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 MillitusMillitus
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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 loss24
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
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Insulin excessInsulin excessOver dose insulinInsulinoma
HypoglycemiaNeuroglycopenia
HungerDizzinessComa
Cathecolamine: anxiety, sweating, tachycardia
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GlucagonGlucagon29 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 (opposite effect of insulin)glucose levels (opposite effect of insulin)
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EnteroglucagonEnteroglucagon
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Factor affecting Factor affecting glucagonglucagonsecretionsecretion
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Glucagon actions
• Stimulates breakdown of glycogen stored in the liver and inhibits glycogen synthesis
• Stimulates gluconeogenesis in the liver
Metabolic effect
CarbohydrateCarbohydrate
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• Stimulates amino acids uptake in the liver
ProteinProtein
Glucagon actions
• Stimulates protein breakdown and inhibits protein
synthesis
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• Stimulates lipolysis in fat and liver
• Stimulates ketone formation in the liver
Glucagon actions
LipidLipid
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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
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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 38
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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
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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.
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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.
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