Download Pancreatic Hormones

Pancreatic Hormones
สุวัฒณี คุปติวุฒิ
ตึกจุฑาธุช หอง 111
Aims
„
„
„
Pancreatic hormones
„ Insulin
„ Glucagon
Describe the fundamental physiological
mechanisms controlling of the secretion of
insulin and glucagon into the blood stream.
Understand the effects of insulin and glucagon
on glucose, fatty acid, and amino acid
metabolism in the various body tissues.
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Anatomy and histological of
pancreas
Exocrine gland: enzymes
Islet of langerhans:
Insulin, Glucagon
Islet of Langerhans
Parasympathetic fibers
B cells
A, α
20-30 % Glucagon
B, β
60-80%
D, σ
∼8%
Insulin
Somatostatin
Sympathetic fibers
D cells
A cells
F
∼2%
Pancreatic
polypeptide
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Chain A: 21 aa
Disulfide bridge
Chain B: 30 aa
Insulin
™ Peptide hormone
™ MW ∼6000
3
Preproinsulin
Rough ER
Proinsulin
Insulin
processing
Insulin :: CC peptide
peptide
Insulin
1:1
1:1
Vesicle
Golgi
Processing
in vesicles
Cleavage of
proinsulin
Insulin secretion
Insulin
C peptide
Clinical Application
Hemoglobin A1C (HbA1C)
• Glycosylated hemoglobin
Glucose
Hemoglobin
HbA1C
• HbA1C lives for 8-12 wks
• Normal value for HbA1C = 3.5-5.5 mM
4
Uncontrolled diabetes,
more glucose,
much more glycosylated
haemoglobin
Controlled diabetes,
diabetes,
not much glucose,
glucose,
not much glycosylated
haemoglobin
Factor affecting insulin
secretion
• Glucose
•Amino acids
• GI hormones
Mixed meal
•• Diabetogenic
Diabetogenic H
H
•• Parasympathetic
Parasympathetic
+
+
β cells
Sympathetic
•• Sympathetic
Insulin
•• Insulin
Somatostatin
•• Somatostatin
-
Insulin
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Normal blood
blood glucose
glucose ∼100
∼100 mg/dl
mg/dl (3-5
(3-5 mM)
mM)
Normal
Basal
plasma
insulin
concentration
∼
10
microU/ml
Basal plasma insulin concentration ∼ 10 microU/ml
Glucose
Meals
1 st phase
2 nd phase
Insulin
Glucose
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Glucoseinduced
insulin
secretion
G
ATP
Ca2+
Ca2+
Ca2+
Insulin secretion
ATP
dependent
Non ATP
dependent
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Insulin secretion
GLP-1
M2 receptor
GRP40
NEFA
Incretin effect
Incretins: GLP-1, GIP
B-cells
+ Glucose
Insulin secretion
www.incretininfo.co.kr/.../incretin_diagram1.jpg
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Insulin transport
Insulin (peptide hormone)
Dissolve in blood plasma
Half life of insulin is less than 10 minutes
Insulin Action on Cells:
Dominates in Fed State Metabolism
9
Insulin signaling
α−subunit
containing tyrosine kinase
Insulin
Insulin receptor
β−subunit
Glucose
transport
Protein
Lipid
glycogen Growth and
synthesis synthesis synthesis Gene expression
Insulin actions
Metabolic effect
Glucose
uptake
Glucose
usage
Glycolysis
Carbohydrate
• 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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Insulin actions
• inhibits glucose synthesis (gluconeogenesis) in liver
Protein
• Facilitates amino acids into muscle and other
tissues
• Stimulates protein synthesis and inhibits protein
breakdown
Insulin actions
Lipid
• Facilitates free fatty acids into cells ( lipoprotein
lipase)
• Promotes formation of fatty acids and glycerol
from glucose
• Promotes synthesis of triglyceride and inhibits
their breakdown ( hormone sensitive lipase)
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Insulin actions
Growth
• Promotes growth of the fetus
• Promotes postnatal growth by inhibiting protein
degradation
• Needed for promotion of IGFs
Insulin actions
Protein
Amino acid uptake &
protein synthesis
Amino acid output &
amino acid oxidation
CHO
Glycogen synthesis
Glycogenolysis
Gluconeogenesis
Hepatic glucose
production
Lipid
Triglyceride
synthesis
Lipolysis
12
Insulin deficit
„
„
Diabetes Mellitus
Absolute: Insulin dependent diabetes
mellitus (IDDM)/ Type I ∼ 5-10%
Relative: Non insulin dependent diabetes
mellitus (NIDDM)/ Type II ∼ 90-95%
„
Defect in insulin secretion
„
Insulin resistance
Receptor
„Postreceptor
„
Diagnosis Diabetes
Diabetes Millitus
Millitus
Diagnosis
ADA: American Diabetes Association
•A casual plasma glucose level (taken at any
time of day) of 200 mg/dL or greater when
the symptoms of diabetes are present.
•A fasting plasma glucose value of 126 mg/dL
or greater.
•An OGTT value in the blood of 200 mg/dL
or greater measured at the 2-hour interval.
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Insulin deficiency
Glucose uptake
Glycogenolysis
Gluconeogenesis
Change
in blood
Change
in urine
Protein breakdown
Plasma glucose
(hyperglycemia)
Glucose in urine
(glycosuria)
glycosuria)
Osmotic diuresis
Sign and
symptoms
Frequency of urination
(polyurea)
polyurea)
Dehydration, Thirst
(polydipsia)
polydipsia)
Food consumption
(polyphagia)
polyphagia)
Weight loss
Insulin deficiency
Lipolysis
Change
in blood
Change
in urine
Plasma lipid used as fuel
Ketosis
Ketones in the urine
(ketonurea)
ketonurea)
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Signs and symptoms of
diabetes mellitus
„
Hyperglycemia
„
Hyperlipidemia
Glucosuria
(Osmotic diuresis)
Ketonemia
„
Protein wasting
Weight loss
Insulin excess
„
„
Over dose insulin
Insulinoma
„
Hypoglycemia
„
Neuroglycopenia
„
„
„
„
Hunger
Dizziness
Coma
Cathecolamine: anxiety, sweating,
tachycardia
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Glucagon
„
29 amino acids identical to
enteroglucagon
Glucagon act by binding to its receptor and
activated G protein which cause an increase
in cAMP.
„ Glucagon has the effect of increasing blood
glucose levels (opposite effect of insulin)
„
16
Enteroglucagon
Factor affecting glucagon
secretion
17
Glucagon actions
Metabolic effect
Carbohydrate
• Stimulates breakdown of glycogen stored in the
Liver and inhibits glycogen synthesis
• Stimulates gluconeogenesis in the liver
Glucagon actions
Protein
• Stimulates amino acids uptake in the liver
• Stimulates protein breakdown and inhibits protein
synthesis
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Glucagon actions
Lipid
• Stimulates lipolysis in fat and liver
• Stimulates ketone formation in the liver
Glucagon actions
CHO
Glycogen synthesis
Glycogenolysis
Lipid
Lipolysis
Gluconeogenesis
Hepatic glucose
production
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Insulin & Glucagon Regulate
Metabolism
Fed state
insulin dominates
Insulin & Glucagon Regulate
Metabolism
Fast state
glucagon dominates
20
Low blood
glucose
Glucagon released by
A cells of pancreas
Liver releases Glucose
into blood
High blood
glucose
Insulin released by
B cells of pancreas
Fat cells take in
glucose from blood
Achieve Normal blood
Glucose levels
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Insulin and glucagon cause the
tight control of blood glucose
concentration
Catecholamines
Corticosteroids
Growth H
Counter
regulatory
hormone
Glucagon excess and deficit are
rare
„
„
Glucagon excess: cancer of alpha
cells (glucagonomas)
There is no report of glucagon
deficit.
22
Somatostatin
„
„
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Somatotrophin-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 moter
activity and cognitive functions.
Pancreatic polypeptide (PP)
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36 amino acids
Secretion of PP is mainly under
autonomic control.
PP is released following feeding or
during hypoglycaemia
Role of PP is still not understood.
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