Transcript Slayt 1 - Cumhuriyet University

The Pancreas
Glucose homeostasis
Pancreatic Hormones, Insulin &
Glucagon Regulate Metabolism
Actions of insulin and glucagon
Insulin
Glucagon
Signal of feeding.
Signal of fasting.
Target tissues:
liver, adipose
skeletal muscle
Target tissues:
liver, adipose
Affects metabolism of:
carbohydrates, lipids
proteins
Affects metabolism of:
carbohydrates, lipids
Actions are anabolic
Actions are catabolic
Why keep blood glucose concentration constant?
Some tissues only metabolise glucose:
CNS, PNS, red blood cells, kidney, eye
Metabolise glucose at constant rate.
Rate of glucose uptake determined by blood [glucose].
Keep blood [glucose] constant to enable metabolism to proceed
at constant rate.
Control of insulin & glucagon secretion
Factor
Nutrients:
glucose  5mM
glucose  5mM
 amino acids
 fatty acids
Insulin
Glucagon
+
+
+
+
+
0
Hormones/neurotransmitters:
GI tract
+
adrenaline
noradrenaline
-
0
+
+
Preproinsulin
A|F1
KTRR|E33
KR|G66
Ins B-chain
110aa
Ins A-Chain
C-peptide
Preproglucagon
Q|R1
KR|H33
KR|H72
KR|N64
Glicentin
RGRR|D111
R|H78
GRR|H125
Glucagon
Oxyntomodulin
GLP-1
GLP-2
GLP-1 (7-37amide)
Preprosomatostatin
G|A25
Q|R89
F|L34
116aa
RERK|A103
Antrin ?
Somatostatin 28
SS-14
Prepro Pancreatic polypeptide
E|P33
Pancreatic polypeptide
Islet Prohormones
RK160
RPRYGKR|H69
95 aa
180aa
Synthesis of insulin - 1
Preproinsulin (110aa)
NH2
S
S
S
S
HOOC
S
S
ESR10-07
Synthesis of insulin - 2
Proinsulin (86aa)
NH2
S
S
S
S
HOOC
S
S
ESR10-08
Synthesis of insulin - 3
Insulin (21 + 30aa)
HOOC
NH2
S
S
S
S
HOOC
NH2
S
 - chain
 - chain
S
C - peptide (35aa)
ESR10-09
Regulation of glucose transport by insulin
Binding of insulin to cell-surface receptors
Intracellular vesicles containing membrane-imbedded GLUT4
transporters fuse with the plasma membrane
GLUT4 transporters in muscle or adipose cell surface increases
capacity of the cell to transport glucose.
Basal levels of
glucose transport
are maintained
by GLUT1 and
GLUT3 forms of
the glucose
transporter (in
most tissues).
Activation of glycogen synthase and
inactivation of glycogen phosphorylase
Binding of insulin by
the liver or muscle
cell leads to
stimulation of protein
phosphatase-1
Hydrolysis of
phosphate catalyzed
by protein
phosphatase-1
increases the activity
of glycogen
synthase but
deactivates glycogen
phosphorylase.
Insulin switches ON
glycogen synthetase (GS)
Insulin
Pi
(+)
Phosphoprotein phosphatase
GS
GS
Inactive
ADP
cAMPINDEPENDENT
kinase
GSK3
(-)
Insulin
Active
ATP
ESR10-26
Insulin Inhibition of TAG Degradation in Adipose
In high insulin/low glucagon state:
cAMP falls in adipose
HSL is not phosporylated and is inactive
Remember: epinephrine as shown here is a
counterregulatory hormone
Insulin Action on Cells:
Dominates in Fed State Metabolism
Stimulation - insulin secretion
• Increased [ glucose ]
• Increased [ free aa ]
Mixed
Meal
• Increased [ GI hormones ]
(gastrin, secretin, CCK, GIP)
• Increased [ glucagon ]
• Noradrenaline
(low [ ]; α-adrenergic receptors)
• Acetylcholine
ESR10-12
Inhibition - insulin secretion
• Decreased [ glucose ]
• Increased [ somatostatin ]
(pancreatic + gastric)
• Noradrenaline
(high [ ]; β-adrenergic receptors)
• Adrenaline
(β-adrenergic receptors)
ESR10-13
Hypoglycaemia
Blood glucose < 3.0mM
Uptake of glucose by glucose-dependent tissues not adequate to
maintain tissue function.
CNS very sensitive:
Impaired vision, slurred speech, staggered walk
Mood change – aggressive
Confusion, coma, death
Stress response (release of adrenaline):
Pale
Sweating – clammy
Diabetes Mellitus
Group of metabolic diseases.
Affect 1-2% of population in UK.
Characterised by:
• chronic hyperglycaemia (prolonged elevation of blood glucose)
• leading to long-term clinical complications
Caused by:
• Insulin deficiency – failure to secrete adequate amounts of
insulin from -cells.
and/or
• Insulin resistance – tissues become insensitive to insulin.
Classification of Diabetes
Two major types recognised clinically
Type 1 – absolute insulin deficiency (loss of -cells).
Type 2 – relative insulin deficiency and/or insulin resistance.
Also Gestational Diabetes (only occurs during pregnancy).
Other pancreatic hormones
Glucagon (29aa) - synthesised from
preproglucagon
• Zn not required for secretion
• metal ions decrease clearance
Somatostatin (14aa)
• physiological role unclear
• can suppress insulin and glucagon
ESR10-10
Stimulation glucagon secretion
• Decreased [ glucose ]
• Increased [ free aa ]*
• Adrenaline
Inhibition glucagon secretion
• Increased [ glucose ]
ESR10-14
Activation of glycogen phosphorylase and
inactivation of glycogen synthase
Glucagon as a signal of
hunger. In its
presence, the liver
carries out
glycogenolysis to
provide glucose to the
bloodstream and the
rest of the body.
Epinephrine is a signal
of stress. Stimulates
muscle glycogenolysis
to provide glucose to
support contraction and
movement
6-phosphofructo-2-kinase/fructose-2,6bisphosphatase (PFK-2/F-2,6-P2ase)
Fructose-6-P
Glycolysis
Gluconeogenesis
cAMP-Dependent
Protein Kinase
Active
F-2,6-Pase
F-1,6-P2ase
Inactive
PFK-2
-
-
P
Glucagon
Inactive
F-2,6-Pase
Active
PFK-2
Protein
Phosphatase-2
Fructose-2,6-P2
Fructose-1,6-P2
+
PFK-1
Glucagon switches OFF
glycogen synthetase (GS)
Glucagon
(+)
Glycogen
phosphorylase a
(-)
Pi
Phosphoprotein phosphatase
GS
GS
Inactive
cAMPdependent
kinase
ADP
(+)
Glucagon
Active
ATP
ESR10-25
HSL and futile cycling
Glycerol
Cytosolic
Acetyl CoA
TAG
FA
Mitochondrial
Acetyl CoA
Glycerol
HSL
Insulin
(-)
(+)
(+)
Glucocorticoids
cAMPdependent
kinase
Glucagon
(+)
ESR10-32
Somatostatin
(somatotropin release-inhibiting factor,
SRIF)
• Secreted by hypothalamic anterior
periventricular region and by d cells of
the pancreatic islets
• Secretion  by GH, IGF-I, thyroid
hormones
• Chemistr S
S
y: Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys
A single peptide of 14 amino acids
A 28-amino acid form is found in the gut
Stimulation somatostatin secretion
• Carbohydrates
• Proteins
• Fats
Mixed
Meal
• Decreased pH in duodenum
(by gastric acid - bulbogastrone
mechanism)
ESR10-15
Somatostatin
• Actions:
•
Inhibits GH secretion but not its synthesis
•
•
•
Inhibits basal and TRH-stimulated TSH secretion
Inhibits secretion of GI peptide hormones:
insulin, glucagon, VIP, gastrin, and others
• Mechanism of action:
•
Gi protein-coupled receptors with tissue-specific
•
expression
Reduces cAMP production and Ca2+