Glucose homeostasis The Pancreas
Feb 02, 2016
Actions of insulin and glucagon
Insulin
Signal of feeding.
Target tissues:
liver, adipose
skeletal muscle
Affects metabolism of:
carbohydrates, lipidsproteins
Actions are anabolic
Glucagon
Signal of fasting.
Target tissues:
liver, adipose
Affects metabolism of:
carbohydrates, lipids
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 Insulin Glucagon
Nutrients:
glucose 5mM + -
glucose 5mM - +
amino acids + +
fatty acids + 0
Hormones/neurotransmitters:
GI tract + 0
adrenaline - +
noradrenaline - +
110aa
Preproglucagon
PreproinsulinA|F1 KTRR|E33 KR|G66
Ins B-chain
C-peptide
Ins A-Chain
180aaQ|R1 KR|H33
KR|N64
KR|H72
R|H78
RGRR|D111
GRR|H125
RK160
Glicentin Glucagon
Oxyntomodulin GLP-1 GLP-2
GLP-1 (7-37amide)
116aa
PreprosomatostatinG|A25
F|L34
Q|R89
Antrin ?
SS-14
Somatostatin 28
RERK|A103
95 aa
Prepro Pancreatic polypeptideE|P33 RPRYGKR|H69
Pancreatic polypeptide
Islet Prohormones
Synthesis of insulin - 3
ESR10-09
S
S
S
S
HOOC
SS
NH2
Insulin (21 + 30aa)HOOC
NH2
- chain
- chain
C - peptide (35aa)
Regulation of glucose transport by insulin
Binding of insulin to cell-surface receptorsIntracellular vesicles containing membrane-imbedded GLUT4 transporters fuse with the plasma membraneGLUT4 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)
ESR10-26
GSGS
ActiveInactive
Pi
ATPADP
Phosphoprotein phosphatase
cAMP-INDEPENDENT
kinase
Insulin
( + )
Insulin
( - )GSK3
Insulin Inhibition of TAG Degradation in Adipose
In high insulin/low glucagon state:cAMP falls in adiposeHSL is not phosporylated and is inactiveRemember: epinephrine as shown here is a counterregulatory hormone
Stimulation - insulin secretion
ESR10-12
• Increased [ glucose ]
• Increased [ free aa ]
• Increased [ GI hormones ]
(gastrin, secretin, CCK, GIP)
MixedMeal
• Increased [ glucagon ]
• Noradrenaline
(low [ ]; α-adrenergic receptors)
• Acetylcholine
Inhibition - insulin secretion
ESR10-13
• Decreased [ glucose ]
• Increased [ somatostatin ]
(pancreatic + gastric)
• Noradrenaline
(high [ ]; β-adrenergic receptors)
• Adrenaline
(β-adrenergic receptors)
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
ESR10-10
Glucagon (29aa) - synthesised from preproglucagon
• Zn not required for secretion
• metal ions decrease clearance
Somatostatin (14aa)
• physiological role unclear
• can suppress insulin and glucagon
Stimulation - glucagon secretion
ESR10-14
• Decreased [ glucose ]
• Increased [ free aa ]*
• Adrenaline
Inhibition - glucagon secretion
• Increased [ glucose ]
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-2,6-bisphosphatase (PFK-2/F-2,6-P2ase)
Fructose-6-P
Fructose-1,6-P2
Fructose-2,6-P2
PFK-1F-1,6-P2ase
+-
ActiveF-2,6-Pase
InactiveF-2,6-Pase
InactivePFK-2
ActivePFK-2
cAMP-DependentProtein Kinase
ProteinPhosphatase-2
P-Glucagon
Glycolysis Gluconeogenesis
Glucagon switches OFF glycogen synthetase (GS)
ESR10-25
GSGS
ActiveInactive
Pi
ATPADP
Phosphoprotein phosphatase
cAMP-dependent
kinase
Glucagon
Glycogenphosphorylase a
( - )
( + )Glucagon
( + )
HSL and futile cycling
ESR10-32
CytosolicAcetyl CoA
MitochondrialAcetyl CoA
FA TAG
Glycerol
GlycerolHSL Insulin
( - )
cAMP-dependent
kinaseGlucagon
( + )
( + )( + )
Glucocorticoids
Somatostatin (somatotropin release-inhibiting factor,
SRIF)
• Chemistry:
Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys
S S
A single peptide of 14 amino acids
A 28-amino acid form is found in the gut
• Secreted by hypothalamic anterior periventricular region and by cells of the pancreatic islets• Secretion by GH, IGF-I, thyroid hormones
Stimulation - somatostatin secretion
ESR10-15
• Carbohydrates
• Proteins
• Fats
MixedMeal
• Decreased pH in duodenum
(by gastric acid - bulbogastrone
mechanism)
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+