Transcript presentation source

Hormones and metabolism
an overview
Saffron Whitehead
Metabolic paths of
glucose
Glycogen
glycogenolysis
GLUTs
+
Circulation
+
+
Glucose -6
phosphate
Glucose
-
glycolysis
PROTEIN
+
gluconeogenesis
lipolysis
Pyruvate
FAT
lipogenesis
+
TCA
cycle
+
Stimulatory and inhibitory
effects of insulin on the
fate of glucose
-
Hepatic portal
vein
The liver sits at the head of the portal vein. It has a high
capacity to take up glucose and can buffer increases in
blood sugar concentration
The major pathways of glucose
metabolism in the liver
Gluconeogenesis
Glucose
Glycogenolysis
Glycogen
Glucose-6-phosophate
Glycolysis
Phosphoenol pyruvate
Lipolysis
Fatty acids
Amino acids
(triglycerides)
Keto acids
Pyruvate
Acetyl CoA
Oxaloacetate
TCA
Keto acids
Major metabolic
pathways in skeletal
muscle
Glycogen
Glucose
++
+
G 6-P
GLUT 4
Pyruvate
Lactate
+
Stimulated by
insulin
+
Stimulated by
adrenaline
TCA
Amino acids
Fatty acids
Fatty acids
+
LPL
TAG
TAG in lipoprotein
particles
Exogenous pathway of lipoprotein metabolism
Dietary fat
HDL
Hydrolysis by
lipoprotein lipase in
capillary beds of fat
and muscle
Chylomicrons
FA
Muscle
LPL action
Chylomicron
remnants taken
up by liver
Fat
FA
Action of lipoprotein lipase in white adipose tissue
Lipoprotein lipase is
attached to the
glycocalyx and acts on
lipoprotein particles in
the capillary
From Metabolic Regulation by KN Fryan
Endogenous pathway of
lipoprotein metabolism
Liver
Direct reuptake of
some VLDL
particles
TAG
HDL
Hydrolysis by
lipoprotein lipase in
capillary beds of fat
and muscle
VLDL particles
FA
Muscle
LPL action
LDL particles
taken up by
tissues
Tissues
Fat
FA
The LDL receptor and regulation of cellular cholesterol
content
Cholesterol ester is
hydrolysed in the
lysosomes
Raised cholesterol
reduces synthesis of LDL
receptors and inhibits
cholesterol synthesis
Fatty acid and glucose metabolism in white fat
Chylomicron
TAG
capillary
VLDL
TAG
Lipoprotein lipase
+
Fatty acids esterification
lipogenesis
+
GLUT 4
+
Stimulated
by insulin
TAG
Nor-adrenline +
+
Glucose
Glycerol-3phosphate
Fatty acids/
glycerol
Hormones of the endocrine pancreas
Arrangement of cells in a
single islet -  cells
constitute approximately
60% of each islet
Single islet surrounded by
exocrine acini
Islets 1-1.5% of pancreatic
mass
~ 1 million islets
Control of insulin and glucagon secretion
Arterial blood
Arteriole
GLUT 2
o
o
o
o
Insulin
o
o
o
o
Glucagon
o
Insulin secreting
granules
o
Som, PP
o
o
Venule
Venous blood
Fenestrated
capillaries to aid
entry of hormones
into circulation
Dose reponse curve of insulin secretion in
relation to blood glucose concentrations
Insulin secretion is
stimulated by
• raised blood glucose
concentrations
Insulin release
• most amino acids (to somewhat
differing extents)
• NEFAs?
Threshold for
insulin release
~ 5 mmol/l
glucose
0
5
10
15
20
Glucose concentration (mmol/l)
Secretion regulated by autonomic
nervous system
~ 50% insulin reaching the liver is
removed in its ‘first passage’
Family of glucose transporters
Metabolic paths of
glucose
Glycogen
glycogenolysis
GLUTs
+
Circulation
+
+
Glucose -6
phosphate
Glucose
-
glycolysis
PROTEIN
+
gluconeogenesis
lipolysis
Pyruvate
FAT
lipogenesis
+
TCA
cycle
+
Stimulatory and inhibitory
effects of insulin on the
fate of glucose
-
Glucagon secretion is
• suppressed by a rise in blood glucose concentration
• stimulated by amino acids
Raised blood glucose concentrations lower
insulin:glucagon ratio. The reverse occurs when blood
glucose concentrations fall
Only significant effects of glucagon are on the liver
stimulating the production of glucose gluconeogenesis, glycogenolysis
10-15% is removed in its ‘first passage’ effect
Growth hormone
• stimulates the production of IGFs -->
stimulatory effect on growth
• stimulates fat mobilization: delayed
effect compared with rapid effects of
adrenaline
• stimulates hepatic glucose production gluconeogenesis and glycogenolysis
Cortisol
• Stimulates fat mobilization (increases
hormone sensitive lipase)
• stimulates gluconeogenesis
• inhibits uptake of glucose by muscle
(mechanism?)
• stimulates breakdown of muscle protein
Diabetogenic hormone
Symptoms of Cushing’s
Adrenergic receptors, second messenger and effects of catecholamines
•Net effect of adrenaline and nor adrenaline will depend on relative
abundance of different receptors in different tissues and on
concentration of hormones.
• High’ish concentrations - increased heart rate, rise in circulating
concentrations of glucose and NEFAs e.g. mobilization of stores of
glycogen and TAG
•Very high concentrations - increased TPR and some inhibition of
metabolic processes
Thyroid hormone (T3)
•
Stimulates metabolic rate by increasing size
and number of mitochondria, stimulating
Na+- K+-ATPase activity.
This accounts for 15-40% of a cells resting energy
expenditure
• Stimulates proteolysis
Graves’ disease
Hormonal regulation of proteins synthesis and
breakdown in muscle
+
-
Protein synthesis
Protein catabolism
From Metabolic Regulation by KN Fryan
Amino acid metabolism in
the liver
Amino acid
Amino acid
Transamination
Glutamate + NH3
Keto acid
TCA cycle
Ketogenesis
Acetyl CoA
Lipogenesis
Pyruvate/TCA
intermediate
Urea cycle
Gluconeogenesis
Insulin stimulates
lipoprotein lipase (LPL)
and the insertion of GLUT
4 channels into the
membrane
Insulin stimulates
the esterification of
fatty acids to
triaglycerol, the
main store of
chemical energy in
white adipose tissue
Fatty acid and glucose
metabolism in white fat
Adrenaline stimulates
hormone sensitive
lipase (HSL) and
insulin inhibits HSL
From Metabolic Regulation by KN Fryan
Non-esterified fatty acid (NEFA) metabolism
after an overnight fast. Triacylglycerol
(TAG) is converted back to fatty acids and
released into the circulation for use by
muscle and formation of ketone bodies in
the liver and formation of TAG for
recirculation as VLDL
Other energy sources in the post
absorptive state are through hepatic
gluconeogenesis and glycogenolysis
From Metabolic Regulation by KN Fryan
Glucose metabolism
after breakfast
From Metabolic Regulation by KN Fryan
Metabolic pattern in untreated diabetes mellitus type 1
+
-
Pathways
stimulated
by lack of
insulin
Pathways
inhibited by
lack of
insulin
Formation of ketone bodies
Insulin inhibits -oxidation
and lipolysis
In diabetes oxaloacetate
is consumed by the
gluconeogenic pathway
Excess acetyl CoA is
shunted into formation
of ketone bodies
Integration of the utilization of fatty acids and glucose
Oxidation of fatty acids
in muscle reduces
uptake and oxidation of
glucose
This leads to
impairment of
glucose uptake and
loss of the action of
insulin (resistance)
From Metabolic Regulation by KN Fryan