1. Hormones and metabolism an overview
Saffron Whitehead

2. Metabolic paths of glucose
Glycogen
glycogenolysis +
GLUTs + +
Glucose -6
phosphate
Glucose
Circulation -
glycolysis
gluconeogenesis -
lipolysis -
Pyruvate
PROTEIN
FAT
lipogenesis + +
TCA
cycle
Stimulatory and inhibitory
effects of insulin on the
fate of glucose + -

3. 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

4. The major pathways of glucose metabolism in the liver
Glycogenolysis
Glycogen
Gluconeogenesis
Glycolysis
Glucose
Glucose-6-phosophate
Phosphoenol pyruvate
Lipolysis
Amino acids
Fatty acids
(triglycerides)
Pyruvate
Keto acids
Keto acids
Acetyl CoA
Oxaloacetate
TCA

5. + + + + + + Major metabolic pathways in skeletal muscle Glycogen
Glucose
G 6-P +
Stimulated by insulin
GLUT 4
Pyruvate +
Stimulated by adrenaline
Lactate
TCA
Amino acids
Fatty acids
Fatty acids +
LPL
TAG
TAG in lipoprotein particles

6. Exogenous pathway of lipoprotein metabolism Chylomicrons
Dietary fat
HDL
Hydrolysis by lipoprotein lipase in capillary beds of fat and muscle
Chylomicrons
LPL action FA FA
Muscle
Fat
Chylomicron remnants taken up by liver

7. 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

8. LDL particles taken up by tissues
Direct reuptake of some VLDL particles
Endogenous pathway of lipoprotein metabolism
Liver
TAG
HDL
Hydrolysis by lipoprotein lipase in capillary beds of fat and muscle
VLDL particles
LPL action FA FA
Muscle
Fat
LDL particles taken up by tissues
Tissues

9. Cholesterol ester is hydrolysed in the lysosomes
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

10. Fatty acid and glucose metabolism in white fat
Chylomicron
TAG
VLDL
TAG
capillary
Lipoprotein lipase +
esterification
Fatty acids
TAG
Nor-adrenline +
lipogenesis + +
Glucose
Glycerol-3-phosphate
GLUT 4
Fatty acids/
glycerol +
Stimulated by insulin

11. 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

12. Control of insulin and glucagon secretion
Arterial blood
Arteriole
GLUT 2 o
Insulin
Glucagon
Som, PP o o o o o o o o
Insulin secreting
granules o o o o o o o o
Venule
Venous blood
Fenestrated capillaries to aid entry of hormones into circulation

13. Insulin secretion is stimulated by
Dose reponse curve of insulin secretion in relation to blood glucose concentrations
Insulin secretion is stimulated by
raised blood glucose concentrations
most amino acids (to somewhat differing extents)
NEFAs?
Secretion regulated by autonomic nervous system
~ 50% insulin reaching the liver is removed in its ‘first passage’
Insulin release
Threshold for insulin release ~ 5 mmol/l glucose
Glucose concentration (mmol/l)

14. Family of glucose transporters

15. Metabolic paths of glucose
Glycogen
glycogenolysis +
GLUTs + +
Glucose -6
phosphate
Glucose
Circulation -
glycolysis
gluconeogenesis -
lipolysis -
Pyruvate
PROTEIN
FAT
lipogenesis + +
TCA
cycle
Stimulatory and inhibitory
effects of insulin on the
fate of glucose + -

16. 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

17. 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

18. Stimulates fat mobilization (increases hormone sensitive lipase)
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

19. 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

20. Stimulates proteolysis Graves’ disease
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

21. Hormonal regulation of proteins synthesis and breakdown in muscle+ -
Protein synthesis
Protein catabolism
From Metabolic Regulation by KN Fryan

22. Amino acid metabolism in the liver Pyruvate/TCA intermediate
Transamination
Glutamate + NH3
Keto acid
TCA cycle
Acetyl CoA
Pyruvate/TCA intermediate
Urea cycle
Ketogenesis
Lipogenesis
Gluconeogenesis

23. Fatty acid and glucose metabolism in white fat
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
Insulin stimulates lipoprotein lipase (LPL) and the insertion of GLUT 4 channels into the membrane
Adrenaline stimulates hormone sensitive lipase (HSL) and insulin inhibits HSL
From Metabolic Regulation by KN Fryan

24. Non-esterified fatty acid (NEFA) metabolism after an overnight fast
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

25. Glucose metabolism after breakfast
From Metabolic Regulation by KN Fryan

26. - + Metabolic pattern in untreated diabetes mellitus type 1
Pathways stimulated by lack of insulin
Pathways inhibited by lack of insulin + -

27. 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

28. 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