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Outline the synthesis of glucagon

Preproglucagon is synthesised by the pancreatic alpha cells, this molecule is cleaved to form proglucagon. This proglucagon is then cleaved to form glucagon in the alpha pancreatic cells, or other molecules such as GLP-1 in the brain or L-intestinal cells


What is glucagon secretion stimulated by?

Reduced blood glucose concentration or increase blood amino acids (especially alanine and arginine as glucagon stimulates the synthesis of glucose from these substrates --> gluconeogenesis), and exercise


What is glucagon secretion inhibited by?

Insulin and somatostatin


How does insulin work to inhibit glucagon secretion?

Insulin works to convert cAMP into 5' AMP via the action of a phosphodiesterase enzyme, and thd therefore glucagon can no longer activate protein kinase A (PKA) and this inhibits glucagon's mechanism of action


What type of receptor is the glucagon receptor?

G-protein coupled receptor


What are the main actions of glucagon?

Increase glycogenolysis, increased gluconeogenesis, inhibition of glycolysis, increased lipolysis in adipose tissue


What are the main substrates used in gluconeogenesis?

Amino acids, glycerol and lactate


How does glucagon work to encourage gluconeogenesis but inhibit glycolysis?

These processes are effectively the reverse of each other, where the direction of committance is determined by pyruvate kinase (PK) and phosphofructokinase 1 (PFK-1); glucagon inhibits PK and PFK-1 in order to encourage gluconeogenesis and inhibit glycolysis.


How does glucagon work to encourage lipolysis in adipose tissue?

Glucagon activates hormone-sensitive lipase to encourage lipolysis. The glycerol --> glujconeogenesis in the liver whereas the fatty acids can be used in beta oxidation and converted to acetyl CoA


What is the carnitine shuttle?

The carnitine shuttle is responsible for transferring long-chain fatty acids across the barrier of the inner mitochondrial membrane to gain access to the enzymes of beta-oxidation


How does insulin affect the carnitine shuttle, and what is the consequence of this?

The carnitine shuttle is responsible for transferring long-chain fatty acids across the barrier of the inner mitochondrial membrane to gain access to the enzymes of beta-oxidation; the CPT-1 enzyme is a main factor in this shuttle and is inhibited by insulin to prevent acetyl CoA production (ketogenesis substrate)


What enzyme is involved in the transfer of free fatty acids across the inner mitochondrial membrane?

Carnitine shuttle (CPT-1 especially)


How does glucagon affect the carnitine shuttle and what are the consequences of this?

It activates the CPT-1 enzyme and therefore this permits greater amount of beta oxidation and therefore there is more acetyl CoA production and thus greater substrate for ketogenesis.


How does the body facilitate a switch to ketogenesis to prevent excess muscle wasting?

Although there is an increase in free fatty acids as a result of increased lipolysis in adipocytes, beta oxidation of these substrates is prevented by the liver using the oxaloacetate in the mitochondria (from the Krebs cycle) as a substrate for gluconeogenesis; as a result the oxaloacetate:acetyl CoA ratio is reduced, and this leads to an excess of acetyl CoA which can then be used by the liver in ketogenesis.


What are catecholamines?

Adrenaline and noradrenaline


What causes the stimulation of catecholamine release?

Catecholamines are released in response to stress and hypoglycaemia


What substrates are involved in the synthesis of catecholamines?

Phenylalanine and tyrosine


What is the action of catecholamines on the metabolism?

- Inhibits insulin secretion and stimulates glucagon secretion
- stimulates glycogenolysis in the liver and muscle
- increases lipolysis in the adipose tissue


What is the mechanism of sympathetic response which leads to the release of catecholamines?

The hypothalamus is stimulated by stress etc. and this causes the propagation of an action potential down the sympathetic fibres directly to the adrenal medulla where adrenaline and noradrenaline are released as a result. These molecules then stimulate glycogenolysis, lipolysis and glucagon secretion


How is cortisol synthesised?

Stress is acknowledged ad stimulates the hypothalamus which then secretes CRP (corticotrophin releasing hormone) which then causes the release of ACTH from the pituitary gland (corticotropes) and this ACTH stimulates the adrenal cortex to produce glucocorticoids (and mineralocorticoids)


What causes the release of glucocorticoids/cortisol?

Stress etc.


What are the three layers of the adrenal cortex?

Zona glomerulosa (most superficial), zona fasciculata and zona reticularis (just above medulla)


What hormone is secreted by the adrenal zona glomerulosa?



What hormone is secreted by the adrenal zona fasciculata?



What hormone is secreted by the adrenal zona reticularis?



How does cortisol affect metabolism?

Enhances gluconeogenesis, inhibits liver glucose uptake, stimulates muscle proteolysis and stimulate adipocyte lipolysis


How does cortisol exert it's effects on metabolism?

It affects the DNA within cells in order to affect the protein translation and transcription in order to affect the gene expression


What complications can arise with persistent raised cortisol levels?

Can induce proteolysis and muscle wasting


What is the action of growth hormone?

Increases lipolysis in adipose tissue, and reduces glucose uptake in skeletal muscle and increases production and uptake of lipoproteins in the liver