57) Endocrine control of metabolism

Question 1

What molecules can be used as fuel for energy metabolism in the body?

Answer 1

• Glucose
• Amino acids
• Fatty acids
• Lactate
• Ketone bodies

Question 2

What is the overview of energy metabolism in all types of molecules in the body?

Answer 2

• All fuels are converted into Acetyl CoA which is eventually fed into the TCA cycle
• From here (through electron transport chains) we make ATP

Question 3

How are carbohydrates used to produce ATP?

Answer 3

• Glucose is converted to Glucose-6-Phosphate
• Through glycolysis G-6-P is converted to pyruvate (which produces ATP)
• Pyruvate is then converted to acetyl CoA which is then fed into the TCA cycle where it can go on to produce ATP via electron transport chains

Question 4

How are amino acids used to produce ATP?

Answer 4

• Amino acids are converted (through various mechanisms depending on the amino acid) into acetyl CoA directly.
• This can then be fed into the TCA cycle where it can then produce ATP via electron transport chains

Question 5

How are ketone bodies used to produce ATP?

Answer 5

• Ketone bodies are converted into acetyl CoA directly.

- This can then be fed into the TCA cycle where it can then produce ATP via electron transport chains

Question 6

How is lactate used to produce ATP?

Answer 6

• Lactate is converted into pyruvate first
• This pyruvate is then converted into Acetyl CoA which can be fed into the TCA cycle and then produce ATP via electron transport chains

Question 7

How are fatty acids used to produce ATP?

Answer 7

• Fatty acids are converted to Acetyl CoA through Beta-oxidation
• This can then be fed into the TCA cycle and then (via electron transport chains) be used to produce ATP

Question 8

What happens to pyruvate in anaerobic conditions?

Answer 8

• In anaerobic conditions pyruvate is converted to lactate which circulates in the blood
• It can then be converted back to pyruvate when oxygen is available where it can then be converted into Acetyl CoA and fed into the TCA

Question 9

What happens when we produce an excess of Acetyl CoA?

Answer 9

• Excess Acetyl CoA will be converted into ketone bodies via ketoneogenesis in the hepatocytes (liver)
• The major source of ketogenesis is from the Beta-oxidation of fatty acids
• When low on fuel these ketone bodies can be then be taken up by tissues in the body from circulation and can be converted back to Acetyl CoA which is fed into the TCA cycle

Question 10

What are the circulating nutrients within the body?

Answer 10

• Glucose
• Fatty acids
• Amino acids
• Ketone bodies
• Lactate

Question 11

What are the stored nutrients?

Answer 11

• Glycogen
• Triglycerides
• Body proteins

Question 12

Why are nutrients converted into storage molecules?

Answer 12

• Nutrients such as glucose and fatty acids are excellent sources of energy but are also reactive
• This means they cannot be allowed to accumulate within the blood stream as it is dangerous (leads to toxicity) and hence they cannot be used for storage
• These nutrients are converted into storage molecules as these are unreactive and so accumulation of storage molecules causes no harm to the body

Question 13

What are the effects of altered plasma glucose levels on the body?

Answer 13

• Hypoglycaemia can lead to coma and death. This is because the brain is unable to metabolise fatty acids for energy (due to the blood brain barrier) and so solely relies on glucose metabolism for energy. By removing this glucose the brain becomes energy starved
• Hyperglycaemia is not as dangerous. However chronic exposure to raised glucose concentrations can lead to protein damage via non-enzymatic glycation. This protein damage can mainly occur in the endothelium of vasculature and so is the main cause of micro- and macro-vascular complications that are associated with poorly controlled diabetes

Question 14

What are the sources of plasma glucose?

Answer 14

• Diet

- Organs that can export glucose into circulation

Question 15

What are the different phases of metabolism?

Answer 15

• Absorptive: Nutrients are absorbed from the gut, enter circulation and travel to other part of the body where they are first taken out of circulation and stored (follows immediately after a meal)
• Fasting/ Post-absorptive: Nutrients are released from storage back into circulation (a few hours after a meal)

Question 16

How are plasma glucose levels regulated?

Answer 16

• Hormones regulate the integration of carbohydrate, fat and protein metabolism to maintain constant plasma glucose levels
• They do this by regulating the absorptive and fasting phases in glucose metabolism
• Insulin: Promotes storage of nutrients which decreases plasma glucose. It is released from the pancreas
• Counter regulatory hormones: Promotes release of nutrients which raises plasma glucose. Examples of these are glucagon (from the pancreas), adrenaline (from the adrenal cortex) and cortisol/growth hormone (anterior pituitary)

Question 17

What are the major effects of insulin?

Answer 17

• It stimulates nutrient storage. It does this in a few ways.
• Firstly it promotes the uptake of glucose by skeletal muscle, adipose tissue and other tissues
• Furthermore it increases glycogen synthesis in liver and skeletal muscles
• Finally increases the uptake of fatty acids and amino acids
• It also inhibits the release of nutrients from storage. It achieves this in a few ways
• Firstly it inhibits the release of glucose from the liver by preventing hepatic glucose production (which encompasses gluconeogenesis and glycogenolysis)
• Secondly it inhibits the breakdown of stored fats (lipolysis) and protein breakdown (proteolysis)

Question 18

What is gluconeogenesis?

Answer 18

• The metabolic pathway that converts non-carbohydrate substrates (e.g. amino acids) into glucose
• It takes place in the hepatocytes

Question 19

What is glycogenolysis?

Answer 19

• Conversion of glycogen (storage molecule) back to glucose (active molecule) in hepatocytes

Question 20

What are the major effects of the counter-regulatory hormones?

Answer 20

• Glucagon: Stimulates hepatic hepatic glucose production (gluconeogenesis and glycogenolysis)
• Adrenaline: Stimulates hepatic glucose production and also stimulates lipolysis which releases stored fatty acids into circulation
• Growth hormone: Stimulates hepatic glucose production and lipolysis
• Cortisol: Stimulates hepatic glucose production, lipolysis and proteolysis (which releases amino acids into circulation)

Question 21

What metabolic pathways take charge when energy balance is positive (energy intake is greater than demand)?

Answer 21

• Glycogenesis: Production of glycogen from glucose
• Lipogenesis: Production of fatty acids from Acetyl CoA
• Triglycerides synthesis: Esterification of fatty acids from triglyceride stores

Question 22

What happens when the liver’s capacity to store glycogen is exceeded?

Answer 22

• When there is an increase in plasma glucose then glycogenesis will occur where glucose is converted to glycogen and stored in hepatocytes
• However there is only a finite capacity in hepatocytes and so eventually they cannot store anymore glycogen
• Instead what happens now is that the excess glucose left over is converted to acetyl CoA (via glycolysis) which is then converted to fatty acid from lipogenesis
• These fatty acids are esterified for storage as triglycerides (triglyceride synthesis)

Question 23

What metabolic pathways take charge when energy balance is negative (energy demand is greater than intake)?

Answer 23

• Glycogenolysis: Release of glucose from glycogen stores
• Gluconeogenesis: Synthesis of glucose from non-carbohydrate substrates
• Lipolysis: Release of fatty acids from triglyceride breakdown
• Beta-oxidation: Conversion of fatty acids to Acetyl CoA
• Ketogenesis: Production of ketone bodies from Acetyl CoA

Question 24

What is the mechanism of metabolic responses to hypoglycaemia?

Answer 24

• When glucose levels drop it is detected by the endocrine cells of the pancreas which increases glucagon secretion (from the alpha cells)
• Glucagon stimulates the liver to increase hepatic glucose production which raises glucose levels back up. Hence this is a negative feedback loop that is purely endocrine
• The drop in glucose can also be detected by glucose sensing neurones in the brainstem of the CNS
• This causes an increase in sympathetic outflow which can stimulate the liver to stimulate (to increase gluconeogenesis) and alpha pancreatic cells (to increase secretion of glucagon).
• Both these processes counter the drop in glucose.
• Finally The drop in glucose can again be detected by glucose sensing neurones in the brainstem of the CNS
• It will again causes an increase in sympathetic outflow however this time it can stimulate the the neuroendocrine cells of the adrenal medulla (chromaffin cells)
• This increases the secretion of adrenalins (epinephrine) which stimulates alpha pancreatic cells (to increase glucagon secretion) and hepatocytes (to increase hepatic glucose production)
• This response is the neuro-endocrine response

Question 25

What are the different defences against hypoglycaemia?

Answer 25

• In the short term we increase glucagon, epinephrine (adrenaline) and sympathetic nervous system. When there are mild levels of hypoglycaemia then low levels of glucagon are released. As the severity increases then amount of glucagon secreted also increases. Furthermore the body will also adopt the other defence mechanisms
• In the medium term most of the glucose in circulation are used up. In this case fat reserves are used as a substrate for ketogenesis. This is because the Beta oxidation of fatty acids produces Acetyl CoA which is fed into ketogenesis (rather than the TCA). This spares whatever glucose is left in circulation and also prevents the breakdown of body proteins and muscle (which would otherwise be used to produce amino acids for gluconeogenesis).
• In the long term fat reserves are eventually depleted. Ketogenesis is no longer viable and so the only way to prevent glucose levels falling to dangerous levels is through continued gluconeogenesis. As a result Cortisol is released which will stimulate proteolysis to supply amino acid substrates for gluconeogenesis. This means that body proteins will be broken down (mainly skeletal muscles)

Question 26

What are the different defences against hyperglycaemia?

Answer 26

• We increase secretion of insulin which increases glucose uptake by tissues and inhibits hepatic glucose production

Question 27

What happens when there is a lack of insulin action?

Answer 27

• Lack of insulin action leads to hyperglycaemia (called diabetes mellitus)
• Type 1 DM: Insulin deficiency due to the failure of the pancreatic cells which secrete insulin
• Type 2 DM: Insulin insufficiency combined with insulin resistance (target tissues do not respond to insulin)

Question 28

Where are major insulin sensitive tissues located within the body?

Answer 28

• Liver
• Skeletal muscles
• Adipose tissue

Question 29

What is the mechanism by which glucose is converted to energy?

Answer 29

• Glucose diffuses into the cell from circulation (via GLUT transporters) down its concentration gradient and is immediately metabolised to Glucose-6-Phosphate (G-6-P)
• To meet immediate energy needs G-6-P can enters glycolysis where it is converted to Pyruvate (producing tiny amounts of ATP)
• Pyruvate enters the mitochondria where it is converted to Acetyl CoA which then enters the TCA cycle which generates many molecules of ATP

Question 30

What happens when there is an excess of glucose circulating?

Answer 30

• Glucose is taken in by cells but is then stored for future use in the form of glycogen.
• This is done by converting glucose to G-6-P and from G-6-P to glycogen (via glycogenesis) in hepatocytes and skeletal muscles

Question 31

What happens when glycogen stores in hepatocytes are full?

Answer 31

• When glycogen stores are full excess glucose is converted to G-6-P which is then converted to pyruvate (via glycolysis)
• Pyruvate is transported to the mitochondria and converted into Acetyl CoA .
• However instead of going into the TCA cycle this Acetyl CoA is converted to fatty acids (via lipogenesis).
• These fatty acids can be combined with glycerol to form triglycerides which can be stored.
• If this occurs in the liver the triglycerides are exported as VLDLs and are stored in adipose tissue

Question 32

How can glucose be put back into circulation from storage?

Answer 32

• In liver the enzyme Glucose-6-Phosphatase which can convert G-6-P into Glucose which would then pass into circulation.
• However this process is unable to occur in skeletal muscle as they lack the necessary enzyme
• Gluconeogenesis can also occur where compounds (e.g. amino acid from proteolysis) can be converted into pyruvate which is then metabolised to G-6-P which can then be converted to Glucose for transport back into circulation

Question 33

What are fats stored as?

Answer 33

• Triacylglycerides

Question 34

What is the mechanism by which fats are stored in adipose tissue?

Answer 34

• Since fats are insoluble in water they are packaged into lipoprotein particles
• In circulation triglycerides are either transported as chylomicrons (formed from the digestion and absorption of fats) which are then stored in adipose tissue or as VLDLs (formed from lipogenesis of in the liver)
• Lipoprotein lipase is an enzyme found on the endothelial lining of capillaries in adipose tissue and is stimulated by insulin.
• These enzymes break down the chylomicrons and VLDLs back down into fatty acids which can be transported across the adipocyte membrane
• These fatty acids are then esterified into triacylglycerides for storage

Question 35

How is glucose taken into adipocytes for storage?

Answer 35

• Adipocytes also express GLUT4 transporters which is also insulin dependent (in the absence of insulin they are low levels of the transporter present).
• Glucose can be taken up by the adipocytes in this manner where it can either be converted to fatty acids (via lipogenesis) which in turn are esterified to form triacylglycerides or they can be converted to glycerol-3-phosphate which can then be esterified into triacylglycerides

Question 36

How are fuels mobilised from adipocytes?

Answer 36

• When energy balance is negative, energy stores must be mobilised.
• To do this stored triacylglycerides are broken down into fatty acids and glycerol with the help of many enzymes.
• One of the enzymes used in this pathway is hormone sensitive lipase which is stimulated by nor-epinephrine and epinephrine (noradrenaline and adrenaline).
• These fatty acids are then released into circulation (bound to albumin) which will then undergo Beta-oxidation (in different tissues )for energy or ketogenesis (in the liver) to produce ketones for fuel
• The glycerol is taken up by the liver to be used in gluconeogenesis

Question 37

How is glucose taken into skeletal muscles?

Answer 37

• Glucose uptake into muscle through GLUT 4 transporters which is insulin dependent
• The amount of GLUT 4 transporters found on the muscle can be increased by increasing the amount of insulin secreted and through increased muscle contraction (i.e. increased exercise)

Question 38

How is glucose stored in skeletal muscle?

Answer 38

• Upon entering the muscle the glucose is converted into G-6-P
• In resting muscle majority of the G-6-P will be converted to glycogen through glycogenesis (stimulated by insulin).

Question 39

How is glucose used as a fuel source in skeletal muscles?

Answer 39

• During exercise the stored glycogen is converted to G-6-P which is then metabolised to Pyruvate (which produces a tiny amount of energy)
• In anaerobic conditions pyruvate is converted to lactate which is transported out of the cell and into circulation where it is used for gluconeogenesis in other tissues
• In aerobic conditions the pyruvate is funnelled into the TCA cycle to produce energy

Question 40

How are fatty acids used as a fuel source in skeletal muscles?

Answer 40

• Free fatty acids in circulation (bound to albumin) can also be taken into muscles during endurance/long term exercise and prolonged fasting to be used as a fuel.
• Triglycerides can also be taken up with the help of lipoprotein lipase enzyme (present on the endothelium of skeletal muscle capillaries)
• They then undergo Beta-oxidation and are then pumped into the TCA cycle to produce energy.

Question 41

How is glucose taken into hepatocytes?

Answer 41

• Glucose enters the liver from circulation via GLUT2 transporters where it is converted to G-6-P

Question 42

How is glucose stored in hepatocytes?

Answer 42

• When insulin levels are high this G-6-P is converted to Glycogen (through glycogenesis) for storage
• When glycogen stores are full G-6-P is converted to phophophenol pyruvate and then to pyruvate and finally to Acetyl CoA (via glycolysis)
• This Acetyl CoA then takes part in lipogenesis where it produces fatty acids that are stored as triacylglycerides

Question 43

What is the fate of amino acids when there are higher levels of insulin?

Answer 43

• When there are higher levels of insulin in the body amino acids are mainly used in the production of protein to be used by the body for growth and repair

Question 44

How is fuel mobilised in hepatocytes?

Answer 44

• When glucagon levels are high glycogen is converted to G-6-P and is then converted to phophophenol pyruvate
• Phophophenol pyruvate is then converted to pyruvate and finally to Acetyl CoA (via glycolysis)
• Acetyl CoA can also be produced by stored triacylglycerides through lipolysis
• Amino acids can also be used as fuel in severe cases through gluconeogenesis.
• Due to the variation in the different amino acids some are converted to phophophenol pyruvate, some are converted to pyruvate and some are converted to Acetyl CoA.
• Other amino acids form intermediates found within the TCA cycle (e.g. oxaloacetate)
• In doing so amino acids loose an NH3 which enters the urea cycle

Question 45

How can amino acids contribute to levels of circulating glucose in the blood?

Answer 45

• Some amino acids can be converted to phophophenol pyruvate in the liver (when there are high levels of glucagon)
• Phophophenol pyruvate can then be converted into G-6-P which can reform glucose
• This is the gluconeogenesis
• The increase in intracellular glucose causes diffusion of glucose out of the hepatocyte into circulation

Question 46

How are fatty acids metabolised in the liver?

Answer 46

• When fatty acids enter hepatocytes from circulation they are converted into free fatty acyl-CoA
• Fatty acyl-CoA can combine with glycerol-3-phosphate to form triacylglycerides which is either stored in the liver or exported out of the liver into circulation as VLDLs
• In my mitochondria it is converted to Acetyl CoA through Beta-oxidation which is stimulated by glucagon
• Acetyl CoA can either enter the TCA cycle for energy production or it can be used to form ketone bodies (via ketogenesis)
• These ketone bodies can be exported into circulation where they are taken up by other tissue which can use these ketone bodies as fuel (as they reverse the process to form Acetyl CoA and then funnel it into the TCA cycle).

Question 47

How is glucose metabolised in the liver?

Answer 47

• Glucose in the liver is converted to pyruvate (via glycolysis) which is then converted to acetyl CoA in the mitochondria.
• In the presence of insulin the Acetyl CoA will be converted into malonyl CoA
• Malonyl CoA is then used in lipogenesis to form fatty acids
• It can also inhibit CPT which is a transport protein that transports the fatty acyl CoA to the mitochondria during Beta-oxidation
• By inhibiting CPT malonyl Co-A inhibits transport of fatty Acyl Co-A into the mitochondria and hence inhibits Beta-oxidation of fatty acyl Co-A by

Question 48

What happens in the hepatocytes when there is a lack of insulin in circulation (Type 1 diabetes mellitus)?

Answer 48

• We suffer from diabetic ketoacidosis where we have an excess of ketone bodies/acids forming in the liver

Question 49

How does ketoacidosis occur?

Answer 49

• In the absence of insulin Beta-oxidation and gluconeogenesis is unregulated and so there is no inhibition hence more acetyl CoA is produced
• Oxaloacetate is a substrate that can be used in gluconeogenesis and so unregulated gluconeogenesis can deplete oxaloacetate levels
• Normally acetyl CoA produced from glycolysis (of glucose) and from the Beta oxidation of fatty acids is funnelled into the TCA cycle to provide energy
• However for acetyl CoA to enter the TCA cycle it must combine with oxaloacetate (which is now depleted)
• This leads to an accumulation of acetyl CoA which is then converted to ketone bodies which are acidic
• In diabetic acidosis the production of these ketone bodies is high enough to overwhelm buffering systems of the body