Integration of Metabolism

Question 1

What are the general metabolic features of muscles?

Answer 1

Make up 40 % of total body weight. Can have periods of very high ATP requirement during vigorous contraction and mainly rely on carbohydrate and fatty acid oxidation.

Question 2

What are the general metabolic features of brain and nervous tissue?

Answer 2

Makes up 2 % of total body weight. Uses 20 % of resting metabolic rate as it has a continuous high ATP requirement. Cannot respire fatty acids and hence solely dependent on carbohydrates and ketone bodies.

Question 3

What are the general metabolic requirements of adipose tissue?

Answer 3

Makes up 15 % of total body weight. Long term storage site for fatty acids in the form of triglycerides.

Question 4

What is the general metabolic requirements of the heart?

Answer 4

Makes up 1 % of total body weight. 10 % of resting metabolic rate. Respires fatty acids and carbohydrates.

Question 5

What is the general metabolic requirements of the liver?

Answer 5

2.5 % of total body weight. 20 % of resting metabolic rate. The body’s main carbohydrate store (glycogen) and a source of blood glucose.

Question 6

How do metabolic features of skeletal muscle change with energy demand?

Answer 6

Skeletal muscle is capable of large and rapid increases in ATP demands during exercise. During light contraction, ATP consumption is met by oxidative phosphorylation (O2 and bloodborne glucose and fatty acids are used as fuel). During vigorous contraction, ATP consumption is faster than the ATP supply by oxidative phosphorylation (O2 and blood-borne substrate diffusion is limiting). Muscle stores of glycogen are subsequently broken down to produce ATP. Under anaerobic conditions, pyruvate is converted to lactate, which can leave muscle and reach the liver via the blood.

Question 7

What are the specific metabolic features of the brain?

Answer 7

The brain requires a continuous supply of glucose. The brain cannot metabolise fatty acids. Ketone bodies (e.g. β-hydroxy-butyrate) can partially substitute for glucose. Too little glucose (hypoglycaemia) causes faintness and coma. Too much glucose (hyperglycaemia) can cause irreversible damage.

Question 8

How are the heart’s metabolic features adapted to its function?

Answer 8

The heart must beat constantly. It is designed for completely aerobic metabolism, and is rich in mitochondria. The heart utilises TCA cycle substrates, e.g. free fatty acids, ketone bodies. Loss of O2 supply to the heart is devastating, leading to cell death and myocardial infarction (energy demand&raquo_space;> energy supply).

Question 9

How are the liver’s metabolic features adapted to its function?

Answer 9

The liver is the immediate recipient of nutrients absorbed by the intestines. Undertakes a wide repertoire of metabolic processes (e.g. glycolysis, gluconeogenesis, transamination). Is highly metabolically active  (only 2.5 % of body mass, but contributes > 20 % of metabolic rate). Can interconvert nutrient types. Plays a central role in maintaining blood [glucose] at 4.0-5.5 mM. Is a glucose storage organ (glycogen). Plays a key role in lipoprotein metabolism (transport of triglycerides & cholesterol)

Question 10

Summarise carbohydrate metabolism

Answer 10

Carbohydrates are broken down into simple sugars and enter the glycolytic pathway leading to the production of pyruvate. Decarboxylation and reduction of pyruvate produces acetyl CoA which can enter the TCA cycle. This cycle produces reduced co-factors which are reoxidised by the electron transport chain which in turn is coupled to ATP production (Oxidative phosphorylation). Excess glucose-6-phosphate can be used to generate glycogen in liver and muscle. Similarly, excess Acetyl CoA can be used to generate fatty acids, which are stored as triglycerides in adipose tissue.

Question 11

How does metabolism change with exercise?

Answer 11

During extreme exercise, the ATP demands of the muscle outstrip the oxygen supply needed for aerobic respiration and lactate is produced. During fasting, rather than enter the TCA, much of the acetyl CoA produced results in ketone body production.

Question 12

What can the products of carbohydrate metabolism also be used for?

Answer 12

Pyruvate and other TCA cycle intermediates can also be a source of some amino acids. The backbone of these molecules can be used to used to make nucleotides. Glucose-6-phosphate via the pentose phosphate pathway can also be used as a source for nucleotide production in a pathway that generates the bulk of the NADPH needed for anabolic pathways e.g. cholesterol synthesis.

Question 13

How are glucose levels maintained during periods of fasting?

Answer 13

During fasting, if plasma glucose concentrations fall below 3mM then the body will enter a hypoglycaemic coma. In the short term, to avoid hypoglycaemia the body can: Breakdown liver glycogen stores occurs to maintain plasma glucose levels; Release free fatty acids from adipose tissue; Convert Acetyl CoA into ketone bodies via the liver.
Both fatty acids and ketone bodies can be used by muscle, making more of the plasma glucose available for the brain.

Question 14

What is the general strategy of gluconeogenesis?

Answer 14

The overall aim of pathway is to generate glucose from pyruvate. Non-carbohydrate precursors enter the gluconeogenesis pathway at the points shown, namely lactate, amino acids and glycerol. Lactate is generated by skeletal muscle during strenuous exercise, when the rate of glycolysis exceeds the rate of the TCA cycle and the electron transport chain. Lactate can be taken up by the liver and utilised to regenerate pyruvate by lactate dehydrogenase (LDH), also known as the Cori cycle. Amino acids can be derived from the diet or during times of starvation, e.g. from the breakdown of skeletal muscle. Triglyceride hydrolysis yields fatty acids and glycerol, the glycerol backbone being used to generate dihydroxyacetone phosphate (DHAP).

Question 15

What are the bypass reactions of gluconeogenesis?

Answer 15

Glycolysis has three essentially irreversible reactions, catalysed by the kinases hexokinase, phosphofructokinase and pyruvate kinase. Gluconeogenesis therefore requires bypass of these reactions. The first reaction catalysed by pyruvate carboxylase occurs in the mitrochondria, whereas the remaining reactions are cytosolic.

Question 16

Why are amino acids categorised as glucogenic and ketogenic?

Answer 16

The glucogenic amino acids are so-called because their skeletons can give rise to glucose via gluconeogenesis (dashed line). Ketogenic amino acids give rise to skeletons which cannot enter gluconeogenesis but can be used to synthesis fatty acids and ketone bodies

Question 17

Summarise triglyceride metabolism

Answer 17

Triglycerides are broken down into fatty acids and glycerol. Glycerol can be converted to DHAP and enter the gluconeogenic pathway upstream. Fatty acids cannot be converted into glucose by gluconeogenesis. If you recall, 2C atoms enter the TCA cycle as acetyl CoA by combining with oxaloacetate to form citrate. As the cycle progresses, two carbon atoms are sequentially lost as CO2 before oxaloacetate is eventually regenerated. Hence, no net synthesis of oxaloacetate or pyruvate is possible from acetyl CoA. Fatty acids can be converted into ketone bodies and used by tissues such as muscle and brain.

Question 18

How does muscle contraction affect metabolism?

Answer 18

During moderate levels of exercise, where oxygen supply is adequate, the ATP demands of muscle can be met by oxidative phosphorylation using glucose and other substrates as fuels. Glucose is transported from the blood into muscle cells where it can undergo metabolism by glycolysis and the TCA cycle to ultimately generate ATP by the re-oxidation of cofactors. As muscle contracts, the demand for ATP increases e.g. requirements of muscle actomyosin ATPase and cation balance. Increased demand for glucose is met by an increase in the number of glucose transporters on the membranes of muscle cells.

Question 19

What is the role of adrenalin?

Answer 19

Adrenalin plays a key role in meeting the demand for ATP by increasing the rate of glycolysis in muscle, increasing the rate of gluconeogensis by the liver and increasing the release of fatty acids from adipocytes.

Question 20

What occurs in muscles under anaerobic conditions?

Answer 20

Under anaerobic conditions, the demands of the contracting muscle for ATP cannot be met by oxidative phosphorylation and similarly, the transport of glucose from the blood cannot keep up with the demands of glycolysis. Glycogen within the muscle is therefore broken down to meet these demands. To replenish NAD+ levels and maintain glycolysis, pyruvate is taken up by the liver and converted into lactate by lactate dehydrogenase. Lactate can then be used by the liver to generate glucose by gluconeogenesis.

Question 21

How are metabolic pathways controlled?

Answer 21

Control of metabolic pathways is typically centred around reactions that are irreversible steps.  At these points, increases in the rate of enzyme activity greatly increases the rate of the downstream steps. For the greatest levels of control it is desirable that these control steps are reasonably early in the pathway. Control can be at several levels including:
Product inhibition and Under the influence of signalling molecules such as hormones.

Question 22

What is the difference in hexokinase in the liver and muscle?

Answer 22

Muscle and liver contain suitably different forms (isoforms). Both isoforms catalyse the same reaction. However they are maximally active at different concentrations of glucose. We can compare the relative activities of enzymes by using parameters such as the Michaelis constant KM which is the concentration of substrate at which an enzyme functions at a half-maximal rate (Vmax).

Question 23

What are the properties of the hexokinase found in muscles?

Answer 23

The KM of Hexokinase I found in muscle is 0.1mM which means it is active at low concentrations of glucose and is essentially operating at maximal velocity at all times. Hexokinase I is also highly sensitive to inhibition by the product glucose-6-phosptate. This means that under anaerobic conditions when the rate of the TCA cycle drops, and glycolysis therefore slows, Hexokinase I is inhibited by accumulating levels of glucose-6-phosptate.

Question 24

What are the properties of the hexokinase found in the liver?

Answer 24

Hexokinase IV found in liver behaves a little differently, having a much higher KM of around 4mM and therefore is much less sensitive to blood glucose concentrations. It is also less senstive to the inhibitory effects of  glucose-6-phosptate (G-6-P). Glucose 6-phophatase (found in the liver but not in muscle) can catalyse the reverse reaction to hexokinase, generating glucose from glucose-6-phosphate

Question 25

What hormones are involved in control of blood glucose?

Answer 25

Insulin is secreted when glucose levels rise: it stimulates uptake and use of glucose and storage as glycogen and fat. Glucagon is secreted when glucose levels fall: it stimulates production of glucose by gluconeogenesis and breakdown of glycogen and fat. Adrenalin (or epinephrine): strong and fast metabolic effects to mobilise glucose for “flight or fight”. Glucocorticoids: steroid hormones which increase synthesis of metabolic enzymes concerned with glucose availability.

Question 26

What are the effects of insulin?

Answer 26

1. Increased glucose uptake by liver – used for glycogen synthesis and glycolysis (acetyl-CoA produced is used for fatty acid synthesis).
2. Increased glucose uptake and glycogen synthesis in muscle.
3. Increased triglyceride synthesis in adipose tissue.
4. Increased usage of metabolic intermediates throughout the body due to a general stimulatory effect on synthesis and growth.

Question 27

What happens when blood glucose first begins to fall?

Answer 27

1. Increased glucagon secretion (and reduced insulin) from islets.
2. Glucose production in liver resulting from glycogen breakdown and gluconeogenesis.
3. Utilisation of fatty acid breakdown as alternative substrate for ATP production (important for preserving glucose for brain).
   Adrenalin has similar effects on liver, but also stimulates skeletal muscle towards glycogen breakdown and glycolysis, and adipose tissue towards fat lipolysis to provide other tissues with alternative substrate to glucose.

Question 28

What happens after prolonged fasting?

Answer 28

1. Glucagon/insulin ratio increases further
2. Adipose tissue begins to hydrolyse triglyceride to provide fatty acids for metabolism (lipolysis)
3. TCA cycle intermediates are reduced in amount to provide substrate for gluconeogenesis
4. Protein breakdown provides amino acid substrates for gluconeogenesis (proteolysis)
5. Ketone bodies are produced from fatty acids and amino acids in liver to substitute partially the brain’s requirement for glucose.

Question 29

What is diabetes mellitus?

Answer 29

Diabetes mellitus is a disorder of insulin release and signalling, resulting in an impaired ability to regulate blood glucose concentrations. There are two main types of diabetes mellitus: Type I diabetes in which individuals fail to secrete enough insulin (β-cell dysfunction). Type II diabetes in which individuals fail to respond appropriately to insulin levels (insulin resistance). The overall effect is that metabolism is controlled as if the person is undergoing starvation, regardless of dietary glucose uptake

Question 30

What are the complications of diabetes?

Answer 30

1. Hyperglycaemia with progressive tissue damage (e.g. retina, kidney, peripheral nerves)
2. Increase in plasma fatty acids and lipoprotein levels with possible cardiovascular complications
3. Increase in ketone bodies with the risk of acidosis
4. Hypoglycaemia with consequent coma if insulin dosage is imperfectly controlled

Question 31

Why is glucagon important against hypoglycaemia?

Answer 31

Major site of action is the liver where glucagon stimulates gluconeogenesis and glycogenolysis.
Insulin deficiency and relative excess of glucagon leads to increased hepatic output of glucose and, thus, hyperglycaemia.

Question 32

What is ketoacidosis?

Answer 32

The high plasma glucose will disturb solute balance in the brain. There are also issues with renal function, leading to dehydration. The levels of ketone bodies (and fatty acids) will significantly lower the plasma pH disrupting ion transport in the CNS, leading to coma. High blood glucose drives urine production leading to dehydration.

Question 33

What happens in type 1 diabetes?

Answer 33

Little/no secretion of insulin and hence people living with this condition entirely dependent on injections. Although part of the hyperglycaemic response seen in type 1 diabetes is due to lack of insulin to stimulate tissue glucose uptake, unopposed action of glucagon also contributes to this and drives ketoacidosis.

Question 34

What happens in type 2 diaebtes?

Answer 34

In initial stages, problem is the insulin sensitivity of tissues. However, with progression may shift to insufficient insulin secretion and injections may be needed. There is insulin however likely to be present to oppose action of glucagon even if not enough to maintain normal glycaemic control.

Question 35

How can lack of glycaemic control result in a coma?

Answer 35

Both hypoglycaemia and hyperglycaemia lead to coma. Hypoglycaemia leads to coma due to lack of glucose metabolism in brain cells. Hyperglycaemia leads to coma due to increased osmolarity of body fluids (directly and due to diuresis caused by glucose expulsion in urine). Excess insulin adminstration leads to hypoglycaemia. Plasma fatty acid and ketone body conc also low as insulin inhibits lipolysis and ketogenesis. Failure of people with type1 injecting insulin leads to hyperglycaemia with increased plasma fatty acids and ketone bodies.