Metabolism Module

session 6

Control of Energy Metabolism

Dr. Jamal M. Salih

 Control of Energy Metabolism

Aims of the session: Have an overview of the ways in which

energy metabolism as a whole is controlled

Fuel concentration: Glucose, Fat and protein

Hypo- and hyperglycaemia
Feeding and fasting cycle
 Control of fuel concentration

• Fuel concentrations are controlled hormonally

• Insulin lowers fuel concentrations in the blood while glucagon,

adrenaline, growth hormone and cortisol increase their

concentrations

• Those hormones oppose insulin action

• So, they are called anti-insulin hormones

 Diversity of fuel

Glucose: can be used by all cells and is the preferred fuel.

Very little free glucose (12g) is present in the body fluids & this
would support the metabolism of the CNS for ~2hr.

Around (300g) is stored as glycogen, in liver and muscle.

Only the glucose stored in the liver (~100 g) can be made available
to the CNS.

Many cells (except RBCS & CNS) can also use fatty acids
 Diversity of fuel

Fat:
In a typical 70kg individual there is 10-15kg of fat, which is enough
to supply the body's fuel needs for about 2 months (80% of the
total fuel reserve)

Fatty acids can be converted to ketone bodies in the liver to be

used as fuel by the tissues and the CNS.
 Diversity of fuel

Protein:
In muscle (~6kg) can be broken down (proteolysis) to amino
acids that can be used to provide fuel in times of shortage

This fuel reserve corresponds to ≈ 2 weeks supply of fuel

 Importance of Glucose for CNS

 CNS depends on glucose to produce energy & it has to be

available at all the times as CNS utilizes ~140g glucose /24hr

 Other glucose-dependent tissues ~40g/24hr.

 The rate of glucose uptake by the CNS depends on the blood

glucose concentration

 In a healthy individual, blood glucose concentration is maintained

in the range 72-109 mg/dl (4.0-6.0mM)

 The blood glucose is controlled via the neuro-endocrine system

 Hypoglycaemia

A reduction in blood glucose to 54mg/dl (3 mM) or lower, is known

as hypoglycaemia

The acute effects of hypoglycaemia can include:

trembling, weakness, tiredness, headache, sweating, tingling around
the lips, palpitations, changes in mood (angry/bad temper),
slurred speech, and a staggering walk and confusion.

Hypoglycaemia may rapidly lead to unconsciousness and death if

untreated as the CNS is starved of glucose.
 Fating hypoglycaemia
Fasting hypoglycaemia is caused by abnormality in CHO metabolism
Either too much glucose is being used or too little is being produced.

In response to fasting, normally the body maintains:

o Glucose level above 55mg/dl (3 mM), and
o pH at around 7.4
o Lactate and pyruvate levels constant or decrease.

Maintaining of glucose level above 55mg/dl for 10 hours fasting indicates

normal liver glycogen metabolism

Low PH (metabolic acidosis) may be associated with hypoglycaemia, which

is caused by presence of acidic metabolites (lactate, pyruvate, amino acids,
fatty acids, ketoacids)…
 Biochemical investigations of hypoglycaemia

• When does the hypoglycaemia begin?

• What metabolites are producing the acidosis?

• Measure blood levels of metabolites at various stages during fasting

• Measure fasting plasma insulin, glucagon, cortisol and growth hormone

• Measure enzyme activities in red blood cells and the liver.

• Evaluation of glucose utilization and gluconeogenesis:

Measure glucose levels following ingestion of various substances that should
be converted to glucose or stored as glycogen e.g. glucose, galactose, fructose,
glycerol
 Evaluation of glucose utilization:

Glucose tolerance test (GTT):

1g glucose/kg body weight is taken orally after an overnight fast & blood
glucose concentration at 30 min intervals will be measured.
Normally, a peak glucose at ~1hr & a return to the initial value by 2hr, is
seen
Time (minute) Blood glucose concentration mg/dl (mM)
0 72 (4)
30 97 (5.4)
60 126 (7)
90 108 (6)
120 72 (4)

This shows that the utilisation and storage of glucose is normal.

 Evaluation of gluconeogenesis
The liver’s ability to produce glucose can be tested by giving the patient gluconeogenic
substrates orally (1g/Kg body weight), after 8 hour fast, and determining whether they
are converted to glucose by measuring the blood glucose level

Normally, after 8 hr of fasting gluconeogenesis becomes active. There would be an initial

increase in glucose and then a return to normal values as the glucose is utilised.

The response to galactose is normal while the responses to fructose and glycerol are
abnormal and suggest that they are not converted to glucose
 Hyperglycaemia
Is elevation of the fasting blood glucose >126 mg/dl (7.0mM)

Hyperglycaemia can reduce both the quality and duration of life.

The nervous, cardiovascular and renal systems may be affected.

There is glucosuria , polyuria and polydipsia.

Hyperglycaemia activates the non-enzymatic glycosylation of

plasma proteins (lipoproteins) that impairs their function
 Feeding/fasting cycle

Feeding:
The absorption of glucose, amino acids and lipids from the gut
stimulates the endocrine pancreas to release insulin which has
the following actions:

- increases glucose uptake & utilisation by muscle & adipose tissue.

- promotes storage of glucose as glycogen in liver and muscle.

- promotes amino acid uptake & protein synthesis in liver & muscle.

- promotes lipogenesis and storage of fatty acids as triacylglycerols

 Feeding/fasting cycle
Fasting:
Low glucose concentration inhibits insulin secretion.
This reduces the uptake of glucose by adipose tissue and muscle.

Low blood glucose concentration also stimulates glucagon secretion

i.e. insulin/anti-insulin ratio ↓. This stimulates:
• Glycogenolysis in the liver
• Lipolysis in adipose tissue (to provide fatty acids)
• Gluconeogenesis

To maintain blood glucose for the brain and fatty acids for other
tissues
 Feeding/fasting cycle
Starvation:
Fasting must proceed for more than 10 hrs in order to start the
changes associated with starvation
Response to Starvation:
At first blood glucose falls, but is maintained at an adequate level
63mg/dl by the actions of glucagon, which stimulates the
breakdown of hepatic glycogen.

• low BGL stimulates cortisol secretion which enhances lipolysis

& proteolysis (to glycerol & alanine).

• Free fatty acids in blood rise to 2mM (fed state level~0.3mM)

 Feeding/fasting cycle

Starvation:
Cortisol also prevent peripheral utilization of glucose

Both cortisol and glucagon stimulate gluconeogenesis.

Glycerol is an important substrate for gluconeogenesis, reducing

the need for breakdown of proteins.

low insulin/anti-insulin ratio, leads to ketone bodies production

from fatty acids in the liver, which can replace glucose as a fuel
for the brain
 Feeding/fasting cycle
Starvation:
Ketone concentrations rise from 0.01mM in the fed state to 2mM
after 3 days of starvation and 7mM after 1-2 weeks (physiological
ketosis)
This further reduces the need for gluconeogenesis, and further spares
body protein.

As adaptation to starvation proceeds two factors become

important:
- The brain becomes able to use ketones as fuel, reducing its glucose
requirement from 140g/day to 40g/day.
- The kidneys begin to contribute to gluconeogenesis
 Feeding/fasting cycle
Starvation:
After 4 weeks starvation, gluconeogenesis has fallen to ~30%

Urinary nitrogen excretion initially about 12g/day (mostly urea)

eventually falls to about 4g/day (≈ equal amount of urea &NH4+)

The reduction in urea synthesis leads to a marked decrease in the

amount and activities of the enzymes involved in urea synthesis.

This has important implications during the re-feeding. Where the

temptation to give large amounts of protein and/or amino acids,
in the early stages, must be resisted and the protein content of
the diet increased gradually.
 Feeding/fasting cycle

Starvation:
When all of the body fat stores are depleted, the body will use
proteins rapidly & death follows shortly

Death results from a number of causes related to loss of muscle

mass including serious respiratory infections due to loss of
respiratory muscle.
Thank you