Integration of Metabolism: the fed and fasting state Flashcards
Describe the demand and supply of fuel
The demand for fuel is constant but the supply intermittent
What do changes in the circulating concentrations of hormones allow the body to do?
Changes in the circulating concentrations of hormones
allow the body to:
1. STORE metabolic fuel
* when it is available
2. MOBILISE it in starvation,
* injury and stress
How are changes in metabolic pattern
achieved?
- variation in the amount of available substrate
- allosteric effects on enzymes
- covalent modification of enzymes
- changes in enzyme synthesis
Variation in the amount of available
substrate are
achieved by?
FA use in starvation
Allosteric effects on enzymes are
achieved by?
AMP and PFK in muscle
(Activation by phophorlation)
Covalent modification of enzymes are
achieved by?
- phosphorylation of glycogen
- phosphorylase and synthetase
Changes in enzyme synthesis are
achieved by?
- Glucokinase and dietary CHO
- HMG CoA reductase and cholesterol synthesis
Two Main hormones controlling intermediary
metabolism
- Insulin
- glucagon
Insulin and glucagon are the prime regulators of metabolism
* Insulin is the only hypoglycaemic hormone. (reduces BG)
* Glucagon is a hyperglycaemic hormone (Increases BG)
Other insulin counter-regulatory hormones?
- adrenaline (adrenal medulla)
- cortisol (adrenal cortex)
- growth hormone (anterior pituitary)
Location for metabolism?
Slide 5
- Location of pancreatic islets reflects their functional role
- Proximity of gut, prantantic and liver
What are the Islets of Langerhans?
- The endocrine part of the pancreas
- 2% of total pancreatic mass
- adult pancreas contains about 1 million islets
What are Islets of Langerhans made up of?
- β cells (60-70%) secrete insulin
- α cells (30-40%) secrete glucagon
- δ cells secrete somatostatin
How is Insulin secretion stimulated?
- A rise in blood glucose
- A rise in amino acid concentration in the blood
- Gut hormones.
– Secretin and other GI hormones released after food
intake before blood glucose is elevated. -
Glucagon.
– glucagon leads to insulin secretion providing fine tuning of blood glucose homeostasis.
Control of insulin secretion?
Processing of pro-insulin into
insulin and C peptide?
How is secretion of glucagon is stimulated?
- Low blood glucose
-
High conc of amino acids in the blood.
– **prevents hypoglycaemia **after protein meal - Adrenaline.
– In periods of stress glucagon secretion is stimulated
regardless of blood glucose. (insulin secretion is
suppressed)
What are the metabolic effects of insulin?
- promotes fuel storage after a meal
- promotes growth
- stimulates glycogen synthesis and storage
- stimulates fatty acid synthesis and storage from CHO when the intake exceeds glycogen storing capacity
- stimulates aa uptake and protein synthesis
Structure of the insulin
receptor
Metabolic effects of insulin
Activation of Akt protein kinase
Effect of insulin on glucose transport (muscle and adipose) and glycogen synthesis in muscle and liver)
Inhibition of lipolysis in adipocytes by insulin through activation of Akt/PKB, and
inhibition of hormone sensitive lipase
effect of insulin on gene expression through Ras and MAPK
Insulin
- promotes the appearance of GLUT4 (glucose transporters) in muscle and adipose tissue.
- Brain liver, erythrocyte and pancreas** have GLUT** which are not insulin dependent
- High concentrations of insulin lead to down regulation of its receptors
- Insulin effects vary in time. Glc transport and enzyme activation are very rapid, synthesis of enzymes slow
Roles of Glucagon?
- mobilises fuel
- maintains blood glucose during fasting
- activates glycogenolysis (liver)
- activates gluconeogenesis (liver)
- activates uptake of amino acids by the liver
for gluconeogenesis - activates FA release from adipose tissue
- activates FA oxidation and ketone body
formation in the liver
Roles of Adrenaline?
- mobilises fuel during stress
– stimulates glycogenolysis (muscle and liver)
– stimulates fatty acid release from adipose tissue
Roles of Cortisol?
- provides for long term requirements
– stimulates aa mobilisation from muscle
– stimulates gluconeogenesis
– stimulates FA release from adipose tissue
Graph of Blood glucose, insulin and glucagonafter a high carbohydrate
meal
Blood glucose, insulin and glucagon in a normal person over 24 hours of normal eating behaviour (mixed meals)
metabolism in the fed state
What is the fed (absorptive) state?
What occurs during this state?
- 2-4 hours after a meal
- increase in blood glc, amino acids and TAG as chylomicrons (1,2,3)
- synthesis/storage of glycogen,TAG and protein
- (6,11,13,14)
- the liver is very important, it receives nutrients before other tissues from the hepatic portal vein
What is the carbohydrate metabolism in the liver?
Liver engaged in gluconeogenesis at all times except the fed state (high ins/glucagon ratio)
* In the fed state glycolysis is activated through the
activation of GLUCOKINASE (5,6)
* (high Km for glucose and so no competition with the
brain when glc is low)
What is the carbohydrate metabolism in the liver after glycolysis?
- Glycogen synthesis is activated (6)
- glycogen synthase is activated and phosphorylase inhibited
- glycolysis is activated through PFK and pyruvate
kinase (5)
Gluconeogenesis is inhibited
Process of liver fat metabolism in fed state ?
- Fatty acid and TAG synthesis are activated (7)
- Acetyl Co A carboxylase is activated (rate limiting step)
- malonyl Co A inhibits carnitine transferase
- in this way, newly synthesised FA does not enter the
mitochondrion for oxidation but becomes esterified to
TAG
Metabolism in Brain and erythrocyte?
- Both rely on glc. FA cannot cross the blood-brain
barrier and erythrocyte has no mitochondria - glc transport into brain and erythrocyte is
independent of insulin (glut1) (8,9) - This allows use of glc at both high and low
concentrations
Metabolism in Muscle during fed state?
- glucose transport into muscle is increased (10)
- GLUT 4 transporters increase in number
- Glycogen synthetase is activated and
phosphorylase inhibited as in liver (11) - amino acid uptake is activated and protein
synthesis is increased (14)
Metabolism of Adipose tissue?
- Lipoprotein lipase is activated by insulin (12,13)
- this allows entry of FA for esterification and storage of TAG
- Glc transport is increased through glut4 (10)
- glc is needed for production of glycerol phosphate and
esterification of TAG - Hormone sensitive lipase in the adipocyte is inhibited so TAG is not degraded
types of fuel reserves?
- glycogen (iver)
- glycogen (muscle)
- glucose
- TAG
- protein
glycogen location?
quantity (g)?
Energy value (Kcal)?
Energy value MJ
Muscle - 300g - 1460Kcal - 6.1MJ
Liver - 80g - 330Kcal - 1.4MJ
glucose location?
quantity (g)?
Energy value (Kcal)?
Energy value MJ
Body fluids - 15g - 60Kcal - 0.3Mj
TAG location?
quantity (g)?
Energy value (Kcal)?
Energy value MJ
Adipose tissue - 15 kg - 140 000Kcal - 580Mj
protein location?
quantity (g)?
Energy value (Kcal)?
Energy value MJ
muscle 6 kg - 26 000Kcal - 110Mj
What is the fasting state?
What occurs during this state?
Post-absorptive state
* Blood glc concentrations peak an hour after eating
* they return to normal by two hours after a meal
* Blood glc is removed for oxidation or storage
* Concentration of insulin drops and glucagon rises
Metabolism in the fasting state
What are the early events of liver and adipose tissue?
- The liver maintains blood glc concentrations at about 4 mM
- Adipose tissue provides the greatest source of energy as TAGs
- **Hormone sensitive lipase **activated by glucagon and adrenaline
- FA transported to the liver bound to albumin
Glucose production by the liver
- The first supplier of blood glc is liver glycogen
- gluconeogenesis follows from lactate
(erythrocytes and muscle), glycerol (from adipose
tissue) and amino acids (from muscle) - after 24 hours fasting all blood glc comes from
gluconeogenesis
Graph of Sources of blood glucose after ingestion of 100 g
glucose
What can’t be used in gluconeogenesis?
Why?
Fatty acids are NOT gluconeogenic precursors
* Reaction catalysed by Pyruvate dehydrogenase is IRREVERSIBLE
* pyruvate acetyl CoA
* PDH is activated by insulin and inhibited by glucagon
* ensures that in fasting gluconeogenic substrates are channelled into glucose
production not acetyl CoA formation
What occurs in liver during fed state?
- glycolytic enzymes are activated
- pyruvate ddehydrogenase is activated
- excess acetyl CoA is channelled into FA synthesis bythe activation of acetyl CoA carboxylase
glc ———-> pyruvate ———>acetyl Co A ————>FA
What occurs in liver during the fed state?
As FA can be used as fuel by liver adipose tissue and muscle, the draining of
gluconeogenic substrates into acetyl CoA is inhibited and conversion to glc is
favoured
How does Ketone body (KB) formation take place?
- FA oxidation in the hepatocyte leads to high concentrations of Acetyl Co A
- it exceeds the capacity of the TCA cycle
- it is channelled into ketone body formation
- acetoacetate and β hydroxybutyrate are released into the bloodstream
* most tissues oxidise a mixture of FA and KB
* erythrocyte uses glc
* brain uses glc and small amount KB
What would happen to the body with prolonged fasting (starvation)?
- If the early pattern were to continue in prolonged starvation body
protein would be severely depleted - only about a third of body protein can be lost without severe or fatal
consequences
Graph of fuel concentration in the blood in prolonged
fasting?
metabolism in starvation?
Urea excretion in the fed and fasting state?
What occurs as starvation continues?
- more KB are recovered from the kidney
- muscle uses FA rather than KB
- FA concentrations plateau and KB rise
- the brain can use more KB and less glc
- the need for gluconeogenesis is reduced and muscle protein breakdown decreases
- urea production decreases
What is the role of Ketone bodies?
- act on the pancreas to stimulate insulin release
- this limits muscle proteolysis
- and it limits adipose tissue lipolysis
- so, muscle tissue is conserved
When does death occur in fasting state?
- amount of adipose tissue is an important determinant of survival
- death comes from fuel exhaustion, loss of function from loss of protein and from
impairment of the immune system - death from starvation is very often due to infection
- about 40 days (young and fit, may be longer)
Graph of Glucose tolerance curves of normal and diabetic
subjects?
Who does Diabetes mellitus affect?
Consequences?
- affects 6% of population in UK
- 90% of all endocrine disorders
- major cause of blindness, amputations, premature deaths
- 10% of total health care budget
Different types of Diabetes Mellitus?
* Type 1 or **Insulin dependent **diabetes mellitus (IDDM)
* **Type 2 or non-insulin dependent** diabetes mellitus (NIDDM)
* 10-20% of diabetics are type 1
What is type 1 Diabetes?
How is it diagnosed?
- autoimmune destruction of β cells
- early onset
- hallmarks are hyperglycaemia and ketoacidosis.
- needs insulin treatment
Symptoms of type 1 diabeties?
- Polyuria, polydipsia, polyphagia, fatigue, weight loss, muscle
wasting,weakness
What is Diabetes type 2?
How is it diagnosed?
- usually later onset
- insulin resistance (target tissues non responsive
- usually milder than type 1
- association with diet and lifestyle e.g. obesity
- major increase in incidence (including children)
- hyperglycaemia but usually no ketoacidosis
- often responds to diet and oral hypoglycaemic agents
What is the Metabolic pattern in uncontrolled diabetes mellitus ?
Metabolic pattern in uncontrolled diabetes mellitus resembles that of starvation but the effects are more exaggerated
In starvation insulin is low
* In type 1 diabetes insulin is absent
* Glucagon acts unopposed
* KB produced in starvation stimulate insulin release
* this limits muscle protein breakdown, release of FA from adipocytes and the
uncontrolled production of KB.
* This important mechanism does not operate in diabetes
Metabolism in diabetes?
Chronic complications of diabetes mellitus?
- Microangiopathy
- changes in walls of small blood vessels seen as thickening of basement membrane
- Retinopathy
- blindness is 25 x more common in the diabetic patient
- Nephropathy
- renal failure 17 x more common
- Neuropathy
- postural hypotension
- impotence
- foot ulcers
Treatment of type 1 diabeties?
- exogenous insulin by injection
- Important to balance dosage with amount of food to avoid hypoglycaemic incidents, the most common complication of insulin therapy
Treatment of type 2 diabeties?
- weight reduction, dietary modification, oral hypoglycaemic agents
- biguanides increase the number of GLUT 4
- sulphonylureas act on the β cell to improve insulin secretion
What is metabolic syndrome?
Classified by the world health organisation as:
* High fasting glc/insulin resistance/diabetes type 2/impaired GT
Plus 2 of:
* Hypertension
* Dyslipidaemia (high TAG/low HDL
* Central obesity
* microalbuminuria
