Download Metabolic Interrelationship

METABOLIC
INTERRELATIONSHIPS
Prof Tan Nget Hong
Learning Objectives
This package consists of 2 lectures. After attending this
series, students are expected to:
• know the general principles of metabolic regulation
• understand the roles of insulin, glucagon and epinephrine in
metabolic regulation
• Understand how metabolism in various organs changes in
response to well-fed and starvation state.
Lecture Outline
• Metabolic regulation: overall view. Interrelationships of metabolic
pathways. Regulation of metabolic pathways (general).
• Key enzymes in the metabolic pathways.
• Metabolic effects of insulin, glucagons and epinephrine.
• Insulin: structure, regulation of secretion and metabolic effects.
• Glucagon: structure, regulation of secretion and metabolic effects.
• Epinephrine: structure and metabolic effects Metabolism in the
well-fed state: metabolic changes in liver, muscle, adipose tissue
and brain.
• Metabolism in starvation: metabolic changes in liver, muscle,
adipose tissue and brain.
Metabolic regulation: overall view
Mobilization of TG at adipose tissue:
regulatory enzyme is hormone sensitive
lipase
Uptake of TG from VLDL or
chylomicrons:
Regulatory enzyme is Lipoprotein lipase
Glucagon
Carbohydrate
Metabolism
Lipid metabolism
Metabolism pathways
1) The availability of substrates (response time: min)
2) Allosteric activation and inhibition of enzyme.
(eg: PFK by F-2,6 P2; Acetyl CoA carboxylase by citrate; response
time: min)
1) Covalent modification of enzymes (eg: glycogen synthase,
phosphorylase; response time: min to hr)
2) Induction-repression of enzyme synthesis (eg: effect of
glucagon on gluconeogenesis, response time: hr to days)
Note: (3) and (4) usually involve action of hormones
The key hormones regulating metabolism
The key hormones regulating metabolism:
Insulin (anabolic)
Epinephrine (catabolic)
Glucagon
Insulin
• Insulin, MW 6000. Human insulin (β-cells of the islets of
Langerhans), 51 amino acids in two polypeptide chains,
linked by disulfide bridges.
• Metabolic effects: anabolic, ⇑ synthesis glikogen, TG and
protein. Half life < 6 minutes
Insulin (anabolic)
Regulation of Insulin Secretion
•
•
•
•
•
•
Stimulation of Insulin Secretion:
Glucose: main stimulus
⇑ insulin secretion
Amino asids:
⇑ plasma amino acid levels  ⇑ insulin secretion
Gastrointestinal hormones: e.g. secretin.
(food intake ⇑ gastrointestinal hormones ⇑ insulin)
Inhibition of Insulin Secretion
a. When glucose levels < 50 mg/dL
 insulin secretion stops
b. During periods of trauma –
mediated by epinephrine, secreted
in response to stress/trauma.
Epinephrine  rapid mobilization
of energy and override the normal
glucose-stimulated release of
insulin.
In emergency, sympathetic nervous system largely replaces plasma
glucose concentration as controlling influence over insulin secretion.
Insulin increases muscle glucose
• Insulin increases muscle glucose uptake by increasing the
number of glucose transporters in the cell membrane
Glucagon
Polypeptide hormone with MW 3500, secreted by the α-cells of
the islets of Lengerhans. Half-life 5-10 min.
Main functions: along with epinephrine, cortisol and growth
hormones (counterregulatory hormones) opposes metabolic
actions of insulin and helps to maintain blood glucose levels
(⇑ glycogenolysis and gluconeogenesis, and ⇓ glycolysis)
Stimulation of Glucagon Secretion
a. Low blood glucose
b. Amino acids: amino acids from diet
stimulate glucagon (and insulin)
release, effectively prevents
hypoglycaemia by insulin, also
stimualted by aa’s
c. Epinephrine and norepinephrine:
during stress/trauma
Summary: Effects of Glucagon
and Insulin on metabolism
Glucagon
Glucose uptake by cells
--
Glycogen synthesis
⇓
⇑
⇑
⇓
⇓
⇑
⇑
Glycogenolysis
Gluconeogenesis
Glycolysis
Lipogenesis
Lipolysis
Ketogenesis
Insulin
⇑
⇑
⇓
⇓
⇑
⇑
⇓
⇓
Epinephrine
Epinephrine (adrenaline) secretion ⇑ at low glucose levels or
stress/trauma.
Metabolic actions of epinephrine:
⇑ glycogenolysis (muscle and liver)
⇑ mobilization of TG
⇓ glucose uptake by muscle
⇑ glucose release from liver
Liver, Adipose Tissues, Muscle and
Brain
Carbohydrate Metabolism
Carbohydrate metabolism in liver in the absorptive state
⇑ Utilization of glucose (60% of glucose from portal system
metabolized by liver, the high Km glukokinase become active)
⇑ glycogen synthesis : glycogen phosphorylase inactivated, glycogen
synthase activated.
⇑HMP (PPP) ⇑ NADPH production and utilization; 5-10% glucose
metabolized via this pathway
⇑glycolysis (PFK and pyruvate kinase activated)
⇓gluconeogenesis ( F,1.6 bisphosphatase ⇓)
Carbohydrate Metabolism
Lipid metabolisme in liver in absorptive state
Synthesis fatty acid ⇑ due to high levels of acetyl CoA (from
carbohydrate metabolism) and NADPH, acetyl CoA carboxylase ⇑.
Synthesis TG ⇑. Glycolysis supplies glycerol-3-P for TG synthesis 
VLDL⇑
Amino acid metabolism in liver in absorptive state
Degradation of amino acids ⇑ (branched chain amino acids such as
Leu, Ileu, Val are metabolized by muslce)
Protein synthesis ⇑ (transiently)
Metabolic Changes in the
Absorptive State
Metabolic Changes in Liver
in the Absorptive State
Metabolic Changes in
Adipose Tissue in
Absorptive State
Metabolic Changes in Brain
in Absorptive State
Metabolic Changes in
Muscle in Absorptive State
Metabolic Changes in Liver in the
Absorptive State
Main Menu
Metabolic Changes in Adipose Tissue
in Absorptive State
Main Menu
Metabolic Changes in Brain
in Absorptive State
Main Menu
Metabolic Changes in Muscle
in Absorptive State
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Inter-tissue Relationships in
the Absorptive (Well-Fed) State
Metabolic changes in Fasting/Starvation
Plasma glucose, amino acid and TG ⇓,  decline in insulin secretion
and increase in glucagon release (insulin/glucagon ratio can drop from
50 to <1)
Nutrient deprivation  catabolic state  metabolic adjustments in
liver, adipose tissue and brain so as to:
1. Maintain adequate plasma glucose levels to sustain brain
metabolism and other glucose-requiring tissues.
2. Mobilize fatty acids from adipose tissue and ketone bodies from
liver to supply energy
Metabolic fuels in a normal subject
In a normal 70-kg man: 159800 kcal
15 kg fat (135000 kcal)
6 kg protein (24000 kcal)
0.2 kg glikogen (800 kcal)
Carbohydrate Metabolism in liver
during starvation
Carbohydrate Metabolism.
• Liver supplies glucose for brain and other glucose-requiring
tissues by degradation of glycogen and gluconeogenesis – both
stimulated by glucagon
• Glycolysis inhibited
Lipid Metabolism in Liver During
Starvation
Fatty acid oxidation ⇑: fatty acids
released from adipose tissue are the major
energy source for liver in starvation.
Fatty acid synthesis ⇓ as acetyl CoA
carboxylase ⇓
Ketone bodies synthesis ⇑ as acetyl CoA
produced exceeds oxidative capacity of
TCA.
↑Ketone bodies synthesis starts during the
first days of starvation.
Metabolic Changes in Liver in
Starvation
Metabolic changes in Adipose Tissue in
Starvation
Carbohydrate metabolism
Glucose uptake and breakdown ⇓ due to ⇓ insulin levels.
Lipid metabolism
Degradation of TG ⇑ with hormone sensitive lipase very active
(⇓ insulin levels and ⇑ in glucagon/epinephrine)
Increased release of fatty acids –transport as albumin-FFA.
Glycerol produced for gluconeogensis.
Decreased uptake of fatty acids due to ⇓ in lipoprotein lipase, also ⇓ TG
synthesis
Metabolic Changes in Adipose Tissue in
Starvation
Protein Metabolism in Muscle during
Starvation
First few days rapid breakdown of muslce protein to release amino acids
(mainly Ala, Gln). After several weeks, proteolysis ⇓ due to ⇓ glucose
utilization by brain
Metabolic Changes in Brain during
Starvation
3 days after starvation, 1/3 fuels from ketone bodies.
In prolonged starvation glucose only supplies 30% of energy requirement.
Inter-tissue Relationships During
Starvation
Amounts of Fuel Molecules Generated/Utilized
in Prolonged Starvation
Information
Fuels used by brain
Glucose
Ketone bodies
Mobilization of fuel molecules
Lipolysis at adipose tissue
Proteolysis of muscle protein
Fuel molecules generated from liver
Glucose
Ketone bodies
Fuels used by brain
3rd Day
40th Day
100 gm
50 gm
40 gm
100gm
180 gm
75 gm
180 gm
20 gm
150 gm
150 gm
80 gm
150 gm
Thank you
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