Lecture 11 On Regulation of Metabolism

Regulation of Metabolism
1. Allosteric interactions:
Enzyme: amount and activity
Substrate: available amount
2. Covalent modification:
Phosphorylation & dephosphorylation (usually
under hormonal control) of enzymes.
3. Enzyme levels:
Rates of synthesis and degradation. (genetic
control), with protein turnover
4. Compartmentation: located in different intracellular
compartments, e.g. cytosol, mitochondria, etc.
5. Metabolic specialization of organs: Organs with
different metabolic roles
Physical actions of Insulin and insulin counterregulatory
hormones
Hormone Function Major pathways affected
Insulin Fuel storage Stimulate glucose uptake and glycogen

after a meal synthesis in muscle and liver
Stimulates fatty acid synthesis (acetyl CoA
carboxylase) and storage after a high
carbohydrate meal
Stimulates amino acid uptake and protein
synthesis
Glucagon Mobilizes fuels Stimulates gluconeogenesis and glycogenolysis

Maintains blood in the liver during fasting
glucose during Stimulates fatty acid release from adipose tissue
fasting Inhibits acetyl CoA carboxylase
Epinephrine Mobilizes fuels Stimulates glucose production from muscle and

during acute liver glycogen
stress Stimulates fatty acid release from adipose
tissue.
Each Organ has a Unique Metabolic Profile
Brain:
Glucose is normally the sole fuel for human brain. In
starvation, ketone bodies generated by liver can serve as fuel.
The blood-brain barrier excludes transport of many molecules
into the brain (unusual compared to other parts of the body).
Allows transport of essential amino acids.
So basically interaction with brain and circulatory system like this
Ammonia is toxic to the CNS (swells brain), so brain has an
active glutamine synthetase that produces glutamine.
Excess nitrogen produced
Muscle:
The major fuels are fatty acids, glucose, and ketone bodies.
Muscle has a large store of glycogen but does not release glucose
into the blood (bc glucose glycosylated in glucose 1 phosphate
form)
Releases lactate, alanine, and glutamine into the blood
Skeletal muscle can go anaerobic, but heart muscle cannot, so
heart uses fatty acids, lactate, and ketone bodies for fuel.
Liver:
The metabolic activities of the liver provide fuel to the brain,
muscle and other peripheral organs.
Contains glucose-6-phosphatase (chops phosphate off, allows
glucose to go to blood), which is used to control blood glucose
after glycogen mobilization.
Also plays a central role in lipid metabolism in times of
abundance, secretes lipids into the bloodstream; during fasting,
converts lipids to ketone bodies. Choice depends on activity of
acetyl CoA carboxylase.
Also plays a central role in nitrogen metabolism. Location of
urea cycle. Produces 20-30 g/day urea.
Gets energy from the a-keto acids derived from amino acids.
Adipose Tissue:
The triacylglycerols [stored] are a reservoir of metabolic fuel.
Precursors for synthesis and storage come from blood (glucose),
from the liver (lipoproteins), from the diet (chylomicrons from
intestine).
Hormone-sensitive lipase releases fatty acids (for transport to
peripheral tissues) and glycerol (for transport to the liver).
Availability of glucose inside adipose cells is a major factor in
determining whether fatty acids are released into blood
Consider the consequences of four states:
1) Well fed state insulin stimulates storage
2) Starvation low blood glucose in the short

and long term
3) Diabetes (type I) high blood glucose but no uptake
4) Alcoholism generation of NADH from

ethanol oxidation rather than
glucose oxidation
1) Well fed state Insulin levels rise:
Stimulates uptake of glucose into both muscle

and adipose tissue
Stimulates glycogen synthesis in both muscle and liver
Suppresses gluconeogenesis by liver
Accelerates glycolysis in liver results in increased

fatty acid synthesis
Also activates acetyl CoA carboxylase
Glucokinase in liver (high Km) traps glucose as G-6-P

2. Fasting low blood glucose
Glucagon is released from pancreas, and epinephrine

from the adrenal signaling starved state
Both initiated cAMP cascade that triggers glycogen

breakdown and inhibits glycogen synthase
Glucagon (specific) action inhibits acetyl CoA carboxylase
Lowered levels of F-2,6 bisP inhibits glycolysis, and

activates gluconeogenesis
Liver releases glucose into blood, and adipose tissue

releases F.A.s
Extended fast or type I diabetes
Gluconeogenesis depletes OAA and TCA cycle

intermediates to create pyruvate
Proteins can be degraded to produce amino acids whose
carbon skeletons are fed into TCA cycle
After 3 days shift to fatty acids and keto acids for fuel
After several weeks ketone bodies become the major fuel

of the brain, resulting in decreased protein
breakdown for glucose synthesis
Diabetes all tissues act as if they are starving
Glucagon is high, triggers breakdown of glycogen and

fat, stimulates gluconeogenesis loss of OAA,
breakdown of body proteins
Blood glucose is extremely high excreted in urine,

taking water with it dehydration
Ketone bodies produce ketosis, altering acid-base

balance
Starvation in the midst of plenty

Consequences of excess ethanol consumption
1. Accompanied by NADH production from ethanol
dehydrogenase production of NADH and acetaldehyde
followed by oxidation of acetaldehyde to NADH and
acetic acid.
2. NADH forces pyruvate-lactate equilibrium toward

lactate, with resultant inhibition of gluconeogenesis
3. Consequences of excess NADH:

lactic acidosis,
hypoglycemia,
inhibition of FA breakdown,
increased FA synthesis and triglycerides - fatty liver,
inhibition of TCA cycle enzymes,
ketosis acid/base imbalance problems
Effect of Alcohol consumption on Diabetics
Increases blood glucose in well-fed state

reasons are not clear perhaps some
interaction between alcohol and insulin
secretion/activity
or
alcohol decreases self-monitoring and
compliance with insulin administration
Decreases blood glucose in starved state

glycogen depleted, gluconeogenesis inhibited
Alterations in fat metabolism
Free fatty acids produce triglycerides and
ketones making diabetics more prone
to ketoacidosis and fatty liver

Lecture 11 On Regulation of Metabolism

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Regulation of Metabolism

Hormone Function Major pathways affected

Insulin Fuel storage Stimulate glucose uptake and glycogen

Glucagon Mobilizes fuels Stimulates gluconeogenesis and glycogenolysis

Epinephrine Mobilizes fuels Stimulates glucose production from muscle and

1) Well fed state insulin stimulates storage

2) Starvation low blood glucose in the short

3) Diabetes (type I) high blood glucose but no uptake

4) Alcoholism generation of NADH from

Stimulates uptake of glucose into both muscle

Stimulates glycogen synthesis in both muscle and liver

Suppresses gluconeogenesis by liver

Accelerates glycolysis in liver results in increased

Also activates acetyl CoA carboxylase

Glucokinase in liver (high Km) traps glucose as G-6-P

Glucagon is released from pancreas, and epinephrine

Both initiated cAMP cascade that triggers glycogen

Glucagon (specific) action inhibits acetyl CoA carboxylase

Lowered levels of F-2,6 bisP inhibits glycolysis, and

Liver releases glucose into blood, and adipose tissue

Gluconeogenesis depletes OAA and TCA cycle

After several weeks ketone bodies become the major fuel

Glucagon is high, triggers breakdown of glycogen and

Blood glucose is extremely high excreted in urine,

Ketone bodies produce ketosis, altering acid-base

Starvation in the midst of plenty

2. NADH forces pyruvate-lactate equilibrium toward

3. Consequences of excess NADH:

Increases blood glucose in well-fed state

Decreases blood glucose in starved state

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