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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
Each Organ has a Unique Metabolic Profile

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.
Each Organ has a Unique Metabolic Profile

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.
Each Organ has a Unique Metabolic Profile

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