‫القائد ابو عبيدة‬

Fuel Metabolism During Exercise

Definitions of total energy expenditure and its major components (basal (resting) metabolic rate
and various factors it depends on, physical activity, thermogenesis). Indirect calorimetry,
respiratory quotient, its use in practice (caloric equivalent for different nutrients).
Total Energy expenditure
Basal metabolic rate: Minimum amount of calories
body needs to perform basic actions such as:
→ Pumping blood → Digesting food
→ Breathing
→ Keeping stable body temp → Growing Hair and skin
→ Maintaining homeostasis

Resting metabolic rate (RMR): Amount of energy

required for body to function at rest
This value accounts for additional low effort daily
activities on top of the basic body function including:
→ Eating →Walking →Using bathroom
→Consume caffeine →Sweating or Shivering
RMR is more than than the basal metabolic rate as it includes other activities, but physical
activity and thermogenesis is not included.

How to measure? Indirect calorimetry

Measured in the morning after fasting for 12h and rested for 30 minutes in a thermo-neutral
environment. Then measuring volume of gas exchange determines nutrients oxidized and
calculates energy released from each nutrient.

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Average person consumption: 0.3L/min O2 or 432L/day

First column : Tells how much heat would be produced in a bomb calorimeter
Second column: Tells how much energy/heat would be produced in the body hypothetically
Third column: How much actual energy would be produced in the human metabolism with
inefficiencies.

Caloric equivalent of respiratory exchange ratio (RER) shows where we get the energy if it is
from fats, carbohydrates, etc. The ratio shows that there is more O2 required to metabolize fats
than carbohydrates. This is due to the fact that fats are more dense and need to take in more
oxygen.

In practical use RER values approach 1.0 means carbohydrates are being used, BUT not always,
as during intensive workout lactate production is increased and thus CO2 is produced without O2
and this gives misleading values or RER while actually we are using other fuels.

Colloq questions:
1. Define total basal metabolic rate and the difference between resting metabolic rate and
highlight the difference between them
Answer: Basal metabolic rate, is everything at rest in the fasted state. RMR is similar but
not at fasting and not as strict an environment, typically higher as it includes foot intake
and the most basic movements such as breathing etc.
2. Discuss respiratory quotient (RQ), how values vary with oxidation of different nutrients
and what implication it shows on fuel being metabolized?
Answer: RQ is the CO2 / O2 ratio to metabolize food, showing how much oxygen
required for metabolizing to carbon dioxide, lower the RQ more oxygen is needed to
metabolize.
3. Why does RQ increase when exercising intense?
Answer: Often wanting to use carbohydrates and because of lactate production leading to
anaerobic conditions leading to more CO2 production showing that the RER values go to
1 or over which is not accurate.

Body stores of energy fuels and organs/tissues contributing the most for its use during resting
conditions – explanation why.

Carbohydrates (Glycogen storage)

Liver → 110g → 451 kcal
Muscle → 500g → 2050 kcal
Glucose in body → 15g → 62 kcal

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Fat
Subcutaneous and visceral → 7800g → 72540 kcal
Intramuscular → 161g → 1497 kcal

Contributions of different organs and tissues to the RMR differ.

Heart, liver, kidney and brain stand for 60% of total RMR but 5% of body weight.

Different tissues need different energy needs as well as storage. The brain always needs glucose
and needs to always be ready, the heart always needs energy to pump blood, while the liver also
filtrates blood and metabolites. However muscles in rest don't work thus not requiring the energy.

Factor influencing RMR:

→ Genes → Physiological stress
→ Pregnancy → Hypothermia
→ Growth → Sex
→ Age → Hormones
Diet induced thermogenesis:
Different foods require different energy to digest and intake, thus influencing thermogenesis. For
fat it's 0-3%, 5-10% for Carbohydrates, 20-30% for proteins.

Colloq questions:
1. Why does the organs take so much energy even though we are at rest?
Answer: Because these tissues are always active as they are responsible for important
aspects of the body and thus oxidize energy always, mostly from fats.
2. Discuss interplay between liver, regulation and energy homeostasis during fasting and
how interaction between tissues change in response to prolonged fasting, what are the
biochemical mechanisms involved?
Answer: Mostly energy is prioritized to vital organs like brain, liver and heart where then
glycogen storage is broken down to glucose and give, then during prolonged period body
increases lipolysis to use FA and glycerol converting to ketone bodies as alternative fuel.

Three energy systems and their relations. Capacity to explain what system will be dominant in
what kind of physical activity and what will be the corresponding ATP source and ATP amount
generated by these systems. Factors (duration, intensity, availability of nutrients) that determine
the time frame for each energy system.
a. Phosphocreatine system – synthesis, application during physical activity. Reasoning of
creatine supplementation.
b. Aerobic energy system (list of all metabolic pathways that ensure aerobic oxidation of
carbohydrates, lipids and proteins). Factors which determine oxidative capacity of muscles

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(enzyme activity, types of muscle fibres and their typical characteristics, oxygen availability and
myoglobin).
c. Anaerobic energy system (list of all metabolic pathways that ensure anaerobic oxidation of
carbohydrates).

The 3 Energy systems used are:

Phosphocreatine system
Aerobic system
Anaerobic system

Oxidative capacity: Determined by oxidative enzyme activity

meaning muscles ability to perform exercise with oxidative
enzymes such as citrate synthase and succinate dehydrogenase
etc. Athletes have 2-4x greater capacity than untrained people.

Enzyme table shows that anaerobically trained have more of

one form of enzymes than others while aerobically trained will
have more of oxidative system enzymes.

Oxidative capacity: Depend on muscle fiber type

● Slow twitch fibers (RED): Greater aerobic
capacity, more mitochondria, low tension, highly resistant
to fatigue, dense BV network.
● Fast twitch fibers (WHITE): Endurance training
enhance capacity to do more work in less time, greater
tension, quick to fatigue.

Oxidative capacity also depends on oxygen availability.

● Myoglobin - Has higher affinity to O2, has storage of oxygen during low O2 supply,
Endurance training increases muscle myoglobin by 75-80%

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Phosphocreatine System
Source: Meat and dairy products. Synthesized from Glycine and Arginine.
Place of synthesis: Primarily in liver and kidney
Place of use: Primarily in skeletal muscle, heart muscle, and brain.

Used for the first few seconds of intense muscular activity, sprinting, weight lift
or other fast exercise. 5-10 seconds of storage. Creatine kinase has isoenzymes,
meaning different forms. Cytosolic creatine kinase - Present in regions of high
ATP use such as myofibrils (muscles) and prevent accumulation of ADP in
cytosol. Mitochondrial creatine kinase - present in mitochondria serving as shuttle
ATP to produce the actual ATP.

Supplement: Used to increase muscle mass and improve performance in high

intensity short duration workout by adding creatine, converted to phosphocreatine
and thus having more saturation of creatine by also pulling water to it. Adding water weight as
well as help with muscle recovery to replenish ATP. Because creatine also increases leading to
AMPK increasing which translocates GLUT-4 which takes up glucose easier.

Anaerobic glycolysis
Occurs in 3 conditions:
● Short high intensity workout (400m sprint) such as transition from walking to all out
sprint.
● Beginning of exercise, due to difference in oxygen needs and oxygen supply.
● Once intensity increases above lactate threshold (>80% VO2Max)
Used for around 1-3 minutes (almost 2 minutes) of the anaerobic energy system.
Pathways involved: Pathways involved are:
→ Glycolysis (Glucose →Pyruvate)
→ Glycogenolysis (Glycogen → Glucose)
→ Lactic acid formation (Pyruvate → Lactate) (Lactate dehydrogenase)

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Aerobic system
Fat oxidation uses more oxygen as more prevalent in lower intensity exercise, proteins are used
for a maximum of 5% of energy. Ingestion of CHO rich meal, meaning fat, increases muscle
glycogen and maintains blood glucose late in exercise.
Pathways:
→ Glycolysis → ETC
→ Krebs cycle → Beta oxidation (fat)
→ Oxidative decarboxylation → Proteolysis
→ Deamination → Ketogenesis

When is everything used? Pattern of substrate utilization

changes with time even when intensity remains constant, as the
longer the time spent exercising the higher the contribution of
fat as an energy substrate.

25% of VO2 Max: Mostly Plasma FFA

65% of VO2 Max: Equal muscle glycogen, plasma FFA, Muscle TAG
85% of VO2 Max: Muscle glycogen mostly.

Colloq questions:
1. During a 400 meter sprint, describe how the energy systems interplay with eachother?
Answer: At the start the body uses ATP available for a couple of seconds then the
Phosphocreatine system for about 10 seconds. After that anaerobic system is activated
which will be the primary source of ATP lasting about 45-60 seconds. The aerobic does
not come into play until relaxation where it replenishes the depleted ATP stores and
removes lactic acid as well as restoring PCr levels.
2. During a test where intensity increases progressively, what happens with the 3 energy
systems and how does the interplay work reaching then VO2 Max?
Answer: Firstly free ATP is used, then moving on to PCr system as well as kicking in the
aerobic system when moderate level and produce with help of O2, but if it is high
intensity we use the anaerobic system giving us more ATP but with less efficiency as it
does not keep on as long and when that is depleted we will reach exhaustion as only
aerobic system will work.

Methods determining oxidative capacity of muscles: VO2max and lactate threshold. Reasons for
post exercise oxygen consumption.

Postexercise oxygen consumption: Most common method for estimating anaerobic effort. This
is due to oxygen needs and supply differences during transition from rest to exercise and the

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body is in deficit, so by depleting energy stores the time for restoration estimates anaerobic
effort. Thus it involves
● O2 required for restoration of PCr used during exercise
● Removal of lactate
● Replenishment of myoglobin
● Clearing CO2 accumulated in tissues
● Increased body temperature keeping metabolic and respiratory rates high
● Elevated norepinephrine and epinephrine

Lactate threshold: Another common method to estimate anaerobic

effort and show the shift from anaerobic to aerobic system. On the
graph it shows intensity from where lactate starts to accumulate
significantly. As blood lactate is calculated by subtraction of
clearance from productions.
Colloq questions:
1. Describe significance of VO2 max and lactate threshold in
assessing oxidative capacity of muscles as well as reason for
elevated oxygen after exercise?
Answer: VO2 max shows aerobic capacity by showing how much your body can take up.
The reason for elevated oxygen is because we need more oxygen to replenish the ATP
levels and remove lactate from the stream as well as repair.
2. During a high intensity exercise, describe lactate threshold influencing performance and
subsequent reliance on energy systems of approaching athletes VO2 max?
Answer: As the intensity increases in the beginning we use aerobic energy system and the
PCr to endure but higher intensity leading to the higher VO2 max approaching athlete
level will then kick in the anaerobic system showing peak for aerobic metabolism and
show what the capacity is.

Hormonal regulation of fuel metabolism during exercise: hormones that maintain glucose
homeostasis by providing glucose, fats, proteins for energy metabolism, related upregulated and
downregulated metabolic pathways

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Glucagon: Prompts liver glycogen breakdown and forming glucose formation from amino acids
and increases during the exercise.
Adrenaline (80%) & Noradrenaline (20%): Stimulate further increase of glycogenolysis, more
exercise, more catecholamine release.
During the high intensity but short term exercise there is more glucose released than uptaken by
40-50%.
Cortisol: Slight drop after 30 minutes of exercise, stimulating gluconeogenesis, catabolism of
amino acids, and lipolysis. Growth hormone stimulate mobilization of FFA to spare glucose and
use another energy source to not deplete the glucose completely. Produced by thyroid gland.

Down: Everything which builds up energy storage

Up: Everything to breakdown energy storage
Insulin Sensitivity: Improved during training
Usually it tends to decrease during prolonged exercise, as well as enhance insulin binding to
receptors on muscle fiber reducing need for high concentrations of plasma insulin to transport
glucose across muscle cell membrane to cell. Basically adapt.

Hormonal regulation of fat metabolism during exercise:

Mobilization and oxidation of FFA increase in case of prolonged exercise, when CH is low
endocrine system signal to accelerate lipolysis. The rate of lipolysis is controlled by;
→ Mostly Insulin decreased → NE / E
→ Cortisol → Growth hormone
→ Thyroid hormones (rarely)

Colloq questions:
1. How do NE / E , glucagon and cortisol work together during medium to high intensity
exercise sessions?
Answer: NE/E facilitate breakdown of glycogen in liver and release glucose to blood
while stimulating lipolysis, glucagon will also interplay by signalling cell to take up the
energy freed and breakdown more. While cortisol will mobilize further amino acids from
muscle proteins to be used as energy fuel in the body.

Causes for fatigue (depletion of different nutrients for various energy systems, accumulation of
metabolic by-products, neuromuscular fatigue).

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ATP is depleted less rapidly than Phosphocreatine, to delay fatigue the athlete must control the
rate of effort through proper pacing. Such as in sprinting, muscle glycogen content decreases
35-40 times faster than walking, used mostly in the first few minutes of exercising. Glycogen can
only be depleted in one type of muscle fibers or type of muscles.

Lactic acid accumulates in lead to fatigue when performing highly intense muscular effort
accumulating H+ leading to acidification, normally its 7.1 pH, but at exhaustion lowest is 6.4-6.6
pH. When pH is under 6.9 it leads to PFK inhibition.

Neuromuscular fatigue is when Acetylcholine is reduced. This can be caused by cholinesterase

becoming hyperactive degrading Acetylcholine which then cant initiate AP. It can be used as a
protective mechanism to protect the muscle to not get broken down

Colloq questions:
1. How do alterations in concentration gradient lead to neuromuscular fatigue, discuss
interplay in coupling and reduction in muscle force?
Answer: Repeated muscle contraction leads to extracellular concentration gradient
increase and results in depolarization reducing muscle ability to generate AP as well as
fatigue impairing the excitation and contraction coupling leading to less force produced.

Adaptations to aerobic and anaerobic training.

Changes in aerobic power such as cycling 2 hours 5-6 times a week * 8 lead to:
● Muscle type fiber (slow twitch) become larger, switching between types of fibers
● Increase number of capillaries
● Increase muscle myoglobin
● Increase number, size and efficiency of mitochondria
● Increased aerobic enzymes
● Better intake of glycogen stored in muscle and more TAGs stored.

Changes in anaerobic such as sprint and resistance training lead to:

● Muscle type increase (fast twitch fibers) having larger cross sectional areas
● Improved activity of creatine kinase and myokinase
● Increased activity of glycolytic enzymes
● Adaptations in lactate threshold including buffering capacity.

Colloq questions for ALL:

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Learn the components of this picture as it has been in previous colloq

Explain how shivering produces additional heat. Mention metabolic pathways that would be
additionally activated if a person wakes up shivering from cold at night in winter because of
windows left open. Explain why we sweat during physical activity but stay warm also when we
are sleeping. In both situations mention tissues producing most of the heat.
Answer: Shivering produces additional heat through involuntary muscle contractions which
produce heat to warm the body up as well as with the help of uncouplers which uncouple the
mitochondria allowing for more heat release. However when exercising we sweat to cool off as
the skeletal muscles release a lot of heat and we release it from exocrine glands to brind the body
temperature down,

Answer →

High altitude training is practiced by endurance athletes to increase their performance.

Training is performed above 2400 meters above sea level. The idea of benefit of such
training became popular after the 1968 Olympics, which took place in Mexico City,
Mexico: elevation 2,240 meters. It was during these Olympic Games that endurance
events saw significant below-record finishes while anaerobic, sprint events broke all
types of records.

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a) Propose how endurance athletes would benefit from high altitude training. In
explanation mention muscle energy systems that would be stimulated (3p)

b) Let suppose a hypothetical situation. If you would have taken blood analysis from
endurance athletes of Netherlands team after their performance during 1968 Olympics
and week before during their training sessions in home country, how would analysis
differ? Explain your assumptions (3p)"

Answer:
a) Endurance athletes would get used to less oxygen at higher amplitudes and thus the body
would develop more RBC and mitochondria getting more slow fiber types, increasing also
capillaries as well as aerobic enzymes.
b) Blood analysis of the netherlands team because their country is below sea level indicates that
the blood analysis would show higher hemoglobin concentration, RBC, as their oxygen carrying
capacity would increase and more aerobic enzymes

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Obesity, Regulation of body weight

Characteristics and functions of white adipose tissue (list of all metabolic pathways of
carbohydrates, lipids and proteins that ensure these functions)

White adipose tissues: Made of large spherical cells filled with one lipid droplet (65% of cell)
with few mitochondria squeezed to a layer near the membrane, widely distributed tissue mostly
under skin, around BV and in the abdominal cavity. 15% of body mass in healthy adults.
Function: Store TAGs to be used as energy
Pathways: (For carbohydrates)
→ Glycolysis through oxidative phosphorylation
→ Convert Acetyl-CoA to FA
→ Uses FA to make TAGs
→ Release FA when tissues need them
(For lipids)
→ TAGs broken down to FA and glycerol
→ FA re-esterified to store as TAG (TAG cycle)
→ Beta oxidation is used when FA are needed for energy
(For proteins)
→Amino acids deaminated
→ Carbon skeleton feed krebs cycle or convert to pyruvate
→ Intermediates become Acetyl-CoA contributing to FA synthesis.

Accelerated by epinephrine as it gives HSL access to lipid droplets and hydrolyze TAGs, but
insulin inhibits access for lipase.

Characteristics and functions of brown adipose tissue (list of all metabolic pathways of
carbohydrates, lipids and proteins that ensure these functions)

Brown adipose tissue: Smaller cells not round having several small lipid droplets, and have
more mitochondria and richer supply of capillaries. The increase of cytochrome gives it grown
color. Primarily BAT is located around kidneys, spine and other locations of vital organs
providing warmth during low temperature. In adults BAT makes up 0.1% of body mass.

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Functions: Human fetus differentiation starts and at birth reaches 1-5% of body mass.
● Thermogenesis in BAT uncouples protein UCP1 (thermogenin) allowing for H+ gradient
dissipation to release heat and not ATP. (Main source is from fats→ Beta oxidation)
Pathways:
→ Acyl-CoA transporter → Krebs cycle
→ Beta-oxidation
→ ETC
Cause of obesity: kcal intake versus expenditure.

Imbalance in food intake or energy expenditure leads to increased body weight, when WAT
becomes saturated, lipids can be redirected to peripheral organs accumulating fat on muscles,
liver or pancreas etc. If more than that fat accumulates it leads to lipotoxicity targeting other
cells.

Hormonal regulation of food intake (in relation to Top down and Bottom up hierarchy (week 5, II
semester): place of synthesis, action mechanism, and final outcome of hormones insulin, leptin,
neuropeptide Y, α-melanocyte stimulating hormone, PYY, ghrelin.

Insulin:
Place of synthesis: Beta cells of pancreas (bottom up)
Action mechanism: Insulin produced is released from pancreas traveling to the circulatory
system including the brain, the brain senses in the hypothalamus which is important in energy
homeostasis influencing the appetite and peripheral metabolism. In the body it promotes uptake
of glucose as well as energy requiring processes such as glycogenesis. Peptide hormone
→ Insulin also suppresses appetite by interacting with hypothalamus as orexigenic neurons have
insulin receptors as they also cross talk with leptin.

Leptin:
Place of synthesis: Adipocytes release leptin when receiving food (bottom up)
Action mechanism: The adipokines are released as peptide hormones acting locally and
systemically carrying information about fuel storage. This includes leptin and adiponectin
changing the behavior and appetite regulation. Leptin is an appetite suppressant. Peptide
hormone
OB gene - codes for leptin and in case you have a defect you will not have leptin and will
become obese as you do not have an appetite suppressant.
DB gene - encodes leptin receptors in the brain to sense the leptin.
→ Leptin makes muscle and liver more sensitive to insulin, as common messenger enables leptin
and insulin

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Leptin resistance occurring in obese individuals means that even when administering leptin to
humans is different to mice where they get restored body mass. The human body on the other
hand can develop resistance and only if a person can develop leptin this works.

Leptin itself affects 2 types of appetite related hormones which are:

● Neuropeptide Y (NPY): Appetite stimulating sending signal to eat, reverse uncoupling
and rise in ob/ob and db/db mice. The hormone is inhibited by leptin and insulin.
Released from the hypothalamus
● alpha-Melanocyte (alpha-MSH): Appetite suppressing hormone, stimulated by leptin
and released from hypothalamus.

PYY:
Place of synthesis: L cells in the colon and bind to receptors in the brain to bind NPY and
decrease appetite by “Eat less”.
Action mechanism: PYY is released into the bloodstream from cells in the lower intestine
reaching the brain and binding to hypothalamus and inhibiting NPY which is a hormone that
makes you feel hungry. Resulting in reduced hunger.

Ghrelin:
Place of synthesis: Mainly in the stomach in the upper part.
Action mechanism: Signaling the body that we are hungry by increasing the NPY in
hypothalamus which then increases sensation of hunger stimulating higher motility. Short
duration of the hormone before and after meal. Receptors of ghrelin appear in the brain, heart,
and adipose tissues working via G-protein.

Colloquium Questions:
1. A person has fasted for a long time and feels very hungry, explain the interplay and
dominance of the hormones
Answer: Ghrelin would be high as it is the hunger hormone as well as NPY while others
hormones would be low concentration.
2. If a person has chronically elevated levels of leptin what potential effects would this lead
to in relation to obesity, metabolic disorder etc. How could this be treated if it can?
Answer: Firstly the leptin will lead to reduced appetite and with time will develop leptin
resistance. When that occurs there will be increased food intake and weight gain
increasing risk for obesity. The treatment would be the same as for diabetes type 2,
mostly exercise and regulate the diet.

Adiponectin - place of synthesis, action mechanism, influence on metabolic processes in body

Adiponectin

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Synthesized in adipose tissue mostly white, enhancing sensitivity to insulin. Meaning that every
pathway connected to storing energy is activated and all pathways “down” will be inhibited. It
also increases FA oxidation in muscle and glucose uptake for catabolism. Inhibits FA synthesis
and gluconeogenesis in the liver.
Action mechanism of it will be working via
AMP activated kinase pathway. In case of
depletion of ATP it will lead to AMPK
phosphorylating and inactivating Acetyl-CoA
carboxylase making malonyl-CoA. Thus
when inhibited this enzyme leads to inhibition
of FA import to mitochondria. Thus FA enters
freely to the mitochondria for oxidation.

Summary: Adiponectin leads to fat use and

produces energy.

mTORC: Ser/Thr kinase activate factors for growth, protein synthesis, membrane synthesis etc.

Peroxisome Proliferator−Activated Receptors (PPARs) α, γ, ; their mode of action, general

metabolic effects

Diet regulates expression of genes controlling body mass, this is due to Peroxisome proliferator
activated receptors altering expression for genes for fat and carbohydrate metabolism.
Action: Ligand → FA / derivative (PPAR) → Bind retinoid X receptor (RXR) + Ligand →
becoming a powerful transcriptional factor → PPAR-gamma, PPAR-alpha, PPAR-delta.

PPAR-Gamma:
Location: Liver & Adipose Tissue
Turns on genes for differentiation of fibroblast → Adipocytes and proteins for FA synthesis
Activated by Thiazolidinediones - Treating drug type 2 diabetes.

PPAR-alpha:
Location: Liver & Kidney & Heart & Muscle & BAT
Activated by FA, eicosanoids, and coronary heart
disease drugs raising HDL, lowering TAG in blood. In
hepatocytes it turns on genes for uptake and oxidation of
FA and for ketone body formation during fasting.

PPAR-delta & PPAR-beta:

Location: Liver & Muscle

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Regulates fat oxidation by sensing dietary lipids, turning on genes for FA oxidation and
uncoupling of mitochondria to increase heat.
Mice overfed don't get obese if PPAR-delta works even when leptin is lacking meaning there is
mitochondrial uncoupling.

Colloquium Questions:
1. A drug activates PPAR-alpha on a metabolic syndrome patient, what would happen to
this person and metabolic pathways? Was this drug the most suitable, why not use other
PPARs?
Answer: PPAR-alpha would lead to increased FA oxidation in liver helping clear TAG
and increase HDL, as well as improving insulin sensitivity. However in PPAR-gamma it
would lead to more focus on adipose tissue generation leading to the patient eating more
and thus being more obese even though it can aid in glucose homeostasis. The
PPAR-delta would enhance FA oxidation in muscles, reducing TAG and turning on
uncouplers generating heat.

Role of microbiome in obesity; metabolic processes affected.

Adult person has 10^14 microbial cells functioning as endocrine glands affecting metabolism
and feeding behavior as well as body mass. Some create fermentation products affecting adipose
tissue. Mostly short FA, acetate, propionate, butyrate and lactate going to the bloodstream
affecting adipose tissue.
Propionate: act as a precursor cell stimulating them to become adipocytes → Less lipolysis →
more WAT → OBESITY.
Bile acids: Primary bile acids → Secondary bile acids by gut bacteria → GPCRs and steroid
receptor activating beige adipocytes to produce UCP1 (uncouplers) → Increase use of
energy/heat and increase sensitivity to insulin.
Foods: Conversion of phosphatidylcholine + L-carnitine → TMA → TMAO in the liver →
Atherosclerotic plaque, less reverse cholesterol transport and increase in macrophage activity.

Prebiotics - feed already available bacteria nurturing the bacteria.

Probiotics - Live bacteria, from fermented foods
Decrease luminal pH, recrease pathogen growth and regulate the immune system promoting
enhanced oxidative metabolism.
Pathways to include: Reverse cholesterol transport, Bile acid metabolism, xenobiotics
metabolism, metabolism of Amino acids, glycolysis & gluconeogenesis, modulation of intake.

Colloquium Questions:

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1. Patient undergoes treatment and takes a lot of antibiotics shifting the gut microbiome,
what are the consequences of such a shift and how could this be treated?
Answer: It will disrupt the gut microbiome meaning that carbohydrate fermentation,
glucose intolerance and lipid metabolism can be altered as the gut microbiome helps with
this, thus increasing the obesity risk and inflammation. Treatment for this would be eating
fibers to contribute with prebiotics and plants to get probiotics.
Types of diabetes, symptoms, stages of disease development.

Type 1 Diabetes: Autoimmune reaction attacking insulin producing beta pancreas cells, leading
to no production of insulin, thus needing lifelong treatment.
→ Body tries to dilute glucose leading to urination and thirst
→ Increased fat breakdown
→ High ketone body production (Ketoacidosis)
→ Breakdown of ketone body acetoacetate produces acetone altering breathing as well because
of the bicarbonate system active.

Type 2 Diabetes: Most common, high blood glucose as a result of the body not responding fully
to insulin uptake “insulin resistance”.
→ Body tries to dilute glucose leading to urination and thirst
→ Development of insulin resistance
→ EARLY STAGE: Pancreatic Beta cells producing so much insulin leads to failure and fatigue
of the cells leading to lack of insulin causing the body’s inability to regulate glucose at early
stage.
→ INTERMEDIATE STAGE: Abdominal obesity, high TAG and LDL, low HDL, high BP.
→ Reduced ability to clear glucose after ingestion, as well as changes in blood proteins such as
abnormal clotting, and inflammation.

Gestational diabetes: High blood glucose during pregnancy, disappear after pregnancy

Development of insulin resistance based on “lipid burden” hypothesis (all related metabolic
pathways involved)

Obese individuals with metabolic syndrome lead to diabetes type 2 as 80% of type 2 diabetics
are obese, but a minority of obese people have diabetes. As well as inability to deposit TAG
leading to high FA in blood leading to organs losing sensitivity to insulin.

Stages: Lean person balanced, overweight person has increased intake than breakdown.
Pro-inflammatory state - Enlarged adipocytes release MCP1 attracting macrophages in the
Chronic inflammation stage. Macrophages in adipose tissue produce TNF favoring export of FA

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going to muscle and deposit where ectopic lipid interferes with GLUT4 producing the insulin
resistance.
Pathways:
→ Glycolysis (down) → Glycogenesis (down)
→ Lipid metabolism (up) → Anaerobic (up)
→ Gluconeogensis (up)

Long term effects of increased blood glucose levels.

→ Proteins become glycosylated (mostly at Amino acids)

→ Hemoglobin having free AA during formation will bind glucose to erythrocytes, which
compromises O2 delivery, mostly in extremities.
→ Increased risk of CVD, renal failure, damage to BV & nerves.
Normally blood glucose is determined after hours of fasting.
→ High = 126 or higher, warning for diabetes
→ Low= 50 or lower (men) (40 for women) warning for hypoglycemic condition
→ After meal typically = 145 mg/100mL

Complications of Diabetes:
Microvascular:
● Eye - BP can damage eye BV causing retinopathy, cataracts and glaucoma
● Kidney - High BP damages small BV resulting in nephropathy
● Neuropathy - Damages nerves resulting in pain or numbness getting infected.
Macrovascular:
● Brain - Increased risk of stroke, cognitive impairment
● Heart - High BP and insulin resistance lead to CVD
● Extremities - Narrowing of BV lead to lack of blood flow leading to swelling.

Treatment methods of diabetes (drugs, lifestyle modifications, surgeries)

Treatment differs for each targeting and effect

Weight loss → Adipose tissues reduce → Reduce lipid burden, restore insulin sensitivity

Exercise → AMPK increase → Aids weight loss

Bariatric surgery → Unknown → Leading to weight loss and better control of blood glucose

Sulfonylureas → Pancreatic cells, K channels block → Stimulate insulin secretion

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Biguanides → AMPK activated → Increase glucose uptake by cells

Thiazoladinediones → PPAR-gamma → Stimulating genes to activate insulin production.

GLP-1 → Glucagon like peptide 1 → Enhance secretion by pancrease

Irisin → Shivering/exercise of muscle lead to circulation in the body → Browning of adipose,

meaning more heat less ATP.

Colloq questions for all:

Hormone H1 → Leptin
Hormone H2 → PYY3-36
Hormone H3 → Ghrelin Hormone
H4 → Insulin
Hormone H5 →
Proopiomelanocortin (POMC)
As the result (R1) appetite will →
INCREASE The brain region that
ensures the regulation of appetite
is called → Hypothalamus In case
of regular physical activities H1
concentration will →DECREASE

2. Describe dominating metabolic pathways in adipose tissues

during absorption and postabsorptive phase.
Answer: Absorptive Phase:
Lipogenesis: Glucose → Fatty Acids (FA) → Triglycerides
(TAG). Stimulated by insulin, which also enhances
glucose uptake.
Enzymes like acetyl-CoA carboxylase and fatty acid
synthase are active.

Postabsorptive Phase:Lipolysis: TAG → Glycerol + Free

Fatty Acids (FFA). Triggered by lower insulin and higher
epinephrine and glucagon.FFA used for energy; glycerol supports gluconeogenesis.
Adipokines like leptin regulate energy balance.

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Molecule M1 → Oxaloacetate Molecule M3 → Citrate Molecule M5 → Pyruvate Metabolic

process P1 → Lipid synthesis Metabolic Process P2 → Glycolysis Cofactor marked with A →
NADPH
GLUT expression in cancer cells → INCREASE
Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a new group of
oral medications used for treating type 2 diabetes. The drugs work by
helping the kidneys to lower blood glucose levels. SGLT2 inhibitors work
by preventing the kidneys from reabsorbing glucose back into the blood.
This allows the kidneys to lower blood glucose levels and excess glucose
in the blood is removed from the body via urine.
a) how would diuresis change for persons taking this drug, explain your
answer
b) Propose benefits of this therapy. Mention and explain three aspects.
Answer: a) Diuresis would increase as the blocking of reabsorbtion of
glucose through the kidney would increase it in the urine and thus
through osmosis increase the water going out and require more water.
b) Improved glycemic control, no more high blood glucose at rest. Weight loss as glucose exiting
the body leads to less calories. Less insulin resistance as the less glucose available it will lead to
adapting to small quantities.

Would these drugs be suitable for type 1 diabetes mellitus? Explain your answer,
Answer: This would not work as it would lead to lower glucose concentration while the Diabetes
typ1 has insulin production problems meaning lower glucose concentration would just make it
less available and lead to acidosis as the body wants more energy.

Explain how fasting blood sugar level would change in case of insulin resistance. Mention three
tissues that influence that, for each tissue mention corresponding metabolic pathways and
explain how blood sugar level is affected. Explain how this blood sugar level affects health.
Answer:
Liver→ Would not stop releasing glucose due to impaired signalling and thus there would be
more glucose in the blood as it is not taken up.
Muscle → Not taking up the glucose leading to increased concentration of glucose outside.
Adipose tissue → Breaks down even more fats and worsens the uptake as it interrupts the uptake
of glucose by cells and thus also contributing to the higher glucose concentrations in the cell.

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 ‫القائد ابو عبيدة‬

Liver Metabolism
Functions of the liver
● Metabolism - Lipids, Carbohydrates, Amino acids
● Production - To the blood
● Endocrine - Hormone metabolism
● Exocrine function - Bile
● Storage - Vitamins, iron, minerals, glycogen, fat
● Detoxification - Toxins, hormones, ammonia,
xenobiotics
● Trash can - Phagocyte cells removing old substances.

Bile acid production: Mostly consists of water, salts,

cholesterol, bilirubin and lecithin.
0.2-0.6 g Bile salts synthesized per day. Storage in the human
body is 2-4 g.
Function - Emulsify TAG from diet and get rid of toxins

Metabolism of carbohydrates in liver and related pathologies

(list and interconnections between all relevant metabolic pathways).

The liver controls glucose homeostasis including the distribution of glucose to the blood and
their energy use. Pathways included:
→ Glycolysis → Gluconeogenesis → Glycogenolysis
→ Glycogenesis → PPP → Fructose metabolism
→ Galactose metabolism

Pathologies:
Fructose:
● Fructokinase deficiency, often symptomless. Detected with high fructose in the urine, No
treatment except some diet constriction but not required.
● Aldolase B deficiency - Fructose-1-P accumulate in hepatocytes leading to liver toxicity,
low blood sugar, uric acid accumulation as well as lactic acidosis. Treatment is dietary
management.
Galactose:
● Galactokinase deficiency - Lead to cataract formation (galactitol) in the eye as well as
galactosuria (galactose in urine). Treatment is strict diet

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 ‫القائد ابو عبيدة‬

● Galactose-1-P-Uridyltransferase - leading to galactosemia, galactosuria, hypoglycemia,

cataract formation, uric acid accumulation. Treatment is a strict diet as it is really toxic.

Glycogen:
Not required to know by heart

● Glycogenolysis disease leads to not mobilizing energy when needed, symptoms can be
fast fatigue after small amounts of exercise.
● Glycogenesis disease can be seen in a person with low blood glucose, enlarged liver,
elevated FFA and acidosis because of increased lactate production as a result of the
patient not having energy reserve.
Glucose:
● G6PD deficiency - important for PPP symptoms lead to increased oxidative stress and
require vitamins and antioxidants often.
Other glucose deficiency are very rare and often lead to severe symptoms not like any other as
ATP is vital when it comes to glucose metabolism.

Colloq questions:
1. A 25-year-old patient is admitted to the hospital with symptoms of severe abdominal pain,
vomiting, and hypoglycemia. The patient mentions a family history of similar symptoms.
Laboratory tests indicate elevated liver enzymes and mild jaundice. Further inquiry reveals that
symptoms often occur following consumption of sweetened foods and fruits. What carbohydrate
is involved? How could this be detected?
Answer: The sweeteners and fruits point to fructose. The pathway disrupted is fructose
metabolism specifically in enzyme Aldolase B as there is acidosis leading to vomiting and
abdominal pain as fructokinase would be symptomless.
2. A 20-year-old college student is brought to the emergency room with jaundice, disorientation, and
speaking difficulties. These symptoms appeared after a fasting period followed by a meal that
included dairy products. The patient's family history is unknown. Blood tests reveal low blood
glucose, elevated liver enzymes, and abnormal liver function. The patient's urine test shows the
presence of reducing substances, but glucose is absent. What carbohydrate is affected? How is
that understood from the symptoms?

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 ‫القائد ابو عبيدة‬

Answer: Galactose as it is from dairy products and the specific enzyme would be G-1-P-UDP as
galalctokinase would not have these affects and no cataract in the eye, here we have more severe
effects on the liver and the rest of the body.

Metabolism of lipids in liver and related pathologies (list and interconnections between all
relevant metabolic pathways).

Liver lipid metabolism involves transformation of FA including breakdown or synthesis.

Synthesis of lipoproteins, ketone bodies, and retinoids all occur in the liver.

Beta oxidation: Breaks down FA in mitochondria of the liver cells to generate ATP (goes
through Acyl-CoA transporter).
Pathology: CPT deficiency leading to transport of FA into mitochondria is impaired → Swelling
and accumulation of FA as well as acidosis.

Cholesterol synthesis: Synthesis of cholesterol in different steps when there is surplus of ATP
and FA.
Pathology: Defect in enzymes lead to abnormal cholesterol synthesis thus not able to use and
store the energy (dangerous)

FA synthesis: Surplus of Acetyl-CoA leads to synthesis of FA to produce TAGs stored in

adipocytes.
Pathology: Fatty liver disease in case of excessive lipid synthesis caused by for example
alcoholics because Acetyl-CoA are not made into FA.

Ketogenesis: When there is not enough energy in the body and Acetyl-CoA are used to produce
energy.
Pathology: A person can not fast as they do not have reserve volume and thus also affects
generation of ketones to get secreted by the body.

Phospholipid synthesis: Used to make membranes for cells and build up the cell.
Pathology: Defects lead to defect in membranes, affecting bone, brain etc (dangerous)

Lipoprotein metabolism: Makes LDL,HDL,VLDL, Chylomicrons.

Pathology: LDLR receptor doesn't work leading to hypercholesterolemia, deposits of fat in the
body where it shouldn't be.

Colloquium questions:
1. Describe how a disturbance in one of the lipid metabolic pathways in the liver
could result in altered levels of liver enzymes commonly measured in clinical
practice.

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 ‫القائد ابو عبيدة‬

Answer: Disturbance in Beta-Oxidation can lead to accumulation of FFA outside

and TAG leading to stress and damage leading to higher ALT levels and AST
resulting in detection.

Metabolism of proteins in liver and related pathologies (list and interconnections between all
relevant metabolic pathways).

Metabolism of the amino acids include a variety of pathways, mostly urine, deamination and
transportation.
Amino acid metabolism: Involves deamination of aminoacid and sending it to other pathways
while the carbon skeleton is used for energy. This can also be used to break down proteins in the
body when the body needs energy.
Pathology: Phenylketonuria, disorder when phenylalanine hydroxylase enzyme stops working.
Leading to intellectual disability, toxic and neurotransmitters not produced.
Maple syrup urine disease is also a disease affecting BCAA dehydrogenase complex leading to
neurological damages.

Urea cycle: NH3 filtered out and excreted through the urine here out of the body.
Pathology: Ammonia detoxification such as ornithine transcarbamylase deficiency leading to
neurological disorder as it is in the mitochondria stage and really dangerous while the enzyme
deficiencies after are less dangerous as they are in the cytosol.

Gluconeogenesis: Amino acids can be used to make glucose when needed.

Colloq questions:
1. In the context of the urea cycle in the liver, describe a scenario where a defect in
one of the cycle's enzymes could lead to a specific pathology. Explain how this
defect impacts protein metabolism and the resulting clinical implications.
Answer: Defect in Ornithine transcarbamylase deficiency leading to accumulation
of NH3 in mitochondria and thus neurological and other cognitive disorders and
swellings.

Hormonal regulation and prevalent metabolic processes in absorption and post-absorption

period

Absorption period (Fed state), Insulin:

Pancreas secretes insulin which when interacting with liver will increase storage of energy and
uptake.
Glucose → Liver → Glycogen (Can also become fat when converted to acetyl-CoA

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Amino Acids → Build up proteins or become keto acids which become acetyl-CoA and stored
as fat. Goes through VLDL to reach adipose tissue.
Fats → TAGs get broken down and re-esterified to then also be transported by VLDL to the
adipose tissue as TAG.

Post-Absorption (fasting state), Glucagon:

Pancreas release glucagon taken up by the liver increasing breakdown of storages to make
glucose that can be used as energy by the body.
Glycogen → Glucose
Amino acids → Become ketone bodies → Fat or Become glucose through pyrivate.
TAG → Adipose tissue breaks down fat breakwaonto give FA going to B oxidation.

Functions and examples of plasma proteins: albumins, α1, α2, β and γ globulins. Main factors of
blood coagulation.

Albumins:
→ Transport protein → Oncotic pressure regulation
→ Hydrophilic → Deficiency leads to edema

Globulins:
Globular proteins with higher molecular weight than albumins are 3 categories.
Normally globulins are in the body → 26-35 g/l
● Alpha globulins - alpha 1 is retinol binding protein, thyroxine, transcortin,
transcobalamin, antitrypsin and prothrombin binding. Alpha 2 is haptoglobins
● Beta globulins - Include transferrin, hemopexin, fibrinogen, and involved in lipoprotein
formation.
● Gamma globulins - lgG, lgA, lgM, lgE, lgD, pathological proteins.

Acute phase proteins: C reactive protein which is used to determine infection in the body. They
are Alpha 1 globulins rapidly produced by the liver in response to inflammation. However, too
high means bacterial infection.

Albumin / Globulin ratio: Normal at 1.5-2 when lower → Autoimmune disease. Higher →
Genetic disorder or leukemia.

Complement factors: Part of the immune system facilitating removal of microbes and destroyed
cells. Patients with chronic liver disease typically have lower plasma concentrations of
complement factors.

Coagulation factors:

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 ‫القائد ابو عبيدة‬

→ Fibrinogen → Prothrombin
→ V, VII, IX, X, XI → Protein S,C
→ Antithrombin
All these are produced in the liver to help with blood clotting

Heme synthesis and bilirubin metabolism. Pre-, intra-, and post- hepatic jaundice;
corresponding intermediates of bilirubin metabolism found in blood, urine and feces in each
condition.

Heme synthesis: Made of porphyrin rings which is made of glycine and succinyl-CoA.
Glycine + Succinyl-CoA → Aminolevulinate → Porphobilinogen.
→ Occurs in mitochondria

Heme degradation: Heme from erythrocyte is degraded and excreted in the urine.
Heme → Biliverdin (green) → Bilirubin (yellow) (not water soluble)
→ Occur in macrophages
→ Done by P450 enzyme

Jaundice
Accumulation of bilirubin lead to jaundice which can be seen in patients with yellowing of skin
and eyeballs, it causes bile to leak to blood.
● Normal bilirubin in blood plasma - 5-25 micromol/l
Pre: Caused my increased breakdown of red blood cells. In blood there is increased
unconjugated bilirubin levels
● Urine normal just increased urobilinogen and bilirubin is absent
● Feces is normal or dark due to stercobilin
● Diagnosed when ALAT & ASAT normal and alkaline phosphatase normal.
Intra: Caused by liver dysfunction leading to elevated conjugated and unconjugated bilirubin in
the blood.
● Urine will be dark due to conjugated bilirubin
● Feces will be normal or pale
● Diagnosed when ALAT & ASAT is very high, alkaline phosphatase is high
Post: Obstruction in bile ducts such as gallstones will lead to elevated conjugated bilirubin in
blood.
● Urine will be dark due to conjugated bilirubin, with reduced urobilinogen
● Feces will be pale mostly.
● Diagnosed when ALAT & ASAT is normal or high, alkaline phosphatase is very high

Colloquiom questions:

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 ‫القائد ابو عبيدة‬

1. A patient presents with jaundice, but without pain or fever. Laboratory tests show
elevated levels of indirect (unconjugated) bilirubin in the blood and increased
urobilinogen in the urine, but no bilirubin in the urine. Fecal analysis shows
normal stercobilin levels. Based on these findings, determine the type of jaundice
(pre-hepatic, intra-hepatic, or post-hepatic) and explain the underlying disorder in
bilirubin metabolism
Answer: Pre hepatic jaundice as the elevated unconjugated bilirubin means not
taken up by the liver and the problem is also seen in symptoms such as
increased urobilinogen in urine, no bilirubin in urine and fecal analysis is normal.

Liver detoxification. Phase I: substrates (exogenous and endogenous),

main enzymes, their action mechanism, cofactors. Phase II: substrates,
main enzymes, their action mechanism, cofactors. Consequences of
disturbances in detoxification processes.

Xenobiotics: Chemicals not produced and foreign to the human body.

Phase I: Makes metabolite more polar, often inactive and can be
sufficient to excrete.
Enzymes; → CYP450 → MFO
Mostly in smooth ER or inner mitochondrial membrane
CYP450 is made of FMN and FAD, activity of this enzyme is enhanced
by exposure to their substances. For example if you eat something that can't be broken down
normally you will have an increase in drug metabolism as a result.
● Exogenous substrates: Drugs, alcohol, toxins from environment
● Endogenous substrates: Steroid hormones, bilirubin, some FA, waste products in
general.
Action mechanism: Oxidation is the most common reaction, or reduction, hydrolysis.
Cofactors: NADPH or Oxygen

Phase II: Actual detoxification step, substrates for this is from phase I detox, endogenous
compounds would be hormones and bilirubin and exogenous same which form the outside
environment.
Enzymes: → Glucuronosyltransferases (UGTs) → Sulfotransferases (SULTs)
→ Glutathione s-transferase (GSTs) → Acetylation (Acyltransferase)
Action mechanism:
● Glucuronidation - Conjugation to glucuronic acid, the most important pathway and
mostly excreted as bile, requires high energy intermediate (ATP). Works at high substrate
concentrations.

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 ‫القائد ابو عبيدة‬

● Sulfation - Conjugation to sulfate also requires ATP and is dominant at low substrate
concentrations. Basically transfers sulfate to OH group.
● Glutathione - uses glutathione which is tripeptide and conjugated by the enzyme GST to
be attacked by other metabolites to detoxify.
Cofactors:
● UDP-Glucuronic Acid
● Glutathione
● Acetyl-CoA
● Adenosylmethionine (SAM)

Colloquium question:
1. A patient on long-term medication therapy presents with signs of drug toxicity.
Blood tests show impaired liver function. The patient's medication is known to be
metabolized primarily by the Cytochrome P450 3A4 (CYP3A4) enzyme. Which
phase of liver detoxification is most likely impaired in this patient, and what could
be a potential cause for this impairment?
Answer: Phase I, specifically involving the Cytochrome P450 3A4 (CYP3A4)
enzyme. A potential cause for this impairment could be the concurrent use of
another medication that inhibits CYP3A4, leading to reduced metabolism and
clearance of the primary medication and subsequent drug toxicity.

Alcohol metabolism in liver (short and long term effects).

Alcohol metabolism pathway similar to the

lactate pathway. Both are non-oxidative
carbohydrate metabolism.

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Alcohol through peroxisome: H2O2 with Catalse → H2O. Alcohol becomes acetylaldehyde
Alcohol through Cytosol: Ethanol becomes acetylaldehyde with alcohol dehydrogenase when
NAD+ converted to NADH.
Alcohol for alcoholics in microsomes: With CYP2E1 becoming NADPH+H leaves H+ and
becomes NADP+ with water, this pathway is developed for alcoholics who have chronic abuse.

For people who don't drink or drink less they have a slower elimination rate of alcohol. For those
who are chronic drinkers.

Treatment for alcoholics: Use metronidazole, an antibiotic to block acetaldehyde

dehydrogenase thus giving you hypotension, nausea, vomiting and discomfort when just taking
in small amounts of alcohol, basically you make them hate alcohol.

Toxic effects of non-oxidative: Ethanol leads to tissue injury and signaling.

Toxic effects of oxidative: Increases ROS formation and NADH/NAD ratio.
Consequences:
● Changes in FA metabolism → High TAG
● Ketoacidosis → Low pH
● Changes in glucose metabolism → Hypoglycemia
● Lactic acidemia → NADH high leading to lactate formation
● Changes in purine metabolism → Hyperuricemia → high lactate inhibiting urate
excretion.
● Aldehyde toxicity as a result of cysteine binding to acetaldehyde.
● High ROS binding to AA, lipids, membranes, mitochondrial dysfunction.

Colloquium Questions:
1. Describe the enzymatic processes involved in the metabolism of alcohol
(ethanol) in the liver, including the enzymes responsible for both short-term and
long-term metabolic effects. How do these enzymes contribute to the
physiological effects seen with acute and chronic alcohol consumption
Answer: ADH cruicial for processing of alcohol and to make sure no
accumulation of acetylaldehyde occurs. Accumulation leads to hangover
symptoms. Cytochrome P450, needs to be more active but when not working fast
enough such as in alcohol consumption lead to oxidative stress, inflammation
and long term to chronic liver disease.

Enzymes/proteins determining liver and general health: alanine amino transferase, aspartate
amino transferase, alkaline phosphatase, lactate dehydrogenase, different forms of bilirubin,
C-reactive protein, albumins.

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 ‫القائد ابو عبيدة‬

ALAT - Lightly increased “2-5x reference”, Moderate increase “5-10x reference”, Very high
“10-50x reference”

AST - Shows liver health and elevation can show problems in heart, liver or skeletal muscles.

ALP - Enzyme in liver, bones breaking down proteins and can show when high levels higher bile
duct obstruction, liver disease or bone disorder.

Lactate Dehydrogenase - Converts lactate to pyruvate, elevated can show damage to muscle
mainly or alcohol intake.

Bilirubin forms - Conjugated shows process of liver and bile. Unconjugated shows circulation
in blood before processing.

C-Reactive protein - Inflammation response, elevated shows inflammation but too high shows
bacterial.

Albumins - Main protein for transportation and too low shows malnutrition, chronic disease or
liver problems.

Colloqiom queestions:
1. A 45-year-old patient presents with general malaise, mild abdominal pain, and a
sensation of fullness in the right upper quadrant of the abdomen. There's a history
of occasional alcohol use and a family history of gallstones. The patient's skin and
eyes have a slightly yellowish tint. No fever or significant weight changes are
reported.
Answer: ALT & AST would show liver damage to know how severe it is, the ALP
would show conjugation of bilirubin, LDH would access the tissue damage but not
so specific, Bilirubin to detect in urine if it is pre, post or intra. CRP to determine
inflammation and Albumins to detect if there are synthesis problems of
transporters.

Colloq questions FOR ALL:

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Molecule M4 → Acetyl-CoA
Molecule M5 → Glycogen Metabolic process
P2 → Gluconeogenesis Metabolic process
P9 → TAG synthesis / lipogenesis
Number 2 in the scheme represents → Low Density lipoprotein Name hormone
represented with
H2 → Insulin

Which pathways are impaired in case of vitamin B7 deficiency?

Answer: FA synthesis as it requires acetyl-CoA carboxylase, Amino acid catabolism,
Gluconeogenesis

2. Together with a meal often various drinks are used. Red wine contains up to 12% of
alcohol and among other constituents coming from grapes and fermentation,
resveratrol that is considered to be an antioxidant. Describe fate of these two molecules
in our liver, mention process or enzymes, cofactors that would be using these
molecules.
Answer: Alcohol from red wine is metabolized in the liver primarily by the enzyme
alcohol dehydrogenase (ADH), converting it to acetaldehyde, with NAD+ as a cofactor,
which is then further metabolized to acetate by aldehyde dehydrogenase (ALDH).
Resveratrol, also found in red wine, undergoes metabolism in the liver where it can be
modified by phase I enzymes, such as cytochrome P450s, and is then conjugated in
phase II reactions, often involving glucuronidation and sulfation for increased solubility
and excretion. While resveratrol is an antioxidant and may have health benefits,
excessive alcohol intake can lead to liver damage and may negate the potential benefits
of resveratrol.

a. Glucose uptake in muscle cells →

DECREASE
b. Glycogen synthesis in muscle cells →
DECREASE

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 ‫القائد ابو عبيدة‬

c. Glucose uptake in the liver → DECREASE

d. Gluconeogenesis → INCREASE
e. Hepatic glucose production → INCREASE
f. Lypolysis in adipose tissues → INCREASE
Which pathway is marked with C in the scheme? → Gluconeogenesis
What is marked with B in the scheme? → Glycogen

Gilbert Syndrome is a mild genetic liver disorder. Individuals with Gilbert syndrome have
elevated bilirubin (hyperbilirubinemia) following stress, exertion, dehydration, alcohol
consumption, or infection. In some individuals, jaundice may only be apparent when triggered by
one of these conditions. Observe blood analysis of a Gilbert syndrome patient after highly
stressful week of studies.

Analysis | Result | Reference value

● Urea: 5.4 | 2.5-8.5 mmol/L

● Creatinine: 69 | 55-110 umol/L
● Total protein: 71 | 63-82 g/L
● Albumin: 39 | 34-44 g/L
● AST: 38 | 10-40 U/L
● ALT: 70 | 5-40 U/L
● LDH: 137 | 120-250 U/L
● Direct (conjugated) bilirubin: 2.1 | <5 umol/L
● Indirect (unconjugated) bilirubin: 31.1 | <28 umol/L
● Total bilirubin: 33.3 | <21 umol/L

Propose which process is disturbed in individuals with Gilberts syndrome. (2p)

Has the affected enzyme lost its activity completely? Explain your answer. (2p)

Compare symptoms of Gilberts syndrome and sclerosing cholangitis (causes subhepatic bile
duct obstruction). Make three comparisons (6p)

Answer: The process disturbed is the Conjugation of bilirubin as a result of reduced

activity of the conjugation and leads to unconjugated bilirubin released in the urine. The
enzyme has not lost its ability completely as seen because there is still conjugation
occurring and not too much deviation for the unconjugated bilirubin. The symptoms of
Gilbert syndrome and bile duct obstruction differ as the bile duct obstruction is more
severe, cause worse jaundice, as well as potential liver damage which can be chronic.

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Metabolic aspects of oncological disease

General definition and causes of cancer. Cancer hallmarks.

Cancer: Disease characterized by occurence in abnormal function and uncontrollable

proliferation. This can be caused by DNA damage, abnormal proliferation, as they usually result
from accumulation of damages in DNA. Causes can be exogenous and endogenous amongst
them factors such as:
→ Genetic → Environmental
→ Lifestyle → Infections
→ Age → Random mutations
Cancer hallmarks include:
→ Sustaining proliferative signaling → Activating invasion & Metastasis
→ Evading growth suppressors → Deregulating cellular energetics
→ Resisting cell death → Avoiding destruction
→ Enabling replicative immortality → Inducing angiogenesis
(10% of cancers are mutation acquired from parents)

Types of oxidants (ROS, NOS)

ROS: Reactive oxygen species including OH*, LOO*, O2*. Have unpaired electrons thus
violently reactive. Which can be caused by endogenous and exogenous factors.

NOS: Nitric oxide synthase enzyme responsible for producing Nitric oxide critical for
physiological but also pathological processes in transmission, immune system and regulation.

Types of antioxidants (enzymes and non-enzymes; endogenous and exogenous).

Antioxidants: Molecules decreasing oxidative stress and inhibiting enzymes involved in ROS
production.
● Endogenous antioxidants: Superoxide dismutase (SOD), Se-GPx
● Exogenous antioxidants: Beta carotene, Vitamin C, flavonoids, Vitamin E. Can be found
in fruits and vegetables
Non-Enzymatic antioxidants - Endogenous include glutathione, uric acid, Coenzyme Q10.
Exogenous will be Vitamin C, Vitamine E.

Environmental factors contributing to cancer development (obesity, red meat, salt, alcohol), their
mode of action

Obesity
Obese people have excess energy from food leading to stocked adipose tissue and saturation of
ånot only adipose tissues but also other peripheral extremities and tissues such as muscle, liver
and heart. This leads to inflammation and increases the risk for chronic disease and cancers in
most parts of the body. As obesity leads to insulin resistance, sugar forms glucocorticoids.
Changes in hormone profiles also indicate higher risk for cancers, such as high estrogen leading
to breast cancer.

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IGF-1 which is insulin like growth factor becomes inhibited leading to inhibition of apoptosis →
cell proliferation and damages the DNA and cells.

Red meat
The recommendation is less than 500 grams per week, the way it is connected to cancer as
depending on the denaturation of the proteins such as boiling, grilling etc, this leads to formation
of heterocyclic amines and with presence of heme iron in red meat lead to N-nitroso compounds
which are carcinogenic and can develop tumors.

Salt
90% of stomach cancers are attributed to Helicobacter pylori which is a bacteria accumulating in
the lower part of the stomach leading to inflammation of ulcer leading to cancer as they secrete
Cag A protein which is cancerogenic.

Alcohol
Consumption of alcohol lead to major intake of acetaldehyde disrupting DNA synthesis and
DNA repair as well as makes it easier for molecules to cross membranes (which shouldn't be
there). So alcohol affects by:
→ Increasing toxic metabolites
→ Enhance membrane crossing
→ Increase ROS formation
→ Changes endocrine metabolism

Environmental factors preventing cancer development (fruit and vegetable consumption;

physical activity); daily recommendations.

Fruit/Vegetables:
Include:
→ Carotenoids → Vitamin C → Dietary fibers
→ Folate (B9) → Vitamin E → Phytoestrogens
Recommended to decrease risk of cancers because they include antioxidants and antiproliferative
activities. The antiproliferation occurs as microflora fermentation in colon lead to dietary fibers
transform to short chain fatty acids. Exception - Vitamin B1 which is fungi.

Physical activity:
Decreases risk of cancer by:
● Reducing insulin resistance decreasing fasting level insulin and degrease IGFs
● Stimulate digestion reducing transit time in intestine leading to less inflammation
● Aerobic exercise decreases oxidative stress (ROS)
● Weight loss decreases obesity and risk accompanied with it.
● Improve immune response

Recommended activity is 150 min of moderate physical activity or 75 minutes of intensive

workout.
Recommended vegetables are 400 grams of vegetables or fruit per day for overall health
benefits. Tabbouleh included.

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 ‫القائد ابو عبيدة‬

Role of multi drug resistance and drug-drug interactions in cancer treatment (the role of the
most common enzymes and transporters affected). Importance of food drug interactions in
cancer treatment.

MDR - Multidrug resistance: Resistance of an organism to at least one drug in a treatment.

DDI - Drug-Drug interaction: When one drug inhibits another in treatment (Competitive).

Role of using a lot of drugs is that cancer pathologies are complex and require a combination to
combat the symptoms and kill the cancer.
Most common proteins involved in MDR and DDI are:
● CYP & UGT (MDR) which are metabolic enzymes
● SLC & ABC (DDI) which are membrane transporters for influx and outflux.
An example of drugs used to combat solid organ cancers is 5FU (5-fluorouracil) where mostly
is converted in the liver to be degraded and eliminated by DPD. The rest of 20% is active by
other enzymes of uracil to UH2. But if DPD is inactive leading to high 5FU accumulation and
toxicity than the drug can not be used.
Recommendations are thus: Do phenotype and measure U/UH2 ratio.

Irinotecan: Used in digestive cancers which is prodrug to be activated in the liver ensured by
UGT1A1 but if polymorphism exists (28) lead to UGT dysfunction and high toxicity.

CYP modulators:
Many drugs against cancers are substrates for CYP. However CYP has regulators
→ Caffeine inhibits CYP1A2 decreasing action
→ Tramadol & Oxycodone inhibit CYP2D6 decreasing action

Food-drug interaction: Phytocemicals can modulate activity of CYP or ABC transportes which
are responsible for drug clearance. After food intake when inside the bloodstream and can lead to
inhibition of cancer drug treatments leading to high toxicity while synergic effects such as herbal
medicine can also have that but are unlikely and random.
Difficult to studies as most is done in labs and with high concentrations while in the body more
diversity occurs.

Transporters:
Various enzymes such as UGT and CYP are
involved in DDI and MDR which can happen
in the following way: Drug enters under the
outer membrane and enters enzyme. The
protein transporters ABC and SLC are
important for transportation thus impairment
can lead to toxicity.

Colloquium questions:
1. A 58-year-old patient with a history of colorectal cancer, treated with a
combination chemotherapy regimen, reports new dietary changes including
increased red meat consumption and decreased physical activity. Considering

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the factors affecting cancer development and treatment response, address the
following. How can this affect the treatment, and why?
Answer: The patients' changed diet leads to higher accelerated cancer
progression as well as the decreased physical activity leads to higher risk of
inflammation and ROS leading to damage to the DNA and tissues in the body. For
the treatment the CYP450 in the ETC would be affected and not metabolize the
drugs as efficiently leading to toxicity.
2. A 45-year-old individual with a genetic predisposition to cancer (BRCA1 mutation)
follows a lifestyle characterized by high alcohol consumption, low physical
activity, and a diet rich in processed foods and red meat. Recently diagnosed with
early-stage breast cancer, the patient is prescribed a chemotherapeutic regimen
known to be susceptible to P-glycoprotein-mediated drug resistance. Discuss the
multifaceted risk factors in this patient's cancer development and potential
challenges in treatment, considering the interplay of genetic predisposition,
environmental factors, oxidative stress, and multi-drug resistance mechanisms.
Answer: Genetic predisposition puts the patient at risk in combination with the
lifestyle increasing this risk such as alcohol leading to higher ROS and toxicity,
the low physical activity takes away the benefits of lesser risk of inflammation,
damage to DNA and lead to less metabolism of toxic waste in the body. The
treatment challenge lies in that the patients predisposition for metabolism of
xenobiotics can lead to toxicity in the body and thus part of the defense
mechanism in combination with drugs would not treat the patient but could kill
them.

Colloq questions for all:

1. Cancer cachexia is a syndrome developed by many cancer patients characterized by anorexia
and a progressive loss of adipose tissues and keletal muscle mass. Cancer cachexia is
characterized by systemic inflammation, negative protein and energy balance, and an involuntary
loss of lean body mass. One proposed mechanism of cancer cachexia is that it is an integrated
physiological response of substrate mobilization driven by inflammation. Propose three
molecules that would be in elevated levels in such patients, explain your choice of molecules.
Answer: Cortisol would be increased as it is main hormone stimulating gluconeogenesis and
breakdown of proteins. Epinephrine would also be elevated as it is the body’s reaction to stress
as well as stimulate glycogenolysis and lypolysis. Acetyl-CoA would be higher as it is product of
breaking down fats and to transform in ketogensis to use for energy.

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Marked with A → Lacrate

Marked with B → Glut 3
Marked with C → Glutamate
Enzyme E1 → Lactate dehydrogenase
Metabolic process P1 → Glucose

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Metabolic syndrome
Criteria for metabolic syndrome, type II diabetes, obesity, hypertension, dyslipidemia and global
prevalence of these conditions

Metabolic syndrome:
Diagnosed in patients when Abdominal adiposity (>94cm men, 80cm women) or BMI is over
30kg/m^2 + 2 of the following criterias:
● Elevated TAG - >1.7 mM
● Low HDL-Cholesterol - <1.03 mM (men), <1.29 mM (women)
● Hypertension - >130/>85 mmHg BP
● Elevated fasting glucose - >5.6 mM or Type 2 Diabetes

Global prevalence:
Children → 2.8%
Adolescents → 4.8%

20-25% worldwide with metabolic syndrome.

Pathophysiology of type II diabetes / development of insulin resistance

Start: Insulin resistance occurs as a result of multifactorial risks such as genetics for diabetes, or
acquired traits such as obesity or inactivity. Others can be hormonal disorder, prolonged steroid
hormone or cortisol, or abnormal degenerative conditions of adipose tissue. All these risks
develop insulin resistance which increases the Beta cell insulin productive cells in the pancreas
to compensate.

Intermediate stage: beta cells stress and dysfunction and fatigue as they can not keep up with
the demand. Leading to rising blood glucose levels and continued insulin resistance.
Beta cell dysfunction can also be a result of disposition by genetics, or glucotoxicity, or
lipotoxicity.

End stage: Beta cells loss, increased blood sugar leading to impaired glucose tolerance and
insulin deficiency secretion as well as uptake of glucose amongst other actions of insulin.

Insulin effects in various metabolically active tissues.

In Muscle:
● Increased glucose uptake (GLUT 4 translocation)
● Increased glycogen synthesis
● Increased protein synthesis & less degradation
● Increased potassium uptake
● Stimulation of uptake for ketone bodies
Liver:
● Decreased glucose uptake
● Decreased formation of ketone bodies

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● Increased lipid synthesis

● Increased protein synthesis & less degradation
Adipose tissue:
● Increased glucose uptake
● Inhibition of lipolysis
● Stimulation of lipoprotein lipase to take up FA
● Increase potassium uptake

Insulin on GLUT4 works by translocation GLUT4 vesicles to the surface making more glucose
transport into the tissues.

Methods for estimating insulin sensitivity / resistance (OGTT, IVGTT, Hyperinsulinemic clamps,
glucose infusion rate, glucose clearance rate)

Methods for estimating insulin sensitivity:

Oral glucose tolerance test: Inject patients with glucose in mouth and measure the
concentration in the body throughout time as well as the insulin to see how much insulin per unit
of glucose.

Intravenous glucose tolerance test: Inject glucose directly to blood to and measure
concentration with time as well as insulin which is then compared to a person with type 2
diabetes would show low insulin secretion as the pancreas reached fatigue or dysfunction.

Hyperinsulinemic clamp: Works by pumpkin in insulin and glucose at the same time but
different rates to measure the amount of insulin required to ratio of glucose to bring it back.
Lower glucose requirement means better sensitivity.

Glucose infusion rate: Used in combination with training to see the comparison when a person
is training how much of the infused glucose will be cleared expressing how effective the insulin
works.

The effect of training on skeletal muscle, different types of exercise modalities

Insulin sensitivity: Increased in trained skeletal muscles and clears glucose much faster,
however this must be uphelt with training and not stop training. This applies for aerobic /
endurance training as well as strength training and HIIT. The effects occur as a result of protein
mechanisms central in the signaling cascade work more leading to higher insulin sensitivity and
work. This is also because the muscle and body deplete the glycogen and build it up again.

The effect of training on obesity.

Obesity is defined as overweight and saturation of adipose tissues leading to arthritis, decreased
fertility, cancer, type 2 diabetes. CVD, hypertension etc. Therefore exercising to decrease the
amount of stored fat and glycogen not only increases the insulin sensitivity helping type 2
diabetes but also makes you lose weight decreasing the chances of dying early, having a hard

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life, and everything miserable associated with it. However for obese people they should also
include diet restrictions.
The effect of training on dyslipidemia.

Dyslipidemia is elevated bad cholesterol and lower of the good cholesterol as well as elevated
TAG and overall cholesterol. Exercising would lead to:
→ Cholesterol decrease 2%
→ HDL increase 3-5%
→ LDL increase 1-5%
→ TAG decrease 10%
In this case the exercise would help some however the most effective would be pharmacological
treatment with Statins.

This leads to more drastic changes:

→ 16-46% decrease of cholesterol
→ 21-60% decrease of LDL
→ 3-16 % increase of HDL
→ 6-53% reduced TAG
Conclusion is exercise has mino effect.

The effect of training on hypertension.

Aerobic training: Can help decrease the blood pressure by:
→ 5-6 mmHg Systolic → 3-4 mmHg diastolic

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Colloq questions:
1. A 48-year-old patient with metabolic syndrome, characterized by central obesity,
hypertension, elevated fasting glucose, and a high triglyceride-to-HDL ratio,
expresses concern about developing type II diabetes. They are seeking advice on
an exercise regimen. You decide to use an advanced approach to assess and
tailor their exercise program. Explain with method you would use to determine
this and what potential treatment would you prescribe to combat this?
Answer: Assessment would be done using the different test to test for insulin
sensitivity and then design an exercise program to increase the insulin sensitivity,
combat the high TAG and also in case of too high TAG or low HDl give statins
drug.

Observe blood lipid panels from a group of persons.

(M - males, F - females) that were diagnosed with
metabolic syndrome.
a. Name the factors why doctors gave these persons
such a diagnosis. How many factors should be
elevated for a person to be diagnosed with metabolic
syndrome?
b. Choose two measurements that are elevated,
explain how we get this molecule/particle in the
bloodstream, mentioning tissues and pathways that
are producing them.
c. Most of the people studied were taking stains.
Explain what is the purpose of this drug, where it
works and what health benefits are expected while
using it

Answer:
a) Metabolic syndrome is diagnosed when the person has Obesity/High waist
circumference + 2 more factors as seen most patients have that.
b) TAG is elevated as more fats are consumed in food and build up the storage and
release, this is done with VLDL which transports out the fats. The increased Glucose is a
result of the decreased uptake meaning insulin resistance is also a factor which can be
considered for type 2 diabetes.
c) The statins are expected and help with lowering cholesterol levels mostly LDL and
increase HDL. This is done by inhibiting HMG-CoA reductase which is important for the
cholesterol synthesis leading to slowed progression of atherosclerosis.

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