BIOCHEMISTRY

METABOLIC INTEGRATION I
Dr. Milagros U. Magat | April 30, 2019 LE6 TRANS7

I. CASE 1
 Semi starvation → lowers blood glucose and increase hepatic
CASE INFORMATION insulin sensitivity before any weight loss occurs
Shakee Jolly Bels, a 30-year old female employee, came to you for  Dietary restriction and weight loss: major drivers of
consult as she has decided to have a healthier lifestyle henceforth. improvements in glucose homeostasis after bariatric surgeries
Body weight = 150 kg, Height = 1.65 m
Elevated blood sugar, VLDL, LDL levels Potential Mechanisms
BP = 160/100, BMI = 55.1  Enhanced incretin effect and GLP-1 secreting cells
QUESTIONS  Incretin effect is the ability of glucose to stimulate insulin
secretion when delivered via the GIT as opposed to directly
QUESTION 1: Evaluate the value of bariatric surgery in SJB by
into circulation
applying molecular mechanisms in her case.
 Under the influence of intestinal secreted incretin hormones
 Causes weight loss by restricting the amount of food that the
like GLP-1 and GIP.
stomach can hold or causing malabsorption.
 Assumption: Bariatric surgery compromises the ability to
 Severe obesity cases: alters the path of food through the
regulate the rate of gastric emptying that results in increased
stomach and the upper region of the small intestine
rate of nutrients reaching the distal small intestine where these
hormones are secreted.
Roux-en-Y Gastric Bypass (RYGPB)
 GLP-1, GIP, and glucagon receptors induced superior
 stomach is reduced to a small pouch attached to the esophagus,
effects on weight loss and type 2 diabetes remission
and the middle part of the small intestine (jejunum) that would be
 Increased circulating Peptide YY (PYY) levels
directly attached to the pouch
 Secreted by L cells in combination with GLP-1 and is (-) on
 food would bypass the stomach and the duodenum, passing only
insulin secretion.
the “Roux limb” of the intestine
 Success of surgery is attributed to its cleaved form PYY3-36
 significant weight loss (as much as 5 lbs/week) and would feel
induces satiety by acting on Y2 receptors located in the
less hungry
hypothalamus.
 also done for blood glucose regulation of Type 2 DM patients
 Potential contributions include increased satiety and weight
loss, improved glucose tolerance, increased postprandial
insulin secretion and increased intestinal hyperplasia
 Increased bile acid levels, which were correlated to
increased GIP levels
 Thought to increase glucose tolerance
 Bile acid receptor TGR5 binds bile acids, which activates
deiodinases that increase energy expenditure by converting
thyroxine (T4) to triiodothyronine (T3)
 Active thyroid hormones increase metabolic rate of the body,
thus increasing energy expenditure and decreasing storage of
glucose/TAGs

QUESTION 2: Using your knowledge of biochemical concepts,

prescribe SJB pharmacological and non-pharmacological
interventions to aid her on her journey to a normal BMI, BP,
blood sugar, VLDL, and LDL.
Figure 1. (R) Normal GIT, (L) After RYGBP  According to Lehninger, the body can deal with an excess of
dietary calories in three ways:
Vertical Gastric Sleeve Surgery 1. convert excess fuel to fat and store it in adipose tissue,
 Newer 2. burn excess fuel by extra exercise, and
 Yields same results 3. “waste” fuel by diverting it to heat production
 The biochemical and physiological bases for these effects are not (thermogenesis) by uncoupled mitochondria
well understood, but presumably include changes in peptide
hormone signaling that result from rerouting food through the GIT Pharmacologic interventions
 Appetite suppressants
 HMG-CoA reductase inhibitors (Pravastatin, Atorvastatin),
fibric acid derivatives and Ezetimibe
 **Tested on mice: Drugs that target PPARδ is a potential
target for drugs to treat obesity
 PPARδ (acts on liver and muscles) and PPARβ  key
regulators of fat oxidation which act by sensing changes in
dietary lipid.

Non-Pharmacologic Interventions
 Caloric Restriction
 Reduction in: dietary fat, sodium, refined Sugars
 Intake of Cholesterol Lowering Food
 Almonds and Nuts: healthy unsaturated fatty acids
Figure 2. Major factors and pathways involved in the beneficial effects of bariatric
surgery [American Diabetes Association]  Lowering cholesterol levels by reducing cholesterol
reabsorption in the intestine
L.E. # 6 - Trans # 7 Group T: Trinidad, Y., Triviño, Tuazon, Ursulom, Valeros 1 of 12
  Reduce oxidation of LDL-cholesterol which could possibly
block arteries
 Avocados and Fish
 antioxidants that scavenge free radicals and inhibit lipid
oxidation
 Fish/fish oil is rich in omega-3 polyunsaturated fatty acids
 Immunosuppressant, anti-inflammatory effects, increase
erythrocyte deformability, reduce platelet aggregation and
monocyte adhesion, lower blood pressure, plasma TAGs,
and LDLs, etc.
 Green Vegetables and Fruits
 Fruits: accumulate antioxidant components
 Monitored program of aerobic exercise (30mins-1hr, 3-5x/week)
 Weight loss
 Avoidance of excessive alcohol intake
 Cessation of smoking
II. CASE 2 Figure 3. Mechanism of Action of PCSK9 [Lambert G. Et al]

CASE INFORMATION III. CASE 3

NotSo Jolly Bells, the cousin of Shakee, is a 30 y/o male employee
who sought consult because his cousin encouraged him to do so. CASE INFORMATION
NJ’s body weight = 78kg, height= 1.65m; BP = 120/80. He is Kitty Hello There, a 25 year old medical student who decided to
diagnosed case of type 2 diabetes mellitus. He has normal blood adopt a healthier lifestyle. Body weight = 65 kg, height = 1.52m,
sugar, elevated VLDL and LDL. He takes statin regularly but could BP = 120/80, blood sugar and lipid profile normal, goal weight to
not comply with lifestyle modification. On history, his father and lose is 15kg in 3 months. Kitty is evaluating the value (safety,
grandfather had MI (myocardial infarction) and underwent coronary efficacy and sustainability) of Ketogenic Vs Atkins diet.
arterial bypass graft (CABG). QUESTIONS
QUESTIONS QUESTION 1: Compare and contrast the components of
QUESTION 1: Evaluate the value of bariatric surgery in NJ, is Ketogenic Vs Atkins diet.
it helpful to him? Why or why not?  Ketogenic Diet
 Bariatric Surgery  Characterized by marked reduction in carbohydrates and
 Procedure for weight loss by restricting amount of food the a relative increase in proportions of proteins and fat.
stomach can hold, causing malabsorption of nutrients  A diet with a fat to carbohydrate and protein ratio of 4:1 or
 Causes weight loss → reduce the risk of GERD, heart 3:1 kcal
disease, hypertension, severe sleep apnea, stroke, and  Atkins Diet
type II DM  Restricts intake of carbohydrates and give emphasis on
 Usually an option for people with a BMI of 40 or higher, proteins and fat.
people with BMI of 35 to 39.9, and weight related health  Change an individual’s eating habits for weight loss and
problem or if the efforts to lose weight with diet and for improvement of certain health problems.
exercise have been unsuccessful  It has 4 phases:
Table 1. Advantages and Disadvantages of Bariatric Surgery  Phase 1 (Induction) - restricts to not more than 20g of
ADVANTAGES DISADVANTAGES carbohydrates a day, which can be sourced from dark,
Produce significant long term Surgery may result to leafy vegetables
weight loss complications  Phase 2 (Balancing) - begin to incorporate more nuts,
Restricts the amount of food Can lead to long-term low-carbohydrate vegetables, and small amounts of
that can be consumed micronutrient deficiencies (e.g. fruit until you’re 10 pounds from your goal weight
Vit. B12, Fe, Ca, Folate  Phase 3 (Fine tuning) - You can add more
Post-bariatric surgery can Requires adherence to dietary carbohydrates until you reach your goal weight, but you
improve patient’s health by recommendations, life-long must cut back if weight loss stops
obtaining weight loss, and supplementation, and follow-  Phase 4 (Maintenance) - Consumption of high-fiber
improved VLDL metabolism up complications carbohydrates to maintain weight
and insulin sensitivity Table 2. Summary of Ketogenic and Atkins diet
COMPONENTS KETOGENIC DIET ATKINS DIET
 Given that the patient only has a BMI of 28.65 kg/m , 2
Proteins Adequate protein No limit
bariatric surgery may not be helpful for him.
Ketosis Body is in ketosis Body is in ketosis
the entire duration of ONLY in phase one
QUESTION 2: Given his persistent dyslipidemia, how can the diet and two
PCSK-9 inhibitors benefit him? What are the molecular Carbohydrate Always limited (10- Eventually
mechanisms of these meds? 30g) to induce reintroduce back
 PCSK-9 inhibitors reduce the degradation of LDL receptors ketosis into the diet
 By keeping LDL-R in circulation, LDL clearance is increased Other sources of Can eventually add
from blood nutrition back to the diet as
 Therefore, PCSK-9 inhibitors help patients manage quinoa, oatmeal,
dyslipidemia. and fruit

QUESTION 2: Evaluate the safety profile as to the long term

effects with regards to the brain, liver, kidney, etc.
 When glucose has been fully depleted, the body begins to
use fat as its primary fuel. The liver produces ketone bodies

Biochemistry Metabolic Integration I 2 of 12

 from fat, which can accumulate in the blood and will result to
ketosis.
 Healthy individuals experience mild ketosis during periods of
fasting and strenuous exercise. Excessive ketone bodies can
produce dangerously toxic level of acid in the blood, called
ketoacidosis, altering blood pH to acidotic state.
 Ketogenic Diet
 Weight loss is due to water loss (diuretic effect) followed
by fat loss
 ↓ serum triglycerides, ↓ total cholesterol, ↑ HDL
 May show short term effects in improvements in sugar
levels for type 2 DM and CVD risk factors such as obesity
 Adverse effects include:
 Muscle cramps, bad breath, changes in bowel habits,
keto-flu and energy loss
 Long term: hepatic steatosis, hypoproteinemia, kidney
stones, and vitamin and mineral deficiencies
 Atkins Diet
 Lipolysis results in ketones production
 Ketosis is triggered and appetite is suppressed
 Fatigue and constipation may occur
 Can lead to osteoporosis when relying on too much
saturated fat
 Can also cause electrolyte imbalance, decreased muscle
mass, and weakened bones
QUESTION 3: What can you advise Kitty on her immediate
goal?
 The rate of weight loss is directly proportional to the
individual’s energy intake and expenditure. Therefore,
reduction of caloric intake should be the main focus of her
diet.
 To implement a successful dietary intervention, she must
know the significance of:
 Eliminating all caloric beverages and processed foods
 Portion control
 Self-monitoring
 Adopting a healthy, long term approach to eating.
 Since her goal is to lose 15 kg (33lbs) in 3 month, it is not
ideal because the healthy weight loss is 1-2lbs only. That
is 24lbs maximum for 3 months.
 Kitty should understand that gradual weight loss is the key
for a healthier life
IV. CASE 4
CASE INFORMATION
Jyllo G. a 40-year old male employee has been diagnosed to have
T2DM and prescribed metformin as well as lifestyle modification. JG
decided to have a vegan diet and regular trip (3x a week) to gym but
refused to take metformin. After 1 month, he started to lose weight
but complained of getting tired easily. He also noticed that even with
an almost 10kg weight in 4 weeks, his capillary blood sugar soon
after waking up remains elevated.
QUESTIONS
QUESTION 1: Explain the biochemical basis why Jyllo’s early
AM blood sugar remains elevated? What causes high blood
sugar levels in the morning?
 The causes of high blood sugar levels in the morning:
 High-carb bedtime snacks and not enough diabetes
medications.
 Dawn phenomenon
 Somogyi effect
 Dawn Phenomenon
 The body uses glucose (sugar) for energy and it is
important to have enough extra energy to be able to
wake up in the morning.
 For a period of time in the early morning hours,
usually between 3 a.m. and 8 a.m., the body starts
Biochemistry Metabolic Integration I
churning out stored glucose to prepare for the
upcoming day.
 At the same time, the body releases hormones that
reduce the sensitivity to insulin. In addition, these
events may be happening while the diabetes
medication doses taken the day before are wearing
off.
 These events cause the body's blood sugar levels to
rise in the morning (at "dawn").
 Somogyi Effect
 also called rebound hyperglycemia
 If the blood sugar drops too low in the middle of the
night while sleeping, the body will release hormones
in an attempt to “rescue” the person from the
dangerously low blood sugar.
 The hormones do this by prompting the liver to
release stored glucose in larger amounts than usual.
 But this system isn’t perfect in a person with diabetes,
so the liver releases more sugar than needed which
leads to a high blood sugar level in the morning.
QUESTION 2: What is the biochemical basis why metformin
control blood sugar in T2DM?
 Metformin
 Drug under the class Biguanide
 Effects are all mediated by the ability of metformin to
activate the AMP-Activated Protein Kinase or
AMPK.
 AMPK: heterotrimeric protein complex that
activates glucose and fatty acid uptake and
oxidation when cellular energy is low
 Produces three main effects:
 Decrease blood glucose by decreasing hepatic
glucose production.
 Decrease intestinal absorption of glucose.
 Improve insulin sensitivity by increasing the
peripheral glucose uptake and utilization in the
body.
 Mechanism
Figure 4. Mechanism of Metformin
 In Type 2 DM, there is increased gluconeogenesis
 The primary site of metformin action is the
mitochondrion.
 Metformin can directly inhibit complex I in the
mitochondria which will lower ATP in the body.
 Remember that Complex I (NADH:ubiquinone
oxidoreductase) is the largest multimeric enzyme
complex of the mitochondrial respiratory chain, which
is responsible for electron transport and the
generation of a proton gradient across the
mitochondrial inner membrane to drive ATP
production.
 ↓ ATP levels in the cell may then lead to ↓
gluconeogenesis.
 ↑ AMP:ATP ratio will activate AMPK.
 AMPK will then inhibit CREB, CRTC2, and CBP
which are gluconeogenic gene transcriptions. In turn,
this will lower the rate of gluconeogenesis.
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  ↑ AMP:ATP ratio may also affect another pathway that  Lack of insulin will cause increase in glucagon → lipolysis,
involves the transformation of ATP to cAMP via Adenylate proteolysis → high blood sugar, production of ketones
cyclase.  Venous blood gas, Acidic
 It inhibits this process thus resulting to the reduced  Increased H+, decreased HCO3
activation of PKA as well as the gluconeogenic gene  Acidic from ketoacidosis
transcriptions mentioned.
 Serum sodium
 Activated AMPK may also result to opening of GLUT-4
channels which then increases the insulin independent
 125-135 meq/L
glucose uptake.  Serum potassium
 Summary of Effects  Normal to high (>4 meq/L)
 increase glucose uptake and utilization, increase fatty  In DKA, ketonuria occurs
acid oxidation, increase autophagy, decrease  Increased blood sugar  glucosuria  increased
glycogen synthesis, decrease fatty acid synthesis, urine osmolality  water is excreted more  drains
inhibits protein synthesis, inhibits cholesterol potassium with it
synthesis  Serum chloride
 Normal (105 meq/L)
QUESTION 3: What could be the reason behind Jyllo’s rapid  Plasma ketone bodies (++++)
weight loss?
 Sudden weight loss with diabetes could occur as a result - Administration of IV fluids to address dehydration.
of dehydration, breakdown of muscles and high blood  Fluid replacement
sugar as well as problems emanating from the thyroid.  Initial rehydration therapy
 Dehydration is a symptom linked with frequent urination.  To compensate for fluid and electrolyte losses
People with diabetes urinate more because the kidneys  0.9% NaCl – isotonic solution
work harder than usual to filter the excess sugar  Potassium therapy
accumulating in the blood. As one urinates, glucose and  For maintenance of proper cell function
calories are lost. This leads to severe dehydration and
 Replace lost potassium due to osmotic diuresis
ultimately, weight loss.
 Insulin therapy
 Type 2 DM: resists insulin or doesn’t produce enough
insulin to maintain normal glucose levels. Insufficient  Regulate glucose levels for hyperglycemia and
insulin prevents body from getting the glucose from blood ketoacidosis
into the body’s cells, to use as energy. Therefore, the body  Potassium levels must be corrected first before
will start burning fat and muscles for energy - causing the introducing insulin because it is needed for insulin to be
reduction in overall body weight. absorbed by the cell → signal the body for availability of
 Insulin deficiency can also decrease muscle synthesis and energy → stop production of ketones
increase muscle breakdown. Steps in Early DKA Management
V. CASE 5 1. Collect blood for metabolic profile before initiation of IV fluids
2. Infuse 1L of 0.9% NaCl over 1 hour after initial blood samples
CASE INFORMATION
3. Ensure potassium level of 3.3 mEq/L before initiation of insulin
Ally Tree, an 18 year old female is diagnosed with a case of type 1
therapy
diabetes mellitus. She has to monitor her capillary blood sugar level
4. Initiate insulin therapy only when steps 1-3 are executed
and is on insulin injections 2x a day. Although her mom did not allow
her to go to an outdoor concert due to the extremely hot weather VI. CASE 6
lately, she insisted on going there together with her friends and
CASE INFORMATION
cousins. Two hours into the concert, she felt dizzy. She thought she
had low blood sugar since she felt thirsty and hungry, so she asked Taylor Slow a 25 y/o employee is pregnant. She is on her 1st
trimester now. She read all about the body changes during
for soda. However, she fainted and was not coherent so her
companions decided to bring her to the ER. pregnancy. She wants to understand the biochemical changes she
should expect from the 1st trimester to the 3rd trimester and beyond
QUESTIONS (lactation). As a loving/concerned friend, what should you tell her?
QUESTION 1: What are Ally’s metabolic derangements? QUESTIONS
 Type I Diabetes QUESTION 1: What are the biochemical changes that are
 Inability to produce insulin expected of a normal pregnancy?
 Hyperglycemia from missed insulin shot and blood sugar
monitor  Hormones
 Soda intake  Human chorionic gonadotropin (hCG)
 Elevated during pregnancy
 Diabetic Ketoacidosis
 Dominant hormone in the first trimester of pregnancy
 Increased plasma ketones  Produced by syncytiotrophoblasts
 May be due to high insulin requirements because of  Detectable in:
stress, excess fat breakdown, and ketogenesis  blood 1 week after conception
 Dehydration  urine 2 weeks after
 Decreased electrolytes  Peak concentration around 8-10 weeks
 Hyperglycemia causes osmotic diuresis → loss of water  Progesterone
and electrolytes in the urine  Induces breast growth and differentiation
 Potassium levels may fall, and if not treated in time, may  Produced by the placenta
result to hypokalemia  Functions in the maintenance of pregnancy
 Increased levels during late pregnancy
QUESTION 2: Important laboratory tests and expected results  Induce lipoprotein lipase in mammary gland together
 Random blood sugar with prolactin → high milk secreting cells and ducts
 High (250-600 mg/dl)  Estrogen
 Patient drank soda with a high glycemic index → glucose  Increased throughout the duration of pregnancy
peaks
Biochemistry Metabolic Integration I 4 of 12
  50-fold increase in estradiol and estrone
 100-fold increase in estriol
 Stimulates prolactin secretion but downregulates
prolactin receptors
 Stimulates breast development
 Human placental lactogen (hPL)
 Detectable in the syncytiotrophoblast by 10 days after
conception; in maternal serum 3 weeks after conception
 Functions:
 Protein anabolic
 Lipolytic
 Antagonizes insulin action → diabetogenicity of
pregnancy
o Inhibits maternal glucose uptake which may lead
to increased levels of glucose in maternal serum
 Highest during last half of pregnancy
 Leads to accelerated starvation and B-cell
hyperplasia
 Other substances:
 Folate
 Decreased levels → neural tube defects
 Alpha-fetoprotein
 Produced in the developing fetal liver
 Changes in concentration may be indicative of
complications
 Too much → neural tube defects or twins
 Too little → down syndrome
 Parathyroid related protein (PTHrp)
 Increases calcium and phosphorus absorption from
gut and bone
 Controlled by calcium receptors that coordinate
calcium mobilization
 Thyroxine-binding globulin, total thyroid hormone
 Increase during pregnancy due to decreased
breakdown by liver
 More TBG → increased levels of total T3/T4
QUESTION 2: Taylor is concerned about her having gestational
diabetes. Can this be prevented?
 Hormones from placenta
 Placental lactogen
 Stimulates lipolysis in adipose tissue
 Estradiol, progesterone
 Induce insulin-resistant state
 Pregnancy: perturbed starve-feed cycle
 Pregnant women enter the starved state more rapidly than
non-pregnant women
 Results from increased consumption of glucose and amino
acids by the fetus, which may cause
hypoglycemia
QUESTION 3: What are the biochemical changes that are
expected of a normal lactation?
 Early stages of pregnancy
 Breast develops and prepare for lactation
 Post-partum
 Estrogen and progesterone decreases
 Prolactin increases → initiate milk productions
 Oxytocin – milk let-down reflex
 Shift in hormonal levels induces a period of infertility which
provide optimal birth spacing
 Glucose
 Main energy source for lactose and TAG synthesis during
lactation
 Increase in AA for protein synthesis
 Increased nutrient needs to support lactogenesis are from
maternal diet and mobilized fat stores
 Glucose is diverted to lactogenesis for noninsulin mediated
pathway for uptake by the mammary gland
Biochemistry Metabolic Integration I
 Results to lower maternal blood glucose, insulin and lipid
concentrations
 Increased carbohydrate utilization
 Secretion of PTHrp by the lactating breasts
 Aids in phosphorus and calcium absorption in bone and
gut
 Controlled by calcium sensitive receptors
 Difference in composition between milk released from the
breast and mature milk
 Colostrum – contains a lot of essential amino acids and
proteins for immunization
 Other hormones that play a role in lactation:
 Adrenocorticotropin
 Growth hormone
 Thyrotropin
VII. CASE 7
CASE INFORMATION
Gon Yoo Sales, an aspiring athlete is training daily to compete for
the 100 meter dash or sprint. His cousin, Guy Yon, on the other hand
is training for the 10, 000 meter track running event.
QUESTIONS
QUESTION 1: Compare and contrast the fuel utilized by the
muscle in short sprints (100 meter dash) and in longer
duration marathons
 Sprinting
 Considered as anaerobic exercise
 Energy sources
 Creatine Phosphate
 Glycogen
 Creatine phosphate serves as energy source until
glycogenolysis and glycolysis are activated
 During a short sprint Creatine Kinase
Creatine phosphate + ADP ATP + Creatine
 At the end of the 100m sprint
 Muscle ATP drops to half
 Creatine Phosphate is completely depleted
 Lactate and H+ increase dramatically
 Longer Duration Marathon
 Moderate-intensity aerobic exercise
 Sustains oxygen for longer periods of time
 Energy sources:
 Muscle Glycogen (aerobic glycolysis)
 Switches to Fatty Acids (FA Oxidation) when glucose
stores are depleted
 Adipocytes: ↑ lipolysis → FA oxidation
 Skeletal muscles: ↑AMPK/insulin → (-) acetyl CoA
maternal
carboxylase / (+) malonyl decarboxylase → ↓malonyl CoA
and ↑Acetyl CoA → ↑CPT1 activity → FA oxidation
 Brain: ↑ lactate due to increased anaerobic glycolysis →
10-20 mM crosses blood brain barrier → used as alternate
fuel by the brain
Figure 5. Metabolism Integration by AMPK
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QUESTION 2: Summarize the biochemical basis of creatine
supplement in these athletes, including long term safety to
vital organs
 Creatine Supplementation
 Creatine in Venous blood gas
Creatine Kinase
Creatine phosphate + ADP ATP + Creatine
 Creatine supplementation increases the Creatine
available to carry the phosphate of ATP. Thus providing
more ATP from Creatine phosphate via Creatine Kinase
boosting the amount of energy for muscle contraction.
 Effects in Exercise and Performance
 Increase in body mass, strength, power, and efficacy in
short-duration, high-intense exercises
 Inconsistent results (responders and nonresponders)
 Improved performance when in conjunction with a
resistance training program
 Thought to be detrimental to renal function
 Safety of Creatine Supplementation
 No scientific evidence of harmful effects
 Weight gain is the only consistent result
 Short-term use is safe, but there is insufficient data
regarding long-term use
 Case reports of injury with creatine use was due to
inappropriate creatine use or multiple ergogenic aids and
supplements
CASE 8
CASE INFORMATION
Johnny DB WhiteWalker, a 55 y/o devoted lifelong fan of alcohol
and alcohol infused drinks claims to drink alcohol only on social
occasions. He came for consult due to weakness, weight loss, and
irritability. You commit to the diagnosis of alcoholic liver disease. On
further history, he admits that he consumes almost half a bottle of
hard drinks (whiskey or brandy) since he was around 20 yrs old.
QUESTIONS
QUESTION 1: On the background of his chronic liver
condition, how will you explain his:
WEGHT LOSS
 Alcoholic liver disease is increasingly common and is often
accompanied by malnutrition as a result of reduced
absorption, processing and storage of nutrients. The
underlying cause for the said malnutrition in patients with
liver disease is related to many factors:
 Inadequate/ poor quality intake of food
 Maldigestion and malabsorption: due to toxic effects of
alcohol on small intestinal ultrastructure and brush border
enzymes
 Muscle Wasting: IGF-1 deficiency
WEAKNESS
 Fatigue likely occurs as a result of changes in
neurotransmission within the brain.
 Peripheral fatigue relates to neuromuscular dysfunction and
occurs with muscle overutilization and associated metabolic
changes
 Central fatigue arises within the central nervous system
(CNS) and is characterized by a difficulty in performing
physical (and often mental) activities
 Include the corticotropin-releasing hormone (CRH),
serotonin, noradrenaline and other neurotransmitter
systems.
 Possibly caused by anemia, nutritional deficiencies,
disturbances in fluid balance and impaired renal function
 May also be due to psychological distress associated with
anxiety and depression
Biochemistry Metabolic Integration I
IRRITABILITY
 Alcohol withdrawal symptoms
 Insomnia
 Tremulousness
 Mild anxiety
 Gastrointestinal upset, anorexia
 Headache
 Diaphoresis - sweating (unusual amounts)
 Palpitations
 Alcohol is a central nervous system depressant
 Abrupt cessation unmasks the adaptive responses to chronic
ethanol use, resulting in over activity of the central nervous
system.
QUESTION 2: What are the changes in:
CARBOHYDRATE METABOLISM
 Metabolism of ethanol generates a high NADH/NAD+ ratio
 ADH is not a very effective product inhibitor of Alcohol
dehydrogenase
 NADH generated in the cytosol and mitochondria tends to
accumulate, increasing the NADH/NAD+ ratio to high
levels
 Hypoglycemia (Fasting patient)
 The high NADH/ NAD+ ratio shifts the lactate
dehydrogenase equilibrium to lactate, so that pyruvate
formed from alanine is converted to lactate and cannot
enter gluconeogenesis
 Also prevents other major gluconeogenic precursors, such
as oxaloacetate and glycerol, from entering the
gluconeogenic pathway.
 Transient hyperglycemia (Fed patient)
 The high NADH/NAD+ ratio inhibits glycolysis at the
glyceraldehyde-3-phosphate dehydrogenase step
LIPID METABOLISM
 Changes in FA metabolism
 (-) FOXO: FA accumulation in the liver → Increased VLDL
(hyperlipidemia)
 Increased lipolysis due to epinephrine
 Alcohol-induced Ketoacidosis
 Increased NADH generated from ethanol oxidation ->
Acetyl CoA used in ketogenesis
 Alcohol-Induced Hepatitis
 Mechanism:
 Acetaldehyde-tubulin adduct → decreased secretion of
VLDL & serum CHONs from the liver to the systemic
circulation
 CHONs & lipids accumulate in the liver → High H2O
influx → swelling of hepatocytes → disruption of liver
architecture → Portal Hypertension
 Chronic parenchymal liver disease
 Reduced activity of lecithin cholesterol acyltransferase
(LCAT). This plasma enzyme is responsible for the
production of cholesterol ester and lysolecithin by
catalyzing the transfer of a fatty acid from the 2-position of
lecithin to the 3B-OH group of free cholesterol. Decreased
activity results to a reduced plasma levels of cholesterol
ester and normal/increased free cholesterol levels
 Acute/Chronic Hepatitis
 Relatively increased levels of plasma TAGs due to
reduced activity of LPL and HTGL
PROTEIN METABOLISM
 Protein deficiency due to poor dietary intake
6 of 12
 Amino acid concentration in the blood is elevated
 Significantly increased rate of protein turnover and impaired
amino acid uptake by the diseased liver
 The muscle is the major source of elevated plasma levels of
AA seen in catabolic states such as in ALD
 Elevation in blood ammonia
 The liver is unable to convert ammonia into urea and
glutamine rapidly enough
 May be due to abnormalities in blood flow in the liver which
affects the glutamine cycle, decreases in the enzymes
involved in the urea cycle, and smaller functional hepatic
mass
 Can lead to CNS toxicity and coma
CASE 9
CASE INFORMATION
Chennelyn Leon is a 25 yr old female who quit her job to focus on
her business venture. She’s a co-owner of a restaurant and decided
to expand the business. So she loaned P10 million from a corporate
bank. After one year, she began having frequent dizzy spells
attributed to lack of sleep, unintended weight loss of 10kg in two
months, elevated BP (140/90 mmHG), and elevated blood sugar
levels.
QUESTIONS
QUESTION 1: Summarize the biochemical effects of chronic
stress and injury to explain Chennelyn’s symptoms.
 Stress
 Hypercatabolic state
 May lead to insulin resistance
 Increase in counter-insulin hormones:
 Cortisol which causes the increase in heart rate
and blood pressure and strengthens heart
muscles.
 Catecholamines which causes the activation of
the sympathetic nervous system (SNS) which
also causes the heart rate to increase.
 Glucagon
 Growth Hormones
 Increase BMR due to increase in nutritional
requirement
 Increase blood glucose and FFAs
 Stimulation of glycogenolysis, gluconeogenesis,
and lipolysis
 Decrease muscle glutamine and branched chain AA
pool
 Decrease protein synthesis and increase protein
degradation.
QUESTION 2: She asks her if her condition is still reversible
given her age, what is the most appropriate response to a
young adult?
 Lifestyle changes
 Exercise
 Medication
X. CASE 10
CASE INFORMATION
Francois Bass, a 50-year old male is diagnosed to have chronic
kidney disease after 3 decades of a life filled with debauchery. He
was brought to the emergency room because he was found to be
incoherent and pale. His blood sugar was low.
QUESTIONS
QUESTION 1: What is the expected arterial blood gas results
in Francois given his condition?
CHRONIC KIDNEY DISEASE
 Increasing tendency to retain hydrogen ions
Biochemistry Metabolic Integration I
 As the number of functioning nephrons declines, acid
excretion is initially maintained by an increase in the
ammonium excreted per nephron.
 Can lead to a progressive metabolic acidosis, with the serum
HCO3 concentration tending to stabilize between 12 and 20
mEq/L and rarely falling below 10 mEq/L (uptodate)
 a result of damage to kidney and, therefore, any increased
protein consumption could lead to exacerbation of the condition
due to the accumulation of nitrogenous waste products as the
kidney becomes less and less capable of metabolizing certain
amino acids (Gln, Gly, Pro, Citrulline)
 Contributory factors:
 Impaired glucose reabsorption, since the kidney normally
reabsorbs all of the glucose
 With kidney disease, some glucose may end up filtered and
never reabsorbed, resulting in glycosuria
 ABG: decrease in pCO2, increase in HCO3-, increase in pH
(compensated metabolic acidosis)
QUESTION 2: How will the CKD explain his blood sugar and
pallor?
 Pallor
 possibly due to anemia; compromised kidney function
commonly due to EPO deficiency, resulting in anemia
 Mechanisms of Anemia in CKD:
 Inhibited EPO production causing increased circulating
uremic inhibitors
 Shortened RBC survival
 Increased iron losses from blood loss, impaired iron
absorption and release, erythropoiesis-stimulating agent
(ESA) administration
 Low blood sugar (hypoglycemia)
 Alcohol consumption results in hypoglycemia
 Oxidation reaction of liver alcohol dehydrogenase (ethanol →
acetaldehyde) inhibits conversion of lactate to pyruvate
 Lowers gluconeogenesis
 elevated blood levels of acetaldehyde is toxic and highly
reactive in inducing free radical damage
QUESTION 3: What are expected biochemical changes in his
carbohydrate, lipid, and amino acid metabolism?
Changes in Carbohydrate Metabolism
 Favors glycogenolysis and lipolysis
 Increase in glucagon, glucocorticoids, catecholamines, and GH
release
 promotion of catabolic state
 Reduced hepatic and/or skeletal muscle glucose uptake
 Impaired glucose metabolism
 Impaired tissue sensitivity to insulin
 Development of insulin resistance
 Development of spontaneous hypoglycemia
Changes in Amino Acid Metabolism
 Decreased Tyrosine and Phenylalanine levels
 leads to protein depletion and also to impaired synthesis of
aromatic amine modulators such as dopamine,
norepinephrine or epinephrine
Figure 6. Tyrosine and phenylalanine levels decrease
7 of 12

 Decreased Arginine levels
 Decreased Nitric Oxide Levels → reduced hormonal control of
insulin and IGF-1
 rarely observed in CKD patients suggesting the existence of
sources of arginine other than the kidney
Figure 7. Arginine levels decrease
 Increased Sulfur amino acid (Methionine) levels
 associated with atherosclerosis and cardiovascular damage
 accumulation of s-Adenosylhomocysteine (SAH) in body fluids
is associated with vascular disease and tissue damaged
Figure 8. Methionine levels decrease
Changes in Lipid Metabolism
 Urinary protein loss
 Increased LDL synthesis by the liver
 acquired LCAT deficiency
 Impaired clearance of chylomicrons and VLDL
 ApoA1 and A2 levels are decreased (↓HDL)
 Modified ApoA1 decrease HDL binding to macrophages
 LCAT level and activity are impaired
 Accumulation of HDL‐3 and reduced level of HDL‐2
 Impaired activation of LPL
 IDL and remnants accumulate in CKD
 down‐regulation of hepatic lipase (HL) expression and VLDL‐
receptor in myocytes and adipocytes
TREATMENT PLAN FOR CKD
 Each patient should have a clinical action plan based on the
stage of disease, as defined by the K/DOQI classification (level
B recommendation).
 Starting treatment at the right point in the progression of chronic
kidney disease is essential to prevent adverse outcomes.
Defining the stage of chronic kidney disease is the key first step
in developing the appropriate clinical action plan
 Patients with CKD should be referred to a specialist for
consultation and co-management if the patient's personal
physician cannot adequately evaluate and treat the patient
 A nephrologist should participate in the care of patients with a
GFR less than 30 mL/min per 1.73 m2(level B recommendation)
X. CASE 11
CASE INFORMATION
Pierce Vlad, a 30 year old male had unexplained weight loss
(BMI=19) and was diagnosed to have colon cancer. He underwent
surgery (resection of almost half of his large intestines with
colostomy) and a multi-drug chemotherapy regimen. In this process,
his BMI further dropped to 17.
Biochemistry Metabolic Integration I
QUESTIONS
QUESTION 1: How can his condition (cancer) explain his
weight loss (cachexia)?
 Cytokines
 Cancer cells are capable of producing cytokines
constitutively.
 Cytokines play a pivotal role influencing the
imbalance of orexigenic and anorexigenic circuits.
 Cytokines, polypeptides released mainly by immune
cells, are the molecules responsible for some of the
metabolic derangements associated with the
hypermetabolic state that characterizes cancer-
bearing states.
 Pro-inflammatory cytokines such as interleukin-6
superfamily, tumor necrosis factor-alpha,
interleukin-1, and others elicit anorexia, lipolysis,
and muscle breakdown when injected systematically.
 A large set of different transcription factors have been
identified to play important roles in tissue wasting;
many are activated by pro-inflammatory stimuli.
 Cachexia
 Cachexia is a hypercatabolic state defined as
accelerated loss of skeletal muscle in the context of a
chronic inflammatory response.
 Weight loss in cancer patients is due to equal loss
of both adipose tissue and skeletal muscle mass-
unlike weight loss from starvation which is mainly
from the fat and only a small amount from the muscle.
 Potentially important role for several tumor-derived
and potentially cachexia-inducing substances, the
target of which appears to be skeletal muscle gene
products.
 The ubiquitin-proteasome pathway may be the
final common pathway mediating protein degradation
in cancer-related cachexia.
 Other potential contributory factors to the progressive
reduction in lean body mass include changes in
metabolism and caloric intake, aging, lack of
exercise, fatigue, tissue hypoxia, inflammation, and
medications.
 Anorexia
 Anorexia is an important component causing weight
loss in cancer cachexia and it is unrelated to the effect
of chemotherapy.
 Early satiety is considered either as a direct effect of
the tumors in the gastrointestinal tract (GIT)
obstructing the passage of food or due to altered
mucosa leading to malabsorption.
 The release of chemicals by the tumor or host
immune system may induce anorexia.
 Tumor products may inhibit NPY
(orexigenic) transport or release or interfere
with the neuronal downstream of NPY.
 In cancer patients with anorexia, NPY levels are
lower than in the controls.
QUESTION 2: What are the expected metabolic derangement of
having a large segment of his large intestine surgically
removed and being on colostomy?
 Colon/ Large Intestine
 Digest and absorb extra water and electrolytes from
the chyme to form solid feces (proximal half).
 Storage of fecal matter until it can be excreted or
expelled from the body (distal half).
 GIT Tumor Obstruction
 Obstruct the passage of food
 Feeling of fullness
 Altered mucosa
 Difficulty absorbing nutrients
 Tumor chemicals also block nervous system
 Prevents release of neuropeptide Y
8 of 12
  Peptide that plays a role in one’s need to  Reduced Lipogenesis - to favor utilization of carbohydrates
eat food. into energy production
 Colostomy  Alanine Cycle - also an important process because it
 Colostomy is surgical procedure that creates a undergoes transamination to produce Pyruvate; or
stoma (opening) in the abdominal wall by cutting a carboxylated into Oxaloacetate both favoring energy
part of colon that separates healthy segment from production.
diseased segment to allow the latter to heal.
 After a colostomy has been created, the intestines Table 4. Active and inactive key-enzymes during overnight fast
will work just like they did before except: CLASSIFICATION ENZYMES
 The stoma of healthy segment is the one Active Glycogen phosphorylase
the releases the colonic contents while the Pyruvate carboxylase
other stoma may secrete mucus. The PEPCK
feces is collected in a pouch. Fructose-1,6-bisphosphate
 The anus is no longer the exit for stool, but Glucose-6-phosphatase
it will still pass mucus from time to time, Lactate dehydrogenase
which is normal. Alanine transaminase
 If the diseased segment is healed, the Carbamoyl phosphate synthase 1
colostomy is surgically reversed. The Acetyl CoA carboxylase 1
patient can experience normal bowel FAS complex
function again. Hexokinase (brain)
 Dehydration is a serious concern undergone by PFK 1 (brain)
patients who have had this procedure. Inactive Hexokinase
 There’s increased susceptibility to PFK1
electrolyte imbalance. Pyruvate kinase
 Dehydration happens because there’s a Glycogen synthase
lessened ability to absorb water from stool PDH Complex
(due to resected colon). Acetyl CoA carboxylase 1
 This leads to increased thirst, dry mouth, FAS Complex
and decreased urine output. Lipoprotein lipase
Glycerol kinase
Table 3. Manifestations of Na and K loss Glucose-6 phosphate dehydrogenase
Loss of Na Ions Loss of K Ions
o Cramps o Fatigue
o Drowsiness o Muscle weakness After 48 hours
o Loss of appetite o Shortness of breath  Starvation
 More than 48 hours of fasting
X. CASE 12  FA Oxidation - primary process during starvation
CASE INFORMATION  Decreased proteolysis - decreased utilization of essential
amino acid and proteins
 Increased ketone bodies
 Renal gluconeogenesis - compensatory mechanism for
glucose levels
 Decreased usage of glucose and ketone bodies by muscles
and adipose tissues

Table 5. Active and inactive key-enzymes after 48 hours of fasting

CLASSIFICATION ENZYMES
 Robin Green 30 y/o diagnosed to have gallstones and is Glycogen phosphorylase
scheduled for laparoscopic cholecystectomy Pyruvate carboxylase
PEPCK
 Prior to procedure: not to have dinner before his 7:00 AM
Fructose-1,6-bisphosphate
procedure
Glucose-6-phosphatase
 During the procedure: uncontrolled bleeding and to undergo
Lactate dehydrogenase
explorative laparotomy
Alanine transaminase
 RG forgot to disclose that he is an avid believer/consumer of food
Carbamoyl phosphate synthase 1
supplements (garlic extract, gingko biloba, and ginseng) because
Active Hexokinase (brain)
he thought it was not a relevant information.
PFK 1 (brain)
 After the procedure: complete gut obstruction and placed on Pyruvate kinase (brain)
prolonged NPO Proteases
 After 5 days: he was finally allowed sips of water Glutaminase
 After 2 more days: clear soup then 1 cup of plain lugaw HMG CoA synthase
CPT 1
QUESTIONS
HSL
QUESTION 1: Compare and contrast the key enzymes which Pyruvate dehydrogenase
are active/inactive during his: (a) Overnight fast (b) after 48 Hexokinase
hours (c) after 5 days PFK1
Pyruvate kinase
Overnight Fast
Glycogen synthase
 Early Fasting
Inactive PDH Complex
 4 hours to 18 hours of fasting Acetyl CoA carboxylase 1
 Hepatic glycogenolysis - most important biochemical process FAS complex
to sustain energy requirements during early fasting states Lipoprotein lipase
Glycerol kinase
Biochemistry Metabolic Integration I 9 of 12
  During prolonged fasting, hormonal and metabolic changes in
After 5 days the body prevent excessive protein and muscle breakdown.
Table 6. Active and inactive key-enzymes after 5 days of fasting  Muscle and other tissues decrease ketone body utilization and
CLASSIFICATION ENZYMES use fatty acids as their main energy source. The increase in
HMG CoA synthase ketone bodies in the blood stimulates the brain to switch from
Active HSL glucose to ketone bodies as its main energy source.
CPT1  The liver also decreases its rate of gluconeogenesis, further
CPS1 preserving muscle protein. Several minerals become severely
Pyruvate carboxylase depleted, but their serum concentrations may remain normal
PEPCK because they are mainly in the intracellular compartment,
Fructose-1,6-bisphosphate which contracts during starvation.
Glucose-6-phosphatase  During refeeding, glycemia leads to an increase in insulin
Hexokinase secretion and a corresponding decrease in glucagon secretion.
PFK1  Insulin stimulates glycogen, fat, and protein synthesis. These
Inactive Pyruvate kinase processes require minerals to be taken up into cells (e.g.,
Glycogen synthase phosphate, magnesium, cofactors such as thiamine), with
PDH Complex water following via osmosis.
Acetyl CoA carboxylase 1  Further decrease in serum electrolytes (phosphate,
FAS Complex potassium, magnesium), all of which are already depleted
Lipoprotein lipase during starvation.
Glycerol kinase
Glucose-6-phosphate dehydrogenase SUMMARY
Case Patient Complaint Pertinent Important
QUESTION 2: How will metabolic fuel be supplied to/consumed No. Name Findings Concepts
by his organs – heart, RBC, brain, liver? 1 Shakee N/A BW = 150 kg Bariatric Surgery
Jolly Bels Ht = 1.65 m
Table 7. Metabolic Capacities of Various Tissues Elevated blood
Heart RBC Brain Liver sugar, VLDL,
and LDL levels
TCA Cycle +++ - +++ +++ BP = 160/100,
B-oxidation +++ - - +++ BMI = 55.1
Ketogenesis - - - +++ 2 NotSo Weight loss BMI: Bariatric
Ketone body +++ Jolly Bells 28.65kg/m2, Surgery, PCSK-
+++ - - Type 2 DM 9 inhibitors for
utilization (PS)
Elevated VLDL dyslipidemia
Glycolysis +++ - +++ +++ and LDL
Lactate +++ 3 Kitty Hello Weight loss BMI: Ketogenic and
+++ + + There 28.13kg/m2 Atkins diet,
production (E)
Goal: to lose Healthy weight
Glycogen
+++ - + +++ 15kg in 3 loss
metabolism months
Gluconeogenesis - - - +++ 4 Jylio G. Weight loss, T2D Dawn
Urea cycle - - - +++ easily phenomenon,
Lipogenesis - - - +++ fatigue, Somogyi effect,
elevated Metformin,
 Legend: capillary AMPK
 (-) no use of fuel, (+) Minimal use of fuel blood sugar
 (++) use of fuel, (+++) maximum use of fuel when
waking up
 PS – prolonged starvation; E – exercise 5 Ally Tree Type 1 Felt dizzy, lost Diabetic
diabetes consciousness ketoacidosis –
Table 6. Fuel use by Various Tissues during Starvation mellitus; management,
Ketone Diabetic treatment,
Glucose FA ketoacidosis expected
bodies
laboratory
Nervous tissue ++ - ++ results
Skeletal m. - ++ ++ 6 Taylor N/A 1st trimester of Hormonal
Cardiac m. - ++ ++ Slow pregnancy changes in
Liver - ++ - pregnancy;
gestational
Intestinal diabetes;
- - ++
epithelial cells lactation
Kidney - + + 7 Gon Yoo Short sprints N/A Aerobic and
and Guy vs Short anaerobic
 Legend: Yon Marathons; exercise and
 (-) no substrate utilization Creatine energy source;
 (+) low levels substrate utilization supplement AMPK metabolic
safety integration;
 (++) high levels of substrate utilization Creatine
phosphate
QUESTION 3: What is the biochemical basis why he was re-fed 8 Johnny Weight loss, Alcoholic liver Carbohydrate
carefully? DB Irritability, disease; metabolism
WhiteWalk Weakness malnutrition, (Ethanol
 The patient was re-fed carefully to avoid the occurrence of er fatigue, and synthesis); Lipid
refeeding syndrome. alcohol metabolism (↑
 “Refeeding syndrome” results from potentially fatal shifts in withdrawal; lipolysis,
fluids and electrolytes that occur in malnourished patients Ketoacidosis,
Hepatitis);
receiving artificial refeeding. Protein
 Its clinical features occur as a result of the functional deficits metabolism (↑
of phosphate, potassium, and magnesium and the rapid amino acid conc.
change in basal metabolic rate. ↑ ammonia,

Biochemistry Metabolic Integration I 10 of 12

 protein
deficiency)
9 Chennelyn Dizziness, Stress Hormones,
Leon weight loss, Insulin
elevated Resistance
BP,
elevated
blood sugar
level
10 Pierce Weight loss, Cachexia Cytokines,
Vlad colon cancer,
cancer ubiquitin-
proteosome
pathway
11 Francois Incoherent Chronic kidney Blood sugar
Bass and pale disease Pallor
Low blood Arterial blood
sugar gas
12 Robin N/A Gall stones Laparoscopic
Green cholecystectomy
Fasting
Uncontrolled
bleeding
Food
supplements
Complete gut
obstruction

REFERENCES
 Garibotto, G, et al. (2010). Amino acid and protein metabolism in
the human kidney and in patients with chronic kidney disease.
Clinical Nutrition 29(4): 424-433.
 Kovesdy, C. (2018). Pathogenesis, consequences, and
treatment of metabolic acidosis in chronic kidney disease.
Retrieved April 29, 2019
 Lieberman, M., Marks, A., & Peet, A. (2013). Marks’ basic
medical biochemistry: a clinical approach (4th ed.). China:
Lippincott Williams & Wilkins.
 Mehanna HM, Moledina J, Travis J. Refeeding syndrome: what it
is, and how to prevent and treat it. BMJ. 2008;336(7659):1495–
1498. doi:10.1136/bmj.a301
 Rosenberg, M. (2018). Overview of the management of chronic
kidney disease in adults. Retrieved April 29, 2019
 Sood, P., Paul, G. & Puri, S. (2010). Interpretation of arterial
blood gas. Indian J Crit Care Med. 2010 Apr-Jun; 14(2): 57–64.

APPENDIX

Biochemistry Metabolic Integration I 11 of 12

 Figure 9. Main modifications of lipoprotein metabolism induced by chronic kidney disease (CKD)

Biochemistry Metabolic Integration I 12 of 12