NUTR - Topic 4

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  1. what are the protein requirements?
    • EAR = 0.66g/kg/d
    • RDA = 0.8g/kg/d
    • Usual intake = 80-100g/d
  2. how are Amino Acids classified?
    • Indispensable (PVT TIM HLL)
    • phenylalanine
    • methionin
    • leucine
    • isoleucine
    • valine
    • lysine
    • threonine
    • tryptophan
    • histididne

    • Conditionally Indispensable
    • tyrosine
    • arginine
    • glutamine
    • glycine
    • proline

    • Dispensable
    • alanine
    • aspartate
    • asparagine
    • glutamate
    • serine
  3. how is metabolic flux of amino acids determined?
    By following "tracers"
  4. what are the tracer dilution principles (bathtub)?
    • Bath represents all the free amino acids in the body
    • Tap is open = e.g., we are eating

    • Assumptions
    • 1. System at steady state
    • Water level in the bath tub remains constant – homeostasis
    • Rate of appearance (Ra) = Rate of disappearance (Rd)
    • Rate of inflow (influx) = rate of outflow (outflux)
    • We are either at fed, nibbling, or fasting state

    • 2.  Homogeneity of pool
    • Complete mixing of the pool
    • Tracer goes all over the body

    • 3.  Massless tracer = tracee
    • No influence in metabolism and in behaviour
    • Labeled ones act just like un-labeled ones

    • 4.  No tracer recycling
    • Drained water stays out
    • Fast flow of water --> light colour
    • Slow flow of water --> dark colour
  5. what is an isotope?
  6. what are some stable isotope tracers (non-radioactive)?
    • Carbon = 12C, 13C, 14C
    • Hydrogen = 1H, 2H, 3H
    • Nitrogen = 14N, 15N
    • Oxygen = 16O, 18O
    • Sulfur = 32S, 34S, 35S

    • 1st column =  Most common forms
    • 2nd column =  Heavier than common forms – due to an extra neutron /  Ditirium (2H) is a part of heavy water
    • 3rd column =  Radioactive – not stable & might cause a health issue
  7. how does a gas chromatograph mass spectrometer (GCMS) work?
  8. What is a nutritionally indispensable AA?
    Cannot be synthesized by the animal organism out of materials ordinarily available to the cells at a speed commensurate with the demands for normal growth
  9. Why are amino acids needed?
    • Growth
    • Nitrogen Balance
    • Plasma AA response
    • Direct AA oxidation: tracer technique
    • Indicator AA oxidation: tracer technique
    • 24h balance
    • or measure of organ or system function
  10. What are the general aspects of experimental approaches for nitrogen analysis?
    • All methods should give the same answer
    • Subjects should be studied at >6 test AA intake levels above and below requirement: To account for individual variability
    • Endpoint should show a clear response to change in test AA intake: g., deficient à adequate
    • Question of adaptation to test AA intake
    • - N: 7-10 days for urea pool – slow turnover
    • - CO2: hours to a couple of days – fast turnover
    • -  Go out in breathe
    • -  Rapid equilibrium
  11. how does nitrogen balance work?
    • 0 nitrogen balance (healthy): intake = excretion
    • Protein absorption rate = 95%
    • Miscellaneous losses (e.g., sweat secretion, hair growth, finger nail growth)

    Protein is 16% nitrogen 6.25g protein contains 1g nitrogen

    Nitrogen Balance = N intake - Fecal N (5%) - Urinary N (95%)

    • ex. 100g of protein
    • = 16g of N - 1G - 15g
    • = 0 = healthy adult

    0 balance : intake = output (healthy adult)

    • +ive = intake > output
    • growing children, pregnancy
    • depositing protein (recovering from an illness)

    • -ive = intake < output
    • low protein diet - low intake
    • GI problem - low absorption
    • injury - high catabolism
    • losing lean muscle mass
    • muscle wasting
  12. how many grams of protein synthesis per day occurs in a healthy adult?
    • 300 g
    • Broken down amino acids are recycled to be used again
    • Any excess protein intake will be broken down
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  13. what happens when there is a high protein consumption?
    • There is no effect
    • There will be a normal protein absorption rate of 95%

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    • Positive nitrogen balance only if in a building state
    • Growing or gaining lean mass
    • Simply eating more proteins or regular exercise won’t result in positive nitrogen balance

    • Negative nitrogen balance
    • E.g., malnourished or losing lean mass
  14. what is an optimal AA profile?
    • Minimizes catabolism
    • Maximises protein synthesis
    • Oxidation is minimal

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  15. what is a limiting AA profile?
    • Limits protein synthesis
    • Going from sufficient ---> deficient
    • Increase ↑ in catabolism of the excess AA (Extra protein excreted/broken down)
    • Loss of lean body mass
    • Loss of immune proteins
    • Plant-based protein sources are limiting in different amino acids

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  16. Nitrogen Balance
    • 1. Clinical/metabolic
    • COMPLETE intake and collections: Missing one urinary collection hugely affects the result
    • Adaptation of urea pool

    • 2. Analytical
    • Routine analysis of total nitrogen

    • 3. Modelling
    • Miscellaneous losses would increase requirement: eg., sweat, hair growth
    • Sensitivity: small number calculated from 2 large and similar numbers
    • (A huge nitrogen intake (e.g., 200g) – a huge urinary nitrogen loss (e.g., 190g) = nitrogen balance (e.g., 10g))
    • Curvilinear response as balance approaches zero
    • Between-subject variance is high therefore repeated measurements on each subject needed but adaptation issue

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    • Nitrogen balance is progressively more positive as the requirement is met
    • Actual requirement ≠ theoretical requirement
    • The graph plateaus due to adaptation and individual variation
  17. what is the metabolic response to intake of an essential AA: Nitrogen Retention (nitrogen balance)?
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    • Growth increases until the requirement is met
    • Excess amino acid intake will not make you grow more
    • Nitrogen retention (nitrogen balance) has the same curve as growth curve
  18. what is direct AA oxidation?
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    • Labeled amino acids (Phe is labelled with 13C) will either be synthesized into proteins or catabolized
    • When the labeled amino acids are catabolized, they come out of breath
    • Carboxyl groups from amino acids are chopped off to give CO2 --> exhaled --> heavier 13C are measured
  19. why is it not ideal to use the direct AA oxidation method?
    •  A lot of subject cooperation is required
    • Specialized formula tastes bad
    • Other diet sources need to be protein free
    • People on this diet crave textures
    • No fiber in diet causes constipation

    • Researches are usually done on men
    • Due to varying menstrual cycle and etc. 

    • Fast procedure (-4 hours)
    • Can be done on infants, children and animals
  20. what is the metabolic response to intake of an essential AA: Direct oxidation?
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    • 1.  Before requirement:
    • Efficiently used for protein synthesis
    • Minimally catabolized

    • 2. At requirement
    • Optimal level of protein synthesis
    • Minimally catabolized

    • 3. After requirement
    • Optimal level of protein synthesis
    • Excess AA are catabolized
  22. Direct AA oxidation (ADD)
    • 1. Clinical/metabolic
    • Restricted choice of test AAs (branched chain AA, LYS, PHE)
    • Free pool changes with changing test AA intake
    • Non-negligible tracer – can’t study very low intakes

    • 2. Analytical
    • Breath collection
    • Blood samples

    • 3. Modelling
    • Steady state "nibbling" = 24h/meal feeding
    • Breakpoint increase in oxidation with increasing intake
  23. what is the Indicator AA oxidation (IAAO)?
    • Concept: when an indispensable AA is limiting, then all other indispensable AA will be oxidized (remember that AAs cannot be stored)
    • Increasing ↑ intake of limiting amino acid will decrease ↓ IAAO
  24. what is the metabolic response to intake of an essential AA: indicator oxidation?
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    • Eg., test amino acid (lysine); indicator (phenylalanine)
    • When lysine intake is zero, phenylalanine is in a huge excess and will be oxidized
    • As lysine intake increases, oxidation of phenylalanine decreases until lysine intake meets its requirement
  25. Indicator AA oxidation (IAAO)
    • 1.  Clinical/metabolic
    • Free choice of test AA, can study 0 intake
    • Tracer AA pool not perturbed with changing test AA intake
    • PHE, LYS, LEU as indicator AAs

    • 2. Analytical
    • Breath collection
    • Blood samples; urine samples (non-invasive)

    • 3. Modelling
    • Steady state “nibbling” = 24-h/meal feeding
    • Breakpoint decrease ↓ in oxidation with increase intake ↑
  26. what is the minimally invasive IAAO model?
    • 1. Tracer administration
    • Repeated oral “nibbling” of tracer solution after 4-h feeding equilibration

    • 2. Sampling
    • Breath collection for CO2 enrichment
    • Urine in place of blood for plasma AA enrichment :Taking out blood samples from infants is very stressful for the infants
  27. Integrate concepts of determining AA requirement?
    • Common key principles
    • Amino acids are either synthesized into proteins or catabolized in the body (NOT STORED!!)

    • Ethics regarding sampling and specific diets that people are on
    • Infants can undergo oxidation method (a few hours) but not nitrogen balance method (10 days)

    • What is the key endpoint for each method? 
    • 1. Nitrogen Balance: Follows urea production and excretion
    • 2. Direct oxidation: Follows carbon skeleton catabolism
    • 3. Indirect oxidation: Follows carbon skeleton catabolism
  28. Metabolic response to intake of an essential AA: Indicator oxidation
  29. what is the EAR vs what is the RDA?
  30. Estimates of LYS requirement (mg/kg/day)
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  31. Indispensable proteins in AA
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    • Potentially limiting AAs
    • Lysine
    • Threonine
    • Tryptophan
    • Methionine
    • Cysteine
  32. Why is limiting AA important?
    • Omnivores with average protein intake – not an issue
    • Vegans with lower protein intake and lower protein quality – limiting AA is significant issue especially for children (because they have a higher protein requirement)
    • Complementary proteins: Beans and rice and Legumes and grains (e.g., peanut butter sandwich)
    • International : food security and diet diversity – very important especially for children
  33. what happens when Histidine is removed from the diet for 48days?
    • No effect on nitrogen balance
    • Decreased protein turnover, PHE oxidation

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    • Decrease in HIS level in blood over time
    • Hematocrit (Hct) – the percent occupied by cells in blood = decreased
    • Hemoglobin (Hb) decreased = Causing iron-deficiency anemia
    • Ferritin – binds iron when being stored = increased
    • Ferritin level goes down in case of anemia
    • Iron stores are getting higher
    • Transferrin – transports iron in blood = decreased
    • Transferrin level goes up when iron is deficient
    • Albumin – the most abundant protein in plasma = decreased

    • Conclusion
    • Lack of histidine limits red blood cell production
    • Histidine is very important for hemoglobin to bind oxygens
    • Lower capacity to transport oxygen
    • Decrease in these nutrient transport proteins that are high in histidine
    • Accommodation process – more histidine can be available for other things (Functional adaptation)
  34. how are intravenous regimens designed?
    • 1. Metabolism
    • Bypass splanchnic control (gut & liver): All the digestions have to be taken place before infusion

    • 2. Composition (Solubility and Stability)
    • Free AAs, glucose, vitamins and minerals in an infusion bag
    • Tyrosine is not soluble
    • Glutamine is not stable – deconstructed after being in the solution for a while
    • Lipids in a separate infusion bag: TGs stabilized with lecithin (from soybean oils)
    • Omega-6 fatty acids are pro-inflammatory – NOT GOOD

  35. how do we design the optimal AA profile (aromatic AAs)?
    Issues to address: tyrosine insolubility, transient hyperphenylalaninemia and hypertyrosinemia

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    • 1.  Infuse extra phenylalanine
    • – PHE will be hydroxylated to become tyrosine
    • - Used for adults

    • 2.  Infuse more soluble precursor of tyrosine (N-acetyltyrosine)
    • - Used for babies

    • 3.  Dipeptides (e.g., glycine + tyrosine = glycyl-tyrosine)
    • - Cheapest
  36. Nitrogen Retention in Baby Pigs (Study)
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    • 1. Vamin
    • - Modeled after egg white
    • - Extra PHE

    • 2. Vaminolact (VL)
    • - Modeled after breastmilk
    • - Ignored the need of tyrosine: least nitrogen retention and growth

    • 3.  VL + PHE
    • - Increased nitrogen retention and growth

    • 4. VL + NAT (N-acetyltyrosine)
    • - No benefit 

    • 5. VL + GT (dipeptide)
    • - Increased nitrogen retention and growth
  37. Tissue protein synthesis
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    • FSR (fraction synthesis rate)
    • -  Newly made per day
    • -  Measured by using isotope tracers

    • Lower protein synthesis in protein deficient (almost by half)
    • -  Lower protein synthesis in muscles leads to decrease in growth
    • -  Lower protein synthesis in visceral tissues leads to decrease in synthesis of immune-related proteins
  38. what are the protein requirements based on N balance?
    • EAR = 0.66 g/kg/d
    • RDA = 0.80 g/kg/d
  39. why is nitrogen balance (+) on the graph?
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    • Nitrogen balance is positive due to uncounted miscellaneous losses
    • Individual variability in protein metabolism is depicted as solid dots
    • Break point = 0.9g/kg/day
    • Break point + 2 standard deviation = 0.99g/kg/day
    • Oxidation technique with different protein intakes is used
  40. how does a low protein intake, specifically 0.6g/kg/d for 7 days, affect function?
    • ↓ Protein turnover (↓ Protein metabolism)
    • ↓ Albumin synthesis (negative acute phase protein)
    • ↑ Fibrinogen synthesis : involved in tissue repair and the last process of blood coagulation

    • Conclusion
    • Suggests that our current EAR is too low
  41. how does a moderate protein intake, specifically 0.75g/kg/d for 7 days (a little over the EAR), affect function?
    • ↓ Protein turnover
    • ↓ Albumin synthesis
    • ↓ Glutathione synthesis (tripeptide antioxidant)
    •   - antioxidant capacity, increased ↑ susceptibility to oxidative stress


    • Conclusion
    • Studies suggest that our EAR/RDA is too low
  42. what are the different organs involved in the metabolism of AAs?
    Digestion

    • 1.  Pepsin in stomach
    • Pepsinogen --> (acid) --> Pepsin
    • Acid unfolds proteins (not functional) then pepsin breaks down the proteins

    • 2.  Proteases from pancreas in small intestine – luminal digestion
    • Bicarbonate increases ↑ pH – inactivating/denaturing pepsin
    • There are many proteases exist – due to their specificity of cleavage sites

    3.  Peptidases on brush border of intestinal epithelial cells

    • 4.  Active transporters
    • In general, they parallel glucose transporters
    • Responsive to insulin
  43. what happens in the fed state (post prandial)
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    Anabolic state
    = insulin

    Gut: AA go to the liver by the portal vein, excess in the portal vein are catabolized

    Liver: ↑ protein synthesis, ↑ AA oxidation, promotes insulin secretion

    Pancreas: secretes insulin

    Secretion of insulin: ↑ protein synthesis and ↓ protein breakdown
  44. what happens in the fasted state? (fixxxxxxxx)
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    • Catabolic state = glucagon secretion
    • Glucagon = stimulates the Cori and Cahill Cycle to bring lactate and alanine to the liver
    • ↓ PS, ↓ oxidation of AA, ↑ PB
    • We take out blood glucose out of the store for the brain

    Muscles: breakdown of AA
  45. what happens in a long term fast (ADD)?
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    • Gut metabolism slows down
    • β - oxidation of FA generating Acetyl-CoA
    • ↑ Acetyl- Coa generates  in the absence of glucose producing ketones that can be used by the brain
  46. Liver vs Muscle
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    • Liver is much more metabolically active
    • Muscle is very slow in terms of protein and energy metabolism
    • Exercising = increasing very slow process
    • As we age, our muscle metabolism gets slower = less response to insulin
  47. How does the liver play into amino acid metabolism?
    • Anabolic: constitutive protein synthesis (proteins that stay in the liver, proteins that get exported), plasma protein synthesis, gluconeogenesis, lipogenesis
    • Catabolic: AA catabolism, urea cycle
  48. what are the differences in muscle mass?
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    • Hypertrophy (muscles getting bigger): Growth, anabolic, activation of PI3K-Akt pathway and MTOR
    • Atrophy (protein intake ↓ and muscle loss): Wasting, catabolic, Activation of ubiquitin-proteosome pathway
  49. insulin clamp studies (ASK)
  50. What are the enzymes for AA synthesis?
    • Essential AAs
    • 59 enzymes total required
    • We lost the capacity to make these enzymes
    • Expensive to make 
    • Survival advantage to be able to rely on diet

    • Non essential AAs (up to 11)
    • 17 enzymes required
    • Easy to make : directly or indirectly from glucose (except for tyrosine)
    • Survival advantage to maintain capacity to synthesize
    • Are they more important?

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NUTR - Topic 4
Updated:
2016-12-04 02:03:37
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