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Medical Biochemistry and Pathophysiology > Week 4A: Integration Metabolism, Role of Organs, Feast/Famine, Diabetes Mellitus & Alcohol > Flashcards

Week 4A: Integration Metabolism, Role of Organs, Feast/Famine, Diabetes Mellitus & Alcohol Flashcards

HC23-26

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USMLE® Step 1 flashcards
1
Q

Kinetics curve of multidomain enzymes with regulatory and catalytic domains

A

Sigmoidal curve
> sum curve R-state and T-state.
> do not obey Michaelis Menten kinetics

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2
Q

Multidomain, regulated enzymes are usually the ..

A

catalysers of the committed step in a pathway.

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3
Q

is HMG-reductase a monomer?

A

No, a highly regulated dimer: committed step in cholesterol biosynthesis

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4
Q

Which enzyme is targeted by statins?

A

HMG-CoA reductase
> also upregulates LDLR: higher dose used in homozygous FH than heterozygous FH (familial hypercholesterolemia)

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5
Q

Phosphorylation regulation in glycogen metabolism

A

Glycogen phosphorylase (GP): breakdown and glycogen synthase (GS): synthesis.
> a-forms, normally in active R-state
> allosteric metabolites can overrule phosphorylation status
> phosphorylation of GP and GS via PKA for example
> activates GP, inactivates GS

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6
Q

Phosphorylation regulation in fatty acid metabolism (acetyl-CoA carboxylase in synthesis)

A

Active carboxylase when dephosphorylated by PP2A.
Inactive carboxylase when phosphorylated by AMPK (AMP-activated protein kinase)

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7
Q

Difference AMPK and adenylate kinase

A

AMPK uses AMP and ATP to phosphorylate a protein
> result, AMP still bound, ATP to ADP for phosphorylation.
Adenylate kinase: ADP + ADP <=> ATP + AMP for extra energy

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8
Q

Why is the regulation of acetyl-CoA carboxylase logic?

A

When high AMP, low energy, no FA synthesis wanted.
AMPK phosphorylates and inactivates ACC

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9
Q

Metabolite regulation of liver and muscle glycogen phosphorylase

A

Liver: glucose can allosterically bind and inactivate the GP-a for change to T-state (even when phosphorylated in a form)
Muscle: binding AMP to get in R state as GP-b
Binding ATP or G-6-P causes change to T-state. (enough energy, no breakdown glycogen needed)
> not necessarily in a or b form, but it shows the overruling of phosphorylation state

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10
Q

Why isn’t liver GP inactivated by AMP?

A

The liver is the glucose homeostasis regulator and can convert G-6-P to glucose with G6Pase and needs to consider other tissues needs, not only its own

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11
Q

Metabolites may overrule phosphorylation regulation of enzymes: Acetyl-CoA carboxylase

A

Phosphorylated ACC is inactive. But if it binds citrate (shows that there is enough energy, TCA cycle stopped), than partly active ACC. (FA synthesis committed step)

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12
Q

Which enzymes is regulated as regulatory filaments?

A

Acetyl-CoA carboxylase forms regulatory filaments
> Palmitoyl-CoA (intermediate FA oxidation/breakdown) causes filaments to disassemble (product inhibition) to inactive dimers > induces conformational changes as a regulator

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13
Q

Name catabolic pathways and anabolic pathways (interconnected)

A

Catabolic:
- oxidation
- oxidative decarboxylation
- oxidative deamination
Anabolic
- Reductive biosynthesis
- Carboxylation
- Synthesis

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14
Q

Control of metabolic fluxes

A

-Based on energy states: fed, fasted, starvation
-Irreversible steps set the pace

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15
Q

Manipulation of metabolic fluxes

A

-Changing enzyme activities at irreversible steps with the high flux control (short term)
-Changing multiple activities at the same time: controlled gene expression (long term)

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16
Q

An irreversible step is a reaction with a large .. value

A

Keq
= [C][D]/[A][B]
in A + B <=> C + D
And large negative dG0
> change flux by changing enzyme activity or amount of enzyme

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17
Q

Reversible step has a … dG0 and flux can be changed by …

A

small, flux changed by changing concentrations of reactants

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18
Q

ATP yield of 1 glucose

A

Glycolysis: 2 ATP and 2 NADH (22.5=5)= 7 ATP
-Pyruvate oxidation: 2 NADH = 5 ATP
-TCA cycle: 2 acetyl CoA yields 2 times 3 NADH + 1 FADH2 + 1 GTP so 2 (7.5 ATP [3+2.5] + 1.5 [FADH2] + 1 [GTP] = 20 ATP
> total 30-32 ATP

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19
Q

1 glucose yields 30-32 ATP, dependent on

A

Shuttle which is used (redox) across mitochondria for NADH of glycolysis
- Glycerol-3-phosphate
- Malate-aspartate

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20
Q

Glycerol-3-phosphate shuttle

A

shuttle in muscle: DHAP in cytosol converted to glycerol-3-P by cytoplasmic glycerol-3-P dehydrogenase (GAPDH, using NADH) in intermembrane space and glycerol-3-P and this is converted by mitochondrial GAPDH to DHAP (yielding FADH2).
> 2 cytosolic NADH and yields 2 mitochondrial FADH2: 1.5 ATP per FADH2: 3 ATP. 30 ATP total
> turbo glycolysis

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21
Q

Malate-acetate shuttle

A

shuttle in liver, brain and heart muscle: 32 ATP yield. NADH reduces oxaloacetate in cytosol to malate and transport to matrix and in matrix conversion malate to oxaloacetate and through a-ketoglutarate and aspartate (converted from glutamate, coupled to oxaloacetate> a-ketoglutarate) back to cytosol. In cytosol conversion a-ketoglutarate to oxaloacetate (oxidize NADH) and aspartate to glutamate (tranport to matrix)
> 2 cytosolic NADH to 2 NADH in matrix: 2.5 ATP per, total 5, total 32 ATP

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22
Q

What happens to the FADH2 from glycerol-3-phosphate shuttle

A

Flavoprotein which donates electrons to coenzyme Q in ubiquinone (Q) form (reduced to ubiquinol QH2).

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23
Q

What happens to beta-oxidation created FADH2?

A

Electron-transfer protein (ETF) with the FADH2 prosthetic group.
> gives to Q

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24
Q

malate-aspartate shuttle is slower than glycerol-3-phosphate shuttle?

A

More enzymes involved.

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25
Q

Where does the decarboxylation of pyruvate to acetyl-CoA by PDH take place?

A

Mitochondrial matrix

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26
Q

Succinate dehydrogenase (TCA cycle enzyme) is part of the …. complex (complex II)

A

Succinate-Q reductase

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27
Q

Three sources of FADH2 which give electrons to coenzyme Q (ubiquinone (Q))?

A

-Succinate-Q reductase (complex II, with succinate dehydrogenase)
-Electron-transfer flavoprotein (ETF, beta-oxidation > from acyl-CoA dehydrogenase)
-Glycerol-3-phosphate shuttle.

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28
Q

What happens to glycerol (C3) in the liver in the fasted state?

A

Precursor for gluconeogenesis via
-Glycerol > glycerol-3-P
Glycerol-3-P > Triose-P (yields NADH > 2 per glucose)

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29
Q

Extra yield lactate as substrate gluconeogenesis

A

Lactate (C3) requires extra NADH oxidation > yields 2 extra NADH per glucose made

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30
Q

How is the NADPH required for FA synthesis made?

A

Pentose Phosphate Pathway

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31
Q

Committed step enzymes for glycogen and glucose metabolism

A

Glycogenolysis: Glycogen phosphorylase (GP)
Glycolysis: Phosphofructokinase (PFK-1)
Glycolysis > TCA cycle: Pyruvate dehydrogenase
PPP: Glucose-6-P dehydrogenase
Gluconeogenesis: Pyruvate carboxylase (PC)

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32
Q

Committed step enzymes FA metabolism, Cholesterol biosynthesis, ketogenesis and urea cycle

A

FA breakdown: Carnitine Palmitoyl transferase I (CPT-I)
FA synthesis: Acetyl-CoA Carboxylase (ACC)
Cholesterol biosynthesis: HMG-CoA reductase
Ketogenesis: HMG-CoA synthetase
Urea cycle: Carbamoyl-phosphate synthetase

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33
Q

Which intermediate is formed when condensing citrulline and aspartate to argininosuccinate in urea cycle?

A

Citrulline-AMP (adenylated)

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34
Q

Structure urea: central carbon, two amino groups and oxygen atom. Where are the origins?

A

Amino group 1: Deamination
Amino group 2: aspartate
Carbon: Hydrogen carbonate (HCO3-, from hydration of CO2)
Oxygen: from water H2O in last step: Arginine + H2O > Ornithine + Urea

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35
Q

How are the TCA cycle and respiratory chain coupled? What is respiratory control

A

NADH activated carrier
> more oxygen required when more ATP needed in exercise: respiratory control
> halt both when enough ATP

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36
Q

How is ATP synthesis coupled to respiratory chain?

A

Proton gradient
> Halt when enough ATP: proton pumps stop, NADH concentration high and NAD+ low, TCA cycle stops (accumulation of acetyl-CoA and citrate as regulators ….)

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37
Q

How is urea cycle linked to gluconeogenesis?

A

Nitrogen metabolism of fumarate and aspartate
Argininosuccinate to arginine releases fumarate which is converted to oxaloacetate via malate.
> oxaloacetate to gluconeogenesis
> oxaloacetate to aspartate by deaminating an alpha-amino acid
> use aspartate in urea cycle

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38
Q

Pasteur effect glycolytic ATP vs mitochondrial ATP

A

Inhibition glycolysis by respiration
> preference for mitochondrial oxidation of pyruvate.
> in mitochondrial malfunction: glycolysis and lactate formation highly stimulated

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39
Q

Lactate dehydrogenase reaction

A

Lactate donates Hydride ion and hydrogen ion (H+) from the C2 carbon (count from carboxyl end) to NAD+ to form NADH, H+ and pyruvate.
> First: Removal H+
> NAD+ can take up hydride ion (H-: H+ + 2 e-)

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40
Q

Which amino acid side chain can take up H+?

A

Histidine
> in lactate dehydrogenase, lactates H+ transferred to active site His-195 and hydride ion to NAD+

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41
Q

Warburg effect

A

Using glycolysis when oxygen is available
> in tumor cells
> PDH strongly inhibited
> upregulation glycolysis
> downregulation mitochondrial respiration (increased membrane potential)

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42
Q

Important role for this factor in Warburg effect

A

Hypoxia-inducible factor 1-alpha (HIF-1alpha)

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43
Q

Altered gene expression in tumor cells for Warburg effect

A

Hypoxia
> activation HIF-1 transcription factor
> metabolic adaption: block PDH, increase glycolytic enzymes, and blood vessel growth stimulated
> without O2 as electron acceptor: respiratory chain is unable to generate proton motive force

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44
Q

Paradox of the Warburg effect in cancer cells

A

Lactate production with or without oxygen
> little but use of mitochondria
> anaerobic glycolysis rules

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45
Q

Which enzyme inhibits PDH and therefore oxidative phosphorylation

A

Pyruvate dehydrogenase kinase (PDK) phosphorylates and inhibits PDH

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46
Q

Drug to target Warburg effect

A

Dichloroacetate (DCA) activates PDH flux
> normalize mitochondrial protein motive force and inhibits tumor growth
> slows down tumor growth
> PDK inhibited

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47
Q

Fates pyruvate in liver

A

-To oxaloacetate by pyruvate carboxylase (gluconeogenesis, fasting)
-To acetyl-CoA by PDH (fed state)
> metabolic regulator of the fate: acetyl-CoA (accumulated when TCA cycle halted and high energy), activates PC and inactivates PDH.

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48
Q

Reciprocal regulation glycolysis/gluconeogenesis

A

F-2,6-BP
> Activates PFK-1, inactivates F-1,6-BPase
ATP/ADP
> ATP inactivates PFK-1 and PK
> ADP inactivates PC and PEP carboxylase
> AMP inactivates F-1,6-BPase
Citrate
> inactivates PFK-1 and activates F-1,6-BPase
Others
> Low pH (H+) inactivates PFK-1 (lactate production/ anaerobic)
> Alanine inhibits PK (substrate gluconeogenesis, signals starvation)

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49
Q

Reciprocal regulation in FA metabolism

A

Committed enzyme synthesis > ACC; acetyl-CoA carboxylase
> activated by citrate (feedforward stimulation)
> inhibited by palmitoyl-CoA (before committed step beta-oxidation)
Carnitine-palmitoyl transferase-1 (committed in beta-oxidation)
>Inhibited by malonyl-CoA, product of committed step in FA synthesis from Acetyl-CoA, HCO3- and ATP (to ADP + Pi)

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50
Q

HC24: Why do fats contain the most energy?

A

More reduced carbons: more energy for oxidation
> less polar and water attraction
> less osmotic value

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51
Q

Glucose and VLDL or Chylomicrons to TAGs in adipocytes

A

Glucose from liver
> Uptake by GLUT4, Glucose to glycerol-3-P
Fatty acids uptake by FATP and CD36, released by LPL out of VLDL (from liver) or chylomicrons (from intestine)
> FAs to acyl-CoA
> Glycerol-3-P + acyl-CoA > TAGs

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52
Q

TAG products from lipolysis in adipocyte in blood

A

-Glycerol: to liver
-FA-albumin complexes > to peripheral tissue

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53
Q

How are hormones produced by adipocytes called?

A

Adipokines

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54
Q

When are leptins secreted by adipocytes?

A

When the lipid droplet is full > feeling of saturation / satiety > enough eaten

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55
Q

Leptin signaling

A

Bind receptors in the arcuate nucleus (ARC) in the hypothalamus
> insulin has this function as well
> inhibition NPY and AgRP and activation POMC producing neurons > POMC increases MSH expression > decrease food intake

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56
Q

Obesity is often associated with … resistance

A

Leptin resistance

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57
Q

Additional satiety signals to the brain

A

-Response to feeding: intestinal cells secrete hormones cholecystokinin (CCK) from I cells and glucagon-like peptide (GLP-1) from L cells

58
Q

GLP-1 function

A

GLP-1 is an incretin > hormones that prepare pancreatic beta cells to amplify their response to incoming glucose by increasing insulin secretion and biosythesis, while inhibiting glucagon secretion from alpha cells via insulin

59
Q

How is glucagon and GLP-1 made

A

The human glucagon gene encodes for preproglucagon polypeptide (180 AA).
> during translation, signal peptide cleaved off by signal peptidase while proglucagon enters secretory pathway via lumen of RER
> in pancreatic alpha cells, proteases cleave proglucagon into mature glucagon and other peptides
> in intestinal L cells, proteases cleave proglucagon into GLP-1 and other peptides

60
Q

Effect Semaglutide (Ozempic)

A

GLP-1 receptor agonist
> popular anti-obesity medication for treatment T2DM and decreases blood glucose levels in patients

61
Q

Leptin -/- mice symptoms

A

Obese, insulin-resistant, diabetic

62
Q

Molecular mechanism Ozempic

A

Bind to GLP-1 receptors and function as incretin

63
Q

Functions liver in fasted and starved state as central regulator

A

-Fasted: producer glucose and FAs for other organs
-Starved: producer ketone bodies

64
Q

In liver: glycolysis mainly for production …. for …

A

Acetyl-CoA, for FA synthesis, ketone bodies and other buidling blocks

65
Q

Liver as internal energy source: mainly ….

A

Catabolism of amino acids
> transamination and citric acid cycle.

66
Q

Brain as top consumer

A

60% glucose needs, constant needs
> needs a lot of glucose and ketone bodies in starvation

67
Q

Why is FA oxidation not possible in brain

A

Blood brain barrier
> only oxidation glucose and ketone bodies

68
Q

Erythrocytes have no mitochondria and use anaerobic glycolysis using LDH for NAD+ regeneration. Name two other types of this regeneration with cellular location and tissue type

A
  1. Glycerol-3-phosphate shuttle (mitochondria, oxidation, muscle)
  2. Malate-aspartate shuttle (mitochondria, oxidation, liver, brain and heart muscle)
69
Q

Differences metabolism skeletal muscle and heart muscle

A

Fuels
> Skeletal: glucose mainly
> Heart: mainly FAs and ketone bodies
Lactate
>Skeletal: Producer
> Heart: consumer
O2 dependent
> Skeletal: not dependent
> Heart: completely O2 dependent
Shuttle for transport redox equivalents
> Skeletal: Glycerol-3-P shuttle
> Heart: Malate/aspartate shuttle

70
Q

Glucose-alanine cycle

A

Muscle: glucose > pyruvate
Branched-chain amino acids > carbon skeletons for cellular respiration (energy) and glutamate (transamination)
Glutamate+pyruvate > Alanine (/ glutamine)
> blood
Liver: Alanine to pyruvate and glutamate
Glutamate to NH4+ (deamination) to urea (urea cycle)
Pyruvate to glucose (gluconeogenesis)

71
Q

The master regulator of intracellular metabolism”:

A

mTOR complex

72
Q

Lifting weights to failure and feeding lead to increased muscle mass, how?

A

Mechanoreceptors sense activity of muscle
> second signal: certain amino acids from diet like Leucine for which transporter proteins are needed.
> Combination leads to removal of inhibitors of mTOR complex 1 (inactive mTORC1) to active mTORC1
> mTORC1 activates protein synthesis and muscle hypertrophy

73
Q

How does active mTORC1 promote protein synthesis

A

Bind to lysosomes and stimulate release building blocks for myofibrils and other muscle proteins.

74
Q

Nitrogen transport through blood as glutamine

A

In muscle and other peripheral tissues in mitochondria:
NH4+ + Glutamate + ATP > Glutamine + ADP + Pi (glutamine synthase)
-Transport
Reaction in liver
Glutamine + H2O > Glutamate + NH4+ (Glutaminase)
Glutamate > NH4+ (glutamate dehydrogenase)
NH4+ > urea in urea cycle (CPS, carbamoyl-phosphate synthetase)

75
Q

The liver enzymes glutaminase, glutamate dehydrogenase and carbamoyl phosphate synthase are all located in …

A

mitochondria
> NH4+ is toxic (ammonium ion) and should be compartmentilized

76
Q

Protein breakdown is upregulated in starvation, how?

A

Autophagy initiated
> and protein breakdown in GI tract

77
Q

How long does it take of starvation for ketone bodies to be in high level (ketosis)?

A

A week

78
Q

Extreme starving characteristics and risks

A

Survival on vitamin supplements, potassium, sodium, non caloric drinks
> danger: low level of blood glucose, survival but not active, hypoglycemia
> continuous urea production from protein breakdown
> Danger: muscle breakdown
-Not an issue for skeletal muscle: grow it back later
-Issue for heart muscle breakdown

79
Q

Adipocytes can secrete adipokines and …

A

cytokines

80
Q

HC25: Which pathways are active in the fed state?

A

Insulin rules (high blood glucose)
> Uptake glucose by muscle and adipocytes
> Storage as glycogen and fat/TAGs

81
Q

Which pathways are active in the fasted state?

A

Insulin levels drop, glucagon released in circulation by pancreatic alpha cells
> maintain glucose levels: glycogenolysis, gluconeogenesis in liver. Ketone body synthesis in liver.

82
Q

What do muscles make from glucose in the fed state? And adipocytes? And which other tissues need lots of glucose?

A

Muscle: make glycogen and FAs > TAGs.
Adipocyte: make FAs > TAGs
Erythrocytes and brain need glucose

83
Q

Transport lipids in fed state

A

From diet: Chylomicrons (intestine>lymph>blood)
From liver (made from glucose and incoming amino acids in liver) : VLDL
> Uptake by uscle and adipocytes to store as TAGs and use for energy (muscle)
> brain only uses glucose (and ketone bodies, not in fed state)

84
Q

Effects of insulin

A

-Activation glycogen synthase, inhibition glycogen phosphorylase (inactivates GS kinase by phosphorylation by PKB)
-Activation glycolysis enzymes in liver, synthesis glucokinase
-Breakdown of glucose is promoted in liver: cells have enough ATP, but liver has to overrule system because it needs to do something with the glucose (for example by F-2,6-BP) > FA synthesis (high energy) > transport and storage in adipose tissue
-Inhibition gluconeogenesis enzymes
- Activation acetyl-CoA carboxylase synthesis (palmitate synthesis, to store energy in TAGs)
- Inhibition glucagon production > reciprocal regulation (inhibit alpha cells)

85
Q

Glucagon effects

A

-Activation glycogen phosphorylase, inhibition glycogen synthase (through PKA which activates GP kinase and inactivates GS)
-Increase gluconeogenesis enzymes like pyruvate carboxylase
-Increase protein degradation in cell: autophagy
-Increase urea synthesis enzymes in liver
-increase TAG lipases activity in adipocytes (through PKA and Hormone sensitive lipase)
-inhibition acetyl-CoA carboxylase and enzymes Pentose Phosphate Pathway
-increase HMG-CoA synthase (ketone body synthesis committed)

86
Q

Exercise while in the fed state result on glycogen metabolism

A

Overrule signal of fed state (Glycogen phosphorylase-b dephosphorylated, no glucagon yet) > adrenalin will facilitate that calcium can bind to calmodulin in phosphorylase kinase for activation

87
Q

Fast glycogen regulation in liver (spontaneous exercise)

A

Adrenaline binds to alpha-adrenergic receptor
> Activation trimeric G-protein (GDP for GTP swap)
> Active G-protein activates Phospholipase C (PLC)
> PLC cleaves PIP2 to DAG and IP3
> IP3 facilitates Ca2+ release out of ER by binding IP3-sensitive Ca2+ channels.
> Ca2+ facilitates binding DAG to Protein Kinase C (PKC)
> Active PKC
> Ca2+ also activates GP kinase. Activation

88
Q

Fast regulation glycogen breakdown in muscle cell

A

Muscle cell reacts to adrenaline (like liver) and nerve impulses (liver does not)
> Adrenaline binds beta-adrenergic receptor
> Activation G-protein which activates adenylate cyclase which makes cAMP that activates PKA.
> PKA activates GP kinase and inactivates GS
> Nerve impulse opens Ca2+ channels on PM.
> Ca2+ binds calmodulin (delta subunits in GP) in GP kinase
> activation as well

89
Q

General regulation GP kinase by Ca2+ and PKA

A

GP-kinase binds Ca2+ by calmodulin subunits (because of adrenline in liver, muscle contraction in muscle)
> Partly active
GP kinase is also phosphorylated by PKA (because glucagon in liver, adrenaline in muscle)
> fully active
> extra step regulation: finetuning of enzyme activity
> Conversion GP-b to GP-a by GP kinase which is mostly in R-state, unless inhibited by glucose in liver or ATP/G-6-P in muscle (phosphorylation of both monomers using 2 ATP)

90
Q

Allosteric activation GP-b

A

AMP, GP-b will be a bit active (overrules phosphorylation state)

91
Q

When insulin rules in glycogen metabolism

A

Phosphorylation and deactivation GS kinase
PP1 can desphosphorylate and activate GS and inactivate GP
> Inhibition glucagon secretion, so PKA, GP kinase will not be active.

92
Q

What is important during starvation in metabolism

A

-Sufficient glucose in blood (all times for brain and heart)
> amino acids for long term
> Prevent protein degradation by making ketone bodies (ketosis (high concentration ketone bodies in blood, after a week) is healthy back up mechanism)
-Prevent protein degradation
> lower pace at long term because of ketogenesis
> gluconeogenesis also a little active even after a month

93
Q

Difference fasted state and starved state

A

-In starved state, all glycogen is gone (after 1.5 day)
-In muscle, fat breakdown is active, own fat storage. it takes free fatty acids from adipocytes.

94
Q

Lipid metabolism during starvation

A

Lipolysis of TAGs in adipocytes > FFAs to liver.
> Liver uses FAs for beta-oxidation and makes ketone bodies from acetyl-CoA.
> Ketone bodies to brain and muscle
> FFAs also to muscle
> Muscle uses ketone bodies and FAs for fuel.
> Glycerol used by liver for gluconeogenesis: provide energy to brain and red blood cells via glucose

95
Q

What happens to the released amino acids from proteolysis in muscle cells>

A

No storage space, transport alanine / glutamine to liver and breakdown to glucose (carbon skeleton) and urea
> glucose used to provide glucose for brain and red blood cell

96
Q

Precursors gluconeogenesis in liver

A

-Alanine and glutamine from protein
-Lactate from red blood cells
-Glycerol from adipocytes

97
Q

The cell contains limited amounts of ATP/ADP/AMP, NAD+/NADH and NADP+/NADPH. How is this possible during exercise?

A

Recycling of intermediates

98
Q

HC26: Sources of plasma glucose

A

-DIet
-Glycogenolysis
-Gluconeogenesis

99
Q

Insulin levels during day

A

Fluctuate: dependent on glucose intake
> ALWAYS basal level of glucose secretion to suppress alpha cells a bit in glucagon production.

100
Q

Insulin injection during night for diabetics: how much?

A

For the whole night

101
Q

Symtoms Diabetes mellitus type 1: blood glucose and urine

A

Sweet urine
High blood glucose (10 mM +)

102
Q

Untreated T1DM is called starvation in the midst of plenty, explain

A

Beta cells in pancreas destroyed, high glucagon even when high blood glucose (signalling starved state)
> Glycogen breakdown in liver to glucose and release to blood
> No GLUT4 transporters on muscle and adipose
> Protein breakdown in muscle and amino acid breakdown to glucose (carbon skeletons) and urea in liver
> Breakdown fat to FAs in adipocytes, release as FFAs (high concentration in blood)
> FFAs taken up by liver to make ketone bodies: ketoacidosis in blood
> FAs in liver used for making VLDL and TAG transfer (increased in blood)

103
Q

Concentrations of insulin, glucagon, glucose, ketone bodies and TAGs/FFAs in T1DM vs starvation

A

Insulin
> T1DM: absent, starvation: low
Glucagon
> T1DM: extremely high, starvation: increased (basal level insulin)
Glucose
> T1DM: extremely high, starvation: normal low
Ketone bodies
> T1DM: extremely high, starvation: moderately increased
TAGs/FFAs
> T1DM: high, starvation: normal

104
Q

Ketosis means

A

High concentrations of ketone bodies in blood
> healthy back-up mechanism

105
Q

Ketoacidosis meaning and process

A

Excessive amounts of ketone bodies in blood which leads to acidification of the blood.
> Release ketone bodies from hepatocytes: ketone bodies have negative charge and need cotransport of H+ to retain charge and voltage across membrane
> acidosis: dangerous for the blood: blood pH needs to be in brief window. (for function of blood components like HbA)

106
Q

How can T1DM patients get unconscious, and solution?

A

Insulin injection but no meal in a panic situation
> insulin signals glucose uptake, but there is no dietary glucose
> Hypoglycermia: 2 mM
> Solution: inject glucagon or epinephrine intramusclular or intravenous glucose administration

107
Q

Why do T1DM patients have an acetone smell breath?

A

Acetone is a product from the ketone body acetoacetate. Acetoacetate can be converted to acetone in a non-enzymatic spontaneous reaction. Acetone is a gas and in released in the breath and urine. (spontaneous decarboxylation, C4> C3)
> Acetoacetate is instable

108
Q

How can dehydration occur with T1DM untreated?

A

High glucose excretion via urine which takes along a lot of water in the kidneys through osmosis
> a lot of hydrogen bond acceptors (O/N) and donors (OH/NH)

109
Q

Patient with dehydration, deep and frequent acetone breath, and very high blood glucose (28 mM&raquo_space; 10 mM). And acidosis (pH = 7.2, not in frame of 7.32-7.44). What is it and what to do?

A

-Ketoacidosis > untreated T1DM
-Ketone bodies in urine
> Buffer of pH in blood is bicarbonate (HCO3-): binds with H+ and breath out as CO2.
> remove acidity of the blood through CO2: deep and frequent breathing
> unconsciousness possible
Solution: intravenous insulin administration

110
Q

Bond in the glycation of proteins?

A

Schiff base bond
> hemoglobin for example
> HbA1c (glycated) is parameter for blood glucose over time

111
Q

Unconsciousness causes in T1DM

A

-Insulin injection but no meal
-Ketoacidosis very high: untreated T1DM or triggered by infection

112
Q

Glycation of hemoglobin

A

Open chain glucose reducing aldehyde end at carbon-1 reacts with epsilon-amino residue of HbA beta chain N-terminal
> reversible spontaneous non-enzymatic linkage through Schiff base linkage (-HC(nr.1)=N-Lys-HbA)
> irreversible spontaneous non-enzymatic Amadori rearrangement to HbA1c (H2C(nr.1)-N(H)-Lys-HbA)

113
Q

Problem glycation of proteins

A

loss of protein function and impaired elasticity of tissues such as blood vessels, skin, and tendons
> HbA1c increases chance of atherosclerosis and free radicals in erythrocytes

114
Q

T2DM characteristics

A

-Threat at obesity
-BMI: 26 is borderline healthy and overweight
-Insulin resistance (insensitive)
-No deficiency of insulin secretion

115
Q

Effect insulin resistance

A

-High insulin secretion
-GLUT4 inactive: no uptake glucose by muscle and adipocytes for storage
-Glycogen synthesis in liver not possible

116
Q

Is the insulin receptor expressed in T2DM?

A

Yes, but the signal transduction upon insulin binding doesn’t function well.

117
Q

Effects metabolism in T2DM

A

-No glycogen synthesis in liver
-No uptake glucose by GLUT4
-Hyperglycemia
-Glucose and amino acid carbon skeletons in liver (from diet) used to make fat and transport as VLDL secrtion
> Inreased FAs and TAGs in blood
> normal chylomicrons through diet fats.
-Brain and erythrocytes take up glucose like normal

118
Q

Unregulated T2DM is less bad than T1DM, why

A

There is still insulin to dampen the glucagon secretion
> no ketoacidosis

119
Q

How does T2DM develop?

A

-Substrate competition because of high FA in plasma
-Glycolipids in plasma membrane: insulin receptors have reduced affinity for insulin

120
Q

Sources FAs in blood

A

-Food (chylomicrons)
-Fat from adipocytes: FFAs

121
Q

Fatty liver risk in obese persons

A

In healthy persons: adipocytes store TAGs.
Overweight > liver and muscle can store TAGs, fatty liver.

122
Q

Shulman hypothesis in T2DM for signalling and insulin resistance

A

-More fatty acids which can form DAG glycerol-3-P (FAs upregulated)
-DAG activates PKC (isozymes for liver and muscle)
-PKC phosphorylates the insulin receptor on the wrong place (on the serine or threonine, not the tyrosine)
> in some, but not all, insulin receptors
> those receptors are not properly activated
> Insulin binds receptor, but signal not properly transduced
> less signal transduction: insulin resistance

123
Q

Prevention and treatment strategies T2DM

A

-Treatment is reducing weight and FFAs and prevention is lifestyle chages.
> PPAR-gamma (TF) / thiazolidinedione promote conversion FAs to fat in adipocytes
> ATP use promotes beta-oxidation of FAs to generate energy through TCA cycle (oxidized to CO2 and H2O)

124
Q

Alcohol metabolism

A

Ethanol is converted to acetaldehyde by alcohol dehydrogenase. (in cytosol) (oxidation, yields 1 NADH)
Acetaldehyde is converted to acetic acid by aldehyde dehydrogenase (in mitochondria) (oxidation, yields 1 NADH)

125
Q

Asian mutations in alcohol metabolism

A

-Increased activity alcochol dehydrogenase
-Decreased activity aldehyde dehydrogenase
-Accumulation acetaldehyde
> red flush, headache, accelerated heart rate, shortness breath, blurred vision etc

126
Q

When a alcohol molecule is oxidized, it becomes a

A

aldehyde

127
Q

Danger of aldehydes

A

Aldehyde group is reactive
> can cross link and form Schiff bases (think of glycation (schiff base) and glycosylation (cross links)

128
Q

Inhibition of intake alcohol by disulfiram

A

> blocks aldehyde dehydrogenase
faster accumulation acetaldehyde, stop drinking faster because drunk symptoms

129
Q

If a patient is unconscious with hypoglycemia (2.5 mM) and increased alcohol promillage (0.6). There is no creatine kinase in the blood. Is there a heart attack?

A

No.
> If there is no oxygen, (heart) muscle cells can burst > creatine kinase (for conversion creatine in creatine phosphate as reserve for substrate level phosphorylation) in blood.
> no heart attack, because no creatine kinase in blood

130
Q

Alcohol patient has high aspartate aminotransferase in blood. This means:

A

Liver damage
> Increased aspartate deamination (increased urea cycle) in liver
> Aspartate aminotransferase in blood? > liver cells are dying and release enzymes in blood

131
Q

Lactic acidosis in alcohol patient

A
132
Q

Treatment high aspartate aminotransferase and lactate and low pH blood in unconscious alcohol patient

A

Intravenous glucose
> what happened: no meal: low glycogen level reserve
> Glycogenolysis insufficient to maintain blood glucose levels
-Gluconeogenesis in liver, but is damaged: hepatocytes die because of toxic acetaldehyde
> cirrhosis: liver less active
> patient skinny: muscle breakdown to generate amino acids as substrate

133
Q

Consequences alcohol metabolism for glucose metabolism

A

-Generation high amount of NADH+ H+
-Pyruvate converted into lactate to regenerate NAD+
-Less pyruvate available for gluconeogenesis!

134
Q

Gluconeogenesis inhibited by excessive alcohol intake: through NADH+ H+. and other effects

A
  1. Equilibrium lactate-pyruvate towards lactate
  2. equilibrium gycerol-triose phosphates towards glycerol (make NAD+) > fatty liver induced
  3. Transport of oxaloacetate via malate-shuttle towards mitochondria to regenerate NAD+
    > Conversion NADPH into NADP+: glutathione regeneration disturbed: oxidative stress up
    > TCA cycle blocked: Acetyl-CoA converted into ketone bodies: acidosis
135
Q

Liver cirrhosis process

A

Fatty liver > apoptosis > inflammation (hepatitis) > scar tissue (fibrosis)

136
Q

Alcohol and exercise dampens problems?

A

Burining ATP > use electron transport chain > NADH oxidized to NAD+ in oxidative phosphorylation instead of anaerobic glycolysis.

137
Q

Activator of ketogenesis

A

Acetyl-CoA (substrate)
> beta-oxidation FAs

138
Q

Muscles and brain can use ketone bodies for energy but not liver, why

A

No enzyme CoA-transferase for acetoacetate to acetoacetyl-CoA using succinyl-CoA > energy breakdown
> more acetyl-CoA from beta-oxidation, activate ketogenic enzymes
> liver is ketogenic, not ketolytic

139
Q

When ketone body synthesis

A

When concentrations acetyl-CoA rise dramatically
> untreated T1DM and starvation

140
Q

The HCO3- used by acetyl-CoA carboxylase in FA synthesis to make malonyl-CoA, where do these carbons appear in the FA?

A

Nowhere
During condensation in elongation cycle of malonyl-ACP and acetyl-ACP, it is removed as CO2.

141
Q

Ketolysis

A

Acetoacetate + succinyl-CoA > acetoacetate-CoA + succinate (CoA transferase, not in liver)
Acetoacetate-CoA + CoA > 2 Acetyl-CoA (thiolase)

Medical Biochemistry and Pathophysiology (16 decks)

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