Trauma and Gluconeogenesis Flashcards

1
Q

Where does gluconeogenesis occur?

A

Predominantly in the liver

Also occurs in kidney

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2
Q

What activates and inhibits gluconeogenesis?

A

Activated by glucagon

Inhibited by insulin

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3
Q

When is gluconeogenesis very active?

A

Very active following trauma

Very active in Type 2 diabetes and is dysregulated (unopposed glucagon effect because of insulin resistance)

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4
Q

Name the key precursors for gluconeogenesis.

A

Lactate - from muscle glycolysis, from anaerobic metabolism
Glycerol - from lipolysis of TAG in adipose tissue
Alanine - from proteins

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5
Q

Aerobic vs anaerobic metabolism.

A

Aerobic - long duration of exercise, occurs in presence of oxygen
Anaerobic - quick bursts of intense exercise, no oxygen

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6
Q

Name the two irreversible steps which are needed to overcome when converting pyruvate back to glucose (in gluconeogenesis).

A

Pyruvate to phosphoenolpyruvate (PEP)

F1,6bisP to F6P

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7
Q

List the 5 key enzymes which are important in bypassing the enzymic roadblocks in GNG.

A
Glucoses-6-phosphatase
Fructose-bi-phosphatase
Pyruvate carboxylase (PC)
PEP carboxykinase (PEPCK) 
Pyruvate dehydrogenase (PDH)
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8
Q

What is Beta Oxidation?

A

Fatty acids into acetyl CoA

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9
Q

What is ketogenesis?

A

Acetyl CoA into ketone bodies

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10
Q

What is CAC?

A

Acetyl CoA into CO2, ATP, NADH, FADH2

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11
Q

Describe how we convert pyruvate into phosphoenolypyruvate (PEP).

A

Accumulation of acetyl CoA from glycolysis and beta oxidation
This inhibits pyruvate dehydrogenase (PDH) - which would normally convert pyruvate into acetyl CoA
Instead PC is activated, transferring pyruvate into oxaloacetate
Oxaloacetate is converted into PEP via PEPCK
Fasting stimulates gluconeogenesis

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12
Q

What effect does glucagon have on the enzymes involved in Pyruvate –> PEP.

A

Glucagon wants to increase glucose - thereby stimulate gluconeogenesis
Promotes phosphorylation of PK - inhibits PK
Activates PEPCK

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13
Q

What effect does insulin have on the pathway: pyruvate –> PEP.

A

Insulin wants to decrease glucose - thereby promote glycolysis.

  • Activates PK (promotes dephosphorylation of PK)
  • Inhibit PEPCK
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14
Q

List things that inhibit PEPCK. (converts oxaloacetate to PEP) (stimulate gluconeogenesis)

A

Insulin
Metformin
Thiazolidinediones

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15
Q

List substances the activate PEPCK (oxaloacetate to PEP)

A

Cortisol
Thyroid hormone
Glucagon
Adrenaline

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16
Q

What are the effects of insulin resistance on gluconeogenesis?

A

In an insulin resistance state, insulin does not act effectively on PEPCK and G6Pase
So it does not effectively suppress gluconeogenesis

17
Q

What is the function of Fruc-2,6-BP?

A

Fructose-2,6-BP is an important allosteric effector. It stimulates PFK1 promoting glycolysis. It inhibits F-1,6-BP, thus blocking GNG

18
Q

Fruc-1,6-BP into Fru-6-P via F-1,6-BP
Fruc-6-P via PFK-2 into Fruc-2,6-BP
Fruc-2,6-BP via Fru-2,6-Bpase into Fruc-6-P
Fruc-6-P into Glc-6-P

A

Second pathway to overcome

19
Q

What are the effects of insulin resistance?

A

Many steps in gluconeogenesis are downregulated by insulin and upregulated by glucagon.
In an insulin resistant state, the actions which are dependent on insulin won’t be properly executed = leaving the effect of glucagon unopposed
= in type II diabetes - liver makes too much glucose

20
Q

List some conditions with impaired gluconeogenesis.

A

Premature babies with low glycogen stores and undeveloped livers
High alcohol metabolism (increased NADH, low NAD)
Rare genetic diseases (e.g. F1,6-biphosphatase or G-6 phosphatase deficiency)

21
Q

List some conditions with overactive gluconeogenesis.

A

Insulin resistance
Diabetes
Trauma

22
Q

What happens in response to trauma?

A

Elevated metabolic rate
Increased energy needs
Increased gluconeogenesis

23
Q

What are the drivers of the trauma response?

A

Adrenaline
Glucagon
Cortisol
Cytokines

24
Q

Describe the different phases of metabolic response to injury.

A

Pre injury: fight or flight response (under adrenaline - similar effects to glucagon)
24 hours following injury: “Ebb phase/shock” - adrenaline secretion & pituitary secretion (cortisol, ACTH, prolactin, glucagon)
Flow Stage: Catabolic: break things down, adrenaline dies out, following 24 hours
Convalescent: Anabolic - things start to normalize

Pre-injury,/Anticipation Injury, Ebb/Shock Phase, Flow Phase (Catabolic) , Convalescent Phase (Anabolic)

25
Q

Describe the effects of injury and sepsis on metabolism.

A

Both insulin and glucagon are up, but insulin resistance is present.
Glucose oxidation is down - gluconeogenesis is taking place
Fatty acid oxidation: normal and increased in sepsis
Muscle loss, lean body mass loss post injury, catabolic phase

26
Q

Describe the glucose tolerance vs stage of injury.

A

Day of injury: high glucose before oral load, glucose level shoots up after consumption and remains high
1st day post injury: glucose tolerance test is improved, but not back to normal
4th day post injury: back to normal almost

27
Q

Why does alcoholism impair gluconeogenesis?

A

Metabolism of alcohol consumes significant NAD
NAD is needed to convert lactate into pyruvate for gluconeogenesis
Therefore chronic alcoholics may have low pyruvate and develop hypoglycaemia

28
Q

What are the features of the catabolic phase?

A

Increased metabolic rate
Weight loss
Evidence of muscle wasting (negative nitrogen balance)

29
Q

What are the contributing factors of the catabolic phase?

A

Metabolic requirements: tissue repair, immune response
Insulin resistance
Cytokines and inflammatory mediators (TNFalpha, IL-2)
Lack of appetite

30
Q

What are the effects of TNF alpha?

A
Stimulates lipolysis 
Inhibits lipoprotein lipase 
Induces PEPCK (stimulates gluconeogenesis) 
Inhibits insulin secretion 
Causes insulin resistance
31
Q

Describe metabolism in cancer cells.

A
Tumour cells need lots of energy 
Have altered metabolism, especially involving glucose
Tumour cells primarily use glycolysis 
Known as Warburg effect 
Increased glycolysis 
Increased lactate 
Negative nitrogen balance