Trauma and Gluconeogenesis Flashcards
Where does gluconeogenesis occur?
Predominantly in the liver
Also occurs in kidney
What activates and inhibits gluconeogenesis?
Activated by glucagon
Inhibited by insulin
When is gluconeogenesis very active?
Very active following trauma
Very active in Type 2 diabetes and is dysregulated (unopposed glucagon effect because of insulin resistance)
Name the key precursors for gluconeogenesis.
Lactate - from muscle glycolysis, from anaerobic metabolism
Glycerol - from lipolysis of TAG in adipose tissue
Alanine - from proteins
Aerobic vs anaerobic metabolism.
Aerobic - long duration of exercise, occurs in presence of oxygen
Anaerobic - quick bursts of intense exercise, no oxygen
Name the two irreversible steps which are needed to overcome when converting pyruvate back to glucose (in gluconeogenesis).
Pyruvate to phosphoenolpyruvate (PEP)
F1,6bisP to F6P
List the 5 key enzymes which are important in bypassing the enzymic roadblocks in GNG.
Glucoses-6-phosphatase Fructose-bi-phosphatase Pyruvate carboxylase (PC) PEP carboxykinase (PEPCK) Pyruvate dehydrogenase (PDH)
What is Beta Oxidation?
Fatty acids into acetyl CoA
What is ketogenesis?
Acetyl CoA into ketone bodies
What is CAC?
Acetyl CoA into CO2, ATP, NADH, FADH2
Describe how we convert pyruvate into phosphoenolypyruvate (PEP).
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
What effect does glucagon have on the enzymes involved in Pyruvate –> PEP.
Glucagon wants to increase glucose - thereby stimulate gluconeogenesis
Promotes phosphorylation of PK - inhibits PK
Activates PEPCK
What effect does insulin have on the pathway: pyruvate –> PEP.
Insulin wants to decrease glucose - thereby promote glycolysis.
- Activates PK (promotes dephosphorylation of PK)
- Inhibit PEPCK
List things that inhibit PEPCK. (converts oxaloacetate to PEP) (stimulate gluconeogenesis)
Insulin
Metformin
Thiazolidinediones
List substances the activate PEPCK (oxaloacetate to PEP)
Cortisol
Thyroid hormone
Glucagon
Adrenaline
What are the effects of insulin resistance on gluconeogenesis?
In an insulin resistance state, insulin does not act effectively on PEPCK and G6Pase
So it does not effectively suppress gluconeogenesis
What is the function of Fruc-2,6-BP?
Fructose-2,6-BP is an important allosteric effector. It stimulates PFK1 promoting glycolysis. It inhibits F-1,6-BP, thus blocking GNG
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
Second pathway to overcome
What are the effects of insulin resistance?
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
List some conditions with impaired gluconeogenesis.
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)
List some conditions with overactive gluconeogenesis.
Insulin resistance
Diabetes
Trauma
What happens in response to trauma?
Elevated metabolic rate
Increased energy needs
Increased gluconeogenesis
What are the drivers of the trauma response?
Adrenaline
Glucagon
Cortisol
Cytokines
Describe the different phases of metabolic response to injury.
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)
Describe the effects of injury and sepsis on metabolism.
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
Describe the glucose tolerance vs stage of injury.
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
Why does alcoholism impair gluconeogenesis?
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
What are the features of the catabolic phase?
Increased metabolic rate
Weight loss
Evidence of muscle wasting (negative nitrogen balance)
What are the contributing factors of the catabolic phase?
Metabolic requirements: tissue repair, immune response
Insulin resistance
Cytokines and inflammatory mediators (TNFalpha, IL-2)
Lack of appetite
What are the effects of TNF alpha?
Stimulates lipolysis Inhibits lipoprotein lipase Induces PEPCK (stimulates gluconeogenesis) Inhibits insulin secretion Causes insulin resistance
Describe metabolism in cancer cells.
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
