Gluconeogensis Flashcards
what are the sources for liver production of glucose
- glycogen (starch like polymer)
- gluconeogenesis (new synthesis from small molecule precursors)
why two sources of glucose in the liver?
glycogen sustains blood glucose for a few hours after a meal
-gluconeogensis sustains blood glucose for many days in the absence of carb intake
how long does it take for gluconeogenesis to become the primary carb source
-about 16 hours
starting reactant in gluconeogenesis
-pyruvate
where does gluconeogenesis occur?
- Tissue: 80-90% in the liver and the remainder in the kidney but this is primarily for starvation
- subcellular location: pyruvate carboxylation in the mitochondria, most of the reaction in the cytoplasm, removal of phosphate from G6P in the ER
precursors for gluconeogenesis
- pyruvate
- lactate (via pyruvate)
- amino acids (via pyruvate, TCA intermediates)
- glycerol (via DHAP)
transaminases produce what from what
- alpha ketoacids from alpha amino acids
- OAA to aspartate
- alpha KG to glutamate
enzymes unique to gluconeogenesis
- pyruvate carboxylase
- PEP carboxykinase
- FBPase
- glucose 6 phosphatase
adrenergic affects of hypoglycemia
- trembling
- palpitations
- sweating
- anxiety
- nausea
- hunger
- tingling
neuroglycopenic affects of hypoglycemia
- headache
- confusion
- weakness
- drowsiness
- vision changes
- difficulty speaking
- dizziness
- tiredness
- seizures
- coma
- slurred speech
what glucose level or lower will require intervention?
2.8mM or lower
what can pyruvate be derived from?
lactate, alanine
what does it cost molecularly to make glucose
- 4ATP
- 2GTP
- 2NADH
which molecules start at the very beginning of gluconeogenesis?
- pyruvate
- lactate
- alanine
where does glycerol enter gluconeogenesis?
- it goes from glycerol to glycerol 3 P to DHAP and is then converted to F-1,6-BP in order to enter the pathway
- this is in the cytoplasm
where does gluconeogenesis begin
-in the mitochondria with pyruvate carboxylase making OAA
coenzyme for pyruvate carboxylase
- biotin
- its role is to activate CO2 for transfer
biotnidase
- is responsible for recycling biotin
- absence of this enzyme causes a wide spectrum of clinical manifestations
problem with OAA in the mitochondria
- the membrane is impermeable to it, so it can not leave
- to get around this, it is converted to either malate or aspartate and transported into the cytoplasm
- once in the cytoplasm, these are both converted back to OAA
PEPCK
-converts OAA to PEP
when does the process leave the cytoplasm and where does it go/what happens there?
- once G6P is made, gluconeogensis is sent into the ER via G6P transporter on the ER membrane
- this is where G6Pase removes the phosphate group, creating glucose
deficiency in G6Pase or G6P transporter
-this is a serious problem and is called Von Gierke’s disease
regulator of pyruvate carboxylase
- acetyl CoA is an activator
- if we have a lot of this for the krebs cycle then we can make OAA for gluconeogenesis
regulators of F16BPase
- inhibitors: AMP and fructose2,6BP
- activators: citrate
- this is the inverse of PFK1 in the other direction because if you have high AMP that means you have low energy and will want to use F1,6BP to make ATP not glucose
hormonal regulation of PEPCK
- PEPCK activity is increased by glucagon (this is the hormone of starvation) and steroids such as cortisol
- PEPCK is antagonized by insulin
hormonal regulation of glucagon
-glucagon inhibits pyruvate kinase in the liver, therefore promoting gluconeogenesis instead of glycolysis
hormonal regulation through F2,6BP
- when PFK2 is phosphorylated in response to glucagon, it is a phosphatase which hydrolyses F2,6BP
- this reduces the activation of PFK1 and relieves inhibition of FBPase, stimulating gluconeogenesis
- insulin promotes dephospho rylation of PFK2, promoting F2,6BP production to stimulate glycolysis and inhibits gluconeogenesis
overall effect of insulin on gluconeogenesis
- it has an inhibitory effect because if you eat a sugary meal, then your body will not need to make glucose
- this is carried out by insulin dephosphorylating PFK2, promoting F26BP production to stimulate glycolysis and inhibits gluconeogenesis
glucagon
- target tissues
- size and structure
- target metabolism
- signal of…
- liver and adipose
- 29 AA, single polypeptide chain
- carbohydrate and lipid metabolism
- it is a signal of fasting
insulin
- size and structure
- target tissues
- target metabolism
- signal of…
- 51 amino acids, 2 polypeptide chains
- targets the liver, adipose, and muscle tissues
- targets metabolism of acrbohydrates, lipids, and proteins
- signal of feeding
what processes does glucagon stimulate, what does it inhibit, and where
- stimulates gluconeogenesis glycogenolysis in the liver
- inhibits glycogenesis in the liver
- has no affect on glucose uptake
what processes does insulin stimulate, inhibit, and where?
- stimulates glucose uptake in muscle and glycogenesis in the liver
- inhibits gluconeogenesis and glycogenolysis in the liver
how does glucagon regulate F26BP
- through a signalling cascade, glucagon activates PKA which phosphorylates PFK2, rendering it inactive
- if PK2 is inactive, it can not phosphorylate F6P into F26BP which inhibits FBPase and therefore gluconeogenesis
