gluconeogenesis -Mitsouras Flashcards
What is gluconeogenesis and when does it take place?
after the 24 hour fasting glycogen stores in the liver are depleted, gluconeogenesis becomes the only source of blood glucose.
gluconeogenesis=synthesis of glucose from non-sugar precursors (glycogenic AAs from muscle protein degradation, lactate from anaerobic glycolysis, glycerol from lipolysis)
How do insulin and glucagon regulate blood glucose levels?
reciprocal regulation: prevent futile cycling. glycolysis and gluconeogenesis are competing pathways so they are never both simultaneously on. separate reactions and pathways for glucose catabolism and anabolism allow for distinct and independent regulation
glucagon stimulates gluconeogenesis AND glycogenolysis. glycolysis and glycogenesis are OFF.
insulin stimulates glycolysis AND glycogenesis. gluconeogenesis is OFF (in the liver)
where do the different precursors enter gluconeogenesis?
Lactate and alanine are converted to pyruvate (by lactate dehydrogenase and alanine aminotransferase-ALT)
glucogenic AAs are converted to TCA cycle intermediates
glycerol=converted to dihydroxyacetone
What supplies the energy for gluconeogenesis?
Lipolysis generates fatty acids & glycerol
Fatty acids used as fuel via b-oxidation
Glycerol used as a substrate for gluconeogenesis
Fatty acid oxidation provides ATP & NADH for gluconeogenesis
ATP CANNOT be provided from glycolysis because glycolysis is OFF in liver
what molecules cannot be used in gluconeogenesis?
ketone bodies, fatty acids and AcCoA ==> there is no direct route from acetyl CoA to pyruvate because the PDH reaction is irreversible
these things can only be used for ATP synthesis
regulation of glycolysis and gluconeogenesis?
fructose 6P—>fructose 2, 6, BP (via PFK2)
Fructose 2, 6, BP—> Fructose 6P (via fructose 2,6, biphosphotase)
PFK2 and F26 BPase make a bifunctional enzyme=connected==> simultaneous regulation of BOTH from one signaling event \\
insulin
-stimulates protein phosphatase–> dephosphorylates the bifunctional enzyme and
ACTIVATES PFK2 (only in liver!)
-increase in fructose 2, 6, BP
-PFK1 activated by F26 BP–> + glycolysis
-F16 BP ase is inhibited –> - gluconeogenesis
*also induces pyruvate kinase
*also, inhibits PEPCK
glucagon:
-stimulates PKA which phosphorylates the bifunctional enzyme–> activating F2,6, BPase–> converting Fructose 2, 6 BP to fructose 6 P
-decrease in Fructose 2, 6 BP removes the activation of PFK1 and the inhibition of Frictose 1, 6 biphosphotase
==>glycolysis OFF and gluconeogenesis ON
*also inhibits Pyruvate kinase
*activates PEPCK
Pyruvate–> Acetyl CoA –> TCA cycle (via PDH complex) *in the fed state
OR
pyruvate–> oxaloacetate–> gluconeogenesis (via pyruvate carboxylase) *in fasting/starvation
-in fasting, lipolysis is activated increasing the amount of FAs –> acetyl CoA (via beta-oxidation_
-AcCoA inhibits PDH
-AcCoA activated pyruvate carboxylase –> glucose synthesis
How does Diabetes affect gluconeogenesis?
normally insulin represses PEPCK and turns gluconeogenesis OFF
in DM, insulin cannot affect PEPCK (by either problem with the receptor or not enough insulin production) and gluconeogenesis is always ON—> producing glucose even when not needed. –> hyperglycemia
How does alcohol affect gluconeogenesis?
alcohol metabolism: ethanol–> acetaldehyde requires the use of NAD+ –> NADH
-reduces the pool of cytoplasmic NAD+
this depletes the NAD+ store necessary to convert malate to oxaloacetate
alcohol can lead to alcohol induced hypoglycemia by inhibiting gluconeogenesis (worse in persons with already depleted glycogen stores)