Gluconeogenesis and Lactic Acidosis Flashcards
Gluconeogenesis location
Mostly liver
Kidney is secondary
9 enzymes in cytosol
1 in mitochondria
1 in ER
Key enzymes of Gluconeogenesis (4)
G6Pase
FBPase-1
PEPCK
Pyruvate Carboxylase
Malate and Aspartate
Made in mitochondria
Shuttled out into cytosol
Yield OAA
PEPCK
2 OAA –> 2 PEP
GTP –> GDP
FBPase-1
F 1,6 BP –> F6P
H20 –> Pi
G6Pase
G6P –> glucose
H20 –> Pi
Lactate
Taken up by liver
Oxidized to pyruvate in cytosol by LDH
ALanine
Taken up by liveer
Transaminated by ALT to pyruvate
NADH regeneration
Ox of lactate to pyruvate
Ox of malate to OAA
Gluconeogenesis overall
2 pyruvate —-> glucose
4 steps irreversible
6 ATP equivalents used
2 NAD+ produced
Glucose transport
GLUT2 (hepatocyte)
Gradient favors production
FBPase-1 regulation
AMP (-)
F 2,6, BP (-)
Pyruvate Carboxylase regulation
Acetyl CoA (+)
Glucagon effect on Gluconeogenesis
Inc PKA –> phosphorylation of CREB –> Inc transcription of gluconeogenic enzymes
Inc PKA –> phosphorylation of PFK-2/FBPase-2 –> Dec F2,6 BP
Factors that increase Lactate production
Mitochondrial dysfx
Low cellular O2
Cancer Cells
Metformin
Factors the decrease lactate removal
Liver dz
In NADH/NAD+ (e.g., EtOH metab)
Defects in gluconeogenesis
Metformin
Metformin effects
Inc lactate production
Dec lactate clearance
–> Inc Plasma lactate
Okay w/in therapeutic doses because kidney can compensate; only small inc seen.
NOT OKAY w/ DEC Kidney FX
Metformin + Tissue Hypoxia
Inc lactate production –> Inc plasma lactate
Metformin + Liver Dz/Excessive EtOH
Dec lactate clearance from hepatocytes –> Inc plasma lactate
Where in the cell does G6Pase work?
Occurs in ER
