M5 - Gluconeogenesis, Lactic Acidosis Flashcards
Overall Reaction, Gluconeogenesis
-6 ATP “equivalents” are required
* Fatty acid oxidation is a major source ATP
* NAD+ must be reduced to NADH
-depends on precursors used to make pyruvate
Location
Mostly in the liver, with kidney playing a secondary role
* Nine enzymes located in the cytosol
* One enzyme in the mitochondria
* One enzyme in the ER
____ concentration gradient determines direction
Glucose
- Impaired gluconeogenesis can cause fasting ____
- Inappropriate gluconeogenesis can cause fasting ____
- hypoglycemia
- hyperglycemia
Four Key Enzymes
- Glucose-6 Phosphatase (G6Pase)
- Fructose 1,6 bisphosphatase-1 (FBPase-1)
- PEP Carboxykinase (PEPCK)
- Pyruvate Carboxylase
Major Precursors Used to Make Pyruvate
-Lactate is taken up by the liver and oxidized to pyruvate in cytosol by LDH
-Alanine is taken up by the liver and transaminated to pyruvate by ALT
Mechanisms to regenerate NADH
Oxidation of lactate to pyruvate via LDH
-aspartate used as precursor to OAA
Oxidation of malate to OAA via MDH
-malate used as precursor to OAA
Allosteric Regulation of
Gluconeogenesis
- AMP and F2,6 BP inhibit FBPase-1
- Acetyl CoA activates pyruvate carboxylase
Regulation by PKA
Less F2,6 BP
-Decrease glycolysis and increase gluconeogenesis
Regulation by AMPK
More F2,6 BP
-Increase glycolysis and decrease gluconeogenesis
Gluconeogenesis promotes hepatic glucose ____
Production
Glycolysis promotes hepatic glucose ____
Uptake
____ increases protein phosphatases that reverse the effects of PKA
Insulin
Glucagon increases ____
PKA (decreases F26)
Decreases Lactate Removal
- Liver disease
- Increase NADH/NAD+
- defects in gluconeogenesis
- metformin
In therapeutic doses, metformin minimally ___ plasma lactate because kidneys remove the small amount of excess lactate
Increases
In patients with decreased kidney function, plasma metformin increases (exaggerating its effects on lactate balance) and renal lactate clearance ____
Decreases
In patients with tissue hypoxia (e.g. cardiorespiratory insufficiency), increases in lactate production can be enough to cause ___
Lactate Accumulation
In patients with liver disease or excessive alcohol use, hepatic lactate ____ is further impaired enough to cause lactate to accumulate
Clearance
