• Occurs: Primarily in liver, 40% in kidneys but usually only during long-term fasting

·         Substrates: Amino acids (gluconeogenic), Glycerol, Lactate

•  conditions: fasting -overnight or long-term. In muscle- after long duration of strenuous exercise.
• Glycogen is used up after 18- 24 hours, gluconeogenesis begins after 10-18. 
• Hormones: glucagon (activator), insulin (inhbitor) 

• Carbons come from glucogenic amino acids in muscle protein; glycerol from beta-oxidation of FA; lactate from bloodstream (that has come from Cori cycle or anaerobic exercise)
• Energy:  ATP, GTP and NADH are primarily from beta-oxidation of FA in TCA cycle

1.       The availability of gluconeogenic precursors (glucogenic amino acids) from muscle protein when the blood glucose levels, and consequently insulin levels, are low.

2.       Glucagon

3.   Energy: 4 ATP + 2 GTP + 2 NADH  for each glucose synthesized  (from TCA cycle)

4.  Acetyl-CoA - allosteric activator of pyruvate carboxylase.  (and inhibitor of PDH)

     Liver acetyl-CoA is the end-product of fatty acid b-oxidation

5.  Pyruvate kinase - deactivated by glucagon via cAMP-dependent protein kinase A.  

6.  Fructose 1,6-bisphosphatase - inhibited by AMP (i.e. low energy  stores)

1. Pyruvate carboxylase: converts  pyruvate à OAA( stimulated allosterically by acetyl-CoA)

2. PEPCK:  OAA à PEP  (mRNA and protein synthesis increased by glucagon and other signals of low energy)

3. Fructose-1-6-bisphosphatase: F1,6bisP à F6P

   inhibited by AMP, fructose-2,6-bisphosphate 

   stimulated by ATP

4. Glucose-6-phosphatase:  glucose-6-P àGLUCOSE 

How do pyruvate carboxylase and PEPCK work together?

Pyruvate à OAA à malate à cystolic malate à OAA à PEP

1. Pyruvate carboxylase transfers an activated CO2 to its biotin prosthetic group
2. Pyruavte carboxylase transfers its CO2 group to pyruvate which converts it to OAA
3. OAA can’t get through the mitochondrial membrane, so it is reduced to malate so it can.
4.  Once in the cytosol, malate is reoxidized to OAA 
5. PEPCK converts OAA to PEP 

 What happens to pyruvate kinase during GNG?

Through cAMP dependent pKA, glucagon causes the phosphorylation  and inactivation of pyruvate kinase during GNG.  This ensures that PEP can be used for GNG is not converted back to pyruvate.

High glucagon/insulin ratio causes cAMP to activate pKA which favors the phosphorylation of the PFK-2/FBP-2 complex.  This inactivates PFK-2 and activates FBP-2 which inhibits formation of fructose-2,6-bisphosphate. This decreases the inhibition of FBP-1 which causes an increased rate of GNG.  

Which cells have glucose-6-phosphatase?