Regulation of Gluconeogenesis

The moment-to-moment regulation of gluconeogenesis is determined primarily by the circulating level of glucagon and by the availability of gluconeogenic substrates. In addition, slow adaptive changes in enzyme amount result from an alteration in the rate of enzyme synthesis or degradation or both.

 Glucagon This peptide hormone from pancreatic islet α cells stimulates gluconeogenesis by three mechanisms.
1. Changes in allosteric effectors: Glucagon lowers hepatic fructose 2,6-bisphosphate, resulting in fructose 1,6-bisphosphatase activation and PFK-1 inhibition, thereby favoring gluconeogenesis over glycolysis . 
2. Covalent modification of enzyme activity: Glucagon binds its G protein–coupled receptor  and, via an elevation in cyclic AMP (cAMP) level and cAMP-dependent protein kinase A activity, stimulates the conversion of hepatic PK to its inactive (phosphorylated) form. This decreases PEP conversion to pyruvate, which has the effect of diverting PEP to gluconeogenesis (Fig. 1).

Figure 1: Covalent modification of pyruvate kinase results in inactivation of the enzyme. [Note: Only the hepatic isozyme is subject to covalent regulation.] OAA = oxaloacetate; PEP = phosphoenolpyruvate; PPi = pyrophosphate; =phosphate; AMP and ADP = adenosine mono- and diphosphates; cAMP = cyclic AMP.
3. Induction of enzyme synthesis: Glucagon increases transcription of the gene for PEPCK via the transcription factor cAMP response element–binding (CREB) protein, thereby increasing the availability of this enzyme as levels of its substrate rise during fasting. [Note: Cortisol (a glucocorticoid) also increases expression of the gene, whereas insulin decreases expression.]
B. Substrate availability
The availability of gluconeogenic precursors, particularly glucogenic amino acids, significantly influences the rate of glucose synthesis. Decreased insulin levels favor mobilization of amino acids from muscle protein to provide the carbon skeletons for gluconeogenesis. The ATP and NADH coenzymes required for gluconeogenesis are primarily provided by FA oxidation.
C. Allosteric activation by acetyl CoA
Allosteric activation of hepatic PC by acetyl CoA occurs during fasting. As a result of increased TAG hydrolysis in adipose tissue, the liver is flooded with FA (see p. 330). The rate of formation of acetyl CoA by β-oxidation of these FA exceeds the capacity of the liver to oxidize it to CO2 and water. As a result, acetyl CoA accumulates and activates PC. [Note: Acetyl CoA inhibits the PDHC (by activating PDH kinase). Thus, this single compound can divert pyruvate toward gluconeogenesis and away from the TCA cycle (Fig. 2).]

Figure 2 : Acetyl coenzyme A (CoA) diverts pyruvate away from oxidation and toward gluconeogenesis. PDH = pyruvate dehydrogenase; TCA = tricarboxylic acid.
D. Allosteric inhibition by AMP
Fructose 1,6-bisphosphatase is inhibited by AMP, a compound that activates PFK-1. This results in reciprocal regulation of glycolysis and gluconeogenesis seen previously with fructose 2,6-bisphosphate . [Note: Thus, elevated AMP stimulates energy-producing pathways and inhibits energy-requiring ones.]