Gluconeogenesis is a pivotal biochemical pathway in which glucose is synthesised from non‐carbohydrate precursors, that is, lactate, alanine, glutamine and glycerol, during prolonged starvation. This pathway utilises most glycolytic enzymes in the reverse direction, except the three irreversible steps, which are bypassed by four additional enzymes, pyruvate carboxylase (PC), phosphoeonolpyruvate carboxykinase (PEPCK), fructose‐1,6‐bisphosphatase (FBPase) and glucose‐6‐phosphatase (G6Pase), known as the ‘gluconeogenic enzymes’. Elevated levels of glucagon and glucocorticoids during prolonged fasting stimulate gluconeogenesis in the short and long term. A short‐term response to these hormones involves reversible phosphorylation and allosteric modifications, which can alter the activities of the gluconeogenic enzymes. In contrast, a long‐term response involves the modulation of transcriptional activity of their (nuclear) encoded genes. CREB (cAMP‐responsive element binding protein), FoxO1 (forkhead box O1), PPARα (peroxisome proliferator activated receptor alpha) and PGC1α (peroxisome proliferator activated‐receptor gamma coactivator‐1α) are the key transcription factors that control most gluconeogenic enzymes. Deregulation of glucogeneogic enzymes perturbs systemic glucose homeostasis, causing diabetes.

Key Concepts

  • Mammals are well adapted to nutrient deprivation in order to survive during food restriction.
  • Glucose is the sole energy source for brain and red blood cells.
  • Alteration of glucoregulatory hormones during starvation influences glucose production from liver and kidney by programming relevant biochemical pathways.
  • Binding of glucoregulatory hormones to their receptors transmits the biochemical signals or molecules that affect the activity of key gluconeogenic enzymes or transcription of gluconeogenic genes.
  • Loss‐of‐function mutations of gluconeogenic enzyme genes or deregulation of gluconeogenic pathway results in the failure of the body to maintain glucose homeostasis

Keywords: gluconeogeneis; pyruvate carboxylase; phosphoenolpyruvate carboxykinase; fructose‐1,6‐bisphosphatase; glucose‐6‐phosphotase; fasting; liver; kidney; transcription; glucoregulator hormone

Figure 1. Schematic diagram showing gluconeogenic and glycolytic pathways. The former is regulated by four gluconeogenic enzymes: pyruvate carboxylase (PC), cytoplasmic or mitochondrial phosphoenolpyruvate carboxykinase (PEPCK‐C or PEPCK‐M, respectively), fructose‐1,6‐bisphosphatase (FBPase) and glucose‐6‐phosphatase (G6Pase), which are shown by red arrows, while the irreversible reactions catalysed by pyruvate kinase (PK), phosphofructokinase1 (PFK1) and glucokinase (GK) are shown by blue arrows. The gluconeogenic substrates lactate (Cori cycle), alanine (glucose–alanine cycle), glutamine and glycerol via lipolysis are shown by green arrows.
Figure 2. Role of glutamine in renal gluconeogenesis. Increased catabolism of amino acids in muscle increases the levels of plasma glutamine. Metabolic acidosis, a physiological condition characterised by increased acidity in plasma, enhances the rate of glutamine uptake in renal proximal tubules where glutamine is deaminated to glutamate by glutaminase (GLS) and further to α‐ketoglutarate by glutamate dehydrogenase (GDH). α‐Ketoglutarate then enters the rest of the gluconeogenic pathway except PC, as shown in the diagram. The renal ammonium ions (NH4+; blue arrows) formed during deamination reaction are excreted into the urine to neutralise the acidity of the luminal fluid, while the increased bicarbonate ions (HCO3; red arrows) generated during gluconeogenesis are transported into the blood to neutralise the acidity in plasma.
Figure 3. Hormonal regulation of gluconeogenic enzymes at transcriptional and post‐translational levels. During starvation, glucagon and glucocorticoids stimulate the transcription of PC, PEPCK and G6Pase genes through post‐translational modifications of the relevant transcription factors and co‐activators, which in turn affect their bindings to their cognate sequences. Glucagon signalling via PKA activation also results in depleted levels of F26P, which in turn stimulates FBPase I activity while stimulating PC activity via acetyl‐CoA, which is produced during excessive β oxidation. PKA signalling also stimulates the phosphorylation of CREB and interaction with its coactivators CRTC2/CBP/p300 to bind to the CRE of gluconeogenic gene promoters. During this period, FoxO1 also sustains transcription of gluconeogenic genes. Conversely, insulin suppresses transcription of PC, PEPCK and G6Pase genes via phosphorylation of FoxO1, resulting in its cytosolic retention and thus inhibiting transcription of gluconeogenic enzyme genes. Insulin signalling also attenuates PKA signalling, resulting in the disassembly of CREB/CRTC2/CBP/p300 complex, and thus suppressing gluconeogenesis. Insulin signalling via Akt2 activation also causes phosphorylation of PFK2/FBP2 bifunctional enzyme, resulting in the accumulation of F26P, which in turn allosterically inhibits FBPase I activity. A high level of L‐aspartate synthesis, as a consequence of a high rate of oxaloacetate transamination, inhibits PC activity as a feedback regulation loop.


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Further Reading

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Wattanavanitchakorn, Siriluck, and Jitrapakdee, Sarawut(Feb 2016) Gluconeogenesis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000627.pub3]