Gluconeogenesis

Abstract

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