From the Guidelines
Gluconeogenesis is primarily stimulated by low insulin levels and hormones such as glucagon, cortisol, and epinephrine that respond to low blood glucose levels or stress. The process of gluconeogenesis is complex and involves the activation of various enzymes and signaling pathways. According to a study published in Diabetes Care 1, during prolonged fasting, levels of glucagon and catecholamines rise, stimulating the breakdown of glycogen and augmenting gluconeogenesis. Some key points to consider when stimulating gluconeogenesis include:
- Low insulin levels, which are permissive for gluconeogenesis, as insulin typically suppresses this pathway
- Hormones such as glucagon, cortisol, and epinephrine, which activate enzymes like PEPCK and glucose-6-phosphatase through various signaling cascades
- Nutritional factors, such as amino acids from protein breakdown, which provide substrates for glucose production
- The importance of gluconeogenesis in maintaining blood glucose levels during fasting, starvation, or intense exercise when glycogen stores become depleted. As noted in the study 1, this process is crucial for ensuring that glucose-dependent tissues like the brain have an adequate energy supply.
From the Research
Stimulators of Gluconeogenesis
- Glucagon: stimulates gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation, all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1) 2
- Cortisol: augments glucagon-stimulated gluconeogenesis in an additive manner, best explained by changes in gluconeogenic enzymes rather than in substrate availability 3
- Fasting: leads to the chronic activation of gluconeogenesis, which requires increased expression of key enzymes in the pathway 4
- Low insulin levels: allows for the activation of gluconeogenesis, as insulin normally turns off the pathway under feeding conditions 4
Hormonal Regulation
- Insulin and glucagon have a counter-regulatory effect on glucose production, with insulin inhibiting gluconeogenesis and glucagon stimulating it 4, 2
- Cortisol and glucagon interact to enhance hepatic glucose output, with cortisol augmenting glucagon-stimulated gluconeogenesis 3
Organ-Specific Regulation
- The liver is the primary organ responsible for gluconeogenesis, but the kidneys also contribute to endogenous glucose production, especially under certain pathological conditions 5
- The small intestine has also been shown to contribute to gluconeogenesis, especially under high-protein, low-carbohydrate diets 5