From the Guidelines
During prolonged fasting, pyruvate's fate is primarily to be converted to glucose through gluconeogenesis or to lactate and alanine, rather than being oxidized, as the body adapts to utilize ketones as the main energy source. As fasting becomes prolonged for more than several hours, glycogen stores become depleted, and the low levels of circulating insulin allow increased fatty acid release from adipocytes, which generates ketones that can be used as fuel by various tissues, thus sparing glucose for continued utilization by brain and erythrocytes 1. Some key points to consider in this context include:
- Pyruvate production decreases significantly since glycolysis slows down due to reduced carbohydrate intake
- The small amount of pyruvate that is produced is primarily converted to lactate through anaerobic glycolysis or to alanine through transamination reactions
- Pyruvate can serve as a substrate for gluconeogenesis, being converted back to glucose in the liver to maintain minimal blood glucose levels necessary for glucose-dependent tissues, as noted in the management of diabetes during Ramadan 1
- The body relies on ketone bodies produced from fatty acid oxidation in the liver as the primary fuel source for tissues including the brain, which helps preserve protein stores while utilizing fat as the primary energy source during extended periods without food.
From the Research
Fate of Pyruvate in Prolonged Fasting
- In prolonged fasting, pyruvate has two major fates upon entry into mitochondria:
- Oxidative decarboxylation to acetyl-CoA via the pyruvate decarboxylase complex
- Biotin-dependent carboxylation to oxaloacetate via pyruvate carboxylase (Pcx) 2
- The role of Pcx in hepatic mitochondrial metabolism is crucial, especially under disparate physiological states such as fasting, high-fat, and ketogenic diet 2
- Pcx is important for maintaining the proper balance of pyruvate metabolism between oxidative and anaplerotic pathways 2
Pyruvate Carboxylase Deficiency
- A deficiency of hepatic pyruvate carboxylase can lead to severe lactic acidosis, elevated blood concentrations of lactate, pyruvate, and ketone bodies, and decreased blood concentrations of glutamine, aspartate, and citrate 3
- Pyruvate carboxylase is important in modulating the fractional distribution of intracellular acetyl-CoA between the tricarboxylic acid cycle, the beta-hydroxy-beta-methyl-glutaryl-CoA cycle, and fatty acid synthesis 3
Ketone Body Production
- During ketogenesis induced by starvation or prolonged hypoglycemia, the ketone bodies (KB), acetoacetate and β-hydroxybutyrate (BHB), can substitute for glucose as an energy substrate in the brain 4, 5
- Ketone bodies can stimulate the autophagic flux and prevent neuronal death induced by glucose deprivation in cortical cultured neurons 4
- Acetoacetate and β-hydroxybutyrate in combination with other metabolites can release insulin from INS-1 cells and provide clues about pathways in insulin secretion 6