Metabolism of glucose, fats and ketones

A dive into how glucose, fats and ketones works together

In healthy individuals maintenance of stable plasma glucose (PG) concentration is easily performed by the body’s neuroendocrine and metabolic defenses, and potential consequences from prolonged fasting are low. However, a disproportionate balance between cellular glucose entry and glucose outflow secondary to deficient delivery of glucose into circulation, excessive glucose removal from circulation, or both, will place the body in a state of hypoglycemia. 

While glucose entry from the blood to the brain neurons and to liver cells is dependent on glucose concentration gradients, most other tissues (primarily muscle tissue) are dependent on insulin for glucose entry to the cells. As PG begins to fall, the pancreas stops producing insulin and decreases the amount of glucose available to most tissues, with the exception of the brain.

What happens when the plasma glucose falls?

If the PG continues to fall, the counter-regulatory hormones glucagon, cortisol, growth hormone, epinephrine (adrenaline), and norepinephrine (noradrenaline) are released into circulation, and the breakdown of triglycerides to glycerol and fatty acids in the adipocytes (lipolysis) occurs. The glycerol is then converted to glucose in the liver (gluconeogenesis). Both glycerol and amino acids serve as substrates for glucose production in the hormonally controlled gluconeogenesis. 

The free fatty acids from lipolysis are processed by liver cell mitochondria into acetoacetate (AcAc), beta-hydroxybutyrate (BOHB), and, to a lesser degree, acetone, which together are named ketone bodies. These ketone bodies are an alternative source of energy for the brain and muscles when glucose is unavailable.

Fuel production

Fuel production in infants and children is similar to that of adults; however, due to their larger brain size in proportion to their body weight, PG concentrations in infants and children drop more rapidly and elevated ketone body levels (hyperketonemia) develop sooner. 

The brain has back-up stores of fuel in the form of glycogen to compensate for low PG levels. These glycogen stores only last a few minutes, so individuals that cannot regulate their PG levels are at risk for interruption of glucose delivery to the brain, putting them in danger of devastating consequences. Recovery is usually complete from short-lived episodes of hypoglycemia, though prolonged and severe hypoglycemia can cause permanent brain damage.

Source: Drachmann, D., Hoffmann, E., Carrigg, A. et al. Towards enhanced understanding of idiopathic ketotic hypoglycemia: a literature review and introduction of the patient organization, Ketotic Hypoglycemia International. Orphanet J Rare Dis 16, 173 (2021).