Here I will spend some time researching the current literature on fasting ketosis, and summarizing what I find. While I had originally planned on conducting a literature review, my school has been nice enough to provide me with a subscription to UpToDate, the go-to source for medical literature reviews/information for professionals. Thus my primary source will be here (warning: paywall).

Before we begin, here’s my disclaimer from my last post: the following information should NOT be relied upon for any particular diagnosis, treatment, or care. This website is not a substitute for medical advice.

As we said before, ketoacidosis describes any metabolic acidoses associated with an accumulation of ketone bodies. While there are several types of ketoacidosis (diabetes-, alcohol-, and fasting- induced), I will attempt to focus on fasting ketosis.

Ketone Bodies

There’s 3 different types of ketone bodies, and they are all interrelated.

For the sake of discussion I don’t think it makes sense to dive into all the metabolic reactions associated with these three products of metabolism. But the main points can be summarized quite simply:

Acetoacetate (or acetoacetic acid) is the only true keto – acid

– Beta-hydroxybutyrate (or beta-hydroxybutyric acid) is a hydroxy – acid (not a keto-acid) that dominates during ketoacidosis, and is a product of the reduction of acetoacetate by NADH

– (not a keto-acid) that dominates during ketoacidosis, and is a product of the reduction of acetoacetate by NADH Acetone is a ketone, but not an acid. It is formed by the decarboxylation (loss of a CO2) from acetoacetate.

Physiology

Ketone bodies are a fuel source intermediate. They are water-soluble and derived from fat. Their primary use is as an energy source for tissues when glucose levels are low. The direct connection between ketone generation by the liver and the levels of glucose is mediate by the hormones insulin and glucose.

Insulin

Typically, after a meal, beta-cells in the pancreas detect a rise in blood glucose levels (via the GLUT2 transporter that works by concentration gradients) and release insulin in two phases: First, a rapid release of preformed insulin lasting about 10 minutes (sugar-dependent) Second, a sustained, slow release of newly synthesized insulin peaking in 2 to 3 hours (triggered independently of sugar)

Insulin is a peptide hormone that acts on cell’s insulin receptors causing a cascade of signals leading to: the insertion of GLUT4 glucose transporters into the cell membranes of muscle and fat cells the synthesis of glycogen in liver and muscle tissue conversion of glucose into triglycerides in liver, adipose, and lactating mammary gland tissue



The net effect of insulin alone is a decrease in blood glucose levels.

Glucagon

During periods of starvation, alpha-cells in the pancreas secrete a different hormone, glucagon.

Glucagon is a peptide hormone that acts on cell’s glucagon receptors causing a cascade of signals leading to: gluconeogenesis – the synthesis of new glucose from non-carb sources glycogenolysis – the breakdown of glycogen stores into glucose



The net effect of glucagon alone is an increase in blood glucose levels.

Insulin : Glucagon Ratio Levels and Ketone Body Production

During periods of sustained hypoglycemia (such as fasting), the ratio of insulin to glucagon falls harshly. Low enough insulin and high enough glucagon levels activate a insulin-dependent lipase which releases fatty acids and glycerol from triglycerides in adipose (fat) tissue. These fatty acids circulate to the liver into cellular mitochondria to undergo beta-oxidation to generate acetyl-CoA.

This process is great – it uses our long term energy stores, fat, and converts them into an important metabolic intermediate, acetyl-CoA which can feed into different processes for energy. One of the oxidative processes acetyl-CoA is most used, is in the Krebs cycle.

However, the oxidative capacity of the Krebs cycle can be exceeded when acetyl-CoA levels are too high. This results in a redirection of excess acetyl-CoA, derived from Beta-oxidation of fatty acids, to the keto-genic pathway:

Fasting Ketosis and Ketoacidosis

Fasting Ketosis

What we’ve described so far is the simple physiologic response to fasting. This is a processes that happens every night for most people after dinner and 12-14 hours of not eating while sleeping and waking up.

Mild ketosis refers to a ketoacid conc. of 1 mmol/L and is accomplished around the 12-14 hour mark. If ketoacid production is sustained, via a low-carb diet or sustained fasting, then ketoacid conc. continues to rise and peaks after 20-30 days around 8-10 mmol/L. As stated before, B-hydroxybutyrate is the major ketone body that accumulates.

The reason ketone body concentration stabilizes is that the rate of ketone body production eventually matches the rate of ketone body utilization by primarily the brain, muscle and kidney (and whatever is excreted in the urine). This is due to a few things:

The release of fatty acids from fat tissue stabilizes secondary to: stimulation of insulin release DESPITE low glucose levels increased sensitivity of adipose tissue to insulin’s inhibitory effect on fatty acid release direct inhibition of lipolysis by ketone bodies themselves

An increase rate in CNS ketoacid uptake as the brain switches to ketones as its primary source of fuel.

Increased peripheral ketone utilization.

Fasting Ketosis vs Fasting Ketoacidosis

The distinction between ketosis and ketoacidosis is not perfectly described in the literature.

Ketosis is the presence of elevated ketones in the blood or urine – which can occur if you are fasting, on a low-carb diet or have consumed too much alcohol.

– which can occur if you are fasting, on a low-carb diet or have consumed too much alcohol. Ketoacidosis refers to the accumulation of enough ketones to cause overt acidosis.

In the context of fasting, the convention is that because the degree of acidosis during fasting remains relatively mild, the term ketosis is typically used over ketoacidosis.

I will spare you the acid-base physiology as it involves quite a bit of background. The net effect of a sustained plasma ketone body conc. of 8-10 mmol/L is that:

plasma bicarbonate (HCO3-) falls to around 18 meq/L (normal 23-30 meq/L)

the plasma ion gap increases by a similar amount

Bicarbonate is the substance that buffers H+ ion in plasma. Thus, during sustained ketone body production, there is more unbuffered H+ ion, leading to a drop in pH, hence, acidosis.

The fall in bicarbonate is typically less than the rise in ketone bodies because 1) acetone, a ketone body, is not an acid and does not affect bicarb 2 ) some H+ ions from the ketoacids are buffered intra-cellularly rather than extra-cellularly. As a result, the acidosis is significant, but mild.

As of right now, there is no evidence of adverse effects associated with fasting ketosis and the mild metabolic acidosis associated with it. However, under some conditions, fasting ketosis becomes severe enough to lead to ketoacidosis. Often this occurs with fasting in the very young (e.g. neonates) or in pregnant or lactating women. Ketoacidosis has also been described in patients that are not actively fasting, but are on very low-carbohydrate diets. These patients typically presented with moderate hyperglycemia.