Review
The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism

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Abstract

The effects of ketone body metabolism suggests that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. These inferences follow directly from the metabolic effects of ketosis and the higher inherent energy present in d-β-hydroxybutyrate relative to pyruvate, the normal mitochondrial fuel produced by glycolysis leading to an increase in the ΔG′ of ATP hydrolysis. The large categories of disease for which ketones may have therapeutic effects are:

  • (1)

    diseases of substrate insufficiency or insulin resistance,

  • (2)

    diseases resulting from free radical damage,

  • (3)

    disease resulting from hypoxia.

Current ketogenic diets are all characterized by elevations of free fatty acids, which may lead to metabolic inefficiency by activation of the PPAR system and its associated uncoupling mitochondrial uncoupling proteins. New diets comprised of ketone bodies themselves or their esters may obviate this present difficulty.

Section snippets

Metabolic effects of ketone body metabolism

The therapeutic potentials of mild ketosis flow directly from a thorough understanding of their metabolic effects, particularly upon mitochondrial redox states and energetics and upon substrate availability. The data on metabolic effects of ketone body metabolism presented here has been published previously [1], [2]. It presents studies of the isolated working rat heart perfused with 11 mM glucose alone, glucose plus 1 mM acetoacetate and 4 mM d-β-hydroxybutyrate, glucose+100 nM insulin or the

Ketogenic diets in human subjects

Starvation, with attendant ketosis, has been used as a treatment for refractory epilepsy since the early 20th century. Pierre Marie proposed this treatment on the theory that epilepsy resulted from intestinal intoxication. On this assumption, a diet consisting of water only for 30 days was used to successfully treat some refractory epileptics by Hugh Conklin, a Wisconsin osteopath. The inference that ketone bodies themselves were the effective agent, led Russell Wilder of the Mayo Clinic to

Salts of ketone bodies

The salts of ketone bodies have been examined for their therapeutic effects after either parenteral or oral administration.

Insulin resistant states

The excessive production of ketone bodies during diabetic ketoacidosis is a life threatening condition usually seen in type I diabetics after some intercurrent event. It is characterized by profound hyperglycemia with insulin resistance and elevated blood ketone bodies approaching 25 mM, blood HCO3 approaching 0 and blood pH approaching 7 causing hyperventilation and a compensatory low pCO2. Death occurs from the low pH and vascular collapse secondary to urinary loss of Na+ and K+ in an osmotic

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