This article shows that the heart 3 to 8 fold increases in the glycolytic pathway by the liver when there is an infusion of ketone bodies or insulin.  This meets the requirement of some of the brain cell for ATP and the red blood, which don’t have mitochondria.  This is why low blood sugar (hypoglycemia) is toxic:  red cells don’t have the necessary ATP, and can’t get them from fat metabolism.  This also explains why there is the incretins hormone system that stimulates the production of insulin—along with ketone bodies. But this is a lower level of insulin then when there is carbs, one which permits the continued mitochondrial metabolism of fats.   JK has abridged the article.

http://www.coconutketones.com/pdfs/Veech%202004_therapeutic_implications.pdf  September 2003 

Prostaglandins, Leukotrienes and Essential Fatty Acids 70 (2004) 309–319   11 pages 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

Richard L. Veech* Laboratory of Membrane Biochemistry and Biophysics, National Institutes of Alcoholism and Alcohol Abuse, 

Abstract The effects of ketone body metabolism suggests that mild ketosis may offer therapeutic potential l 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-b-hydroxybutyrate relative to pyruvate, the normal mitochondrial fuel produced by glycolysis leading to an increase in the DG0 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 PPARsystem and its associated uncoupling mitochondrial uncoupling proteins. New diets comprised of ketone bodies themselves or their esters may obviate this present difficulty. Published by Elsevier Ltd.

1. 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-b-hydroxybutyrate, glucose+100 nM insulin or the combination of glucose, ketone bodies and insulin. The isolated working perfused heart was studied because of the relative homogeneity of the tissue and the simplicity of its output, the number of parameters which could be accurately measured, particularly O2 consumption relative to actual hydraulic work output of the heart. In our analysis of disease states, it has been assumed that the effects of ketone metabolism in heart would mimic those in brain, which was not analyzed in this detailed manner for a number of technical reasons, most prominently the inhomogeneous nature of the tissue and its lack of quantifiable outputs. A detailed metabolic control strength analysis of glycolysis in heart under the four conditions led to several major conclusions [1]. Firstly, the control of flux through the glycolytic pathway was context dependent and shifted from one enzymatic step to another depending upon the conditions. There was not one key ‘‘rate controlling’’ reaction, but rather control was distributed among a number of steps, including some enzymes that were very close to equilibrium. The absence of a single dominant rate controlling step in a pathway calls into question the assumptions on which many pharmaceutical discovery programs have been based. d [3]. Secondly, when perfused with glucose alone, there was consistent glycogen breakdown, whereas with addition of ketones, insulin or the combination, glycogen synthesis occurred. Addition of either ketones or insulin, increased intracellular [glucose] and the glycolytic intermediates in the first half of the glycolytic pathway from 2 to 8 fold.  Thirdly, addition of either ketones or insulin leads to an increase in the measurable hydraulic work of the heart, but a net decrease in the rate of glycolysis. Associated with the increase in hydraulic work and decrease in glycolytic rate addition of ketones or insulin increased the free cytosolic [ATP]/ [ADP] [Pi] ratio three to five fold and a similar change in the [phosphocreatine]/[creatine] ratio showing that both ketones or insulin increased the energy of the phosphorylation state of heart significantly compared to perfusion with glucose alone.  [Thus insulin secreted with ketone bodies improves performance, and explains the positive why incretins cause the release of insulin response to proteins.]  These data clearly show that addition of either ketone bodies or insulin, markedly improved the energy status of working perfused heart. How ketone bodies could increase the hydraulic efficiency of heart by 28% could not be explained by the changes in the glycolytic pathway alone, but rather by the changes that were induced in mitochondrial ATP production by ketone body metabolism. …

The fundamental reason why the metabolism of ketone bodies produce an increase of 28% in the hydraulic efficiency of heart compared with a heart metabolizing glucose alone is that there is an inherently higher heat of combustion in d-b-hydroxybutyrate than in pyruvate, the mitochondrial substrate which is the end product of glycolysis (Table 1). 

If pyruvate were burned in a bomb calorimeter, it would liberate 185.7 kcal/mole of C2 units, whereas the combustion of d-b-hydroxybutyrate would liberate 243.6, or 31% more calories per C2 unit than pyruvate. Metabolizing d-b-hydroxybutyrate in perfused working heart creates a 28% increase in the hydraulic efficiency of heart when compared to the metabolism of the end product of glycolysis, pyruvate.  The mitochondrial processes of electron transport and ATP synthesis appear to be capable of capturing this inherent energy contained in the substrates being metabolized.

Table 1 Heats of combustion of common non-nitrogenous energy substrates

Substrate                              DHo kcal/mol                    DHo kcal/mol C2               units

C18H32O2 Palmitate          2384.8                               298

C4H8O3 b  HOButyrate     487.2                                  243.6

C6H12O6 Glucose             669.9                                  223.6

C3H4O3 Pyruvate             278.5                                   185.7

The greater energy inherent in d-b-hydroxybutyrate relative to pyruvate derives from the higher ratio of H–C present in each molecule, 2 H per C in the case of d-bhydroxybutyrate versus 1.3 H per C in the case of pyruvate. Put another way, the ketone body is more reduced than pyruvate. One may then ask, why would there not be even more energy released if the heart were to metabolize the fatty acid palmitate, which has even more inherent energy available during combustion than a ketone body. The reasons why the metabolism of fatty acids does not lead to even a greater increase in efficiency than does the metabolism of ketones are of two types: the architecture of the pathway of fatty acid oxidation and the enzymatic changes induced by elevation of free fatty acids.

During b oxidation, only half of the reducing equivalents released enter the respiratory chain at NADH dehydrogenase while the other half enter at a flavoprotein site with a potential above that of the NAD couple. This results in the loss of the synthesis of about 1 of the 6 possible ATP molecules, for a loss of about 5% in efficiency. The remaining reducing equivalents produced from the acetyl CoA produced during b oxidation, are metabolized in the TCA cycle in the normal fashion. However the redox potential of the Q couple is not oxidized as it is during ketone metabolism, but rather reduced, decreasing the DE available for ATP synthesis. In addition, the elevation of free fatty acids, leads to the increased transcription of mitochondrial uncoupling proteins and of the enzymes of peroxisomal b oxidation. Uncoupling proteins allow the proton gradient generated by the respiratory chain to re-enter the mitochondria by pathways which bypass the F1 ATPase generating heat rather than ATP. Fatty acids undergoing b oxidation with peroxisomes have no mechanism for energy conservation and result solely in heat production. Induction of uncoupling proteins, by chronic elevation of free fatty acids or from other causes result not in increased cardiac efficiency, but rather in pathological decreases in cardiac efficiency [10]. Among the common non-nitrogenous substrates for mitochondrial energy generation, ketone bodies deserve the designation of a ‘‘superfuel’’.

In addition to their effects on mitochondrial energetics, the metabolism of ketone bodies has other effects with therapeutic implications. Of major significance is the ability of ketone bodies to increase the concentrations of the metabolites of the first third of the citric acid cycle. Next to causing the translocation of GLUT4 from endoplasmic to plasma membrane, one of the most important acute metabolic effects of insulin, is the stimulation of the activity of the pyruvate dehydrogenase multi-enzyme complex leading to an increased production of mitochondrial acetyl CoA, the essential substrate for the citric acid cycle. The metabolism of ketone bodies or the addition of insulin to working perfused heart both results in increases of cardiac acetyl CoA content 12–18 fold. This increase is associated with increases of 2–8 fold in the cardiac content of citrate and the other constituents of the citric acid cycle down to a-ketoglutarate, and including l-glutamate, an important redox partner of a-ketoglutarate and the mitochondrial NAD couple. Citrate is an important precursor in the generation of cytosolic acetyl CoA for lipid and acetyl choline biosynthesis, while l-glutamate is a necessary precursor for GABA synthesis in neural tissue. The metabolic effects of ketone bodies are of particular relevance to brain metabolism, where Cahill and his colleagues have established that over 60% of the metabolic energy needs of brain can be supplied by ketone bodies, rather than by glucose [11]. They have further established that mild ketosis with blood levels of 5–7 mM is the normal physiological response to prolonged fasting in man [12]. The 1.5 kg human brain utilizes 20% of the total body oxygen consumption at rest, requiring 100–150 g of glucose per day [13]. Although man can make about 10% of the glucose to supply brain needs during fasting from fat [14], prolonged starvation in man leads to the excretion of 4–9 g of nitrogen per day which is equivalent to the destruction of 25–55 g protein/day. This amount of protein catabolism could supply between 17 and 32 g of glucose per day, far below the 100–150 g/day required. To supply the glucose required to support brain from protein alone would lead to death in about 10 days instead of the 57–73 days required to cause death in a young male of normal body composition during a total fast [15]. Cahill also noted that in his subjects undergoing total starvation for 30 days, hunger subsided on about the third day, coincident with the elevation of blood ketones to 7 mM. During prolonged fasting, the human produces about 150 g of ketone bodies per day [16]. This suggests, that even though the Vmax of the monocarboxylate transporter in brain is increased during ketosis [17], the Km at the endothelial cell of approximately 5 mM for ketone body transport of approximately 5 mM would still dominate the ketone effects in brain, so that a blood level only slightly below that of 7 mM ketone bodies would be required to ARTICLE IN PRESS Table 1 Heats of combustion of common non-nitrogenous energy substrates Substrate DHo kcal/mol DHo kcal/mol C2 units C18H32O2 Palmitate 2384.8 298 C4H8O3 b HOButyrate 487.2 243.6 C6H12O6 Glucose 669.9 223.6 C3H4O3 Pyruvate 278.5 185.7 R.L. Veech / Prostaglandins, Leukotrienes and Essential Fatty Acids 70 (2004) 309–319 311 achieve the effects on brain metabolism were elevation of ketones to be achieved by means to achieve similar effects to those observed during prolonged starvation. These amounts are not pharmacological, but rather nutritional, which changes markedly the traditional pharmaceutical industry approaches to therapy. Although brain has insulin receptors, it has either no or very low insulin levels making ketosis the only practical mechanism for increasing the efficiency of oxidation ATP generation in that organ. Finally there are broad therapeutic implications from the ability of ketone body metabolism to oxidize the mitochondrial co-enzyme Q couple. The major source of mitochondrial free radical generation is Q semiquinone [18]. The semiquinone of Q, the half-reduced form, spontaneously reacts with O2 to form free radicals. Oxidation of the Q couple reduces the amount of the semiquinone form and thus would be expected to decrease O2 d production. In addition, the metabolism of ketones causes a reduction of the cytosolic free [NADP+]/[NADPH] couple which is in near-equilibrium with the glutathione couple [19]. Reduced glutathione is the final reductant responsible for the destruction of H2O2. From the multiple effects of the metabolism on the basic pathways of intermediary metabolism, it is clear that there are a number of disease states in which mild ketosis could offer possible therapeutic benefits [Not severe as with type-1 diabetes].  Some of these therapeutic uses of ketosis have been discussed earlier [20].

In a study of 600 patients with a history of 20 seizures per day refractory to over 6 drugs, the Hopkins group reported that the ketogenic diet led to cessation of seizures in slightly less than one third of subjects, a significant decrease in seizure frequency in another third and no effect in one third [22]. Urinary ketone levels correlate poorly with blood levels, so it is difficult to evaluate the effectiveness of the various ketogenic diets.

2. Ketogenic diets in human subjects

… In a study of 600 patients with a history of 20 seizures per day refractory to over 6 drugs, the Hopkins group reported that the ketogenic diet led to cessation of seizures in slightly less than one third of subjects, a significant decrease in seizure frequency in another third and no effect in one third [22]. Urinary ketone levels correlate poorly with blood levels, so it is difficult to evaluate the effectiveness of the various ketogenic diets.  One report of the blood levels of ketone bodies achieved on the diet suggests that blood levels of about 4 mM are required for satisfactory results [23]. In a reverse of the increasing risk of a subsequent seizure after the first one (the Gower effect), Freeman reports that after 2 years on the ketogenic diet, a normal diet can be resumed without recurrence of seizures…..

2.3. Adjuncts to cancer chemotherapy

As discussed earlier, elevation of ketone bodies decrease amino acid release from muscle as well as decreasing hepatic gluconeogenesis from amino acids. Feeding a ketogenic diet to mice with implanted tumors decreased tumor size as well as decreasing muscle wasting associated with tumor transplantation [34]. Similar results have been reported in human cancer patients [35,36]. In human patients with advanced astrocytomas, feeding of a ketogenic diet decreased tumor glucose uptake and in part of the group an increase in patient performance [36]. In a surprising report in mice implanted with astrocytoma, a ketogenic diet associated with caloric restriction resulted in an 80% decrease in tumor mass and a decrease in tumor vascularity implying an inhibition of angiogenesis [37]….

4.1. Insulin resistant states 

Insulin resistant states are extremely common. Insulin resistance is the hallmark of type II diabetes and the socalled ‘‘metabolic syndrome’’ where it is associated with visceral obesity and hypertension [44]. Insulin resistance is present in obese subjects and occurs during ‘‘stressful’’ conditions characterized by elevated adrenal steroids and catechol amines. Insulin resistance also occurs in conditions in which inflammatory cytokines are elevated. Acute insulin resistance is seen in alcohol abusers where elevation of either 2,3 butandiol or 1,2 propandiol inhibits insulin action on adipocytes [45] and impair whole body glucose utilization [46]. Given the metabolic effects of insulin, it is reasonable to suppose that mild ketosis might offer a therapeutic potential which acts directly on the primitive metabolic pathways themselves without requiring the action of the complex insulin signaling pathway.

4.3. Hypoglycemic episodes

A major limitation in achieving ‘‘tight control’’ of diabetics, is the risk of increased episodes of hypoglycemia. This consequence of robust insulin therapy is particularly frequent in type I diabetics. Because of the potentially serious consequences of cognitive impairment associated with hypoglycemia, physicians are reluctant to keep blood glucose within ranges which are thought to be optimum for the prevention of longterm vascular disease. Ketone bodies are an alternative to glucose as a supplier of the metabolic energy needs for brain. Cahill has shown [51] that during prolonged fasting, when total blood ketone bodies are in the 5– 7 mM range, blood glucose concentrations can be decreased to below 1 mM without either convulsions or any discernable impairment of cognitive function. At these concentrations, ketone bodies can provide essentially all of the energy demands in brain to maintain function. The induction of mild ketosis therefore offers a method for obtaining tighter control of blood glucose in brittle diabetics without the induction of the physiological consequences of hypoglycemia on cerebral function.

4.4. Hypoxic states

One non-medical use in this category would be the use of mild ketosis to improve physical performance in settings where extreme exertion is required. Such situations would exist in the military when troops are under extreme combat stress and in certain civilian settings involving emergency personnel. Extreme exertion leads not only to exhausting but also to impairment of cognitive and motor skills under conditions of caloric restriction [52]. Mild ketosis may offer a way to increase muscle and brain function without elevation of free fatty acids which will decrease muscle and cardiac metabolic efficiency through the induction of mitochondrial uncoupling protein.

 Obvious in this cat would be the penumbral damage in heart after coronary occlusion or in brain

2)  K. Sato, Y. Kashiwaya, C.A. Keon, N. Tsuchiya, M.T. King, G.K. Radda, et al., Insulin, ketone bodies, and mitochondrial energy transduction, FASEB J. 9 (1995) 651–658.

[3] D.F. Horrobin, Innovation in the pharmaceutical industry, J. R. Soc. Med. 93 (7) (2000) 341–345. [

4] H.A. Krebs, R.L. Veech, Pyridine nucl