The "Liberalized Ketogenic Diet," Insulin Sensitivity, Resistance Exercise

The authors of this article [Pfeifer and Thiele, 2005: (http://www.direct-ms.org/pdf/NutritionNonAuto/KetogenicDietModifiedEpilepsy.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/16344529)] used a liberalized ketogenic diet in people who had epilepsy, and this essentially meant that the people ate low glycemic index carbohydrates instead of no carbohydrates at all. A food with a low glycemic index is one that doesn't create a spike in plasma glucose and therefore does not cause a lot of insulin to be released. The glycemic index (GI) is the ratio of the area under the plasma glucose vs. time curve for the food in question (a bowl of a specific cereal, for example) [AUC(food)] to the AUC of pure glucose, times 100. So it's AUC(food)/AUC(glucose), and pure glucose has a GI of 100. The concept has been applied to the management of the diets of people who have diabetes, but there's research showing that it may be more important to keep the size of a meal small than to eat big meals with low GI foods. So a person who ate a giant meal of the best quality bread, with a low-GI, the amount of insulin released over the period following the meal (and hence the suppressive effect on ketone formation in the liver or in astrocytes, in theory at least) might well be larger than if a person ate a small meal of candy or something. I don't know the details on the amounts of carbohydrates used in that study, and so this is obviously something a person would want to discuss with one's doctor.

I'm mentioning this because it's relevant to other supposed applications of the "ketogenic diet," and the effect of the use of low GI foods, in combination with the use of low doses of some sort of ketogenic supplement (such as HMB or sodium butyrate, which doesn't provide a lot of calcium and phosphate, added to supposedly compensate for the phosphate-sequestering effect, in the GI tract, of a calcium salt of an organic anion), would be similar to the use of those low-doses of ketogenic substrates with resistance exercise, in my opinion. I'm just saying that resistance exercise generally has, in my opinion, a much stronger insulin-sensitizing effect than endurance exercise, and that's the idea behind this type of modified ketogenic diet. The idea is to increase insulin sensitivity, but it's also relevant that the growth hormone release and elevations of serum IGF-1 (or even IGF-1 released locally from satellite cells, in the muscles) are known to contribute to ketogenesis [so is epinephrine (adrenaline), released much more during resistance exercise than aerobic exercise] [(http://scholar.google.com/scholar?num=100&hl=en&lr=&q=ketogenesis+%22growth+hormone%22+OR+IGF); (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=epinephrine+ketogenesis)]. Doing that type of exercise may or may not be practical for everyone, and a person would obviously want to talk to one's doctor before starting an exercise program. But the other implication of that article is that some factors that improve insulin sensitivity could, under some circumstances, produce "beneficial" effects by increasing ketogenesis and not just by maintaining low plasma glucose and insulin levels, etc.

Potential Problems Associated With Excessive Zinc and Copper Supplementation

These are some more articles that discuss all of the mechanisms by which an excess of intracellular, free zinc can cause mitochondrial dysfunction and toxic effects on many other cellular processes. The authors of this article [Lemire et al., 2008: (http://oldwebsite.laurentian.ca/chem/vappanna/publications/J.%20Applied%20Toxicology%202008.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17582580)] discuss the fact that an excess of zinc can inhibit various TCA cycle enzymes, such as aconitase, and other mitochondrial enzymes. Although the authors note that zinc can interfere in a generalized way with enzymes and proteins that contain iron-sulfur clusters, aconitase is known to also utilize nonheme iron (I mean nonheme iron that is also non-iron-sulfur-cluster-bound iron) [see, for example, Lee et al., 1996: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=aconitase+nonheme+iron)]. Zinc can be utilized to form zinc protoporphyrin, and I wonder if zinc isn't actually incorporated into iron-sulfur clusters. But it wouldn't have to be, and zinc could reasonably be expected to displace, with particular ease, nonheme iron (i.e. Fe2+/Fe3+) from its binding sites on enzymes whose catalytic activities or regulatory functions depend on the presence of bound, nonheme iron.

I think neurotoxicity from excessive zinc supplementation is a very serious issue, and, in my opinion, low-level, pathological changes, such as psychiatric symptoms or gradually-progressing neurotoxicity, may result from dosages of zinc that many people would not view as being especially massive. Only a relatively few authors, as far as I can tell, have written articles, over the last few decades, discussing the potential hazards of zinc supplementation at the more commonly-used dosages. Even fewer articles on the nutritional aspects of zinc have considered that problems with zinc supplementation may have nothing to do with copper depletion, even when copper is depleted as a result of the excess zinc. In my opinion, based on the literature, many of the cases of neurotoxicity associated with excessive zinc supplementation (there are many, many case reports in the literature, and I don't feel like listing dozens of them out, right now, in this posting) may have had relatively little to do with copper depletion, and one sees that copper supplementation, in many cases, did not very effectively ameliorate the neurological disorders and demyelination that researchers had found in association with excessive intakes of zinc. [Some of the articles and case reports are scattered throughout the results of this search: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22zinc+supplementation%22+neurotoxic+OR+neurological+OR+demyelinating+OR+demyelination+OR+%22white+matter%22), and this is an "instructive-but-not-comprehensive" list of articles that google scholar classifies as being related to an article on excessive zinc supplementation: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=related:-bvm-ASLfasJ:scholar.google.com/)]. In most cases, the researchers have discontinued the zinc supplementation at the same times they have initiated copper supplementation, and then the researchers have attributed the modest improvements in the neurological conditions or anemia or thrombocytopenia or pancytopenia to the copper repletion. In reality, the absence of zinc may have been the primary and more important factor that led to the improvements.

I've discussed, in past postings, the extraordinarily complex aspects of zinc metabolism and homeostasis, and another issue is that serum copper and ceruloplasmin are not sensitive or very reliable indicators, in my opinion, of the intracellular copper concentrations or of copper status in people who are not grossly copper-deficient. Serum zinc is also not thought to be a reliable measure of zinc status [Fung et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/16215013)], and Fung et al. (2002) found that, even in people who had evidently been deficient in zinc and who had appeared to respond favorably to zinc supplementation, zinc supplementation did not increase serum zinc. These are major obstacles to nutritional research on zinc, in my opinion, and I would seriously question the validities of many descriptions, in the literature, of "zinc deficiency." Here's an article whose author discusses the potential neurotoxicity of zinc supplementation [Levenson, 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15869126)], and here's a remarkable article, from 1989, in which Fosmire (1989) [Fosmire, 1989: (http://journals.lww.com/nutritiontodayonline/pages/articleviewer.aspx?year=1989&issue=05000&article=00005&type=abstract)] displayed remarkable prescience and subjective insight in relation to the potential problems that, in my opinion, could develop with dosages of zinc that many people would not view as being "excessive." I don't think zinc supplementation is a good idea in most cases, but that's just my opinion. I also don't think copper supplementation, above some tiny dosage (such as ~250-500 micrograms of elemental copper, to reach the RDA in combination with one's specific dietary intake), is a good idea, in many cases, but that's also just my opinion. A person would obviously want to discuss these issues with his or her doctor, given that one's unique, individualized nutritional needs are of paramount importance. I also think that the use of supplemental copper to compensate for the copper-depleting effects of zinc supplementation does not make sense and generally just has the potential to cause copper toxicity, but these are just my opinions.

I know this is a disturbing topic, but there's a kind of insanity in the way the different branches of research on zinc remain separated from one another. There's a vast amount of research showing copper-independent neurotoxic effects and extraordinarily complex, dynamic mechanisms of neurotoxicity from excesses of free zinc (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=zinc+neurotoxicity), and then there's the nutritional research on zinc. People seem to think that zinc-induced neurotoxicity is an all-or-nothing phenomenon. The assumption is that high dosages, such as are discussed in the case reports of neurotoxicity or demyelination, can cause problems but that the absence of overt neurological symptoms, in people taking lower doses, is in some way evidence that those lower dosages are not producing any pathological effects in the brain and spinal cord. It makes no sense to me to think that there would be no potential for problems in response to some of these lower dosage ranges, but that's just my opinion. The main reason I think that is that a multitude of factors can influence the amounts of zinc that are being released from intracellular binding sites, and I would expect that both the amounts of intracellular free zinc in neurons and the consequences of that zinc could be drastically different among different individuals with similar serum zinc levels and zinc intakes. The authors of this article discuss the possibility that the therapeutic intake range for zinc may well be small [Maret and Sandstead, 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16632171)], and it's time to face some of these issues, which I feel are serious, relating to zinc and copper supplementation.

C5 Ketones (3-hydroxypentanoate/3-hydroxyvalerate and 3-ketopentanoate/3-ketovalerate) as Anaplerotic Precursors of Succinyl-CoA (from Propionyl-CoA)

This article [Roe et al., 2002: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=151060&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/12122118)] is one of many articles showing that odd-chain fatty acids, such as the C7 (7-carbon) fatty acid heptanoate (derived from triheptanoin, which is triheptanoylglycerol, in this article), are metabolized into both propionyl-CoA (a C3 fatty acyl-CoA) and acetyl-CoA (a C2 acyl-CoA) and are generally much more effective in the treatment of genetic disorders of beta-oxidation than even-numbered fatty acids are (such as octanoate and decanoate, the prototypical "medium-chain triglycerides," or MCTs). Triheptanoin is a precursor of the C5 ketones 3-hydroxypentanoate (a.k.a. beta-hydroxypentanoate or beta-hydroxyvalerate or 3-hydroxyvalerate) and 3-ketopentanoate (a.k.a. 3-ketovalerate or beta-ketovalerate or beta-ketopentanoate), and these can be oxidized much more readily, by neurons and astrocytes in the brain and also by cells in other extrahepatic tissues, than heptanoate can.

The C5 ketones are advantageous in these contexts because the oxidation of 3-hydroxybutyrate or acetoacetate, the classical ketones, yields only acetyl-CoA and leads to an "overload" of acetyl-CoA in the TCA cycle. I've discussed the reasons this becomes problematic in past postings. In some cases, the administration of citrate or other TCA cycle intermediates other than acetyl-CoA (anaplerotic compounds) has been as useful, in conjunction with C2 precursors (i.e. MCTs), as the use of triheptanoin has been. It's conceivable that in epilepsy, for example, the acetyl-CoA overload is actually therapeutic, up to a point. That's more or less at the root of the arguments that Yudkoff and colleagues have made in their articles, in my opinion. They say that the inhibition of the overall activity of the pyruvate dehydrogenase complex by an excess of acetyl-CoA is one factor (one of several factors) that causes the equilibrium of the mitochondrial glutamate-oxaloacetate transaminase reaction to be shifted toward glutamate formation (and to thereby increase the glutamate/aspartate ratio, both intramitochondrially and extramitochondrially and lead to an increase in GABA formation from the extra glutamate, etc.). But in conditions other than epilepsy, this is less likely to be the case (the excess of acetyl-CoA, derived from the oxidation of C4 ketones, like 3-hydroxybutyrate, is less likely to be beneficial, past a certain point), and researchers should be considering the administration of soluble salts of C5 ketones as an approach to the treatments of some of these supposedly "ketone-responsive" conditions (the potentially therapeutic effects of C4 ketones have been researched and discussed, at length, in the context of many neurodegenerative and psychiatric conditions, etc.).

If it weren't for the fact that massive amounts of glycine are provided along with propionyl-L-carnitine (PLC) in some preparations, I might be inclined say that propionylcarnitine would be a good anaplerotic compound and substitute for triheptanoin. Unfortunately, in my opinion, the glycine provided along with PLC, in some preparations, compromises its usefulness. There are still a lot of problems with the planning that goes into the choices of salts of compounds and in the development of pharmaceutical dosage forms in general. Manufacturers cavalierly choose calcium salts of compounds, for example, and don't consider that high doses of calcium can foster thrombogenicity, in my opinion [as discussed in past postings (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/pyridoxine-calcium-channels-and.html)]. Glycine is an excitatory neurotransmitter in the brain, although most researchers and people seem to still think it's only inhibitory (it's inhibitory in the spinal cord, at the strychnine-sensitive glycine binding sites on NMDA receptors, but it's predominantly excitatory in the brainstem). There's some recent research on mice with loss of function mutations in glycine transporters that illustrates the way glycine behaves in the brain (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22glycine+transporter%22+mouse+deletion), and I think free form glycine should not be used in any nutritional supplements. These are just my opinions, of course.

GABA as a Peripheral Succinate Precursor: Relevance to Not Much of Anything

This is a fringe topic that I wouldn't expect much from, in the way of therapeutic effects in any disease state, but I find it mildly interesting. There are these puzzling articles showing that oral gamma-aminobutyric acid (GABA), a neurotransmitter or "signalling molecule" [if one wants to cling to the notion, as some people apparently do, that it doesn't always act as a neurotransmitter--in fact, the reverse transport/uptake of GABA, from the cytosol to the extracellular fluid, can occur, given that a cytosolic pool, in neurons, is separate from the vesicular pool and can serve to export GABA in a somewhat-frequency-independent manner: Waagepetersen et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11170185)], can reduce blood pressure in humans and animals (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=GABA+antihypertensive+oral+OR+orally) and can release growth hormone in humans [Cavagnini et al., 1980a: (http://www.ncbi.nlm.nih.gov/pubmed/7376786); Cavagnini et al., 1980b: (http://www.ncbi.nlm.nih.gov/pubmed/7419665); Powers et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18091016)]. This seems puzzling at first glance, given that GABA is not known to be able to cross the blood-brain barrier to any significant degree. In contrast to the case of glutamine, in which researchers have drawn erroneous conclusions about the pharmacology of glutamine, I think the research on GABA was done more carefully, back when some of the earlier anticonvulsants were being developed. I think that the oral GABA, administered to the people or animals in those articles, just underwent transamination to glutamate and succinate semialdehyde in hepatocytes and then, after the conversion of succinate semialdehyde to succinate, by succinate semialdehyde dehydrogenase, entered the tricarboxylic acid cycle as succinate. That could produce a decrease in plasma free fatty acid concentrations and induce GH release, even though it doesn't look like GABA is a very strong or reliable GH releaser, in my opinion. The site of action could be in the liver or in adipocytes, I guess. Glutamine probably releases GH, in part, by suppressing lipolysis in adipocytes or in the skeletal muscles, outside the brain, and thereby decreasing FFA levels. Glutamine can also increase the oxidation of fatty acids, under some circumstances, and that type of effect could occur with succinate. Powers et al. (2008) suggested that the metabolism of the GABA in the liver had increased the export of some amino acid by the liver and thereby led to GH release (upon the entry of some amino acid, other than GABA, into the brain), and that's possible. But the use of the 3-gram dosage of GABA would argue against that conclusion, given that no known "metabolite" of GABA is known to induce GH release, by way of its entry from the blood into the brain, in amounts in the range of 3 grams or, I should say, in amounts crudely or even nearly equimolar to the 3-gram dosage of GABA. It's conceivable that changes in plasma amino acids, following the metabolism of GABA in the liver (see Ferenci et al., 1988, cited below), suppressed lipolysis in adipocytes, but I think that the GABA-derived succinate may have just increased fatty acid oxidation in the liver. Succinate is known to stimulate oxidative metabolism, etc. [this is not a great example, but it's still an interesting article: Endlicher et al., 2008: (http://www.biomed.cas.cz/physiolres/pdf/prepress/1635.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/19093725)]. A transient increase in beta-oxidation is a sort of generalized outcome that can result from changes in the ratios of TCA cycle intermediates, but I don't want to get into all of that.

Also, the suggestion by Powers et al. (2008) (and by Cavagnini et al., 1980b, in the abstract of one of those articles I can't get the full texts of) that the reversal of the oral GABA-induced GH release by pimozide and not domperizone provided evidence of a central site of action (i.e. in the brain) of oral GABA is not valid. If GABA reduced the plasma concentration of free fatty acids, the effect would be to disinhibit some of the neurobiological mechanisms that normally inhibit GH release from the pituitary (FFAs act on the pituitary to suppress GH release). The fact that a D2 dopamine receptor antagonist like pimozide blocked the effect does not mean that GABA had to have entered the brain. All that is necessary, in the absence of pimozide or whatever other centrally-acting drug that reduces the GH release in response to a decrease in FFAs, is for a reduction in plasma FFA levels to occur. The research on growth hormone releasers can be mind-bending, because, at first glance, it seems like a study like that is saying that oral GABA has some kind of bizarre, inexplicable, dopaminergic effect. It doesn't mean that. There are all sorts of neurotransmitter systems that converge and interact in complex ways in the hypothalamus and regulate GH release. It's like watching a tire on a green car go flat and cause a traffic jam, when it blocks one of the lanes, and then concluding that traffic jams are caused by green cars but not yellow or red cars (or concluding that the flat tire must have been caused by something on the highway, when it could have been caused by something outside the highway, as in the case of GABA). In reality, a car of just about any color could get a flat tire (analogous to the drug that blocks some GH-releasing effect) and cause a traffic jam, as in the hypothalamic regulatory "highway" that governs GH release. I'm sorry to have to resort to analogies, but it's easier than trying to get into all the nightmarishly-complex neuroanatomy.

Another reason I'm interpreting the research this way is that oral GABA is very efficiently transported into the livers of rats and, following its metabolism into succinate, oxidized to CO2 [Ferenci et al., 1988: (http://www.ncbi.nlm.nih.gov/pubmed/3391367)]. It's also interesting that, in the brain, GABA, through its conversion to succinate in the so-called "GABA shunt," is thought to make a surprisingly large contribution to oxidative energy production in neurons and astrocytes [Patel et al., 2005: (http://www.pnas.org/content/102/15/5588.full.pdf+html)(http://www.ncbi.nlm.nih.gov/pubmed/15809416)]. Also, propionylcarnitine and C5 ketone bodies are thought to exert their anaplerotic effects by entering the TCA cycle as succinyl-CoA, which is then converted to succinate by succinyl-CoA ligase. That enzyme has about 20 different names, and I discussed it in past postings [(http://hardcorephysiologyfun.blogspot.com/2009/01/vitamin-b12-succinyl-coa-ligases-and.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/plausible-mechanism-for-inhibition-of.html)]

I should say that at least one of the articles showing antihypertensive effects of oral GABA, in animals, is bizarre and basically can't be true, because the authors found some effect from 0.5 mg/kg bw of oral GABA. That scales to a human dose of 7.5 mg or something, and I just can't see how that could be true. All of it would be taken up by the liver. Even if one used a dose of 0.5 mg/kg for a human, the dose would be 35 mg for a 70-kg human. How could that possibly produce any biological effects? In any case, I thought this was vaguely interesting, but I can't really see any obvious therapeutic applications.

Potential for Inhibition of Ketogenesis as a Result of Vitamin B12 Deficiency/Depletion: Role of Succinylation of HMG-CoA Synthase & Other Mechanisms

This article [Hegardt, 1999: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1220089)(http://www.ncbi.nlm.nih.gov/pubmed/10051425)] is great and discusses a lot of the mechanisms by which fasting and insulin and other factors regulate ketogenesis. The author discusses the fact that the mitochondrial HMG-CoA synthase (mHMGS) isoform is thought to be rate-limiting for ketogenesis under many different sets of circumstances, and the author discusses the inhibition of mHMGS by its succinylation or mechanism-based (suicide, covalent) inactivation, at an active site cysteine residue, by propionyl-CoA. At first glance, this would seem to suggest that something like cobalamin (vitamin B12, or just B12) depletion would lead to a decrease in the succinylation, thereby, potentially, disinhibiting ketogenesis, but also to an increase in the mechanism-based (noncompetitive) inhibition by propionyl-CoA. Propionyl-CoA accumulates in mitochondria in B12 deficiency [see Brass et al., 1990: (http://jn.nutrition.org/cgi/reprint/120/3/290.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/2319347); (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22coenzyme+A+metabolism%22+B12)], but B12 deficiency also decreases the formation of succinyl-CoA from methylmalonyl-CoA [due to the decrease in 5'-deoxyadenosylcobalamin-dependent methylmalonyl-CoA mutase (MMM) activity] and, as a consequence, may decrease succinate availability intramitochondrially. But succinate can be maintained from other pathways, and B12 deficiency also may inhibit succinate dehydrogenase activity by causing the accumulation of methylmalonate, derived from an excess of methylmalonyl-CoA [see Toyoshima et al., 1995: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22succinate+dehydrogenase%22+cobalamin)]. That might actually increase succinate accumulation, but it's not really possible to tell what the effect of B12 deficiency would be on the steady-state levels of succinate that would be available for mHMGS succinylation (and, consequently, inhibition). Brass et al. (1990) found that B12 deficiency nonsignificantly reduced fasting beta-hydroxybutyrate levels and that hydroxocobalamin[c-lactam], which selectively inhibits MMM activity, did reduce beta-hydroxybutyrate levels (one of the two major plasma ketones). Propionyl-CoA is known to be increased in B12 deficiency, but some articles have found evidence of mitochondrial proliferation [which is clearly pathological, in this case, as discussed by Krahenbuhl et al., 1990: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22succinate+dehydrogenase%22+cobalamin)], and that type of response could temporarily compensate for the deficits in beta-oxidation and ketogenesis that one would expect to see in chronic B12 depletion. There's an article in the journal Annual Review of Nutrition (I don't have time to cite it, but the article is in the one-issue-per-year, 1992 issue), and the authors try to discount the role of decreases in MMM activity in the neuropathy or subacute combined degeneration of B12 depletion. But the reasoning they use is not valid, in general, largely because of the profound and complex changes in mitochondrial functioning that can result from methlmalonic acid and methylcitric acid, etc. (organic acids that accumulate in B12 deficiency). Most people are not aware that B12 deficiency can cause liver damage and dysfunction. Joshi et al. (2008) [Joshi et al., 2008: (http://www.japi.org/june_2008/corr-476.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/18822634)] found evidence of this, and there are other articles on it. I seriously doubt that that jaundice is only due to the intramedullary hemolysis of reticulocytes or erythroblasts. That doesn't make sense to me. I think it's partly or largely the result of impairments in mitochondrial energy metabolism in hepatocytes and other cells of the liver, due to the inhibitory effects of the accumulated acyl-CoAs and organic acids (derived from excesses of their organic acyl-CoAs) on many different mitochondrial enzymes, including mHMGS. I think B12 depletion could reasonably be expected to inhibit both beta-oxidation (there's a great deal of evidence that this is the case) and also ketogenesis (and ketone utilization in neurons, etc.). But that's just my opinion. That first search I linked to (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22coenzyme+A+metabolism%22+B12) looks like it has some articles with some more in-depth data on B12-depletion-induced changes in beta-oxidation or lipogenesis and ketogenesis, and I'll try to look through those at some point. I've discussed the inhibitory effects of organic acids and acyl-CoAs (those that accumulate as a result of B12 depletion) on mitochondrial functioning in general and on TCA cycle enzymes in particular, including succinate dehydrogenase, in many past postings. An impairment in beta-oxidation obviously implies that there will be a deficit in ketone formation, but some of these more specific mechanisms in the regulation of ketogenic enzymes, such as mHMGS, may also become significant in the context of B12 deficiency and other pathological states. I suppose I don't need to say that, in my opinion, cyanocobalamin (one form of vitamin B12) is very inferior to methylcobalamin (another form of vitamin B12). The main reason, as I've discussed in many past postings, is simply that methylcobalamin is *not cyanocobalamin* and does not yield cyanide and is transported much more efficiently than cyanocobalamin is, etc. These are my opinions based on the literature, and there's a vast amount of literature comparing the two forms.

Acyl-CoA Accumulation, Ketogenic Substrates, Fatty Liver Disease, Moderation, and Sustainability

These articles [Aiello et al., 1983: (http://jds.fass.org/cgi/reprint/67/8/1707.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/6480960); Henning and Hird, 1972: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1174516&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/4664932)] show that butyrate, such as from the highly-soluble sodium butyrate, is an effective ketogenic substrate in hepatocytes (in the livers of cows) (Aiello et al., 1983) or in the epithelial cells of parts of the GI tract in rabbits (Henning and Hird, 1972). There's nothing that's really magical about a ketogenic compound, and even glucose is obviously an indirect, ketogenic substrate. But the issues of interest are the efficiencies with which different compounds can be converted into ketones and the extents to which increases in the availabilities of different compounds can increase ketone formation or oxidation, etc. Increasing glucose in one's diet is unlikely to increase ketone formation very efficiently, past a certain point, for example.

I should mention that the accumulation of short-chain or branched-chain or long-chain or any other types of acyl-CoA thioesters can potentially contribute to fatty liver disease in the long term or under other circumstances, in different individuals. That's my opinion, and acyl-CoAs just inhibit all sorts of different mitochondrial enzymes and inhibit ATP production, etc., and are thought to contribute to the development of fatty liver disease (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=acyl-CoA+%22fatty+liver%22+mitochondrial). I've discussed this in past postings. Although there is research showing that high-fat diets can sometimes actually be beneficial to fatty liver disease, to the extent that high-protein, low-carbohydrate diets can reduce insulin levels, I find it hard to believe that most people would be able to sustain very high-fat, "ketogenic" diets. Increasing one's fat intake is not necessarily going to cause fatty liver disease, but the point is that cells in the liver and other parts of the bodies of adult humans (such as in astrocytes, in the brain) do not have as much of a capacity to oxidize fatty acids as the cells of children and adolescents do. Most of the research, in my opinion, shows that high fat diets, in combination with the carbohydrates that most people eat and that are almost impossible not to eat, do increase a person's risk of developing fatty liver disease. It's just something to be aware of, given that ketogenic substrates, such as HMB and butyrate, can cause the accumulation of acyl-CoAs that can become toxic, in my opinion.

I think there can be a tendency for people to think that they have to either commit to a full-blown, restrictive, "ketogenic diet" or to do nothing, but those are not the only approaches. I understand that carbohydrate ingestion tends to suppress ketone formation, but this is only true to a certain point, in my view. It's not an all-or-nothing phenomenon. Eating carbohydrates doesn't shut down ketone formation completely, and one doesn't, in my opinion, need to eat 100 grams a day of liquid fats to slightly increase ketone formation by astrocytes or by the liver or intestinal epithelial cells. One approach would be to, of course, talk to one's doctor before taking anything and to discuss the possibility of taking small doses of some of these ketogenic substrates. Researchers are discussing the potential usefulness of an increase in ketone availability in many different conditions, including Alzheimer's disease and psychiatric conditions, etc. But combining small doses of some of these ketogenic compounds with something like resistance exercise, which tends to increase ketone formation and utilization in a more subtle and physiologically-sustainable way, seems, in my opinion, to be a more rational approach than does the use of one of these drastic, high-dose-or-nothing, dietary interventions.

Ketogenic Amino Acids and the Regulation of Cholesterol Biosynthesis

The authors of this article [Noda and Ichihara, 1976: (http://www.ncbi.nlm.nih.gov/pubmed/1002682)] discuss research showing that the oxidation of ketogenic amino acids to CO2 (under conditions in which they are completely oxidized), such as tyrosine and leucine, provides twice as much ATP as the oxidation of gluconeogenic amino acids. The authors refer to a book, as the cited reference for that statement, and so I'm not sure what they actually mean. I'm assuming they mean that the oxidation of the carbons of acetyl-CoA, derived from the oxidation of the ketones that contain the leucine or tyrosine carbons, in the tricarboxylic acid cycle can serve to generate twice as much net ATP as the oxidation of the amino-acid-derived carbons in glucose formed by gluconeogenesis from amino acids.

It's interesting that the cytosolic enzyme 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) is one of two enzymes that forms HMB, a lipogenic/ketogenic leucine metabolite discussed in previous postings, and is also a key enzyme involved in the oxidation of tyrosine to acetoacetate (ketone formation from tyrosine) [reference 65, p. 728, discussed in: Schofield and Zhang, 1999: (http://alpha.life.nthu.edu.tw/~d888206/Pdf%20papers/2-OXO.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/10607676)]. 4-HPPD is sometimes referred to, in articles about HMB, as "KIC dioxygenase," or alpha-ketoisocaproate (KIC) dioxygenase, but it's more appropriate to say that 4-HPPD has KIC dioxygenase activity, in addition to its usual role of catalyzing the formation of homogentisate, an intermediate in tyrosine catabolism, from 4-hydroxyphenylpyruvate (Schofield and Zhang, 1999). Looking at the factors regulating that enzyme might be a starting point for understanding the mechanisms by which exogenous HMB could reduce leucine catabolism slightly (an effect that has been shown to occur, recently, in an animal study) etc. HMB can also be formed from isovaleryl-CoA, as discussed previously, by crotonase, which is more commonly known as enoyl-CoA hydratase [Rodriguez et al., 2004: (http://www.jbc.org/cgi/content/full/279/6/4578)(http://www.ncbi.nlm.nih.gov/pubmed/14612443?dopt=Abstract)]. Rodriguez et al. (2004) also discuss the fact that HMG-CoA can be converted into various isoprenoids (geranyl-CoA, etc.), which are intermediates in cholesterol biosynthesis, and then recycled back into 3-methylcrotonyl-CoA and HMB-CoA, by the enzymes of the so-called "mevalonate shunt." The authors also mention Smith-Lemli-Opitz syndrome, which is a genetic disorder that causes pathologically low plasma cholesterol levels and psychiatric symptoms. The disorder prevents the conversion of delta7-dehydrocholesterol into cholesterol, because of loss-of-function mutations in 7-DHC reductase, and causes toxic cholesterol precursors to accumulate and cause brain damage, etc. (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=7-dehydrocholesterol+Smith+Lemli+Opitz). Rodriguez et al. (1999) also mention that plasma 3-methylglutaconic acid can increase in people who have that genetic disorder, and researchers could investigate the possibility that the accumulation of intermediates in cholesterol biosynthesis or in the mevalonate pathway contribute to psychiatric symptoms associated with low plasma cholesterol. If that were the case, one might expect HMB or increases in ketone availability from other ketone precursors (other ketogenic substrates, other than HMB) to transiently worsen psychiatric symptoms but ultimately increase cholesterol formation and improve psychiatric symptoms, given that the normalized pool of cholesterol would be able to exert feedback inhibition of HMG-CoA reductase activity and prevent the accumulation of the intermediates. But these are just my opinions and avenues of thought in this area.