Monday, April 23, 2012

GSD type I vs GSD type III: Cornstarch vs ketones

Very briefly: I hit this by accident. Some time ago there was an exchange of comments about whether VLC eating might function as a management for Glycogen Storage Disease type I, von Gierke's disease. I think the question was firmly, and possibly incorrectly, settled by mnature pointing out that raw cornstarch was THE answer. No choice. I realise GSD type III is not GSD type I, but many of the clinical signs are the same, especially hypoglycaemia. There is choice in type III.

The group have tried a high protein diet to provide hepatic glucose from gluconeogenesis, a mildly ketogeneic diet to AVOID providing exogenous glucose because it just drops in to a bottomless pit of stored glycogen and some synthetic ketones à la Veech to provide some glucose-independent ATP.

Just a case report, it worked. So far so good. Interesting.


PS The new blogger format. I hate it. Can you make the links live in preview????


tess said...

re: PS -- i hate the new interface, too! and i couldn't make the links work in preview even before the change....

donny said...

I posted this to the earlier post about GSD and ketosis;

Hi all.

Just an abstract, but it doesn't look promising...

On fasting, subjects with Type I glycogenosis had lower concentrations of β-hydroxybutyrate than did control patients matched for age and degree of hypoglycemia. Also a ketogenic diet provoked less ketosis and the disposal of a standard intravenous load of β-hydroxybutrate was slower than in normal children. These findings indicate that, contrary to what has been widely believed, patients with Type I glycogenosis are less prone to ketosis than are normal children.

So I wonder is glucose 6 phosphatase deficiency is causative?

Hepatic over-sensitivity to insulin might explain hypoglycemia, poor access to glycogen stores, failure to go into ketosis. Perhaps low insulin levels, caused by the poor release of glucose by the liver, is what inhibits ketone use in other tissues?

Chronic hypoglycemia produces secondary metabolic adaptations, including chronically low insulin levels and high levels of glucagon and cortisol.-------------------------------------------

Today me again. At the time I thought this bit made it look bad for a ketogenic diet;

and the disposal of a standard intravenous load of β-hydroxybutrate was slower than in normal children.
But it seems pretty no-brainer to suppose that children who have trouble getting into ketosis in the first place would tend to dispose of intravenous ketones more slowly after an acute load--wouldn't make sense for the metabolism to wrap itself around ketones until some actually start showing up on a regular basis. Any ketones that did show up before such exposure might be particularly precious and conserved.

Peter said...

Donny, perhaps this makes a case for Veech's ketone esters... Give them for a week to induce production of beta hydroxybutyrate dehydrogenase, which I can't see a lot of use for if you are innately bad at producing ketones due to intense insulin sensitivity, then see what happens. To me the good aspect of the GSD III paper is that people are thinking and acting outside of the cornstarch box. If pushed by a fatal therapeutic failure in the cornstarch approach to type III that is...


ItsTheWooo said...

I am refusing to use the new blogger interface. REFUSING. It is part of my mission to hasten my development into a old bat that laments the novelty of modernity.

There is an option to REFUSE, if you like me puke at all these websites trying to macintosh-ize every frigging thing, with crisp white backgrounds and a lack of meaningful words to describe functions.

Peter said...

Ah, you CAN refuse. Phew.


Peter said...

Uh, no you can't. Duh.

Galina L. said...

@Peter, it is about migraine issue. As I commented before mine got better on ketogenic diet but not gone completely. I din't have migraines in ketogenic state when I travel, after major stress, obviously if I din't eat in time, but the most difficult migraine reason to take care of was the hormonal (changes associated with menstrual cycle). So far it looks like the supplement Taurine suggested by the Wooo
has the ability to prevent migraine in that case for me. I decided to let you know because it could be useful for your wife.

Peter said...

Thanks Galina, we will give it a try.

Sam Knox said...

There's always Wordpress.

You can transfer posts from Blogger to Wordpress.

ItsTheWooo said...

at, there is a little "gear" icon, underneath your name/picture. Click the gear and then choose the option "old blogger interface" and viola, we have averted the HORRIBLE UP[down]GRADE.

john said...

Peter you should see what happens to beta hydroxybutyrate dehydrogenase when you add surface receptor cold to the mix. It makes ketogenic diet fire up like a Ferrari.

Peter said...


"The old Blogger interface will be removed in the coming month." Sigh


Yes, I have a lot of time for cold adaptations and UCPs, logical to improved ketone access.


Peter said...

Wordpress, yes Sam, worth thinking about. I'm already registered through wanting to comment on Wordpress blogs in the past...

M said...

Hello, Peter. If you ever find the time you might find interesting this paper on the possibility of cellulite being (yet another) symptom of diabetes and a manifestation of inflammation. I wonder (as an interested party...) if it's possible to completly reverse it simply by following a LC, high fat diet, or if it's one of things that will always be broken.

George Henderson said...

Case studies really ought to replace epidemiology at least half the time. There's the downside of the n=1, but the upside of absolute significance and meaningfulness to the result.

Here are the tables from that paper:

primalodille said...

Re the format, come to Wordpress - re the article - fascinating.
I have an article on a woman whose schizophrenia was cured by low carb!

mnature said...

Peter, this is one of the few blogs where I feel completely inadequate. The amount of expertise and minute detail shown by both you, and the regular posters, is astonishing. In the past I would have said that I had a fair amount of medical knowledge, but mine pales in comparison to everyone here. Therefore, I take the fact that you even noticed my comment as a compliment, even if I am wrong.

My comment about cornstarch was based upon simple searches on the internet, looking at reputable sites and comments by parents of GSD I children. I cannot afford to get genetic testing on myself, but I believe I may have two genetic problems. One is fructose malabsorption, of which I am fairly certain, based on symptoms while eating fructose (most of my life) and after reducing fructose to close to zero levels (yes, no fruits and no vegetables, except for old potatoes, along with avoiding fructans). I use a glucose powder in my tea, which satisfies my (probably somewhat psychotic) need for sweetness. The other problem could be GSD I, and after reading the comments and the abstract that donny posted, it certainly fits with my inability to go into ketosis on zero carbs (I simply go into rather severe hypoglycemia).

I do try to eat a small amount about every four hours, beef and potatoes being my mainstay. For various reasons I am unable to use grains for complex carbohydrate to trickle-charge my glucose needs. I usually have to eat something just before going to bed, because when I forget to do that I wake up with a headache. On the plus side, though, I no longer have constant headaches, nosebleeds, abdominal pain and problems, chest pain, or trouble sleeping. My last eye exam shows that my astigmatisms are going away (I can't explain that one).

TwitchyFirefly said...

"Current treatment of GSD III is based on frequent high-carbohydrate meals that have no effect on the cardiomyopathy."

So why is that still the current treatment? It's an illuminating comment on the state of much "conventional wisdom".

Peter said...

M, any interested party could usefully go for that n=1 study and let us all know. It might have some marked appeal to a significant portion of the population...

George, thanks. I wonder what could have been done without the synthetic ketone ester? But if needs must...

primalodille, yes I have that paper and will (one day perhaps) expand the discussion, which is rather restricted in the publication. There is a long history of suspicion about both gluten and casein, and neurone loss (ATP/apoptosis???) in schizophrenia.

TwitchyFirefly, there is no cardiomyopathy associated with GSD I, so I guess no drive to think outside the box until you hit cardiac problems with Type III. The interesting thing for mnature (hi) is whether the effect might work for their hypoglycaemia and whether it could be achieved with simple coconut oil rather than ketone esters along side a mildly ketogenic, elevated protein diet.

mnature, most of us around here do try to think a little outside the box, but getting real results in the real world, even at n=1, certainly makes me sit up and take notice. I'd be even more interested if I was a recurrent hypoglycaemic. Combined fructose and gluten elimination is certainly a recipe for improved health. A few ketones might help. Are you really ketone free when you consume coconut oil?


George Henderson said...

Interesting papers on lipid metabolism and schizophrenia

In the first link I believe there is increased expression of enzymes burning brain lipids for substrates in schizophrenics; it's not all glucose and ketones, apparently

George Henderson said...

Here's the fulltext of the schizophrenia paper

Biological systems limited in their supply of glucose as an energy source are forced to alter their gene expression in order to utilize alternate energy sources. We found significant increases at the transcript level of several fatty acid beta-oxidation enzymes, including peroxisomal acyl-CoA oxidase, short- and long-chain dehydrogenases (ACADS, ACADL) and DCI that encodes an isomerase required for the breakdown of saturated fatty acids. Conversely, the 'lipid biosynthesis' pathway was significantly downregulated (Figure 1b), which includes several transcripts for key enzymes of fatty acid and lipid biosynthesis, such as long-chain fatty-acid-coenzyme A ligase, acetyl-coenzyme A acyltransferase 2 (ACAT2), ATP citrate lyase and alkylglycerone phosphate synthase (AGPS). Finally, our metabolomics results also showed a decrease in long-chain fatty acids (data not shown).

mnature said...

Peter, I haven't tried coconut oil, and it is due to problems that I have with plastic containers. The tallow seems to work because it is a solid, and therefore doesn't appear to transport as much stuff from the plastic bucket (a very hard plastic, which is also helpful). Any oils I attempt to use appear to have the nasty habit of pulling stuff (yes, very non-technical word, but I'm not sure which stuff it is pulling) which makes me ill. Therefore, unless I can find coconut oil in glass or metal (which I haven't found, so far) I must stick with what I know works. Now, my mostly beef and potatoes diet has kept my cholesterol high, and my doctor keeps insisting I should use meds to pull it down, which I refuse. However, I am now being treated for vitamin D deficiency (test came back with no detectable amounts), and I'm hoping that the vitamin D will help to clear up some of these other problems.

However, the really amazing story is my husband. We have been married ten years, and he had started taking glypicides a few years before we married. Last year he was told he needed to go onto insulin. After some severe hypoglycemia, he found he had to spread the insulin out, and take three injections per day. He decided it was time for drastic action. He had already put himself on a controlled diet when he went on the glypicides, but he upped the ante. Though he never ate anything with added sugar, he had been eating vegetables and occasional grain products (crackers, bread). He went to a diet similar to mine, except for more variety of meat, and absolutely no vegetables at all. That was two months ago. As soon as he started on this spartan diet (though he never went hungry), he was able to start dropping the amount of insulin. When that dropped to zero, he started dropping out the glypicides. He is now not taking any diabetes meds, and his blood sugar was 105 this morning. Plus he dropped about 20 pounds (that was with no change of physical activity). He has also accumulated some kick-ass sausage recipes, and made up some of his own. He also makes a really great chile (no beans) out of roast beef and roast pork.

I'm just trying to survive. He is actually thriving. Closest thing to a miracle I have ever seen.

Galina L. said...

@ mnature,
most of the time I see coconut oil to be sold in glass jars, but I decides to check an internet, and the first choice was CO in glass containers from Tropical Traditions
BTW, when my son was in London during short 2 weeks visit last summer, the only place where he could buy a CO was some ethnic hair product store.

mnature said...

Galina, any idea if coconut oil has sulfites? I can modify sulfites in dry foods, but not sure it would work on oils. It is generally assumed that any coconut product will have sulfites in it. And how long does it take to go into ketosis using coconut oil? Once I cut out all carbohydrates, it takes me between two and three days to slip into severe hypoglycemia.

Galina L. said...

Probably, manufacturers know it better than me . The better I adapted to ketosis, the faster I can enter into such state, especially after I got adapted to the exercising in a fasted state. However, I have to worn you - the perfect adaptation to ketosis often means physiological IR. It is reversible, feels great, but fasted blood sugar may start look abnormal, especially after exercising, and no hypoglycemia, of course. I used to have migraines after not eating in time.
Now I purposely try not to be in a deep ketosis and eat some carbs ones a day in order to make sure FBS doesn't go higher than I prefer.

Peter said...

Here in the UK we can get coconut oil in screw top bottles of about 500ml. You have to go to the seedier streets in Norwich and find ethnic food shops. But it's probably rather nasty industrialy processed and fully hydrogenated stuff with lots of nickel residues etc. But it would generate a few ketones. Certainly hypovitaminosis D will not help your immune function. Emily on plantpoisonsandrotten stuff found, I believe, a lot of her salicylate and amine intolerances improved on correction of hypothyroidism. I have vague memories that coconut is full of sulphites. Butter might be an alternative, though the dose of MCT is lower. MCTs make ketones in a few hours.

Your husband's experience is relatively common. If the ADA etc promulgated his findings then the diabetes industry (ADA included) would go bankrupt in about 4 weeks. We could never allow that to happen.

Galina, amen.

George, in the trawling through papers on metabolic brain injury/VMH changes it became obvious that a, the brain takes up FFAs in small amounts. b, it oxidises about 50% of these. c, the process is increased in metabolic syndrome, and d, schizophrenics have glucose dysregulation issues at first presentation, before the meds worsen this. I suspect it will all go back to metabolic inflexibility and combining hyperglycaemia with a background elevated FFA level. Your genes will probably determine which bits of you break first under this bodged system. Metabolic syndrome is a survival process with significant health costs... No time to follow the links yet, 6.30am and time to feed the chickens and children!


nancan said...

I buy c-oil in jars from Amazon, there are a few brands that come that way.

RE: getting into ketosis-- I found a tablespoon of pure MCT oil a day readily gets me into ketosis. It used to take 3-4 days of vlc, but after times I go out, I get right back in by second day.

+for Wordpress!

Lacie said...

@Peter: "George, thanks. I wonder what could have been done without the synthetic ketone ester? But if needs must..."
Peter, if you're referring to the Ketocal used in the paper, it's not a synthetic ketone ester; it's a ready-made liquid diet aimed at kids with epilepsy that's balanced for a 4:1 fat to protein/carb ratio so the parents don't have to calculate it themselves. First three ingredients are "Refined Vegetable Oil (Palm, Soy), Milk Protein, Lactose (Milk)," followed by a bunch of vitamins and minerals, so it doesn't even rely on MCT oil for ketogensis.

There's a ton of patents out there for synthetic ketone esters, but at this point the only way to actually get your hands on some is to participate in the clinical trial by Veech's partner in the U.K., Kieran Clarke. At this point, Veech and another researcher, Dominic D'Agostino, can only get funding from the U.S. Dept. of Defense for the esters - NIH isn't interested, DoD wants a food pill so soldiers don't have to hump a packful of MREs into a combat zone.

An intermediate step between taking MCT oil and waiting for ketone esters to become available is to make friends with someone in a lab, order some 1,3-butanediol (a food and cosmetics preservative with a decent safety profile), and slug down 50-100ml a day of the stuff. Weirdly, NASA was looking at it as food for astronauts back in the 1970s. Sort of like Tang, hehe, for those old enough to remember. 1,3-butadeniol generates 3-OHB levels about 2-3 times as high as carb restriction plus coconut oil, but only 1/3 as high as ketone esters, which take you up to 6 mmo/l.

I'm satisfied with mild ketosis from time to time via carb restriction and coconut milk for myself, but my BF just got a firm Parkinson's diagnosis, so we want to pursue something more aggressive for him. Dr. Mary Newport has her husband on big doses of MCT oil for his Alzheimer's (admittedly a tougher nut to crack than PD), and although the diet has slowed down his decline, it hasn't stopped or reversed it. Veech has shown that deep ketosis may actually revive the mitochondria in the substantia nigra so the cells start producing dopamine again. I don't think this paper is available free as full text, but it contains a nice history of Veech's work with Hans Krebs in the 1960s:

Galina L. said...

I have been wondering since recently, what difference does it make to be in ketosis and have a BS in a high-normal range or even a pre-diabetic for some, as opposite to be hypoglycemic in ketosis. Sure, for cancer patients scenario #2 is better than number one. With exersise the #1 is optimal. But is it possible for a body of non-diabetic to make more sugar than it needs and be at ketosis at the same time? Where the sugar is going then, into a glycogen storage, or turning into a fat?

Galina L. said...
This comment has been removed by the author.
George Henderson said...

I figure the brain must be able to oxidise fats or there would be no turn over of membrane lipids. Also, what use would DHA supplemennts be if fats were not crossing the BBB? Plus, fatty acid synthesis is a safe way of storing any excess glucose calories that arrive.

"perhaps this makes a case for Veech's ketone esters... Give them for a week to induce production of beta hydroxybutyrate dehydrogenase, which I can't see a lot of use for if you are innately bad at producing ketones due to intense insulin sensitivity"

Inducing beta-HB dehydrogenase would increase NADH/NAD+ ratio,
(NADH is a product of this enzyme)and this might stimulate ketone production:

"...the citric acid cycle is inhibited by the elevated level of NADH resulting from β-oxidation of fatty acids. Unable to be used in the citric acid cycle, the excess acetyl-CoA is therefore rerouted to ketogenesis."

Peter said...

Hi Lacie,

I picked up from the caption of the figures linked to by George that they were using 1,3-butadeniol as a ketone generator, which allowed them to back off on the use for neat Ketocal and add in a little more protein. Nice to have a little more background.

I'm working slowly back through Veech's publications to get to the logic of redox couple states in mathematical terms, which is hard going and may not be necessary except he tends to throw in equations as if we all know exactly what he is taking about... It would be interesting to read the paper you cited and, by happy coincidence, I have recently been presented with access to an enormously powerful Athens account. But the paper doesn't seem to be on line. Hmmm odd for a publication this century!

George, the ApoEs deliver lipids to the brain. But certainly some FFAs get in too. You have to wonder if that's where cerebral insulin resistance comes from...

NADH/NAD: that's why Veech's work is so interesting. And the Q10 couple next door in the ETC, all change with ketones, fats and glycolysis. Differently.... And then there is succunate dehydrogenase and the Q10 redox couple. Veech has looked at them all.

Galina, I suspect the glucose is going nowhere and doing nothing. To replace insulin induced GLUT4 action you need plasma glucose >20mmol/l, and that's assuming there are GLUT1s hanging around. These are regulated chronically by insulin, over a period of weeks. So if cells are insulin resistant GLUT4s are on vacation. Under chronically low insulin GLUT1s are down regulated. Glucose can hang around to get in to brain cells. Oddly enough neither fructose nor glucose are glycating agents. They have to be phosphorylated first. That doesn't happen in plasma... There's a post or two there, been hanging around unwitten for a few years now!


mnature said...

Just as a follow-on comment to coconut oil: I was able to find a reasonably good brand of coconut oil, by Nutiva. Tastes good. And now I definitely know that I have an allergic reaction to coconut oil. A real histamine reaction with throat swelling, difficulty breathing, and an asthma-like reaction that lasted for about a week. I had no idea, but this now explains some odd reactions I have had to various medications and foods. I was actually expecting a sulfite reaction, but didn't have one. Oh, and I also had some really nasty hypoglycemic episodes. That was after taking one tablespoon of coconut oil for two days.

After doing some web searches, it probably wasn't the coconut oil itself, but the fact that the coconut oil was always retain some of the particles of the coconut meat, which would be the actual allergen. Same reason why I can't used clarified butter, because it always contains a little of the milk protein. Oh, well, not all of us are born strong and healthy.

M said...

I wonder if that strong reaction to coconut oil might not be a reaction to the ketogenic state in itself. You usually avoid it by having some potatoes with your meat, but apparently coconut oil always produces some ketones?

I think I may have the same adverse reaction. In spite of all my better efforts I still have not managed to stay completly low carb for even a whole week. There's always some negative reaction, like headaches or gastric reflux, for instance, that in my "normal" state I never used to have; or a come back of back pain.

The last time I felt unwell was when I had a generous table spoon of coconut oil before going to bed, in an effort to keep carb cravings away. The next two days I felt queezy, light headed to the point of almost fainting, could hardly face eating, and feeling of being unwell simply wouldn't go away. When I find that I am no longer functional (needing a lie down, unable to eat, etc), that's when I usually decide I've had enough. The usual cure is just to have some carbs, like yogurt with sugar, or potatoes, works like a charm. The only problem is that, at this rate, I may never lose those few extra stubborn pounds that cling to my belly...

George Henderson said...

Some interesting papers on inflammation, fatty acids and diabetes

CONCLUSIONS Suppression of FoxO1 activity by MEDICA analogs may partly account for their antidiabetic anti-inflammatory efficacy. FoxO1 suppression by LCFA analogs may provide a molecular rational for the beneficial efficacy of carbohydrate-restricted ketogenic diets in treating diabetes.

And in mice, FOX01 suppression causes gut neuroendocrine cells to produce insulin, relieving their diabetes:

Generation of functional insulin-producing cells in the gut by Foxo1 ablation
Chutima Talchai1–3, Shouhong Xuan4, Tadahiro Kitamura5, Ronald A DePinho6 & Domenico Accili1,2
VOLUME 44 | NUMBER 4 | APRIL 2012 Nature Genetics

Restoration of regulated insulin secretion is the ultimate goal of therapy for type 1 diabetes. Here, we show that, unexpectedly, somatic ablation of Foxo1 in Neurog3+ enteroendocrine progenitor cells gives rise to gut insulin-positive (Ins+) cells that express markers of mature b cells and secrete bioactive insulin as well as C-peptide in response to glucose and sulfonylureas. Lineage tracing experiments showed that gut Ins+ cells arise cell autonomously from Foxo1-deficient cells. Inducible Foxo1 ablation in adult mice also resulted in the generation of gut Ins+ cells. Following ablation by the b-cell toxin streptozotocin, gut Ins+ cells regenerate and produce insulin, reversing hyperglycemia in mice. The data indicate that Neurog3+ enteroendocrine progenitors require active Foxo1 to prevent differentiation into Ins+ cells. Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.

Gut insulin from Foxo1 loss
Seung K Kim

Neuroendocrine cells, including those in the gut, have a vast array of functions. A new study shows that conditional inactivation of the gene encoding Foxo1 in mouse intestinal endocrine cells converts them into cells synthesizing and secreting insulin. Ectopic gut insulin production was sufficient to ameliorate glucose control in mice with conditional pancreatic b-cell loss and diabetes mellitus.

nature genetics | volume 44 | number 4 | april 2012