The group which demonstrated that exogenous insulin induces insulin resistance in T1DM NOD mice went on to demonstrate that exogenous insulin induces T2DM in normal* mice on a normal chow diet.
*If you can describe Bl/6 mice as normal, with their failure to assemble mitochondrial super complexes and all of the potential implications that has on all sorts of metabolic effects. But I digress, as always.
Exposure to excess insulin (glargine) induces type 2 diabetes mellitus in mice fed on a chow diet
So you can imagine that I quite like this group. But they are naughty and the naughtiness is very annoying.
If you read about insulin administration in the current paper you will be presented with this bollocks:
"The dose of glargine was determined according to our previous experiments (Liu et al. 2009a )..."
What they did in Liu et al 2009a was to titrate the dose of insulin determir upwards to just achieve normoglycaemia. Different doses were needed in individual mice because that's what diabetes is like in NOD mice. That is NOT what they did in this current paper to the Bl/6 mice. Here they used glargine and they went straight in at a massive supraphysiological dose:
"C57BL/6 (B6) mice (male, 6–9-week old) from Charles River were treated with either saline or a long- and slow-acting insulin reagent, glargine (50 Unit/kg body weight, s.c. injection, once a day), for 8 weeks".
Even allowing for metabolic scaling from humans down to mice this is a massive dose of glargine. It's not remotely what they did with the NOD mice.
EDIT: Going back through the first paper the NOD T1 mice did actually end up with the average group dose of detemir being 25iu/kg twice daily. The difference in protocol is that the group is assuming that glargine 50iu/kg once daily is equivalent to detemir 25iu/kg twice daily. A big assumption. And that this would be fine for all mice. And that going in at the full dose rate on day one rather than titrating up over two weeks would also be equivalent. But the dose rate is more reasonable than I expected. END EDIT.
So there are fibs in the methods. Can you really trust these folks? Not much choice really...
None of the mice died on the glargine 50iu/kg dose, so I think we can assume that they developed a marked and rapid onset insulin-induced insulin resistance.
When you wade through the IRS1 serine phosphorylation, IRS1 tyrosine phosphorylation, Akt phosphorylation, total Akt etc etc etc in the results section the end conclusion is that the liver became insulin resistant but the gastrocnemius muscle (representing what I called "systemic" tissues) did not. Bummer for my nice, plausible and apparently incorrect ideas.
So to ease my cognitative dissonance I went back to our initial paper and waded through the IRS1 serine phosphorylation, IRS1 tyrosine phosphorylation, Akt phosphorylation, total Akt etc etc etc and discoved that, lo and behold, that under a clinical protocol the gastrocnemius did become insulin resistant. So did the liver but I can live with that, after all the liver does have a (bloody enormous) arterial blood supply in addition to receiving flow from the portal vein.
Phew, biases in-tact.
It's interesting to see in the paper that exogenous glargine actually destroys the pancreas. Beta cell mass falls, their mitochondria undergo marked oxidative stress and this allows the failure to deal with the hepatic insulin resistance induced by glargine 50iu/kg, hence the induction of diabetes.
I think the take home message is that taking glargine 50iu/kg won't help your own clinical diabetes, should you be so affected. It's also too high a dose if you are attempting to do harm!
Anyhow. Growth hormone and insulin resistance next, probably.
Peter
Peter, i think a strongly worded postcard admonishing their methodological 'laxity' is called for :)
ReplyDeleteraphi,
ReplyDeleteI went through the original paper and they did end up on 25iu of detemir bid as the mean dose rate of insulin in the NOD mice. So the only real problem is that they have assumed that 50iu/kg glargine is equivalent to 2 x 25iu/kg detemir. I'll put an edit in to this effect.
Peter
Unrelated, but wasn't sure whether you see new comments to older posts:
ReplyDeletehttps://www.nature.com/articles/s41598-018-19154-y
Apparently, Alzheimers is not due to loss of synapses as much as dysfunction, VGLUT1 involved. Right up your alley?
And while we are at this, rapamycin is apparently a panacea according to this guy:
ReplyDeletehttp://roguehealthandfitness.com/preventing-alzheimers-disease-rapamycin/
I kind of get suspicious when a substance is supposed to do too many wonders at a time.
Anyway, the effect on mTOR might be interesting.
Do you get why carriers of that gene are supposed to avoid saturated fats and red meat? Or is this enterprising doc too moored in conventional wisdom about nutrition?
Eric, rapamycin undoubtedly delays ageing. But people who believe that saturated fat and red meat are causal in Alzheimers have to show me the intervention studies. Anything else is religion or epidemiology. Fine if you state it as a belief structure...
ReplyDeletePeter
This comment has been removed by the author.
ReplyDeletePeter, I like it how you sort religion and epidemiology into the same bin.
ReplyDeleteIs rapamycin cut and dried for you? I haven't seen you write about it.
Lastly, do you get an alert when someone posts on an old blog entry?
Thanks
Eric
Re old comments: No, I don't get a report but I check once a week or so. If I desert the blog for a while there can simply be so many I can't remotely reply to any that need relies so they all tend to get approved and posted en block, viagra and the like excepted.
ReplyDeleteRapamycin is convincing but I don't do supplements let alone longevity drugs. I look at the signalling involved and push my choices in the direction suggested. Always bearing in mind that we none of us know what we don't know. Stuff we don't know is a big subject...
Peter
"Stuff we don't know is a big subject..."
ReplyDeleteOnly January 22, and we already have the understatement of the year!
Hello, Peter!
ReplyDeleteI am a new follower of your blog and particularly impressed by your detailed assessment of studies which seem to suffer from publication bias. I was linked to your post analyzing FMD and found it a much better insight into the subject itself than what I have been able to locate.
Within the same spirit, I was wondering if you have a post covering the Green African Monkey study that attempted to establish an intrinsic link between excess fat consumption, especially mono & sat, and a higher percentage likelihood for suffering from atherosclerosis. If not, I was wondering if you could offer some insight regarding the study, or know of an article that offers further insight into that line of logic. This is the study, if you're not familiar or need some refreshing:
http://atvb.ahajournals.org/content/15/12/2101.full
Ji Jay,
ReplyDeleteHere are the key quotes:
"Animals were fed weighed portions of food twice daily to assure that they received 100 kcal·kg−1·d−1"
"Average values (mean±SEM) rose slightly throughout the study (an average rate of 0.1 kg/y) and averaged 6.1±0.4, 6.1±0.4, and 6.5±0.6 kg for the saturated, monounsaturated, and polyunsaturated fat groups, respectively"
and from the first layer back of references at http://www.jlr.org/content/31/10/1873.full.pdf we have the diets as 10% sucrose as a total of the as-fed diet weight.
I love this study. Omega 6 fats increase insulin sensitivity at high signalling levels on the basis of their FADH2:NADH ratio so improve insulin signalling if, and only if, you don't become obese. But that excess insulin sensitivity drives calories in to adipocytes so you get hungry (note the PUFA monkeys got fatter on a fixed number of calories (ns but real). Humans get fatter than the monkeys because hunger can only be resisted for a matter of months unless you are mentally ill. PUFA will cause insulin resistance only once adipocytes are over distended and leak FFAs irrespective of insulin levels. Elevated FFAs + elevated glucose = metabolic syndrome. Forcing the monkeys to stay slim-ish allows the benefits of PUFA to show. These are primarily the offsetting of the insulin resistance cause by the sucrose. The effect of fructose on adipocytes is another post some time.
So the paper (along with others) fits in to the Protons thread ideas that FADH2 oxidation drives reverse electron transport through complex I which has marked effects on insulin signalling, especially when insulin signalling should stop... With PUFA it doesn't, you just get fat with subsequent hunger. Metabolic syndrome starts when you can't get any fatter.
Peter
So I have no doubt that your handle on these studies warrants note, and am greatly appreciative of your analysis offered, but your referents stem from a foundation that I am lacking familiarity with. Which I like, this is good stuff, but could you help me as far as a good place to start with your blog to better internalize some of these ideas you revisit which are crucial components to a solid understanding of the subject at hand? Also you seemed to emphasize a focus on PUFA as opposed to MUFA or SFA, is this just in reference to the portion of the data you referenced or should PUFA be more a focus than other fats?
ReplyDeleteAlso if you could recommend the ideal diet plan for a young 5'10" male weighing 145 lbs with no substantiable health issues (beyond neck pain from poor posture & fatigue periodically, likely resulting from lack of sleep/exercise) for the sake of longevity and high quality of life? I did ketosis with no more than 20 g of carbs for a year's time, and now have been considering Mark's Daily Apple's regimental plan of no more than 100-140 g of carbs. I am currently out of ketosis and eating what's available due to financial issues, curiosity surrounding diets like whole foods/Ornish plans, and being too busy for meal planning. Would you highly recommend LCHF or is there more leeway to reach an "ideal" diet plan?
Jay,
ReplyDeleteI'm no guru. I don't have a diet plan. I follow Jan Kwasniewski's Optimal Diet fairly loosely. The emphasis is on saturated fat, minimal PUFA, mildly restricted protein and 20-30g of carbs per day. It's what the science points me towards. All other options are open, people should do as they feel best. I'm circumspect about the Ornish or vegan options as they have no biochemistry backing and their proponents come over as somewhat odd, to say the least.
The Protons thread on the blog lays out how I view the front end of the electron transport chain. This is where switching between fuels and the fed/fasted state occurs. I agree, I have no shared vocabulary with people who have not understood this thread. It should make logical sense...
Peter
I will check out Jan's diet plan then. Where would you recommend getting a better understanding of the biochemistry aspects? I just basically feel a level of uncertainty when encountering a term like metabolic syndrome, which I've never heard phrased like that, and assume there's more I need to know to appreciate it being phrased in such a fashion. But yes, I was definitely more referring to the Protons thread you mentioned.
ReplyDeleteAlso thank you so much for being receptive! I've been struggling to find a good place to start regarding all these questions.
ReplyDeleteAlso does the minimal PUFA apply to Omega 3s equally?
ReplyDeleteNothing supplies omega 3s in bulk the way a bottle of corn oil supplies omega 6s so I pretty well ignore them rather than actively avoiding them. I probably eat wild caught fish once a week or so and here in the UK most ruminant meat is as grass fed as practical. We only need about a few mg of DHA per day so that's fine by me. Bulk omega 3s are a drug rather than a food substance, they may have their uses but that becomes less important as your omega 6 intake drops.
ReplyDeletePeter
So I have at this point read a weighty amount of your blog. I am wildly impressed with the juxtaposition from dietary conventions naturally rendered through an exceptional scientific approach. I nearly choked on my drink when reading about how an average incorporation of vegetables can result in oxidative damage to DNA. Do you still think this to be the case? And has the following of a high saturated fat diet's potential use surrounding the onset of cancer elicited any more information on the subject?
ReplyDeleteI'm considering trying my hat at the Optimal Diet, but do have concerns. During my past in keto I would eat a large, fatty meal before bed, and would wake up in the middle of the night with my heart palpitating. Now, beyond these episodes I felt generally healthy, though at times my energy levels felt low & focus poor (though this happens generally to me anyway, although perhaps not to the same extent, hard to determine if it related to diet or sleep habits). So postprandial angina seems unlikely, but those episodes inspired great concern.
So two things - if these episodes occur at all should I continue the pursuit of LC stipulated in JK's dietary plan or not? And I noticed that you mentioned these dietary guidelines more pertain to those who have created or inherited a physiology disfunction and that generally healthy people can eat a wide range of diets (provided they limit sucrose, fructose, & PUFA) without encountering noted problems. So if I was, hypothetically speaking, a healthy person, would you find flaw in the application of say an all potato diet, or a veggie diet with little to no fructose included? Would oxidative stress be a concern or is the jury not quite in on that?
I appreciate that you are not trying to proselytize so much as gather valuable info for the public's benefit, but I would absolutely appreciate a strong answer as to if you were in my shoes how would you go forward.
Hi Jay,
ReplyDeleteThe oxidative damage from fruit and vegetables study has not bee replicated as it produced an inappropriate result and funding to destroy your research career is not freely available. But probably so. The real question is: Is this damage beneficial or detrimental? No simple answer there.
Too many unknowns to comment on the palpitations.
You must make your own decisions I’m afraid.
The concept that saturated fats are carcinogenic is unsupported by any convincing evidence. The role of omega six PUFA is clear from a whole raft of laboratory studies.
I’m not sure why anyone would want to go to a potato or plant based diet. If they produce major benefits this would appear to be by accident rather than plan.
In my own shoes I eat broadly to the Optimal Diet. Only for 15 or so years so far.
Peter
Re Jay's question, do you have more search words for that study on oxidative damage from fruit and veggies? Thanks
ReplyDeleteFish oil seems to be something to stay away from, but the odd fish seems fine. DHA damages just as easily as linoleic acid, and it may even promote cancer growth by upregulating angiogenesis:
http://perfecthealthdiet.com/2011/04/omega-3-fats-angiogenesis-and-cancer-part-i/
Re the link to the interview with this Green fellow who said Apo-E4 carriers should stay away from saturated fat, red meat and alcohol, over at Malcolm Kendrick's, Bill from Oz has tried to follow up. This all sounds a bit like FH. How come APO-Ex is never mentioned in discussions of FH?
smartersig
January 23, 2018 at 4:16 pm
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There is a study here that showed increased markers for dementia with sat fat
https://www.ncbi.nlm.nih.gov/pubmed/23779114
And this give a decent overview and suggests Allelle 4 carriers need to pump more Moega 3 to get the same bang for their bucks if any at all
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210928/
Bill In Oz
January 24, 2018 at 11:21 am
0 0 Rate This
Hi Smartersig, I looked at the first link you provided. My understanding is that all the trial patients (54 veterans ) were APOE4 carriers. It supports what Dr Green is saying about APOE4 and saturated fats. However APOE4 carriers according to Wikipedia, constitute only 14% of the human population.
The second link you provided is far more tentative. Here is what it says in the conclusion :
“In this paper, we highlighted that people carrying at least one allele of APOE4 seems to have a deregulated fatty acid metabolism with emphasis on disrupted DHA homeostasis. To date, it is not clear how this could play a role in the risk of developing LOAD and/or CHD but it could involve the following processes.
A shift in fatty acid selection for β-oxidation where DHA becomes highly β-oxidized in APOE4 carriers whereas in the non-carriers, DHA is highly conserved.
In APOE4 carriers, brain uptake of DHA seems lower resulting in lower brain membrane DHA over time. This could play a role in neurotransmission and expression of genes and proteins involved in brain health but this needs further investigation.
APOE4 carriers respond differently than non-carriers to dietary interventions involving lipids such that modulating lipoprotein levels may include managing fatty acid circulating in the blood. Providing higher doses of LC omega-3 to this population could be necessary to obtain a similar response compared to the non-carriers supplemented with lower doses of LC omega-3.”
Again the emphasis is on the difference capacity of individuals with different APOE alleles to deal with saturated fat.
And unfortunately one key issue remains undiscussed. Does having a mix of 2 alleles make a difference ? A ‘double’ APOE4 supposedly is carried by 14% of people I think. But what percentage of people have a mix of APOE4 with either APOE2 or APOE3. And does this have an impact on Alzheimer’s disease ?
Hi Eric,
ReplyDeleteThe original study was https://www.ncbi.nlm.nih.gov/pubmed/12064344. It was published in 2002. The first author, JF Young has published nothing since. The group leader B Sandström has a few more publications (I’d guess from studies already on-going before they published the flavonoid study) and nothing since 2004. Perhaps he retired. Perhaps he kept getting the wrong answers and publishing them.
If you’d like to follow through you are very welcome to simply click on the related articles button for the above study and see what’s going on nowadays…
The study from smartersig is possibly the ultimate proof that saturated fat does NOT trigger pro Alzhiemers markers in humans with Apo E4. Look at the study. Never forget that the future careers of 15 people are riding on this study.
So, they NEED a good result. How do you get it? Easy. All you have to do is change the amount of fat in the diet, the nature of the fat in the diet, the amount of carbohydrate in the diet, the glycaemic quality of the carbohydrate in the diet and, wow, they got pay dirt. Aside, I don’t know why they didn’t alter the protein type/quantity. I mean, if you are going to confound your variables why not go the whole hog? End aside.
To show saturated fat cause Alzhiemers all you nee to do is saturate the saturated fat with sugar, most likely HFCS. This was Washington in the US of A, after all.
If saturated fat really causes Alzhiemers why did they need to stack the deck like this?
The other interesting thought is: How much do they know? They’re stacking the deck. Do they know they are stacking the deck? Do they know the role of sugars in Alzhiemers? I tend to assume they are too dumb, but you never know……… Imagine the cognitive dissonance if they consciously knew they were cooking the books!
Peter
Jay:
ReplyDelete"During my past in keto I would eat a large, fatty meal before bed, and would wake up in the middle of the night with my heart palpitating."
This IMO is typical of too little salt (sodium) in your diet. Going low-carb will increase your sodium needs, at least initially. With too little sodium you lose some capacity to excrete potassium while the lower carb intake stops your cells from taking up the potassium ingested (and low-carb foods typically have a higher potassium content, too), and potassium starts getting out of your cells during rest, so an excess of potassium might be the cause of your tachycardia.
Did you also get a "sense of doom" feeling or a tingling sensation in extremities upon waking up during these episodes ? These would be supporting hints.
Dear Mr Dobromylskyj,
ReplyDeleteAfter several years of following your website, I can't resist not to ask you a few short questions. It's the right moment. NADH, FADH2, etc. etc. - Is it lesser evil to use PUFA (mostly Omega 3 withVitamin E) and reduce blood sugar levels and thus increase adipocytes, or, to first lose weight using saturated fats and only then move over to reducing blood sugar? Ketogenic diet in both cases is understood (process of better diabetes control requires months with high blood sugar + fats in duet, all the time).
Secondly, in your personal case, you're on the verge of ketosis, up and down. Considering the time interval of a few weeks for the body to adjust the brain to ketones as a fuel, the greater period of time brain should be deprived of sugar. You don't seem to have a problem, quite on the contrary. How can that be?
Finally, what is your opinion on intermittent fasting regarding diabetes? If insulin resistance is mostly a consequence of long term high insulin levels?
Thank you in advance for your response. Best regards,
Z.Markovich
I will keep that in mind, jesrad, thanks. Peter, I was meaning to reference your Kwasniewski and cancer post from 2008, and the pursuit by Kasha Mikoda to minimize the impact of cancer in their father by using the Optimal Diet which is high in saturated fat. Has there been any forthcoming research which pursues more understanding as to the potential for high saturated fat low carb diets to demonstrate anti cancer properties?
ReplyDeleteIt's interesting, jesrad, that you say it could be from a release of potassium, because a lot of people recommend supplementing potassium with LCHF diets. I in fact have been supplementing potassium, will just do Sodium & Magnesium to see if that solves the problem. I actually did a search about waking up with heart palpitations on a LCHF diet and a reddit page from ketoscience popped up with the highest voted answer being that it was caused by a potassium deficiency. Is it just the timing of it and that I should only supplement, if at all, in the morning?
ReplyDeleteHi Zoran,
ReplyDeleteThe problem with using PUFA to facilitate insulin signalling is that the normoglycaemia is achieved at the cost of calorie loss in to adipocytes, as you say. There is hunger associated with this. If you respond to the hunger you then get in to adipocyte distension, FFA leakage and subsequent insulin resistance from trying to oxidise FFAs and glucose at the same time… I would say that while you are hungry, if you can maintain this, then you will have improved insulin signalling and lower glucose. But who wants insulin signalling (or hunger)? Depressed signalling through the insulin/IGF-1 axis is what is associated with increased health/life span in the GH dwarves.
So saturated fats for weight loss and carbohydrate restriction for normoglycaemia. BTW alpha linolenic acid should be oxidised through the mitochondria and have the effects you mention. EPA and DHA will be oxidised through peroxisomes and will simply contribute cytoplasmic NADH, worsening the NADH:NAD+ ratio. Once oxidised to C8 the DHA and EPA will be transferred and oxidised in the mitochondria as perfectly acceptable saturated fats.
I think if you are eating LC and on the edge of ketosis in all probability you astrocytes will be oxidising fats to ketones in-situ and supplying these to neurones directly, they don’t have to show in the plasma. You will have low usage whether you are in ketosis or not. Just my guess.
I’ve never been terribly interested in IF so I’ve never dug deeply in to it. Eating fat seems a much nicer way to lower insulin levels without the tedious hunger…
Peter
That would be "low glucose usage" just before the end...
ReplyDeletePeter