las

Welcome all seeking refuge from low carb dogma!

“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact”
~ Charles Darwin (it's evolutionary baybeee!)

Saturday, January 5, 2013

Some Suggested Reading ...

In light of other recent events, I present some suggested posts from this blog on the questionable accuracy of the blogging of one Peter Dobromylskyj aka Hyperlipid.

Summary:  The third post in a series (links to I & II within) outlining how Peter deliberately fudged the data from the "infamous" Grey & Kipnis study.  He even told his readership he was doing it and tips his hat to Ancel Keys.  I feel to this day that if anyone can read this series and take Peter seriously after that.  It was done in all seriousness on his part.  

Summary:  Peter blogged on the LIRKO mouse with a "cute" quiz about making jam from the urine of this mouse.  One problem, LIRKO doesn't get glucosuria.  Other claims made are also easily dispelled including that this mouse's liver (and other cells) can't process glucose so they burn through fatty acids like mad and that's why they don't get fat,  and that this mouse's muscle cells "internalise their insulin receptors".


Summary:  Peter compares putting a mouse on a ketogenic diet to a FIRKO mouse while there is no evidence whatsoever that KD's alter insulin receptors on fat cells, "rendering them insulin resistant" in any way meaningfully comparable to knocking them out entirely.

Summary:  Highlights two definitive statements made by Peter: "Hyperglycaemia causes insulin resistance. This is not controversial, as far as I am aware", and "Excess insulin causes insulin resistance".

30 comments:

Princess Dieter aka Mir said...

First "bloggo" linky needs to be fixed. :D

Nigel Kinbrum said...

I have a question for Dr. Johnson regarding his comment http://high-fat-nutrition.blogspot.co.uk/2012/12/insulin-are-you-hungry-part-2.html?showComment=1356993388945#c7823942010075145224
"LIRKO mice are hypoglycemic in most papers. That is why they don't gain weight - way TOO much insulin. Well outside the physiological range."

I don't want to ask on Hyperlipid as that thread is a car crash!
I see that Evelyn has queried the first part of the comment on Twitter.
My question is this:- If too much insulin causes weight/fat gain, how can way too much insulin have the opposite effect?

Sanjeev said...

I've been out of touch for a while (will be intermittent for some time to come unfortunately) ... did hyper-blind-spot do a repeat or maybe upped the ante?

Kindke said...

Yes id like to see his explanation too, if "way too much insulin" is protective I wonder why localised insulin injections cause hypertrophy and not dystrophy and/or no change.

Unknown said...

Counting calories is kryptonite to true Paleos

http://www.dietdoctor.com/paleo-and-calories-2

Sue Staltari said...

Counting calories is an eating disorder according to dietdoctor

Evelyn aka CarbSane said...

Something quite sickening about that post/his ideas when you put it in context of his penchant for making fun of fat people. Seems these folks are trying to preserve their franchises by finding any means to prevent people from trying a simple "hack" that doesn't involve any new gimmick.

Evelyn aka CarbSane said...

Comments there are classic. Oh it can't work because actual calories can vary by 20%. Newsflash people. Variation is about the mean. Meaningful weight gain or loss is about energy imbalance over time, not day to day. If I choose to follow a basic plan, the chances of eating 120 vs only 80 cals vs the 100 cals stated are equal. It will average out. Furthermore, calorie variations -- even with real whole foods -- can be minimized by choosing foods from the same source and reducing the types of foods, e.g. the number of sources.

Sue Staltari said...

When I read that post I thought what a jerk!

Evelyn aka CarbSane said...

He's upped the ante with bashing Stephan. The comments LIRKO came up and a number of commenters seemed oblivious to the misrepresentations Peter made of LIRKO. Might as well gather it all in one place.

Evelyn aka CarbSane said...

I called him an ass in my tweet ;-) Apparently Eenfeldt doesn't know a real ED when he sees it. Come to think of it, does he have actual patients, or does he just make his living hawking low carb?

Sue Staltari said...

This is what Eenfeldt wrote in a post - How to Lose Weight:
"Based on a decade of experience treating obese patients, reading studies, going to obesity conferences and discussing this topic with the world’s biggest experts, here’s my best advice for maximizing your weight loss."
http://www.dietdoctor.com/how-to-lose-weight

Unknown said...

Grok didn't count calories cause Grok didn't know how to count past one, so once he got past that first calorie it was all the same to him.

Scott said...

Yes, the comments are entertaining. That was my 1st time on that blog & I learned one thing - Razz is still at it.

Harry's Acolyte said...

Art Devany is back on the free internet. (Just an FYI for anyone who didn't know)

JJ said...

You can find my comments on the LIRKO, which is but one of hundreds of mouse models (and a bizarre and poorly understood one at that) on the Twitter discussion I just had with Evelyn. I can see it shows up on this page.

I think the the LIRKO is a red herring, as are many of the other IRKO models. Each only examines the effect of tissue-specific insulin resistance. I don't think there is anyone that would argue that diet induces liver-specific insulin resistance. Even the MIRKO data are tricky, and that is the tissue most people think of being 'resistant' first and foremost.

Basically, I would argue, as I did in my paper, that reducing insulin (in the way that human genetics, environmental factors and drugs can do) is the best way to understand the integrated physiology of this hormone...



Also, Nige, I posted some thoughts on your blog about the effects of insulin on energy expenditure, or at least I tried to... they are below...

"Hi Nige...

I wrote the paper you are commenting on and I have been following it around the internet as it gets discussed/interpreted/misinterpreted. Insulin had multiple effects on the adipose tissue, including regulation of lipolytic genes. I think the evidence that insulin is important in obesity is strong. I don't see any reason why insulin's effects can't include effects on expenditure as well.

As for humans, no one has any idea what CHRONIC (life long) reduction in insulin hypersecretion would do the Ucp1 in WAT. The ACUTE (minute to minute) effects of insulin on EE are less important here.

I think a lot of people are missing the fact that the experiment represents 1/3 of the mouse lifetime and starts just after weening."

Evelyn aka CarbSane said...

Hi Jim,

I think I'm going to avoid Twitter convos as the character limit really makes it difficult to have constructive conversations. For example, @ProfDocHealth made a comment about the liver's pivotal role in energy homeostasis.

On the one hand you seem to be saying that the results of your experiment show that insulin drives DIO, because if you produce an insulin deficient state (for which there is no equivalent in human physiology that I am aware) you can prevent DIO. This was translated into "hyperinsulinemia drives DIO". But as you can see I'm not the only one left wanting by your explanation of how LIRKO doesn't get fat. On Peter's site you said hypoglycemia coupled with extreme levels of insulin. I see that the mice in the paper linked last evening were mildly hypoglycemic, but that appears to be the exception to the rule for LIRKO which is almost universally described as hyperglycemic. In any case, you have a mouse that has 10X insulin but nominal suppression of glucose (112 to 88, stat sig?, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC151923/table/T1/) It seems to be that you are saying hypoglycemia is incompatible with the development of obesity?

What is the mechanism by which you propose hyperinsulinemia causes DIO? How would hypoglycemia (if seen) interfere with this mechanism? It doesn't seem sufficient to just dismiss LIRKO as effed up, but say I'm being silly when I suggest that your mouse doesn't have an equivalent in the human condition.

If LIRKO's adipose was messed up, that would be an explanation, but this does not appear to be so. Forget obesity, since you study lipotoxicity, LIRKO appears to be pretty solid evidence that beta cell dysfunction -- e.g. deficiency -- is a function of NEFA. The pancreata of these mice seem capable of pumping out ever more insulin, GSIS and basal, to at least attempt to control what's being thrown at them. In IR and T2, the basal insulin is often high but GSIS is depressed. LIRKO doesn't suffer lipotoxic effects because fatty acid metabolism in adipose seems to be intact.

It is difficult to get a read on where you stand from Twitter bites. This cannot be simultaneously simple and complex. If demonstrating loss-of-function enables the conclusion that HI drives DIO, then your hypothesis should be able to explain cases like LIRKO where HI is accompanied by normal or even slightly reduced body weight. You have also made some sweeping statements about the translatability of mouse physiology to human physiology yet seem to dismiss when human conditions we actually observe are brought up in discussion.

In the beginning you were careful to point out that your paper referred to basal insulin secretion. And yet a goodly proportion of obese humans have normal basal insulin. So they got that way with elevated basal insulin and what? It went away?

Normal insulin secretion and signaling is almost certainly required for obesity to develop. This does not logically translate to excessive insulin causes obesity.

Diana said...

According to diet doc's definitions, I didn't have an eating disorder when I weighed 180 pounds. I have one at 138.

Eff these people. One big lesson I learned on my way to mastering my eating issues is, if you feel in your gut it's wrong, it's wrong.

Listen to your body!!!! (Remember that one, Evelyn?)

Diana said...

The first commenter, Mike, wrote something very wise and sane. I predict no one in Diet Doc's band of believers will pay it any mind.

rocketmaze said...

Hi Evelyn,
LIRKO mice have insulin signaling problems in the SREBC-1c pathway in the liver. From my understanding, this accounts for the low circulating NEFA in LIRKO. The studies/reviews I've read maintain the LIRKO are muscle/adipose IR.

Hi Dr. Johnson,
Thanks for joining in the comments. I'm curious, did you expect when designing your experiment for your knockout mice to become diabetic on the high fat diet?

Thanks,
Sara

Nigel Kinbrum said...

Hi Jim. As I am in the UK, your comment arrived at 03:01 and didn't get published until 06:55, when I woke up to go for a wee and noticed it on my phone.

Nigel Kinbrum said...
This comment has been removed by the author.
Nigel Kinbrum said...

Hi Sara,

If LIRKO are also adipose IR, this would reduce adipose storage & increase adipose energy expenditure which would explain lack of obesity. Got links?

Evelyn aka CarbSane said...

Hi Sara, Do you have links to those studies/reviews? The study (studies) cited in the LIRKO Wars post referred to here was/were pretty specific in measuring tissue specific IR and muscle and adipose are not significantly so if at all.

I'm not aware that the primary mechanism by which insulin is purportedly causing obesity has changed: trapping fatty acids in adipose tissue. There is no indication that I've seen that LIRKO have impaired triglyceride storage capabilities like FIRKO, C3KO and C2L5KO (latter two are ASP deficient and receptor KO respectively).

Jane said...

Great stuff Evelyn.

rocketmaze said...

Hi Evelyn,
I meant to suggest that since LIRKO mice have low circulating NEFA, they have low NEFA uptake into adipose tissue. Does this make sense? Granted these mice appear to have normal adipose tissue signaling, they still fail glucose tolerance tests, so their adipose tissue are not a signicant source of glucose disposal. The reason the LIRKO mice are not fat despite normal storage capabilities is that perhaps there is not much (i.e., low NEFA)to store. Does this seem plausible? I am just trying to understand the physiology, not trying to support a particular diet.
Thanks,
Sara

Evelyn aka CarbSane said...

Hi Sara, NEFA levels seem to mostly be regulated on the out side. Lipolysis - internal recycle back to triglyceride. To my knowledge, adipose is not a significant glucose disposal depot. LIRKO fails the IGT, but FIRKO does not. LIRKO fails, apparently, because it's liver keeps pumping out glucose. This is all discussed in this paper from the LIRKO Wars post: http://www.sciencedirect.com/science/article/pii/S1097276505000158

These mice eat about the same as normal mice. LIRKO does not appear to alter metabolic rate, fatty acid oxidation, etc. Thus by good old CICO, LIRKO is about the same size as normal mice. This explanation is consistent with what the authors of that study looked at, reported and concluded.

Evelyn aka CarbSane said...

Before someone jumps on me, let me rephrase my first sentence. The recycling of NEFA -> triglyceride in the liver plays a role in NEFA levels, but the results in LIRKO are consistent with this being a passive one. A T2 generally has high NEFA and Trigs, because the liver tries to repackage excess NEFA. LIRKO has both low NEFA and Trigs so it is not packaging them up in the liver. The adipose tissue of LIRKO appears to be responsive to insulin that suppresses NEFA output. This is yet another reason LIRKO counters the Taubesian notion of locking fat away. LIRKO does not over eat because it's fatty acids are low.

JJ said...

Hi all,

I have been on the road (still am) so twitter has been my only option most of the time. I only have a little time at the moment as well but I will try to address a few things.

1. LIRKO - the specific loss of liver insulin sensitive is not found in man or DIO mouse models, as you know. I agree that the lipotoxicity is interesting. I still question it's relevance and I think any one really understands all aspects of its phenotype. There are many interesting models (made by Colin Nicols at Wash U) of PHHI that have hypo turning to hyperglycemia. I think the best analogy related to massive hyperinsulinemia are patients with insulinoma, many of whom do not gain weight. I don't think anyone knows why. Perhaps very very high levels of insulin do have satiety effects that are less apparent at more physiological doses.

2. With regards to relevance. Humans have significant variation in insulin gene expression, the feature modeled in our mice, so they are surely much more relevant than the LIRKOs. Also, as many have noted, diet can affect insulin levels, both acutely and long-term. You will note that throughout my internet discussion I have avoided discussing specific diets. There is a reason for this.

I do think scientific problems can be simple and complex at the same time. The 'genetic logic' of our experiment is clear. The LIRKO and integrating all of the data on insulin is complex.

The sweeping statements are about mammalian physiology and insulin, for which we have the best available model. Better models will permit us to modify these statements.

What I dismiss (mostly) are the correlative/cross-sectional human studies. Finding some percentage of people who are obese with low insulin doesn't mean that much to me if we don't know what their insulin levels were when they were getting obese or even when they were developing and growing. It is like finding a lung cancer patient who doesn't smoke at a specific point in time, but may have smoked for 30 years and quit years ago, and concluding that smoking is unrelated. There is a strong correlation between hyperinsulinemia and obesity, but I don't much care for correlations. I worry even less about seeming exceptions to those correlations.

We have lots to still understand. I think the discussion is constructive, but overly focused on a few tidbits of information. I disagree that every mouse model have to elucidate the details of every other mouse model and every patient. There are many types of human obesity, and obviously to me, many causes. I see hyperinsulinemia as a requirement, but I don't see it as sufficient, especially at all ranges of insulin.



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