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!)

Tuesday, December 18, 2012

Does Hyperinsulinemia Drive Diet-Induced Obesity?

Unless you've been living under the internet equivalent of a rock in this community, no doubt you've heard there was a paper published in Cell and Metabolism entitled Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production.  It's a TWICHOOB's dream title ... until you actually read the paper, or even the abstract and freely available charts and diagrams.  Too bad most did not.  My link is to the full text I'm sharing with my readers through Google docs.   But you actually don't need to read this whole paper get the basic gist of what the study entailed and the results.  However, before we even do that, consider this.  How do you induce obesity in a C57Bl6/J mouse?  You feed it a high fat diet, HFD.    And as the graphic clearly shows, the researchers believe the results of their study warrant a change in the chain of
causality/progression in the development of diet-induce obesity, DIO.  As studies in support of TWICHOO go, this study is about the worst you can come by!  Because on their more natural rather low fat high carb diet, these mice do not fatten.  That is, a low fat, high carb, insulin spiking chow does not induce the hyperinsulinemia that is implicated in the "new model".  It is a high fat diet that does.  At least in C57Bl6/J mice.  

This didn't stop the TWICHOOB brigade from jumping on this study as proof of their theories.  Odd how one sought to mock the researchers, I guess because it's not enough for them to finally "see the light", we must denigrate them anyway.  But this post is not about the response of the low carb community.  Suffice it to say, however, if you are not interested in what this study says outside of the prism of LC-dogma, there is no reason to read on.  This study ain't the scrolls or tablets you've been waiting for!

So what did this study show?  I weighed in ever so briefly on this here:  Remember LIRKO? Grey & Kipnis? which linked to Stephan Guyenet's first response on his blog:  Is it Time to Re-write the Textbooks on Insulin and Obesity?  I must say that I'm so very happy to see lead researcher James D. Johnson venture into the blogosphere to correct some of the misinterpretations and/or criticisms of his interpretations of the study, and I'm honored he chose my blog as one place where he's shared his thoughts (in the comments on my "Remember" post linked above.)  Jim has also taken to Twitter where we've exchanged some thoughts there as well.  I favorited a bunch of tweets hoping I could share a link to those, but no dice (then again I'm a social media spaz so perhaps there's a way).  In the meantime, anyone interested in reading his tweets with me and others, here's his Twitter account ... go while they're still "fresh"!  

Before addressing the study, I want to discuss another culprit in interpretations of the results:  the media.  But "the media" begins with press releases such as this one, from UBC stating:
A serendipitous discovery by a researcher at the University of British Columbia could overturn widely accepted notions about healthy eating habits.
How?  In tweets and comments, Johnson has been adamant to remind folks -- especially those blaming dietary carbs --that they did not test different diets here.  They used a standard HFD known to induce obesity.  So I think to the extent that there is some overzealous interpretation of this study, it begins with this press release!  There's absolutely nothing about this study that tells you, me, or anyone else anything about healthy eating habits.
James Johnson, an associate professor of cellular and physiological sciences, found that in animal models, too much insulin can be harmful.
I challenge that such a conclusion can be drawn from his study, and this is certainly why I harp on the LIRKO mouse -- a mouse that is sick, for sure, but not sick-fat with sick fat, while being profoundly hyperinsulinemic with no ill effects directly attributable to insulin and its action.  I'll cite more from the bulk of the release later, but it is interesting to note that:
Johnson, a member of UBC’s Life Sciences Institute, was not intending to study obesity. He was initially exploring whether beta cells in the pancreas, which produce insulin, were stimulated to multiply by their own insulin secretion. His discovery that low-insulin mice couldn’t gain weight was unexpected – as was the finding that most of those mice, despite dramatically lower insulin levels, still didn’t develop diabetes.
While I don't doubt that Jim has familiarized himself with a lot of the relevant research in this area, I tend to think that were he knee deep in obesity research per se, his findings would not have been all that surprising after all.  In my opinion, the conclusions drawn in the study are over-reaching and not supported, as worded,  by the published data.

OK ... on to the study itself.

In looking into this study, I learned something new about mice vs. humans.  We have one insulin gene, INS, while mice have two, Ins1 and Ins2.  The Ins2 is the homologue to human INS and is expressed in all cells, while the Ins1 gene is pancreas specific.  Here is one paper on the two-gene system in mice (and rats) for anyone interested.  I think this is important to keep in mind, as all genetically altered mice are, in terms of whether or not such a mutation is possible or observed in humans.  For example, the ob/ob mouse has been useful in elucidating many things regarding the role of leptin in obesity.  However, we all know the "end" to that story vis a vis humans ... this sort of leptin deficiency is far too rare in humans to explain even the "baseline" levels of obesity in the couple-three percent range.  
click on picture to enlarge further

So what they did here was create an insulin deficient -- yet sufficient -- mouse that was incapable of insulin hypersecretion.  Indeed in their graphic, they show a half-pancreas for their Ins1 knockout.  At right they show the Ins1 gene expression for each diet (12wks) and the islet insulin content (8wks).  To me it is interesting to note that Ins1 +/- on the normal diet (blue bars) had only slightly lower insulin content than controls (dark vs. light), and on the HFD (dark red) had almost identical insulin content to normal controls.  Thus, the finding that these mice were not diabetic is hardly surprising!  

I'm going to refer to these mice, left to right as CD+, CD-, HFD+ and HFD-.  It's much easier than writing this out over and over.

The major outcome here was that the HFD- mice did not produce excessive insulin and the beta cell mass (measured as cell area) did not increase.   They also did not become obese like their HFD+ cousins.  The fasting insulin is shown next to that data in my cropped images from Figure 2 above.  Curiously, both groups of HFD mice seem to be mildly hyperinsulinemic vs. controls at the 5 week (presumably once weaned onto chow) baseline.  Statistical significance is not noted, but the ** indicates difference between CD- and CD+ where levels for CD- are similar to HFD- and lower than HFD+ at baseline.  It appears that there is a "spike" in the HFD- mice but this falls off, presumably because they don't expand beta cell mass and cannot produce additional insulin.  Meanwhile the other finding in the study is that these mice remain lean and healthy and normoglycemic.  This is attributed to upregulation of UCP1 activity in white adipose tissue, WAT.  UCP1 is the thermogenic uncoupling protein expressed in brown fat that is more abundant and relevant to maintaining whole body temperature for small animals like mice.  It is apparently present in WAT as well.

Rather than storing the excess lipid intake, these mice burned off the fatty acids -- in their fat tissue!  This sounds somewhat similar to what occurs in the FIRKO -- lacking insulin receptors in fat tissue -- on a standard diet:  
At the whole body level, FIRKO mice demonstrated an increase in basal metabolic rate and respiratory exchange ratio. Analysis of gene expression in white adipose tissue (WAT) of FIRKO mice from 6 to 36 months of age revealed persistently high expression of the nuclear-encoded mitochondrial genes involved in glycolysis, tricarboxylic acid cycle, beta-oxidation and oxidative phosphorylation as compared to expression of the same genes in WAT from controls that showed a tendency to decline in expression with age .... these data suggest that maintenance of mitochondrial activity and metabolic rates in adipose tissue may be important contributors to the increased lifespan of the FIRKO mouse.
All of which points to elevated basal insulin levels and intact adipose insulin signaling as requirements for the development and maintenance of obesity.  Before I go into mouse models that refute this, let's harken back to the differences between mice and man, and even before that, let's remember something -- this is a genetically engineered mouse that is not found in any wild-type variant.  As extends to humans, the only examples of reduced insulin production I can think of are some MODY and LADA diabetics.  I doubt their insulin production is mimicked by this model, but this is the closest we get in humans to a relevant physiological state.  We do not see upregulation of metabolism in WAT to process metabolic excesses, and produce normoglycemic, healthy, lean humans.  One could argue that "compensators" -- humans for whom insulin levels are elevated and "seen" by sensitive cells -- are far healthier than these hypoinsulinemics.    These so-called metabolically normal obese people are significant in number.  This is the reason why, however imperfect a perfect measure, but the HOMA index is used to assess IR -- basically [fasting insulin] x [fasting glucose].  Compensators may have elevated fasting insulin, but are not considered IR if their glycemic control remains intact.

The definition of IR was what was behind my last twitter exchange with Jim, as they believe their mouse is unique in being able to isolate the role of hyperinsulinemia without IR complicating the picture.  The HFD- mice are mildly hyperglycemic early on (11 weeks, corresponding with when the slight hyperinsulinemia starts to subside), but goes away.  But here's where the unique observation of the upregulated uncoupling in WAT comes into play, and the role that insulin plays in this.  Do we see that in humans?  I'm struggling to find the relevance here if what would normally happen IS hyperinsulinemia and obesity, but it doesn't happen because of a deliberate genetic defect.  It is interesting that the mice compensate rather than experience elevated NEFA and all the ensuing metabolic havoc, but where's the relevance?  It's not at all unlike comparing what injected insulin does to endogenous insulin production.  If eating carbs doesn't cause a bolus of insulin in your thigh fat, it's not really relevant.  

So the problem as I see it with the wording and notion of insulin "driving" obesity.  If this simplistic model is a good one, you could not have obesity without hyperinsulinemia, and you would always see obesity with hyperinsulinemia.   We do not.  In this study, it was basically demonstrated that hyperinsulinemia was a necessary state for obesity to develop on a high fat diet.  What might be the mechanism?  As we all know insulin "fixes and traps" fatty acids in fat cells.  The results of this study would predict that insulin also suppresses UCP1 activity in WAT.  If this is the case, then the LIRKO mouse should be fat.  I would be interested in a non-inventive (as in making up "facts" easily shown to be false about this mouse) explanation for why LIRKO is not obese.  In this mouse, the lack of insulin receptors in the liver is what induces hyperinsulinemia and increased beta-cell mass instead of the diet.  Yet this mouse doesn't fatten.

I believe that the results here are still consistent (don't prove or support to the exclusion of other hypotheses) with the existing model.  A recent paper showed that just a few days of high fat feeding in mice caused IR of the brain and inappropriate lipolysis of WAT.  That's right -- too much fat let go.  The fatty acids stimulate basal insulin so as to tuck them back in but also overload peripheral mitochondria leading to IR further increasing the need for insulin.  I don't think there is even necessarily a progression occurring.  It's possible that normal mice become obese, IR and HI pretty much concurrently, because their physiology is ill-equipped to trap a high dietary fat load.  The mutant mouse that can't mount the appropriate insulin response to keep up has an "out" -- it can "waste" fatty acids through uncoupling.  Does this happen in humans?   Are the obesity resistant incapable of raising basal insulin?   When insulin production wanes wit the loss of beta cell mass, do obese T2's  suddenly become non-diabetic as their adipose  UCP1's rev up?

Which brings us back to misinterpretations of this study, which brings me back to the press release.  It is clear, both from reading the paper and discussions with the author, that the insulin levels being discussed are basal insulin, not postprandial.
Johnson concluded that extra insulin produced in the normal mice by the high-fat diet caused their obesity, which strongly suggests that mice – and, by extension, humans – may make more insulin than they need. The findings may mean that the key to maintaining a healthy weight is to continually return insulin levels to a healthy baseline by extending the gaps between meals and ignoring the widespread recommendations to consume small amounts throughout the day. In other words, cut out the snacks – and make sure not to overcompensate at mealtime.
Huh?  First ... are obese people known for eating small amounts throughout the day?  

This paragraph seems to have come from other research not included in this paper.  In comments the following study was brought up:  Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet, from which the diagram at right comes  (click to view full size).    I'll save analysis of that one for when I get the full-text of the study (carbsane at gmail dot com) but here's what it boils down to.  Normal mice fed CD or HFD, each diet either ad libitum or time-restricted feeding.  Guess which group got fat?  HFDal, but not HFDtrf ... but also neither regular chow diet.  The HFDal has high fasting insulin and an exaggerated insulin response on glucose challenge.  The "protection" is attributed to increased beta-oxidation in the time-fed group.  But what's that nagging thought in my head?  It's the confusion/conflation of diet-induced postprandial insulin and basal insulin ... and the macronutrient that's causing the change.  
“As crucial as insulin is for storing blood sugar, it can also be too much of a good thing,” Johnson says. “If we can maintain insulin levels at a happy medium, we could reverse the epidemic of obesity that is a risk factor for so many ailments – diabetes, heart disease, and cancer.”
When one thinks diet and insulin, they think carbs -- even the non-low carbers.  So I think statements such as the two above in the press release are contributing to the confusion.   I guess what the timed-feeding study says is that if you are a mouse and you want to consume an obesogenic diet, you should practice intermittent fasting.  But if you want to eat a normal diet ... one that doesn't potentially lead to obesity and metabolic disruption, then meal timing really doesn't matter.  And if you're a human, you don't eat 24 hrs a day anyway.    However the study we're talking about didn't even look at this!  

So does this study demonstrate that insulin is bad?  Not really.  Because you cannot separate the fact that the HFD+ mice got obese and all the changes in adipokines, macrophage infiltration, and all the ensuing inflammation.  So was it the insulin or the obesity?  The HFD- mice didn't get fat, or "skinny fat" for that matter, so there was no NEFA to wreak havoc.  And we're left wondering what causes the hyperinsulinemia anyway.  How does the HFD cause hyperinsulinemia?

On Twitter Jim asked me what I think would stimulate insulin secretion (basal) and my response was NEFA.  He responded that fatty acids are weak stimulators.  Twitter is not the best for such discussions so let me say that I believe FA's are strong enough stimulators of insulin secretion to elevate basal secretion.  They are not on par with glucose, but that's not what we're talking about anyway.  However, when I countered with the question as to what about the HFD stimulated the insulin, Jim said that wasn't known.   My vote is again on NEFA.  It has recently been shown in mice that a few days of HFD leads to insulin resistance in the brain, inappropriate lipolysis of WAT and fatty acid release.  

What we do know, however, is that dietary carbohydrate is not the cause.  And this is actually a pretty damning study for TWICHOO whatever your interpretation of the data.  If carbs somehow caused hyperinsulinemia, then CD+ mice would be fat, and CD- mice would not be.  That's not what we see.    Just how many more studies such as this do we need before the TWICHOOBs finally get that?

No magic obesity pill, yet: While existing insulin-blocking drugs could prevent weight gain, they carry serious side effects that outweigh their benefit. Further research might lead to drugs that block excess insulin production or blunt its effect on certain targeted tissues.
Or we can remove the crap foods from our diet.


This post is not as polished as I would have liked.  But I decided to publish it up anyway so the discussion moves forward.  Jim is going to be on Superhuman Radio tonight (Tues 12/18) to discuss this.  I forget the exact time hopefully someone will stop by and drop a link.  Tune in!

37 comments:

eulerandothers said...

How does this recent study figure in your post?

http://www.ncbi.nlm.nih.gov/pubmed/22556394

'Our data show that insulin sensitivity was impaired after 3 days of inactivity and overfeeding. Impairments in insulin sensitivity occurred before changes in body composition, supporting the notion that the initial steps in impairment of insulin sensitivity may be linked directly to the effects of inactivity and a high calorie intake.'

It is not about hyperinsulinemia. The causes of insulin sensitivity impairment are inactivity and overfeeding (it's pretty easy to see how both cause weight gain - this is easy to demonstrate in the lab, with human subjects, and has been). Carbs are not an issue here, overfeeding and inactivity are the causes.

No pdf to view, it's not free.

Ginny said...

With regard to the Super Human Radio interview, it already aired live this afternoon, but it will be up on iTunes in about thirty minutes for all to download. I haven't had a chance to listen to the whole thing yet, but I think we did try to address some of the common questions directed about the paper.

Ginny said...

Oh, and I forgot to mention - it's a two hour show. Dr. Johnson appears in the second hour.

Stephan Guyenet said...

Diabetics do have higher energy expenditure, though it only amounts to less than 150 kcal/d. Whether it has anything to do with uncoupling in adipose tissue, I don't know, but there's no need to invoke that because it's known that diabetics develop energy-dissipating metabolic futile cycles in the liver.

http://care.diabetesjournals.org/content/27/10/2416.short

I think another issue is that in rodents, the "energy out" side of the equation is much more influential than in humans because they're much better at dissipating energy through uncoupling. That's probably why kcal intake is by far the most important factor shown to affect fat mass in humans. We probably have many of the same "energy out" mechanisms that operate in rodents (including brown fat), but they're less important in humans.

This idea that we should be suppressing insulin secretion in overweight people is strange. Their insulin secretion is already borderline insufficient to maintain metabolic control because they're typically insulin resistant. Diazoxide and those types of drugs cause hyperglycemia-- just what you would expect from creating an insulin deficiency.

Gabriella Kadar said...

Basically rodents cannot replace humans as research animals. The WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects (http://www.wma.net/en/30publications/10policies/b3/) prevents scientific studies that would somewhat elucidate the true situation in our own species.

Plus human beings are capable of opening the door of the refrigerator.

Humans confabulate. Ask them the 'why' question and get ready for all sorts of b.s. Ask them 'what' and they give you either what you want to hear or some variant of whatever it is they actually did. The average and above average human does not understand what is significant and what is not. So, obesity researchers: good luck.



Evelyn aka CarbSane said...

Hi Ginny! Thanks for the information. Here's the link gang:
www.­superhumanradio.­com/­components/­com_podcast/­media/­mp3s/­SHR_Show_1110.­mp3

Not working for me at the moment, hopefully later

Evelyn aka CarbSane said...

Y'know Stephan, Not to put you out of business or anything ;) But your last paragraph really does say it all. Diazoxide has been around for a while, and studies on the obese have been done too. It works for a small subset of people who are insulin hypersecreters. I don't have to tell you, but those are folks that secrete inappropriately high levels of insulin in response to stimuli (sometimes it seems the "off switch" doesn't work, and they secrete too much all the time). Restoring normal insulin levels improves the fat mass issue. But hyperinsulinemia is "appropriate" in the context of "simple" obesity and without it matters are generally made worse. Interesting about the higher EE. Hadn't seen that.

Lerner said...

The host of SHR is Carl Lanore. Over a year ago, he'd posted his own fat picture after he'd gained a ton of weight. He is a long time Taubes-worshipper.

To his credit, he did post the photo instead of concealing his weight gain. But then again, he's also in the business of (sometimes) using his life as the subject of his media career - kind of like being Jimmy with a barbell. Both got fat on Taubes' delusional plan.

Lerner said...

e.g., bragging about drinking a quart of cream per day. It naturally had to be the rebel-approved grass fed, raw.

kb said...

Evelyn, I am confused by your statement, " I guess what the timed-feeding study says is that if you are a mouse and you want to consume an obesogenic diet, you should practice intermittent fasting." Isn't it saying just the opposite? I have read that study and I interpreted their point to be that the liver and has an active and sleep phase, so it functions normally during the active phase and but if HF foods are eaten during its off phase, they can not be metabolized properly and gets stored in the liver causing all the bad stuff. This implies that IF is a positive if done at night, the liver's off-time. It does imply a HF diet to be a challenge in general though, just that a healthy liver is able to handle it better. I do agree with you re the NEFA theory however.

A couple of observations - perhaps that is why for some HCLF works better because insulin spikes but falls to normal quickly (for me anyway), concept being longer time periods not producing insulin... better. Again supporting limited IF... no?

Also may explain why LC diets need to be strictly adhered to - causing such intolerance to carb metabolism and taxing the liver to the point that the introduction of any carbs causes extremes of insulin, high BG and inflammation for extended periods of time and thus the whole gamut of health issues. If the timed theory is correct, imagine what the LC night feeders are doing to their bodies. Interesting that many of the LC gurus promote IF, perhaps to counteract the stress on the liver and keep weight down? Although, I doubt they have that thought process, they are probably noticing weight gain, or BG levels rising. And who can stick to the diet in a strict capacity? Everybody cheats, becoming more and more sick with increasing propensity towards obesity.

Lerner said...

btw, when looking for that superhuman fat picture, I stumbled on this from Greenfeld:
http://superhumancoach.com/become-superhuman-live-event/

“Become Superhuman” – Live Event Coming To Spokane, WA, March 8 & 9, 2013

with Jimmy, plus a guy on "Insulin Potentiation Therapy" plus Attia of war-on-insulin, all together plus more.

Attendees get the super secret stuff, not just the stuff for commoners, at only $300.

Evelyn aka CarbSane said...

It never ends! I can see him speaking at LCDU -- a rah rah fundraiser for LC and he's "the guy" when it comes to LC (leaving aside how pathetic that looks to the outside world.) But anything with "Superhuman" and "Jimmy Moore" ... you have GOT to be kidding me!

Ginny said...

Hmmm...I wouldn't want to speak for Carl, but I am no worshipper of Taubes nor have I ever been. A lot of prominent individuals were very enamored of Taubes and his hypothesis early on, but gradually have become a little more critical. I imagine that Evelyn contributed a great deal to this trend. The interview yesterday was quite good, and I think people might be pleasantly surprised at the direction the show is going to be taking in the future, both in terms of style and content.

Derek H said...

Figured I would post this here. Robb has come out to address the low carb and paleo connection:

http://robbwolf.com/2012/12/19/carb-paleo-thoughts-part-1/

Lighthouse keeper said...

Having listened to the SHR podcast on numerous occasions I would concur that it is coming from a low carb Taubsian position with a touch of biohacking thrown in-just listen to those supplement ads. I think Jim Johnson made some extremely cogent points, e.g. that many bloggers in this field are agenda driven and that not much in biology is black and white.

Lerner said...

It was probably as recent as 6 months ago that Carl was talking about how 'brilliant' that boob Taubes is. I stopped listening about 3 months ago when Carl and Regish were both going on about how great those amino acid transdermal patches are. For me, that was the last straw in the supplement hawking. I used to like Carl. I used to like Regish. But amino acid patches?!? Because the digestion damages proteins, so food is not useful? Supplement slinging brings in even more eager gullibles than diet slingers do.

Add 1" to arms in 1 day? OMG! (and that's the 1st time I've ever posted "OMG"). From Regish, who once gave himself rhabdo.

Yes, maybe hell is the impossibility of reason... at least for some :) But, if Ginny and Keeper are saying the show isn't so bad these days, maybe it's time for a revisit. Maybe :)

We can one day look back at protohormones and the days of "rock hard granite muscles", and laugh...


To Evelyn: I'm sure that Carl would welcome you as a guest, if you were so inclined. You'd also be treated respectfully, IMO.

Lighthouse keeper said...

Yes indeed, add one inch in one day to arms? Assuming thats a bicep to tricep head measurement - could be after a heavy pump up. Used to do bodybuilding years ago and after an intense session would swell up alarmingly only to return to usual dimensions within a couple of hours. Seriously though I do find him to be an engaging character and good interviewer.

Lerner said...

Keeper, they also made the claim that the swelling lasts, presumably beneficially. But medically, the remnant from excessive acute inflammation is fibrosis - not net accretion of contractile proteins.

I do agree with your personal assessment of Carl. He's likeable, he's glib. I'd posted on SuppV in the past about him being a good host. I want to say that friends of Carl should wave him off from the mixing of ads into with what should be honest discussion. Short term gain, long term harm. C'est la vie.

You might remember Carl's plaints about wanting to be donation supported so that he didn't have to pander to sponsors. So he himself knows very well the downsides.

Regish was saying that bargain whey is so useless that you might as well flush it... while extolling his own AA miracle blend. Oh boy. Did Wade also go to the darkside?

Anyway, posting about Carl here was meant to be a comparison to Jimmy's show. The dieting biz shouldn't be seen as unique to LC or Paleo. It's the same all over. You cater to the "stick it to the man" crowd, you go extreme or you go unnoticed, talking always about studies. The democratization of science has a big downside.

Lerner said...

Note to bloggers: http://www.speakpipe.com/

Computers enabled with Flash (so not iPhones etc) can record an audio comment to the site, being easier than typing, and it'd be interesting (at least to me) to hear commenters voices. It might take some effort for the blogger (aka Evie) to make audio comments available to the readers (as opposed to only for themselves to hear), I don't know.

Maybe for the future.

Lerner said...

Derek, can you post a summary?

Derek H said...

Sure. Much like the intro to his book, he opens with his experience of being sick/GI issues. He found Cordain's paleo, combined with the original Atkins template. He ate a diet of mainly "meat, veggies, and fat". His transition to good health and body composition, in his words, led to him to having a bias towards low carb living. However, in retrospect, he admits to participating in about 15+ hours of intense activity per week, all while averaging 200 carbs per day (he ate more of a carb cycle diet, 75-100 grams for a few days, followed by a day of 300 grams.

Moral of the story - carbs are not bad, most active folks will suffer without adequate carbs (and even adequate bodyfat levels), and it's a great tool for the less active/more weight to lose/true insulin resistant club.

And oh yeah, calories matter more than carbs for healthy body composition.

"The insistence on the part of the LC community in adhering to the “no insulin, no fat gain” dogma ends up discrediting the real therapeutic benefit of LC and hurts us all."

Evelyn aka CarbSane said...

Thanks for the summary Derek. I just wrote another On The Record post. It's brave to admit, though I'm not sure he realized it (?) -- but you've got one of the biggest names in paleo saying he was duped. But he passed that along (complete with irreverence towards mainstream medicine) as factual -- as a former research biochemist no less. Ya think he'll mention this on the LC Cruise??

Evelyn aka CarbSane said...

This looks interesting! I tried to copy the code to a "fixed sidebar widget" and it puts the floating Leave a Voicemail thing. I am not a fan of that (or Twitter birds that float down the page, etc.)

If anyone wants to email me or play with the code on my behalf I'd love to add this. Would be easy enough to record w/Audacity and post up a compilation.

Derek H said...

I hope this teaches me to be cautious of trusting credentials and levels of education over my gut sense. I have a decent education in health, but was "duped" into putting too many chips into the low-carb pot based on his biochemistry background. The appeal to "natural" and "evolutionary" helped.

Evelyn aka CarbSane said...

Not sure I understand. When I say IF I usually think of the "eating window" type, which is how the obesity protected mice were fed. So if I'm a mouse and I want to eat cookie dough, I just gotta eat it as they were fed and I'm OK!

This is another area where I think we see some things in animal models that we don't in humans. It's been a while since I looked at the studies but there is a crapload on meal timing and such and I don't recall ever coming across one that demonstrated a difference.

JJ said...

Hi Evelyn,

As I mentioned on Twitter, I’m impressed by the thoughtfulness of your analysis. I think in the grand scheme of things we probably agree on much of the interpretation. However, in the spirit of clarification I have a few comments and corrections to offer your readers.

You write about the diets we used “It is a high fat diet that does… cause hyperinsulinemia. “

Yes, thank you for making this point again. However, we don’t want to over extrapolate too far the other way. Nowhere do we say that another diet that increases basal insulin would not have a similar effect. This remains untested, but we can’t discount it ahead of time. This is where the mouse vs human issue might be relevant, as the relative diets and feeding patterns are not the same.

Thank you for the kind words regarding my attempts at outreach! I can’t claim to completely understand how to Twitter yet either! I tackled a lot of these issues on the Podcast over at Super Human Radio, which I think could be helpful to readers. As for press releases and the media… people don’t care about mice and they just want a bottom line. I was very careful to not tell people which diets modulate insulin (because as I have eluded to, I do not think it is nearly as clear-cut as people think), but I did feel safe saying that any action people could do to keep their fasting insulin down should in theory be helpful. The easiest way to do this is to take longer more complete fasts. This is well established in both humans and animal models and is in fact the basis of the caloric restriction paradigm that increases longevity and improves metabolism in every organism from yeast, to worms, to flies, to rodents, to monkeys, and (some people think) humans.

“I challenge that such a conclusion can be drawn from his study, and this is certainly why I harp on the LIRKO mouse -- a mouse that is sick, for sure, but not sick-fat with sick fat, while being profoundly hyperinsulinemic with no ill effects directly attributable to insulin and its action. I'll cite more from the bulk of the release later, but it is interesting to note that:”

OK. First, I have to thank you for forcing me to re-read the LIRKO papers (there are now 14 papers on the LIRKO and related models). I am of course very familiar with the early ones, but I read them a long time ago. I would caution both yourself and Stephan to not to put too much weight on the LIRKO data when considering the role of insulin. The LIRKO experiment was designed to examine the role of insulin receptors on the liver. By virtue of the presence of hybrid receptors, IGF1 signalling is also affected. Another VERY important issue is the degree of hyperinsulinemia. The LIRKO mice are VERY PROFOUNDLY hyperinsulinemic, much past what you get with dietary changes. In most studies, they also show significant fasting hypoglycemia and fed glucose-intolerance. These are not anything like the mice described in our study and I would really caution about making strong conclusions based on them.

JJ said...

“While I don't doubt that Jim has familiarized himself with a lot of the relevant research in this area, I tend to think that were he knee deep in obesity research per se, his findings would not have been all that surprising after all.“

Well, we have known that these mice were protected from HFD for about 6 years now, so we have had plenty of time to immerse ourselves ‘knee deep’ in the obesity literature. Also, several of our co-authors and colleagues here at UBC and elsewhere are world-renowned experts in obesity, with long track records in the field. I must say that the response of expert academics has been split. Most, including us, were not surprised by the finding but acknowledged that it had never been shown directly. Although it is clear that many members of the public have assumed that the role of insulin is obvious, it is still critical to understand that the experiment needs to be done to know for sure. Of course, there is another half of the world whom are very surprised and reluctant to incorporate these new data into their worldview. I can’t help those people. There are still many people (and academics) who believe that insulin resistance is the overriding force in T2D, but their numbers and influence are shrinking from what I can tell.


In my opinion, the conclusions drawn in the study are over-reaching and not supported, as worded, by the published data.

Not supported by our data in the paper, or not supported by other peoples data in other papers? Data and paper don’t refute each other. Our models and ways of thinking just need to incorporate all the available data.


In looking into this study, I learned something new about mice vs. humans. We have one insulin gene, INS, while mice have two, Ins1 and Ins2. The Ins2 is the homologue to human INS and is expressed in all cells, while the Ins1 gene is pancreas specific. Here is one paper on the two-gene system in mice (and rats) for anyone interested. I think this is important to keep in mind, as all genetically altered mice are, in terms of whether or not such a mutation is possible or observed in humans.

Quick correction. Ins2 is only in the pancreas, brain, and thymus in significant amounts, not in all cells. It is actually the major contributor to islet insulin, when compared to Ins1. It is important to remember that we use genetically engineered mice as TOOLS to understand mammalian biology, since these types of studies cannot be don’t in people. It is assumed for fundamental processes, like energy homeostasis, that the generally architecture of the pathways controls them are similar between people and mice. Indeed, we know that the basic aspects (insulin signalling etc) are well conserved between worms, flies, fish and mice, so it is not a stretch to believe that what we find out in mice will reflect human biology, aside from some minor details.

So, yes, most people with obesity do not have half of their insulin genes deleted, although there are case in MODY that have structurally altered insulin – this leads to beta-cell ER stress and diabetes, so not good for looking at obesity. However, we do know that many people make more or less insulin based on genetic studies, so our work is relevant to them. An example are the many studies on the VNTR variation in the human insulin gene. Early studies actually implicated this in obesity, but more recent studies on other populations failed to find this association. It is really difficult to do these sorts of studies without huge, very well characterized patient populations so I would consider this unsettled at the moment.

“For example, the ob/ob mouse has been useful in elucidating many things regarding the role of leptin in obesity. However, we all know the "end" to that story vis a vis humans ... this sort of leptin deficiency is far too rare in humans to explain even the "baseline" levels of obesity in the couple-three percent range.”
I agree about leptin. It is part of the puzzle, but its lack is not a driver of obesity in most humans.

JJ said...

“Rather than storing the excess lipid intake, these mice burned off the fatty acids -- in their fat tissue! This sounds somewhat similar to what occurs in the FIRKO”
Yes! Our mice are very similar to the FIRKOs.

“So the problem as I see it with the wording and notion of insulin "driving" obesity. “
This is what loss-of-function data allow us to say. It is a semantic argument, but if you take the engine out of a car and it stops moving, you can say it was ‘driving’ the movement. It doesn’t mean that there are not many things (in series) that are involved in driving the car, including the driver (perhaps food intake goes here). However, in our experiment we controlled for the person driving the car and just asked whether a certain component was necessary. i.e. The engine is required for the ‘driver’ to use the ‘gas’ (HFD) to make the car move. The requirement for full Ins1 gene dosage (and by direct extension pancreatic insulin secretion) in diet-induced obesity in this model is irrefutable based on the data in hand.

“I would be interested in a non-inventive (as in making up "facts" easily shown to be false about this mouse) explanation for why LIRKO is not obese.”
Easy. Super-physiological insulin levels and severely altered glucose homeostasis (diabetes). And speaking of situations you will never see in human biology, liver specific OR knockout is about as un-physiological as you can get. Also, I looked hard but could not see a study in older LIRKO mice. We cannot discount that they would have become fat if they waited longer. Remember, our mice only became fat after 20 weeks. This mimics adult onset obesity seen in human beings.

“A recent paper showed that just a few days of high fat feeding in mice caused IR of the brain and inappropriate lipolysis of WAT.”
We too are very interesting in insulin action in the brain. Stay tuned.


“Which brings us back to misinterpretations of this study, which brings me back to the press release. It is clear, both from reading the paper and discussions with the author, that the insulin levels being discussed are basal insulin, not postprandial. Johnson concluded that extra insulin produced in the normal mice by the high-fat diet caused their obesity, which strongly suggests that mice – and, by extension, humans – may make more insulin than they need. The findings may mean that the key to maintaining a healthy weight is to continually return insulin levels to a healthy baseline by extending the gaps between meals and ignoring the widespread recommendations to consume small amounts throughout the day. In other words, cut out the snacks – and make sure not to overcompensate at mealtime. Huh? First ... are obese people known for eating small amounts throughout the day? “

I was asked in by the press people how one could keep basal insulin down. I thought carefully about this and I did not want to recommend a specific type of diet because our study did not compare diets and I am unconvinced that the post-prandial spikes in insulin are the be all and end all. Our study instead implicates the slow increased in basal insulin driven by (and driving) the increase in beta-cell mass. So instead I recommended that people eat less and fast for long. I think this is reasonable. Obese people do eat more often, and more. In general, people snack a lot. Many people eat something a least once an hour from the time they wake up to the time they do to sleep. I don’t think that is a very good idea.

JJ said...

“Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet”
I think I emailed you the study. It is interesting and should be considered carefully.

“As crucial as insulin is for storing blood sugar, it can also be too much of a good thing,” Johnson says. “If we can maintain insulin levels at a happy medium, we could reverse the epidemic of obesity that is a risk factor for so many ailments – diabetes, heart disease, and cancer.” When one thinks diet and insulin, they think carbs -- even the non-low carbers. So I think statements such as the two above in the press release are contributing to the confusion.
I totally agree. But ‘carbs’ does not appear once in the press release or in the paper. I would very much like people in the popular press and blogs and diet books to stop thinking that carbs = insulin. I have been correcting people in twitter, but there are millions and I am falling behind! Insulin can be stimulated acutely by glucose, fatty acids, and several amino acids. In the long term, anything that increases beta-cell mass will probably increase basal insulin hypersecretion. This needs to be tested more directly.

“I guess what the timed-feeding study says is that if you are a mouse and you want to consume an obesogenic diet, you should practice intermittent fasting. But if you want to eat a normal diet ... one that doesn't potentially lead to obesity and metabolic disruption, then meal timing really doesn't matter. And if you're a human, you don't eat 24 hrs a day anyway.”
Some people are pretty close! Also, see data on obesity in shift workers. I think one of your readers made some good comments. I think the prolonged fasts can protect mice from HFD-induced obesity by decreasing insulin. The key study would combine the experiments and see if there is no added effect. Stay tuned.

“So does this study demonstrate that insulin is bad? Not really. Because you cannot separate the fact that the HFD+ mice got obese and all the changes in adipokines, macrophage infiltration, and all the ensuing inflammation. So was it the insulin or the obesity?”
Well, since our manipulation was in insulin, it has to be at ‘upstream’ of the other changes. Of course these can be direct or indirect effects that are ‘downstream’.

“How does the HFD cause hyperinsulinemia? On Twitter Jim asked me what I think would stimulate insulin secretion (basal) and my response was NEFA. He responded that fatty acids are weak stimulators. .”
Actually, I said something to effect of ‘most people think they are weak stimulators’. I didn’t say I believed them! I personally think in the long term, they probably play a major role and I’m guessing you are correct. I think we need much more detailed mechanistic studies to know for sure.

No magic obesity pill, yet: While existing insulin-blocking drugs could prevent weight gain, they carry serious side effects that outweigh their benefit. Further research might lead to drugs that block excess insulin production or blunt its effect on certain targeted tissues. - Or we can remove the crap foods from our diet.
I agree! They asked by about pills, as all news people do. I didn’t bite. One might argue that pills for obesity are doomed to failure. These are very CORE cellular functions and very CORE drives people are trying to play with drug development. I doubt that the side effects will be acceptable for anything that is potent… certainly not better than exercise and a healthy diet.

“Jim is going to be on Superhuman Radio tonight.”
The interview went well and I think I addressed some areas of confusion. The Podcast is published.

JJ said...

eulerandothers

It is too bad you didn’t read the whole paper! The data show significant changes in hyperinsulinemia at 3 days (doubling) and they only show clamp-measured insulin resistance at day 14. So… basically the opposite of what you are suggesting. By the way, the rapid effect of diets on fasting insulin is old news (which is why this is in a specialty journal) and is probably related to the NEFAs that Evelyn discusses above.

By the way, if you ever want to read a paper you should just email the author (respectfully) and ask for a reprint. Most will send it off electronically under the personal use exemptions.

JJ said...

Hi Stephan,

“I think another issue is that in rodents, the "energy out" side of the equation is much more influential than in humans because they're much better at dissipating energy through uncoupling. That's probably why kcal intake is by far the most important factor shown to affect fat mass in humans. We probably have many of the same "energy out" mechanisms that operate in rodents (including brown fat), but they're less important in humans. “
This is hard to really say. It is apples and oranges. Remember the mice are locked in a small cage, which alters their physiology when compared to all by the most bed-ridden people. This means that the way that they expend energy is different. They also have a constant cage temperature, so less need for thermogenesis unless they are put in the cold room. I disagree that ‘energy out’ is not important in humans. I have heard this often repeated by serious scientists, but it is rubbish. There are virtually no fat elite athletes. This is easy to see from the Olympics coverage every 4 years. In fact, they struggle to consume enough calories to keep up. The problem with a lot of ‘exercise trials’ that are done in the general public is that they are done for far to short of a time frame and at levels of intensity that are not even close to what is required. The comparison groups are typically sedentary and slightly less sedentary.

“This idea that we should be suppressing insulin secretion in overweight people is strange. Their insulin secretion is already borderline insufficient to maintain metabolic control because they're typically insulin resistant. Diazoxide and those types of drugs cause hyperglycemia-- just what you would expect from creating an insulin deficiency.”
Luckily we don’t have to guess, because this experiment was already done, 14 years ago by Alemzadeh. They used doses of diazoxide that had no effect on glycemia (either fasting or stimulated) but that resulted in significant weight loss in 9 weeks. Subsequently it was suggested that this drug might act on adipocytes and/or the brain, causing some to question whether the results was specifically due to the effects on insulin. This is where our study comes in. It is like life-long, low-dose diazoxide that specifically targets the pancreas.

JJ said...

I think I need my own Blog! This 4000 character limit is killing me... being long-winded and all.

Naxossa said...

Can't wait :-)

Evelyn aka CarbSane said...

Hi Jim! Thanks for the thoughtful and detailed replies. I'll be responding in greater detail shortly. But I did want to respond to the LIRKO vs. your mouse, because it appears you are misunderstanding me. I know LIRKO is off the charts hyperinsulinemic and bears no resemblance to your mouse that cannot become HI. But that is my point. What is the mechanism by which you believe HI drives obesity? Presumably the action of insulin of fat cells to store fatty acids. If that's the case, then LIRKO's failure to become obese must be explained (and I'm pretty sure that at least one study extended to 6 months so we should have seen it). There is no indication that knocking out insulin receptors in the liver influences the basics of insulin action in the adipocytes (glucose transport and FA esterification) -- LIRKO has low circulating NEFA. What am I missing that this isn't pretty damning to HI driving obesity?

To me, a more reasonable interpretation of your results is that the ability to become/sustain a hyperinsulinemic state is necessary to develop obesity. (Then we still have the non-HI obese to explain ...).

eulerandothers said...

JJ, I didn't read the whole paper because it wasn't available. I guess I can email the author. However, I go by what the study says is its conclusion, that's all. I notice things in a study sometimes, and then I'm tempted to think the study was about that, when it wasn't. I try to stay away from that. There are plenty of studies that actually address hyperinsulinemia. I don't know what I was suggesting, but that this study was about hyperinsulinemia was not it!

Evelyn aka CarbSane said...

Me: In my opinion, the conclusions drawn in the study are over-reaching and not supported, as worded, by the published data.
Jim: Not supported by our data in the paper, or not supported by other peoples data in other papers? Data and paper don’t refute each other. Our models and ways of thinking just need to incorporate all the available data.

It is my opinion that the "new model" is premature. It can be supported by this study, but is inconsistent with other studies. The wording over-reaches. Also, and this goes to the first paragraph, in tweets and comments here and elsewhere you've eluded to a lot of unpublished data (as well as talking about hyperins in that timed feeding study, I've yet to get to that one) ... so it gives the outsider an impression that you are basing your conclusions on information you aren't sharing with them.

That's basically the point I was making about the press release too. Yeah, I mostly blame the media for the types of questions they ask and what parts of which responses to include. Again, to an outsider that release reads nothing like what the paper actually says, and when diet is brought up, people think carbs (and that's not so wrong as carbs do elicit the biggest insulin response in many cases). One of the things I try to do on this blog, however, is dispell this notion that eating carbs causes basal hyperinsulinemia and/or "spiking" insulin by eating carbs leads somehow to IR.

However, we do know that many people make more or less insulin based on genetic studies, so our work is relevant to them. An example are the many studies on the VNTR variation in the human insulin gene. Early studies actually implicated this in obesity, but more recent studies on other populations failed to find this association. It is really difficult to do these sorts of studies without huge, very well characterized patient populations so I would consider this unsettled at the moment.

I believe this is where I keep coming back to (and Stephan has addressed as well). Perhaps if we could establish that the obesity resistant people -- a bunch of recruits who can eat whatever they want and never gain a pound -- were just hypoinsulinemic enough and had higher UCP1 content in their white adipose, this would convince me that one would need to be able to produce excess insulin to become obese. However there are many skinny people who are metabolically unhealthy so my hunch is that we don't see the adaptations we see in your mouse and FIRKO in humans. To be cont.

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