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!)

Thursday, July 4, 2013

July 4, 2013 Over the Hump Bump: Where does insulin resistance start? The adipose tissue

The readership in this blog continues to grow and it is not lost on me that a vast majority of current readers are unfamiliar with the bulk of my work here on this blog.  I think I'm closing in on 1000 posts which would make me one of the more prolific bloggers around ... for better or worse!  As such, I more than understand that it would be darned near impossible to catch up, etc.  So a few comments in that vein.  

  • I do try to link to older relevant content in my posts and I do use a "related posts" widget.  The latter is imperfect as it randomly selects using the labels function, but it's worth more than just glossing over if you're a newer reader.
  • Speaking of labels, while I do have a lot, I do try to only use the labels when there is relevant information in a post.  Not perfect on that account, but I try, so for those looking for more information, there are the labels.
  • There is a search function for this blog.  It works pretty well, but at times I find using plain Google.com with the site:carbsanity.blogspot.com search easier to navigate for relevant hits.
  • I also employ a Chronological Posts widget on the right sidebar.  While there are a lot of posts, my post titles are usually pretty descriptive so scanning through that may be helpful.  I used to have that widget on a page here, that was much easier to read, but when Blogger upgraded, it stopped working.  Sorry about that!
  • You can always ask!  I am in the process of working on some summary pages for most often discussed topics.  It's just not a priority so I can't make any promises.  Since this blog started as merely sharing my research and thoughts, it was never organized around some central mission statement, etc.  Constructive criticism and input on rectifying that is always welcome.

So that of the way, I thought that one more way to highlight older content might be to bump posts.  I have been doing this from time to time, especially when on vacation, but I plan to do this on a more formal basis from here on -- every Thursday.  And since Wednesday is "Hump Day", this will be the Over the Hump Bump.  Feel free to groan.  

Today's Bump was inspired by comments here.  One thing I brought up there is that some of the current issues with obesity and diabetes may be attributable to the increase in low birth weight babies here in the US.  While LBW and premie status are not one and the same, the numbers overlap substantially.  So a few source citations for those interested on this and the link to developing obesity:
  • Born a Bit Too Early: Recent Trends in Late Preterm Births:  The preterm (less than 37 weeks of gestation) birth rate rose by more than 20 percent in the United States between 1990 and 2006 (1). Most of this increase was among infants born toward the end of the preterm period, at 34 to 36 full weeks of pregnancy, or during the period known as “late preterm” (1,2).  Although babies born before the 34th week of pregnancy are at the greatest risk of early death and life-long morbidity (3), it is becoming increasingly recognized that infants born late preterm are less healthy than infants born later in pregnancy (4–9).
  • March of Dimes:  Summary:  about 8% of babies are born prematurely in the US, and about 10% are "growth restricted":  "a baby doesn’t gain the weight she should before birth. You may hear the terms “growth-restricted,” “small-for-gestational age” or “small-for-date” to describe these babies. They may have low birthweight simply because their parents are small. Others may have low birthweight because something slowed or stopped their growth in the womb."
  • Why Low Birth Weight Is Linked to Obesity Later in Life: Study Provides Explanation: Paraphrase, LBW babies develop fewer neurons in appetite control centers.
  • The Effect of Birth Weight on Childhood Obesity:  The Barker Hypothesis (1990) posits that “compromised” growth in utero may be associated with differential organ development (the severity and effects depending upon the timing of the insult) with increased allocation of nutrients to adipose tissue during development. This may then result in an accelerated weight gain during childhood, which could contribute to a relatively greater risk of various illnesses (including cardiovascular diseases) later in life. Our result that the “compromised” subpopulation has a faster postnatal growth rate during childhood (Figure 1(a)) supports the Barker Hypothesis (1990) and tends to resolve the paradox among birth weight, obesity, and cardiovascular diseases. 

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As you can see, it is not enough to explain the full epidemic, but it MAY be part of it ... especially since we have seen an increase in the so-called medically obese normal people or whatever you want to call those with glucose intolerance that are not obese.

My reason for bumping this is that in looking back I saw something that once again caught my eye, but now moreso than before.  It is becoming increasingly clear that the concept of IR as we know it in the progression of Type 2 diabetes is likely wrong.  This is not something I discovered or came up with, but it has been an ongoing point of contention amongst researchers in the realm.  This was the main point of the article I wrote recently for Alan Aragon's Research Review.  I'm sorry that I cannot share that with you as it is premium content for AARR, (you can always subscribe and have access to the archives).  Still, while not all in one place, most of the research referenced in that article has been discussed here over the past several months, and it is a topic I will continue to blog on here.  

The current general knowledge about diabetes is that the muscle cells become insulin resistant causing a backup of glucose in the blood stream.  The low carb line is that the adipose tissue acts as a last-chance glucose "sink" and when the adipose tissue finally becomes insulin resistant, hyperglycemia ensues.  Many have looked into the cause-effect "chicken-and-egg" relationship between hyperinsulinemia and IR, but both general ideas still put the defect in the periphery first.  There is little if any evidence to support this, however.  Meanwhile there is much evidence, such as the paper discussed in the original article below, that the defect may not even involve insulin per se, but further initiates in the adipose tissue.  You see, in the LBW babies, we see a decrease in adipose glucose transporters (GLUT4) and increased adipose tissue.  The GLUT4 in muscle is not reduced.  And, importantly (yet unfortunately), this defect persists even with weight loss. 

All arrows are pointing these days towards glucose uptake and de novo lipogenesis in the adipocyte as being intricately linked to lipolysis from adipose tissue.  So, SO, much to share with you on this!  It is the inappropriate lipolysis from adipose tissue, and thus inappropriate release of NEFA that sets the cascade in motion.  

Lastly, I would note that the original post was made not even a year into my blogging here.  I have left it pretty much "as is" (fixed formatting a bit and may have altered a sentence or two but I have no desire to waste time reversing irrelevant changes) as I think it is important to realize that all of us change and evolve in our thinking and understanding as we learn new information.   I am not sure if "insulin resistance" is as much the proper term any more as it may even be that there are simply fewer GLUT4's in the adipose tissue to "hear" the insulin signal.  This too, may change as more is discovered.  Whatever we call it, however, this much is pretty clear at this point:  Impaired glucose uptake in adipose tissue, not excessive glucose uptake in adipose tissue is seen in the early stages, and may even be genetic/determined at birth, and this is linked in some manner to the inability of the adipocyte to properly regulate NEFA release through lipolysis (and glyceroneogenesis ... shhhhhhhh).



Original Publication:  12/8/2010

Viewpoints on the Way to the Consensus Session: Where does insulin resistance start? The adipose tissue

This is a rather current (2009) fairly long review article that pretty much summarizes what I've come to understand through my research.  The "concensus" in the title kinda caught my eye for reasons my regular readers would probably find obvious.  

Anyway, I thought I would share this find without extensive excerpts.  I'd otherwise probably be quoting half of the piece.  But I'll share the summary graphic of fat being our largest endocrine organ.

One thing that did catch my interest was the summary paragraph:



PRIMACY: INSULIN RESISTANCE STARTS IN ADIPOSE TISSUE— 
Studies in twins, who have been raised apart and together (54), have documented that body fat distribution and metabolic abnormalities are a clustering genetic trait. Heritability in the Framingham study, including genetic and early environment contributions, was 57% for subcutaneous and 36% for visceral fat mass (51). As reviewed by Fernandez-Twinn and Ozanne (55), because of intrauterine nutritional and hormonal factors, low–birth weight newborns have more fat and are at higher risk of metabolic and cardiovascular diseases in adulthood. It is noteworthy that fat accretion occurs during the last trimester and maternal under-nutrition in animals during late pregnancy leads to glucose intolerance in adult offspring, in association with reduced adipose, but not muscle GLUT4, content and increased adipose tissue mass.
I don't know that I had ever read this about low-birth weight babies before.  It seems so counter-intuitive.  Also the influence of maternal nutrition in animals is of interest.  One wonders if in true poverty this is at least in part the cause of those obese moms Taubes so often refers to.
The embryonic origin of adipose tissue, i.e., the paraxial mesoderm, gives rise to truncal fat, whereas the lateral plate mesoderm gives rise to fat in the limbs (35), which also reflects the relationship between fat distribution and adult metabolic risk. 
Never heard this before either.  Makes me wonder even more about my change in fat distribution now well into adulthood since I've low carbed.  (Things that make me go hmmmmm?)
Recent human studies from our lab (16) have documented that whereas systemic inflammation, whole-body/skeletal muscle/hepatic insulin resistance, hypertension, dyslipidemia, and hyperglycemia all are reversed by weight loss, adipose tissue insulin resistance and hypoperfusion are not. This is consistent with the notion that GLUT4 translocation defects are inducible and reversible in myocytes but not in adipocytes (27). Like fat specific insulin resistance in obesity prone individuals, catecholamine resistance of adipose tissue does not regress with weight loss (56), partly explaining a tendency to regain the lost weight.
Now THIS is depressing!  But li'l old CarbSane is very perplexed by this!!  One would think that adipose tissue insulin resistance would mimic insulin deficiency (e.g. Type 1 diabetes) in terms of making one LESS prone to obesity, both through Taubes' insulinocentric theory and observations in T1's.  At the very least, when adipose IR manifests itself fully we seem to get excessive release of NEFA.    Maybe it's that the IR exists all along and it just exascerbates NEFA release from fat cells the fuller they get?  Perhaps researchers are misinterpreting the excessive NEFA release as insulin not being able to do it's thing when it's more that it needs to do it on so many triglycerides?  Head spinning on this one.  Still, if it's the case, and carbs had anything to do with inducing fat accumulation through movement of glucose into the cell, this would again be inconsistent with that theory.
In conclusion, fat-specific insulin resistance appears to be an early and irreversible defect that can explain the causal relationship between adipocyte dysfunction, extra-adipose tissue (i.e.,muscle and liver), and insulin resistance. The origin of this association can be traced to genetic and embryonic programming, long before the development of metabolic disease in adulthood.
Depressed now.  About the permanency thing, although my n=1 personal experience would indicate otherwise, though perhaps not in a good way.  Seems I've increased my IR prone fat while reducing my IS prone fat.  WTF does that mean???? 

10 comments:

Matt Stone said...

This is a beauty. There is no doubt that heredity is the primary determinant of weight gain when exposed to the ol' obesigenic diet and lifestyle. I found it interesting that the Pima indians experienced a large famine right before they were exposed to this diet, which I've postulated was a huge contributor to their shortly-thereafter title of the world's most diabetic and obese individuals. There's no question in my mind that dieting and overexercising in pre-natal women, something that has only been voluntarily done en masse over the past couple of generations, is one of the heads of the 3-headed obesity dragon (the other heads being refined and flavor enhanced food as well as a myriad of modern stressors).

And there's no question that former low-carbers and fruitarians are the ones who gain the most weight on the S.A.D. if they depart from their extreme diets at any point, which 99% do because they either run into health problems or get overwhelmed by cravings, and is something Taubes doesn't seem to pay much attention to, nor anyone else.

Karen said...

Is it an absolute that if a person adds some carbs after eating low carb for 3 yrs weight gain WILL happen?
Carb sane you sure find some great studies. Just wished I could understand them!
So if I'm reading this study correctly there was a certainty I would get diabetes no matter my diet? If so why does lower carb help my glucose numbers?

Sanjeev said...

>> huge contributor to their shortly-thereafter
>> title of the world's most diabetic and obese
>> individuals

As far as I can tell, all first nations peoples experience this effect upon abandoning the traditional diet.

The plains Indians several decades ago, with lower incidence today apparently (maybe the most susceptible died before mating?)

The Inuit, Yupik and their relatives[0] are going through it today (in the villages, towns & cities that are now easily reachable by train / truck, and/or where air drops are cheap, apparently not as much where pasta, bread, McD's, KFC and coke are still expensive)

[0] Toronto doesn't have a huge population of first peoples, but big enough ... "eskimos" is not a preferred term, despite what some Internet posters claim

Jonathan said...

This would not be the first study to indicate that hormone levels or receptor sensitivities are passed on via the material prenatal environment. So children of obese moms might be born with a "predisposition" to be insulin resistant (at least in adipose tissue) and hence gain weight in adulthood.

But biology is not destiny. While it has been estimated that obesity is 70% genetic, that still leaves 30% you can influence. Certainly, strenuous exercise will empty muscle glycogen and increase the insulin sensitivity of muscle and other tissues. To the extent that occurs, should it not take some of the "pressure" off of adipose tissue, since glucose would first go to refilling glycogen before going to adipose tissue?

Also, you have said many times that insulin resistance causes hyperinsulinemia, rather than the other way around. But is it not possible that this is a "vicious circle", where high insulin levels are both cause and effect, mutually reinforcing each other either on the way up or the way down? While articles like this one do make the case that insulin resistance "starts" in the adipose tissue, and that this is (in part) genetically programmed, that does not rule out that IR can also be caused by eating a diet rich in insulin-spiking carbs.

If someone is eating pasta, bread, ice cream and cookies around the clock, and their insulin levels remain high, they will not only store fat, they'll have trouble burning it. Once they get fat enough, IR would be a natural homeostatic response. And that's the case, regardless of whether or not the fat can also accumulate via other pathways, e.g. ASP.

So I don't see that its either IR causing high insulin - or high insulin causing IR. Why can't it be both, in a continuous circle of causation?

Jono

Nigel Kinbrum said...

As glucose homoeostasis is basically a negative feedback control loop with multiple feedback paths, reduction in the sensitivity of any of the feedback paths (due to insulin resistance) always results in an increase in output (hyperinsulinaemia). Whether chronic hyperinsulinaemia then causes a further reduction in insulin sensitivity is an interesting question.

If insulin is required for dietary fat to be stored in fat cells, insulin resistant fat cells would take in less glucose & fatty acids and export more glycerol & fatty acids and become ever-smaller. This doesn't happen.

If exported fatty acids aren't burned by muscles (due to sedentary behaviour), there would be ever-larger amounts of fatty acids sloshing around in the blood with nowhere to go. This doesn't happen.

This suggests that insulin doesn't have that much to do with dietary fat storage in fat cells and that fat cells can take in fatty acids until they become full.

However, the dysregulation in glucose homoeostasis on a high-GL diet caused by insulin resistance does result in increased appetite, overeating (for the level of activity) and weight gain.

CarbSane said...

@Karen: I'm still mulling over the implications of this study ... something's not quite making sense to me in my mind on this. But I don't think it has anything to do with gaining weight eating carbs. If you've lost weight, then, as stated in the paper, muscle and other tissue IR has or can be reversed. Presumably this reversal is due to a lessening of the causative agent, that being elevated NEFA. If that's the case, your body is no longer experiencing the effects of fat tissue insulin resistance, because that is what causes the elevated NEFA. Your fat cells are apparently sufficiently empty (or below their "full line") that insulin can do its job keeping the NEFA levels down below where they cause damage.

I'm still trying to wrap my head around a mechanism by which adipose tissue IR would pre-dispose someone to obesity.

CarbSane said...

Jonathan, I've got some thoughts on the comment you made here, but my feed reader alerted me to a comment you left on my GT email update post regarding the YouTube video/slides citing this blog. However when I click on that in my reader, I'm not seeing the comment in that thread (but I get no error either) nor am I seeing that there was one you removed for whatever reason.

I would gladly address what you wrote in that comment but want to be sure you wanted that content "out there". Let me know here in comments or shoot me an email. If you don't remember what it was, I can email you a copy.

Thanks :)

CarbSane said...

Nevermind Jono, see my post on Comments that explains the mystery :(

CarbSane said...

I've been thinking more on this article in the context of others on IR. This one seems to say that we're predisposed to IR from birth (or before we're even born) because of our nutritional status in the womb and its impact on our fat distribution/mass. This is quite different from genetics. My own marked change in fat distribution makes me wonder how permanent this is. And there are any number of studies on diet and exercise and changing visceral fat levels, etc. Also, nothing can reverse IR in adipose tissue?

I'm also truly unsure how pre-existing IR would pre-dispose someone towards obesity ... the opposite would seem true, and these folks should remain leaner.

Biology/genetics influences destiny, but where bodyweight is concerned, there's an awful lot of free will involved. No, it's NOT fair, but some of us need to be more deliberate than others if we're to maintain a healthy body weight.

Margaret said...

The way I understand it, pre-existing IR could pre-dispose someone to obesity because of the increased glucocorticoid activity that, among other things, stimulates appetite. See

http://www.clinsci.org/cs/096/0513/0960513.pdf

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