Revelations from Gedankenexperiments vs. Wirklichenlebenexperiment

Traffic Bump!

Occasionally I see traffic to old posts whilst perusing stats.  I saw this was getting a few hits and decided to bump it.  Especially since the fervor for finding the single bogeyman dietary agent of all doom seems to be hitting a fever pitch lately.  Even Dr Oz is getting on board, and as the Judith Mazel of the low carb world tells us:

Dr Oz is one of the most well respected conventional doctors—and he has major influence because he is educating millions of people every single day on his show.

{you can stop laughing now ...}

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Celebrity Diabetes ~ Tom Hanks now

Before Paula Deen got in hot water over racial issues, she was the subject of controversy a few years back with her belated disclosure that she had Type 2 diabetes, and then became a spokesperson for Novo Nordisk's Victoza.  The "mainstream" balked, including rebukes from fellow celebrity chefs for using so much butter in her cooking while hiding the effect it had on her health.  When the news hit the LC community, it of course went nuts.  I discussed this pretty thoroughly HERE.  A quick summary might be that the low carbers didn't like that people blamed the fat in her foods and finger pointed at the carbs (ignoring sedentary lifestyle entirely).  Further, they didn't like that she was dieting per mainstream guidelines and using Victoza rather going on a LC diet.   Stress certainly has taken a toll on Deen, but she seems to have maintained her weight loss, perhaps even losing a few more pounds.  It would be interesting to get an update on her condition, but somehow I doubt we will.

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The Vascular Functions of Insulin

Random Replay

Was having a discussion on FB about insulin this morning and while going through some blog posts this one popped up.  I find reading some old stuff interesting at times ... this is over 3 years old.  

If someone goes on a low carb diet and this manages their hyperglycemia, this is a classic example of treating symptoms while not addressing the cause of the problem which is pancreatic beta cell dysfunction, and in the case of the T2, coupled with hepatic insulin resistance.  

What low carb doesn't do is restore normal insulin secretion and signaling, and insulin plays many roles in the body beyond glucose transport.  For one, it also assists amino acid transport (and protein synthesis) which is why the IR often have elevated circulating levels of the most insulinogenic (e.g. insulin requiring) amino acids, the BCAAs.  

This post is a flashback of some of the other things insulin does.  Further it discusses the role of NEFA in all of this ... the forgotten biomarker I think most low carbers with whacky lipids should have measured as they are likely elevated.  

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Aug. 1 Over the Hump Bump: Baby your Pancreas? Part I: The Tired Pancreas

Another two-fer for the Thursday post bumps again this week.  More explanation for why this set in the next bump.

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Original Publish Date:  7/26/11

In the comments on a recent post on beta cell lipotoxicity, Ned Kock (of Health Correlator blog) posted a link to a post he made a while back entitled:  Lipotoxicity or tired pancreas? Abnormal fat metabolism as a possible precondition for type 2 diabetes.  This article deals with the concept of the "tired pancreas" in the development of diabetes.  It seems that (and hopefully he corrects me if I'm wrong here) Ned and I agree that this is not a likely explanation for diabetes.   Ned summarizes the progression of obesity induced T2 diabetes from Unger & Zhou, 2001.  It is worth mentioning that Unger is often summarily dismissed from the "scientific discussion roundtable" by low carbers because of the unfortunately titled "Gluttony and Sloth" paper, that, even more unfortunately also included a biblical verse.   Unger's hypothesis is very leptin-centric, but not at all incompatible with other lipotoxicity based theories.  Basically, lipotoxicity is the result of dysfunctional adipocytes leading to excessive "spill-over" of fatty acids into circulation and accumulation in ectopic tissues.   Unger & Zhou identify dysfunction in leptin secretion and/or signaling as the initiating factor in this process.  One thing that doesn't quite add up for me here is that I keep finding citations indicating leptin action increases free fatty acids which would seem counterintuitive.  In any case ...

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July 18, 2013 Over the Hump Bump II: Insulin Wars II: Mark Sisson

Part II of my CarbSane is so cruel and vitriolic in her criticisms of Mark Sisson bumpfest today.  Crying Wolf II , Bump I

This one is especially  ironic given point 9-of-12 of Mark's email to Grashow blamed lack of dietary discipline and sloth for my weight.   Here he says that doesn't work anyway!  {shakes head}

Be sure to notice how I misquoted, misrepresented and ridiculed Mark Sisson, took pot shots at his appearance and denigrated him on a personal level.  Oh wait.  That didn't happen.  This post was originally viewed by around 400 people and didn't even crack the Top10 list at the time.

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Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.

{shhhhhhhhh .... don't tell Gary Taubes, this might just upset his 21DaySugarDetox approved green apple cart!}

You know how the story goes by now, right? In more recent lectures, Taubes is fond of using the slide below.

source

These are two quotes that Taubes cites from Lehninger's Principles of Biochemistry and he juxtaposes them to convince you how misguided such textbooks are.  How can, on the one hand fat cells "fatten" according to the action of insulin, but human beings get fat due to positive energy balance?   The simple answer is that insulin is not some renegade hormone and your pancreas is not a master organ in the body placating your rebellious adipocyte's every whim.

Yes, tis true that insulin has a stimulatory role in the storage of fatty acids by acting on LPL on the intake side, and yes, tis true that insulin "traps" those fatty acids in the adipocytes by suppressing HSL mediated lipolysis and release of same.  Sounds like a slam dunk.  If there's too much insulin, ostensibly from chronic spiking due to chronic carbohydrate consumption, the fat cells get stuck in storage mode and the horizontal growth disorder is primed for obesity!

Not so fast.  How can the results of this study be then?  Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.   The abstract, bullet-pointed for ease of reading:

• When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. 
• FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. 
• Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet–fed mice. 
• In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. 
• The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. 
• In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. 
• In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. 
• In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. 
• Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.

Cliff Notes Version:  Decreased lipolysis from WAT increased skeletal muscle glucose uptake and DNL in the liver without resulting in increased WAT mass.  In the obese, suppressing WAT lipolysis induces DNL in the fat tissue.  This improves glucose metabolism.

All of the evil things you were told insulin did to you -- turning carbs to fat in your liver and fat tissue and suppressing lipolysis from fat tissue -- are actually good for you.  And the (temporary) trapping of fat in the adipose tissue improves insulin signaling and glucose handling in the skeletal muscle.  

Imagine that ...

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.  

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Ectopic Fat

A nice overview I just thought I'd share here.  Ectopic Fat Depots and Cardiovascular Disease

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Stick a Toothpick in It? Taubes' 4-pronged Carb/Insulin "Fork" Loses its Tines

I'm bumping this today, because in the weeks to come I hope to update, flesh out, and reference it fully.  Looking back at something written almost 2 and a half years ago it seems rough, but nonetheless it  still summarizes what I call TWICHOO and the arguments against it pretty well.  

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This post updated slightly 6/22/2012.   Original publication date 1/23/11

In the comments at Jimmy's blog on my interview podcast, several comments either directly or by inference say I failed to make my case against Taubes.  Well, I think I did pretty much get to what I consider the four prongs of Taubes carb/insulin hypothesis, but I've decided to try and summarize this in a blog post.  Another common comment is that I'm somehow nit-picking at minutia, basically if folks lose weight on low carb, it doesn't matter the details of why.  To those, if they are reading this, I would say that any objective view of my arguments would lead to the conclusion that these are NOT minor details, they are the sum total of Taubes' evidence in support of his hypothesis.  Not only has he NEVER debunked the calorie-based theories on obesity, but almost all evidence in support of his "alternate" theory HAS been.  

I will not be referencing this post, it's all been done before here, and I don't have the time to trace down every link etc.  

So, what do the four prongs of the fork stuck in the potato above represent?  

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Chronic Exposure to Free Fatty Acid Reduces Pancreatic β-Cell Insulin Content by Increasing Basal Insulin Secretion That Is Not Compensated For by a Corresponding Increase in Proinsulin Biosynthesis Translation

Coming next in the discussion of diabetes I am going to discuss insulin secretion in greater detail.  I was reminded of this post in the writing process.  So ... Bump!

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Original Publish Date:  4/4/11

Chronic Exposure to Free Fatty Acid Reduces Pancreatic β-Cell Insulin Content by Increasing Basal Insulin Secretion That Is Not Compensated For by a Corresponding Increase in Proinsulin Biosynthesis Translation

JD McGarry contributing author.

{Please note:  Excerpts from the text will be edited somewhat to avoid "cluttering" references, statistical values, and some rounding of numbers.  Text will sometimes be presented in bullet form or with paragraph breaks to ease reading.  It is not my intent to plagiarize nor to alter the content.  If anyone feels I've altered the content in any meaningful way, do please let me know!}  Direct quotes will be indented.

FFA are an important physiological fuel for islets, and act as a supplemental nutrient secretagogue to potentiate insulin release acutely in the presence of glucose.

Translation:   β-cells run on fatty acids but this fuel also serves to stimulate insulin secretion.

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β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question

β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question

OK Gang.  The first of the two reviews on the changing paradigms on the etiology of type 2 diabetes.  This one thanks to Craig in CT.  

The idea that type 2 diabetes (T2DM) is mainly due to insulin resistance stems from the 1930s, but became dominating from the 1980s. However, evidence since the 1960s indicates that insulin response to glucose is markedly diminished from the earliest signs of glucose intolerance. Insulin pump treatment induces near-normoglycemia in T2DM with doses similar to type 1 diabetes, indicating that hyperglycemia is caused by lack of insulin, insulin resistance acting as an amplifier. Insulin secretion is genetically controlled. T2DM risk gene polymorphisms hint toward mechanisms of reduced insulin secretion in diabetes-prone subjects, in whominsulin response decreases as the number of diabetic alleles increases. I hypothesize that the genetic background of the β cell determines its adaptation capacity to increased insulin demand imposed by augmented caloric intake and insulin resistance; failure to adapt eventually leads to T2DM. Therefore, I regard the “prediabetic” β cell as a normal cell with limited adaptability, diabetes risk being entirely context-dependent (nutritional load and insulin sensitivity). Once hyperglycemia is established, β cells are exposed to continuous nutrient stimulation, with consequent oxidative and endoplasmic reticulum (ER) stresses. The result is increasing functional deficiencies and β-cell apoptosis, hence reduced β-cell mass. Some of its mechanisms are discussed. An intriguing as yet unanswered question is whether the mechanisms of β-cell deficit in the diabetic environment operate before hyperglycemia in overfed, insulin-resistant subjects. Therapeutic agents preventing β-cell oxidative and ER stress could stop the progression and perhaps initiation of T2DM.

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What is Diabetes?

"the proinsulin disorder in diabetes is not 

only ubiquitous but it is also precocious"

As a second post setting up for future discussions on insulin resistance and it's role in diabetes (especially type 2)  I wanted to share the following paper with you here:

PROINSULIN, PROAMYLIN AND THE BETA CELL ENDOPLASMIC RETICULUM: THE KEY FOR THE PATHOGENESIS OF DIFFERENT DIABETES PHENOTYPES

It is a long paper, almost 18 full pages of text, and more than 9 to list the 298 (yikes!) references. I will by no means attempt to address it in its entirety here, rather I shall focus on the section entitled "INCREASED PROINSULIN AS THE MAIN BETA CELL SECRETORY DEFECT".  But first, the abstract of this 2007 paper:

Based on our clinical and epidemiological data, we have sustained for a long time the unitary character of the various phenotypes of the diabetic syndrome. In this paper, we add several arguments sustaining that the unitary character of diabetes is related to a common primary defect in the function of the beta cell endoplasmic reticulum, leading to an inadequate processing of the two main secretory molecules: pre-proinsulin and pre-proamylin. The post-translational changes of these molecules might explain the main proapoptotic and anti-regenerative pathogenic mechanisms leading to a progressive decrease in the β cell mass/function. In our view, the increased proinsulin levels encountered in various diabetes phenotypes could be not only a marker of beta cell dysfunction but also could indicate the main β cell defect, suggesting also its location.

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Book Review: PCOS Unlocked by Stefani Ruper

UPDATE:  Stefani's response and my own, posted ~2:30 pm 1/12/13, search on "Stefani Ruper Responds"

Alternate Title:  The Creation(ism) of a Paleo Guresse

This post has been a long time in coming.  It is in the utter absence of glee or malice that I have finally put it together.  But it is a post that needs to be made, because not to do so means this phenomenon of overnight Paleo guru creation never gets a light shown on it.  

Part I of Book Review

Do not buy this book.  If you want to support Stefani Ruper's work, though I cannot see why, send her a donation instead.  If you are a women suffering from PCOS or who suspects you have PCOS, save whatever money you might spend on this book and use it towards a consultation with a medical professional and/or diagnostic tests that can help you and your doctor figure out what is going on hormonally.  I purchased that $39 paleo book package recently, and to be honest, one specific reason for doing so was to get my paws on PCOS-Unlocked without enriching Ruper's coffers.  For that price, I received 33 ebooks, among them  

PCOS Unlocked: The Manual you will be receiving is 52 pages worth; not the entire guide. Why? It has a specifically unique value and thus $47 selling price. A significant discount code to purchase the rest of the guide is inside.

The 52 pages I received were valued at an inflated $24 towards the bundle value of $479.

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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.

1.  Bloggo Science ~ A Hypothetical Post ~ III: Fasting Insulin & Weight Loss

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.  

2.  Bloggo Science ~ LIRKO Wars Edition

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".

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Hyperinsulinemia, Insulin-Suppressive Drugs & Obesity (and Lustig)

The recent buzz about hyperinsulinemia being at the root of obesity (whatever the mechanism) has had me thinking again about the insulin lowering drugs.   Studies in this regard were referenced in the recent article in Cell from Dr. James Johnson's research group at UBC.   If this is really all there is to it, why not just treat obesity with such drugs?  Or at least give them to the reduced-obese so they won't regain the weight, and/or the so-called pre-obese who start gaining at some point in life before they become obese.  This is really the bottom line of studies like the recent one from UBC.  Because if all we need to do is suppress the hyperinsulinemia (however it is caused) to prevent obesity it would be done.  There is a relatively rare condition, called by many names, but most descriptively neo-natal or infant hyperinsulinism.  These children must be treated ASAP to avoid the consequences of hypoglycemic episodes.  I surmise the drugs octreotide and diazoxide were developed at least in part for treating this condition, though often partial removal of the pancreas is required.

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Insulin Secretion and the Corrected Insulin Response (CIR)

I'm working on a post about hyperinsulinemia and obesity in humans.  It may well turn into several posts.  But in one study I will be discussing they identified hypersecreters according to something called the corrected insulin response, CIR.  Sometimes this is further "standardized" as the CIRgp which is evaluated at the peak glucose reading.  The CIR is value calculated following a standard OGTT.  If you have data from your OGTT, you can calculate your own and determine how you rank.

The CIR was developed by Sluiter and colleagues as outlined in:  Glucose Tolerance and Insulin Release, A Mathematical Approach I. Assay of the Beta-cell Response After Oral Glucose Loading.  

From the dose-response relations between glucose and insulin after oral glucose loading, a reproducible parameter for beta-cell response was deduced. The main advantage of this parameter lies in its independence from the initial or reached glucose level.

Units:  glucose in mg/dL , insulin in μU/mL

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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

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LIRKO vs. TWICHOO X.0

from this study, image from this post

It occurred to me as I was thinking again about LIRKO, that this little mouse not only countered TWICHOO 1.0, but it pretty much puts the lid on TWICHOO X.0.  This profoundly hyperglycemic and hyperinsulinemic liver insulin-receptor knockout mouse, is not fat.  Though not statistically significant, the trend is to eat a tad less, be a tad smaller, and pack on fewer fat grams  than controls.  But let's just call it a wash.

For any newer readers, TWICHOO stands for Taubes Wrong Insulin-Carbohydrate Hypothesis Of Obesity.  Version 1.0 was that which was put forth in Good Calories Bad Calories.  In this version, Taubes put forth four ways by which the carbohydrate could promote obesity:

1.  Carbohydrates stimulate insulin which stimulates fat storage and/or traps fats in our fat cells so fat accumulates.

This was pretty much the "lead singer" of his Barbershop Quartet singing the TWICHOO jingle.  Carbs stimulating insulin basically led to chronically elevated insulin levels.  The other three are:

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Remember LIRKO? Grey & Kipnis?

So a recent research paper has been making the rounds.  It has a "red meat" title for the die hard TWICHOOB:  Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production.  This paper was brought up in my comments section as well.   Every time this happens I really do feel like I'm in some sort of nutritional remake Groundhog Day.    I'm a bit backlogged at the moment, but luckily Stephan Guyenet has weighed in with his analysis and included some additional studies in support of his position.  

Whenever I think hyperinsulinemia causes obesity,  I'm reminded of the LIRKO mouse.  LIRKO is normal except its liver lacks insulin receptors.  The result is a mouse with raging hyperglycemia and hyperinsulinemia throughout much of its young life until its liver poops out.  I blogged on this mouse here:  Bloggo Science ~ LIRKO Wars Edition.  (Incidentally that post links to an older post by Stephan on the role of hyperinsulinemia here.)     Here's the rundown on LIRKO:

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If you drink OJ, might it just as well be Orange Crush?

I'm sure you've heard it many times -- fruit juices, even unsweetened ones, are still just glasses of sugar, and you might as well be drinking a soda or Tang (remember that?). According to nutritiondata.com, a cup of orange juice contains 21g sugars.  They don't "itemize" in the OJ entry, but if we look at the ratios oranges we can calculate that of those 21g, roughly 11 g are sucrose, 4.5 g are glucose and 5.5 g are fructose.  Thus for each cup (8 oz) of OJ, you get around 11g of the dastardly fructose poison.  This is roughly the same as you would get in the same amount (small can!) of orange soda.

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