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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Insulin/Proinsulin/etc. in Normal, IGT and T2 Diabetics

One more on the measurement side of things since these type posts are easier to put the finishing touches on to get out the door.  This is another older paper, and I'm trying to track down more info on newer/current analyses and their specificity.  Unlike the last discussion here, I want to focus on the secretory capacity of the  β-cell through the progression of diabetes.  

Serum proinsulin levels at fasting and after oral glucose load in patients with Type 2 (non-insulin-dependent) diabetes mellitus (1988).  

• 40 newly diagnosed with T2 diabetes + 21 IGT -- No medications or special diet
• BMI < 27 in men, < 25 in women
• Controls were weight matched to study group participants.

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Measuring Insulin Levels, Hyperinsulinemia and Insulin Resistance

A slight detour in my current endeavors to put forth some information regarding the etiology of diabetes, insulin resistance and β-cell function, before I get to the two major reviews that prompted this.

To review, in my last post, discussing this paper, a seminal observation/conclusion can be summed up as follows:   Insulin is formed in stepwise fashion from a larger protein (preproinsulin) that has a terminal signaling chain cleaved forming proinsulin that is then folded, cross-linked and has one of the three main chains cleaved in the last step(s) resulting in a protein with two parallel chains, insulin.  I like this newer representation I found below because it provides the numbers in the amino acid sequence at which the cuts are made.  This is important to better understanding the papers I'm going to discuss here.

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

Building on my last post on this topic ...

So far I've spent most of the blogging on a study comparing 3 doses of octreotide, an insulin suppressing drug, vs. placebo in a subset of obese people pre-tested and determined to be insulin hypersecreters as defined by a corrected ratio for insulin to glucose levels.  This post will focus more on two other studies using this drug, perhaps just the first ... let's see how long this gets ;-)    I think it will be easiest to number the 3 studies, all bearing Lustig's name:

• Study 1: Suppression of insulin secretion is associated with weight loss and altered macronutrient intake and preference in a subset of obese adults (2003)
• Study 2: Obesity, leptin resistance, and the effects of insulin reduction  (2004)
• Study 3: A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion.  (2006)

I've already discussed the rather unimpressive performance of octreotide in Study 3.  While the highest dose group had the highest "response" rate (20.5% losing ≥5% initial weight), the rates were similar between the placebo group (11.4%) compared to the 40mg octreotide group (12.5%), which is important as this is the dose used in Studies 1&2.   Additionally, mean losses for the entire 40 & 60 mg groups were less than 2%, and even the most promising responders, Caucasian hypersecreters with above median CIR, only lost an average of less than 4% over 6 months.

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Lessons from LIRKO

The LIRKO mouse has no insulin receptors in its liver.  It's one pretty sickly mouse.  In most studies it becomes hyperglycemic and hyperinsulinemic very early in life, but by six months or so of age is either normoglycemic or hypoglycemic.  Despite the concurrent hyperglycemia and hyperinsulinemia, the LIRKO remains normal weight, it is even a bit underweight if anything.  This is despite the fact that  circulating free fatty acids (FFA, or my preferred acronym, NEFA)  are suppressed by 40%.  {Here are the two papers I've discussed in previous blog posts: Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction , High Circulating Leptin Receptors with Normal Leptin Sensitivity in Liver-specific Insulin Receptor Knock-out (LIRKO) Mice both links are to free full texts}

LIRKO presents two problems for the TWICHOOB:

1.  Chronic hyperinsulinemia does not cause rampant fat accumulation 

2.  Insulin "locking away" fats does not lead to hyperphagia (overeating)

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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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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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Insulin Doing Its Thang! And Still No Starving Cells

In comments yesterday, Wayne/ProudDaddy wondered whether triglycerides might be the bad guy instead of NEFA based on this study from Keith Frayn's research group: Adipose tissue fatty acid metabolism in insulin-resistant men.

Aims/hypothesis  Increased NEFA production and concentrations may underlie insulin resistance. We examined systemic and adipose tissue NEFA metabolism in insulin-resistant overweight men (BMI 25–35 kg/m²).

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More Bloggo Science

Sigh.  I would normally comment on a person's blog if I read something like this:  Insulin, the Un-dead and coffin nails, but since Peter doesn't want to distract his readership with potentially productive discussions amongst them, I refrain from posting there.  In the article he makes two statements I find rather outrageous:

Hyperglycaemia causes insulin resistance. This is not controversial, as far as I am aware.

It's not controversial in those circles who repeat it uncritically.  It's not really controversial that this statement is wrong.    Let's take this together with another statement:

Let's summarise. This is very, very important:
   Excess insulin causes insulin resistance
End summary.

This is just day to day internal medicine. You have to pay the mortgage somehow.

Only this too is at the very least controversial, and almost certainly not true in most cases.
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Fasting Insulin & Diet ~ Time for some Cognitive Dissonance?

Reader Josh brings this study to our attention:

High saturated fat and low starch and fibre are associated with hyperinsulinaemia in a non-diabetic population

Huh?  They compared dietary intake (24 hour recall) for 1069 non-diabetics (assessed by administering a glucose tolerance test) with fasting insulin levels.  

Subjects were seen for up to three visits from 1984 to 1992. A 24-h diet recall and fasting insulin concentrations were collected at all visits....

... High total and saturated fat intake were associated with higher fasting insulin concentrations after adjusting for age, sex, ethnicity, body mass index, waist circumference, total energy intake and physical activity. Dietary fibre and starch intake were inversely associated with fasting insulin concentrations....

... Associations were similar in men and women and for active and inactive subjects, though associations of fibre and starch intake with insulin concentrations were strongest in lean subjects. 

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Gary Debunks Taubes ~ It's the Fructose Stupid!

The Marquee:  

Gary Debunks Taubes ~ It's the Fructose Stupid!

Starring Gary Taubes

Special guest appearance by Stephan Guyenet

The Scene:

Curtain rises

Gary Taubes, clad in grey corduroy pajamas and bunny slippers is in the basement of his home, that he has fastidiously transformed into an exact replica of the lecture hall where he infamously confronted Stephan Guyenet, PhD.  At the lectern stands a life-sized voodoo doll bearing a striking resemblence to Stephan.  While poking imaginary pins into the doll ...

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24hr Profiles: Insulin Secretion & Clearance in Normal and Obese

In this post I want to discuss two companion studies from the late 80's looking at twenty-four hour profiles of insulin secretion, uptake by the liver, glucose levels, etc.  The studies are available at the links below:

(I)  Quantitative Study of Insulin Secretion and Clearance in Normal and Obese Subjects

(II) Twenty-Four-Hour Profiles and Pulsatile Patterns of Insulin Secretion in Normal and Obese Subjects


Participants:  All non-diabetic with no family history of diabetes.  Age, weight, BMI are group averages.

14 normal weight:  7M/7F,  age 38.5 yrs, weight 70.1 kg, BMI 23.0
15 obese:  5M/10F, age 35.8, weight 105.7 kg, BMI 37.0

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CICO vs. Regulation of Fat Tissue ~ Questions for Gary Taubes

In an interview with Andreas Eenfeldt (some time in 2010, uploaded by Eenfeldt 3/15/11), Gary Taubes makes the following statement (~3 minute mark is a good place to start):

Look it's 2010 we have a disorder of excess fat accumulation, and people are saying that the actual physiological regulation of fat tissue is irrelevant. 

One point Stephan made in his retracted response to Gary's recent blog post needs to be addressed.  So I'll  do so here.   Folks have been letting Taubes get away with this for a very long time, and that is his indiscriminate use of the word "regulation".   The core principal of TWICHOO (Taubes Wrong Insulin-Carbohydrate Hypotheses of Obesity)  is that insulin is the primary regulator of fat tissue metabolism, and thus fat mass.  He's actually ratcheted that up a notch so that in his view insulin acts as virtually the sole regulator.  

I'm going to use a computerized multi-fuel furnace with a fuel tank system depicted below to make my analogies.

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You're as Hyperinsulinemic as You Need to Be †

Recent comments by Todd Becker (Getting Stronger blog) have prompted me to write yet another post on the (infamous on this blog) Grey & Kipnis study.  Perhaps, part of the problem in discussing these issues is a failure to define what it is we're talking about.  For instance with IR, we have chronic/pathologic IR, glucose-sparing IR (physiologic, fasting/carb restriction), and postprandial IR (usually impaired glucose clearance following a high fat meal or large fructose load).  With hyperinsulinemia we can talk about basal insulin levels vs. postprandial insulin levels.  It appears to me, that if we combine the observations in G&K with those of the long term fasting study, with the hypothesis of G&K -- that diet can play a role in basal hyperinsulinemia and therefore contribute to obesity -- perhaps basal insulin levels are comprised of both a chronic component (I would suggest related to NEFA) and a more transient component due to the diet of the previous day(s).  

So, Todd wrote:   Forgive me if I oversimplify the argument in your above post:

1. Obesity leads to spilling of excess fat as NEFA.
2. Excess NEFA leads to insulin resistance in the tissues, including the adipocytes

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Revisiting the Fatty Diets & Diabetes Study ~ How to Make Mickey Fat or Fattier

In her piece over at MDA on the How Fatty Diets Cause Diabetes, Denise Minger spent a bit of time discussing the strain of mouse used in the study.  That being the not-uncute fella you see pictured here:  A C57BL/6J mouse.   Denise describes these mice as:  "uber-susceptible to obesity, high blood sugar, insulin resistance, leptin resistance, and all that other fun stuff plaguing modern humans."  This didn't really square with my memory from when I blogged on a study involving this critter.  Took me a few minutes to remember what that blog was ... Of Mice and (Wo)Men.  That post dealt with a calorie restriction study using this same mouse.  In looking for info on this mouse, I had come across this paper:  The High-Fat Diet–Fed Mouse.  Since I was mostly looking for info on lifespan and such at the time, the subtitle didn't "hit me", that being:  A Model for Studying Mechanisms and Treatment of Impaired Glucose Tolerance and Type 2 Diabetes.  The paper describes this mouse's propensity towards obesity (and IGT and T2 diabetes) when fed a high fat (58%) diet vs. a standard low fat (11%) chow.  However, in the calorie restriction study, these mice did not become obese on standard chow (11%F, 69%C, 20%P, Teklad Global 2016).  Therefore I think it would be more fair to say that they are susceptible to diet-induced obesity (DIO), but not obesity per se on a more appropriate diet.

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Grey & Kipnis ~ Hyperinsulinemia and Diet Paper

It appears that the website that formerly hosted the full text PDF of the Grey & Kipnis study I cite quite frequently here has been taken down.  I'm sad to see this.

I've linked to that hosted copy so many times it would be impossible to go back and change them all at this point.  Instead I'm posting this up if anyone ever needs to find the reference in an older post, and I'll use my new Google docs host link in all future posts.  

Here it is:

Effect of Diet Composition on the Hyperinsulinemia of Obesity

When Insulin Goes Away ...

The very core of LC theory on weight loss is that insulin *causes* fat accumulation through it's action, and basically if we can lower insulin, weight loss occurs.  Sounds simple and straight forward.

From Guyton & Hall's Textbook of Medical Physiology, 11th Edition, p. 966

Insulin Deficiency Increases Use of Fat for Energy

All aspects of fat breakdown and use for providing energy are greatly enhanced in the absence of insulin. This occurs even normally between meals when secretion of insulin is minimal, but it becomes extreme in diabetes mellitus when secretion of insulin is almost zero. The resulting effects are as follows.

Insulin Deficiency Causes Lipolysis of Storage Fat and Release of Free Fatty Acids.

In the absence of insulin, all the effects of insulin noted earlier that cause storage of fat are reversed. The most important effect is that the enzyme hormone-sensitive lipase in the fat cells becomes strongly activated. This causes hydrolysis of the stored triglycerides, releasing large quantities of fatty acids and glycerol into the circulating blood.  Consequently, the plasma concentration of free fatty acids begins to rise within minutes.  This free fatty acid then becomes the main energy substrate used by essentially all tissues of the body besides the brain.

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β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: Impairment in adipocyte-β-cell relationships

β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: Impairment in adipocyte-β-cell relationships

Yes, this is a rat study, but it seems applicable in light of the recent Diabetes "Crash Diet" Cure and the reductions in pancreatic fat seen in the study.  The study and the pancreatic fat issue were discussed here.  Summary:  11 diabetics followed a 600 cal/day diet for 8 weeks and regained normal insulin secretion and glycemic control.  The restored glucose induced insulin secretion (GSIS) was attributed to reduction in pancreatic fat content.

The investigators in the current study had this to say in the introduction:

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