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 ...

The "tired pancreas" theory, nonetheless gets cited in many ways and forms by "experts" and lay folk alike to describe their glucose intolerance and the like.  It sounds plausible, but the evidence just doesn't seem to support it.  The theory goes like this:  Consume lots of carbs → insulin spikes → insulin resistance and/or hyperinsulinemia → exhausted ß-cells can't keep up → diabetes and ß-cell death.   I've seen people liken their pancreas to ovaries -- basically women are born with so many eggs and when we use them up they're gone.  They harken back to their sugar laden pasts and postulate that they've used up most of their insulin so need to be frugal with what they have left.  Only this is not how the pancreas works.  

One issue complicating the matter may well be the irreversibility of Type 1 diabetes.  The T1 has no discernible proper ß-cell function because for one reason or another the cells have been destroyed.  These, at least with our current knowledge level, cannot be regenerated.  This leads to the misconception -- and it is a misconception -- that ß-cells are present in some limited quantity and dying off is a one-way street.  Nothing better illustrates the problem with this notion than the fact that ß-cell mass increases with increased insulin demand.  This is often referred to as compensation.  According to this  cite:

The number of islet beta cells present at birth is mainly generated by the proliferation and differentiation of pancreatic progenitor cells, a process called neogenesis. Shortly after birth, beta-cell neogenesis stops and a small proportion of cycling beta cells can still expand the cell number to compensate for increased insulin demands, albeit at a slow rate. The low capacity for self-replication in the adult is too limited to result in a significant regeneration following extensive tissue injury.

Cell cycling occurs when new cells (neogenesis) are created from progenitor cells, and old cells die by a process called programmed cell death or apoptosis.  Apoptosis is not necessarily a bad thing and occurs in our bodies all the time.   However under normal conditions it is signaled and occurs in a, as the other term implies, "programmed" fashion.  When something goes wrong, however, we can get premature or excessive apoptosis.  If cells are dying off (being killed off) at a faster rate than new ones can be generated,  ß-cell mass decreases.  But what of the compensation brought on by hyperinsulinemia?  Does this not use up those progenitor cells?  It appears that we have more than enough to keep making more.  The ultimate loss of the ß-cell mass seems to be excessive death rates that cannot be compensated for by neogenesis.  

If video killed the radio star (yeah, that song was on the Adult Retro channel the other day), and VHS nixed the Betamax, what kills the ß-cells?   All fingers seem to point to the free fatty acids, FFA/NEFA starting the whole thing, and glucose + NEFA combining to deal the ultimate fatal blow.  Something goes awry in our fat tissue metabolism leading to elevated circulating levels of NEFA, these in turn lead to increased fat accumulation in non-adipose cells or exposure of said cells to toxic levels of NEFA.

The normal pancreatic β cell response to a chronic fuel surfeit and obesity-associated insulin resistance is compensatory insulin hypersecretion in order to maintain normoglycemia. T2D only develops in subjects that are unable to sustain the β cell compensatory response. Longitudinal studies of subjects that develop T2D show a rise in insulin levels in the normoglycemic and prediabetes phases that keep glycemia near normal despite the insulin resistance (β cell compensation), followed by a decline when fasting glycemia surpasses the upper limit of normal of 5.5 mM (β cell failure) ... the natural history of T2D entails progressive deterioration in β cell function, associated with loss of β cell mass due to apoptosis. ... recent evidence points to [the time point in T2D development when β cell dysfunction first appears] being early, long before the onset of prediabetes, when glycemia is still classified as normal glucose tolerance.

This would be consistent with the progression of diabetes in the ZDB rats in the aforementioned post.  Only the rats destined to become diabetic saw the rise in FFA that preceded loss of glycemic control.  It may be that those predisposed towards diabetes have a lower threshold (perhaps somehow related to leptin production) for spillover.

This seems to be a somewhat two phased process.  First, a low grade lipotoxicity, if you will, impairs ß-cell function so that there is a reduced glucose stimulated insulin secretion response (GSIS).  This is where frank diabetes is diagnosed and impaired glucose tolerance.  Blood sugars soar after a carb load and/or take a longer than normal time to return to baseline.  However, at this point the problem seems to be more one of impairment vs. destruction.  (This of course being different from, say, autoimmune induced diabetes).  

The resultant hyperglycemia exerts it's own glucotoxicity, but there is a body of evidence showing that the combined glucolipotoxicity is what ultimately overpowers the cells and induces cell death, apoptosis.

Now, there's no denying that hyperglycemia causes deleterious effects on the body mainly via glycation.  But to me, glucotoxicity in and of itself can't explain the progression of ß-cell decline that is seen even in well treated and controlled diabetics.  If that was all there was to it, then blood sugar control -- whatever the means -- should halt the progression of the disease.  And yet, despite treatment, the majority of T2's do progress to requiring insulin a decade or so down the line as the ß-cell mass continues to decline.  Uncontrolled diabetics decline more rapidly, which is also consistent with the additive or synergistic nature of gluco and lipo toxicity.   However treating for potential glucotoxicity does not stop the effects of lipotoxicity.

I welcome challenges to what I'm about to say, because I certainly could be missing something here or oversimplifying things.  But the combination of the NEFA elevation preceding the loss of glycemic control and restored glycemic control not stopping further ß-cell degeneration both seem to point to the underlying pathology being the dysfunctional adipocyte function leading to elevated free fatty acids.  

So the title of this post came from the urgings of Dr. William - Wheat Belly - Davis in a recent post of that title:  

...if you’ve lived the life of most Americans, your pancreas has had a hard life. Starting as a child, it was forced into the equivalent of hard labor by your eating carbohydrate-rich foods like Lucky Charms, Cocoa Puffs, Hoho’s, Ding Dongs, Scooter Pies, and macaroni and cheese. Into adolescent years and college, it was whipped into subservient labor with pizza, beer, pretzels, and ramen noodles. As an adult ... [you listened to the autorities] ... exposing your overworked pancreas to keep up its relentless work pace, spewing out insulin to accommodate the endless flow of carbohydrate-rich foods. 

Wheat Belly (sorry, I just can't help refer to him by this humorous title ... note to self:  never write a book or produce a movie/DVD with a silly title as it just may stick to you!) continues with a goodly dose of what he's become known for of late:  unsubstantiated hyperbole.

So here we are, middle aged or so, with pancreases that are beaten, worn, hobbling around with a walker, heaving and gasping due to having lost 50% or more of its insulin-producing beta cells. If continued to be forced to work overtime, it will fail, breathing its last breath as you and your doctor come to its rescue with metformin, Actos, Januvia, shots of Byetta, and eventually insulin, all aimed at corralling the blood sugar that your failed pancreas was meant to contain.

Sigh.  

Or, you could put agenda and such aside and look at the research and realize that Byetta -- a GLP-1 incretin mimetic -- may actually work to prevent the decrease of ß-cell mass, perhaps even increase it!  

Wheat Belly goes on to describe your middle aged pancreas as "flagging", exhausted and barely capable of eaking out a drop of insulin.  Clearly a devotee of the old "tired pancreas" dogma.  He goes on to compare your pancreas to a car with 90K miles on it that you want to last to 100K miles.  Don't drive the thing basically and keep it well tuned.

Well, for the latter advice, it would seem that a tune up for the pancreas -- in keeping with the auto analogies -- might be to drain the sludge oil that's accumulated in the pancreas.  Rather than putting in a different fuel and perhaps changing the fuel filter.  If you're in the market for a used car, surely you don't want an old model with excessive mileage.  But you also don't want one that's been sitting around unused for months on end either.  

The truth of the matter is the analogy to an inanimate object is limited at best because our bodies are not only capable of repairing pancreatic islets, it happens routinely, albeit slowly.  What you don't want is to bust a valve (again with the car analogy) because then it goes nowhere.  

A dietary strategy to truly "baby" one's pancreas might include not overstressing it with massive quantities of highly refined carbs.  But there's no evidence, perhaps even evidence to the contrary, that using your pancreas wears it out.  To preserve function one should avoid excessive apoptosis and that requires minimizing potential lipotoxicity.  If you're among the ~80% of T2's with obesity-induced diabetes, weight loss (perhaps rate sensitive as may have been indicated by the Crash Cure) is imperative.  Get your level of adiposity below whatever threshold it exceeded to where spillover started the whole ß-cell demise to begin with.   

Give your pancreas a nice back massage .... Pay your pancreas a compliment or two ...

Weird. He does make one good suggestion -- an occasional fast.  Yes.  To drain the sludge.  

A note of disclaimer here:  I am not saying that LC diets necessarily contribute to lipotoxicity.  It would appear that the answer is almost a definitive "no" in the context of weight loss/caloric deficit.  But at least a "maybe" in maintenance at normal weight, and an almost assured "yes" (but to what degree) in maintenance in an obese state or while gaining weight.  It seems inconceivable that large fat loads do not contribute directly to NEFA levels (the inefficient trapping Frayn talks about), and the lack of a postprandial insulin response to the "unmixed" meal has been shown to both insufficiently suppress the postprandial NEFA release and elevate fasting NEFA.   A ketogenic diet has been demonstrated to increase fuel partitioning towards adipose accumulation accompanied by glucose intolerance in rats.   Several low carbers have reported worsening indications of IR and glucose tolerance, but those are just anecdotes.  Still ... I'm beginning to smell a rat ...