Insulin Resistance ~ Part I: A condition in dire need of diagnostic clarity

I've written many times about how we need some new disease classifications, names or something for the various conditions that are currently termed "diabetes".  This is because hyperglycemia -- the predominant symptom that garners a diabetes diagnosis -- can have many underlying physiological bases.   In this post I'm going to make the same case for the pathologies lumped together under the term "insulin resistance" (from hereon, IR).   The problem with discussions of IR are similar to those of diabetes.  In a nutshell, hyperglycemia is to diabetes as glucose transport/disposal is to IR.  Just as blood glucose is the myopic focus of many discussions of diabetes, so, too, insulin's role in glucose transport is the myopic focus of many discussions of IR.   

Let's begin with a diagnosis of insulin resistance.  The most commonly used single diagnostic parameter for this is something called the HOMA-IR.  This ratio is determined from fasting plasma levels of insulin and glucose.  From the link

HOMA-IR = (Glucose x Insulin)/22.5

The basis for this model was that elevated insulin with respect to glucose was indicative of reduced action of insulin, and elevated insulin and glucose is representative of insulin resistance.  Tis true.  But let's begin by what the HOMA-IR is actually assessing.  Fasting glucose levels are determined largely by endogenous glucose production, EGP, in the liver.  If you haven't yet read  Insulin: understanding its action in health and disease,  I cannot recommend doing so ASAP more highly.  It should be required reading!  In any case, one basic crux of that article is to demonstrate how the glucose-transport action of insulin has been over-emphasized, while it's inhibitory role(s) have been largely downplayed.  The hyperglycemia associated with Type 1 diabetes is due to unchecked EGP by the liver.  This is clearly apparent in the LIRKO mouse, a mouse lacking insulin receptors in it's liver.  The mice become profoundly hyperglycemic and hyperinsulinemic ... and are described as severely IR.  But are they?  Well, by HOMA-IR standards, yes.  Screamingly so.  For a while at least ...

The first lesson we can learn from LIRKO is that despite pegging the HOMA-IR meter, the fat and muscle tissue of this mouse retain insulin action:  insulin-mediated glucose disposal into muscles is similar in LIRKO vs. wild type mice, and free fatty acid (NEFA) levels are actually somewhat lower in LIRKO than wild type (as one would predict for hyperinsulinemia with sensitive adipose tissue).  Thus, the HOMA-IR assessment is (a) for the fasted state, and (b) more indicative of hepatic insulin action than whole-body or peripheral IR.   Further complicating matters, the LIRKO will see "improving" HOMA-IR scores as it ages.  That's right!  Because the livers of these poor mice seem to degrade rather quickly and can no longer keep up with the unrestrained EGP.  Fasting glucose declines to normal by 2 months, and falls below normal by 6 months while the hyperinsulinemia persists.  Nobody would argue that the LIRKO mouse is becoming more insulin sensitive as it ages ...

It becomes clear quite rapidly that IR is in desperate need for some clarified terminology.  Because when someone is diagnosed as IR, this probably means they have hepatic IR based on a HOMA score.   While there is considerable overlap between those with impaired fasting glucose (IFG) and impared glucose tolerance (IGT), either condition can exist in the absence of the other.  IGT is another measure of IR -- those who exhibit delayed clearance of glucose from circulation have skeletal muscle IR.  Here, IR is measured solely on the basis of glucose clearance from circulation (and in in vitro tests, glucose uptake into cells from the medium).  The mechanistic underpinning of IGT is rarely assessed.  Here, again, LIRKO teaches us a lesson.  The LIRKO mouse exhibits "pronounced glucose intolerance" as determined by abdominal glucose injection and measuring plasma glucose through two hours.  Were a human at the doctor's office to respond to such a test in similar manner (this time oral delivery is conventional, the OGTT), this would elicit a diabetes diagnosis.  But LIRKO's hyperglycemia -- even in the postprandial state -- is not attributed to reduced clearance into the usual sink of muscle cells, but yet again to unchecked EGP.  LIRKO is not whole-body IR or skeletal muscle IR or peripheral IR.  

We have a serious problem here and it certainly clouds every aspect of this and related subjects.  We often talk past each other, because a singular term, IR, is used broadly to describe so many different conditions and mechanisms.  I contend that even with all the various types of diabetes, the problem is many-fold worse with IR.     This is because insulin secretion occurs in response to different stimuli in different ways.  Said insulin mediates several processes by various actions.  Insulin action in different tissue/organs can be impaired to different degrees and by differing mechanisms.  By my fundamental counting rule, we've got literally thousands of possible underlying pathologies that can be included under the umbrella of IR.

Stephan Guyenet posted a nice series on What Causes IR:  Part I, Part II, Part III, Part IV, Part V, Part VI, Part VII.  This has elicited a flurry of comments both on his blog and in rants about the net, many of which are in defense of dearly held beliefs on IR courtesy of Taubes & Co.  While there will always be some differences -- after all, there remains much about IR that is unknown -- it appears that many disagreements aren't really disagreements at all.  So, for example, when Stephan talked about overnutrition and IR, most of the complaints came from those talking about another type of IR.  Another example is a discussion I became involved challenging the TWICHOO view that fat tissue loses its insulin sensitivity last.  The MIRKO mouse supposedly demonstrates this because you knock out muscle insulin receptors and glucose uptake and fat synthesis in fat tissue increases in this mouse and it gets fat.  This tells us nothing about the progression of IR because nothing was done to this critter to alter its fat cell insulin receptors, and the muscle cell receptors were altered permanently and completely by genes.  There's no degenerative disease, diet induced or otherwise, that I'm aware of that mimics this.  I'll have a lot more to say about knockouts sometime soon.

What prompted this post is a study that Gretchen cited (no full text available online) that looked at glucose uptake by fat cells in lean vs. obese mice.   It was sort of a tipping point for me to dust this off and put it out there rather than try to make my points in the comments section on someone else's blog.  Basically, the study looked at glucose uptake and utilization.  Obese rats had impaired uptake into muscles but increased uptake into fat cells.  Therefore, we should conclude that muscle IR precedes adipose IR.  I'm not sure we can ever isolate a singular progression of IR, but my money's on something -- whether it's technically IR or not -- initiates in the fat tissue before skeletal IR (as measured by impaired uptake/disposal) manifests itself for the vast majority of lifestyle-induced IR states -- adiposopathy -- "sick fat" -- a term that has fallen a bit out of favor in peer-review circles.  There's far more ambiguity as to whether this comes before, after, in concert with or independently of impairment in the liver.    Lots and lots for other days and future installments.

Here are the issues that need clarity as I see them, although the organization moving forward will not necessarily follow these bullet points:

• Fasting v. postprandial levels and responses
• Assessing single time point vs. several hour exposure levels (AUC)
• Isolated tissue IR (or at least dominated by one tissue) -- brain, liver, adipose tissue, muscle, etc.
• Conditions produced by insulin action/inaction in various tissues
• Underlying mechanisms of the pathological blood levels of insulin, glucose and lipids
• Genetic/Inherent (neonatal, developmental) IR vs. lifestyle IR -- what we can or cannot really change

---

In Part II, I'm going to discuss the implications of the main diagnostic determinants of IR and the drawbacks of these tests.

---

A note to readers:  My regular readers are likely aware that I tend to jump around a lot.  Often topics come up  that take precedence or hit a nerve of sorts on the ideas floating through this noggin of mine as I read the many many peer review studies that I do.  While I may have appeared to have abandoned one topic for another, it's always in the back of my mind to get back there.  This topic has been forming in my head for well over a year now so I figured it was high time I put the stash of half-baked posts together, polished and improved upon them, and got them out the door here.   I'm working on a summary page where I will post links to series here at the Asylum -- past and present -- so new and old readers alike can follow along despite the -- often long -- breaks in the action.  Thanks for bearing with this quirk of mine :-)

Click here for Part II