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


Gretchen said…
Clarification. The "gold standard" of IR is the clamp study. But it's time consuming and expensive (I had one done in a research study, and there were 3 MDs and a nurse working for about 4 hours with multiple IVs to do it). Hence the HOMA calculation, which only approximates IR, is often used in large research studies because it's cheap and they figure individual differences will average out.

Jenny Ruhl wrote a blogpost once (don't have a link) blasting HOMA. I think she went overboard, but I agree it's not 100% accurate. When I put my numbers into a HOMA program, they didn't agree with what the researchers got from the clamp study.

You can download a program that will calculate your HOMA if you've ever had insulin or C-peptide measured.
Tsimblist said…
"If you haven't yet read 'Insulin: understanding its action in health and disease', I cannot recommend doing so ASAP more highly."

Excellent recommendation. Thank you, Evelyn.
CarbSane said…
Thanks Gretchen & Welcome! Funny, I read your comment in my feed reader and thought to myself, did I use that phrase? Well, yep ... I did. Your clarification is correct. Is "standard standard" a phrase? ;) That is more what I meant ... that HOMA-IR is the most frequent diagnostic tool used to diagnose insulin resistance for the reasons you state. I'm going to edit my post but leave the comment in place so it doesn't sound out of place.

If I understand Jenny correctly, she never had much of an issue with fasting blood glucose levels with her type of diabetes though she has severe postprandial glucose spikes. Thus HOMA would probably be pretty useless for her type of diabetes. I think HOMA is more applicable to your standard "diobesetics" and perhaps the "metabolically obese thin people" -- which is the purpose of this and coming posts!
wow - thanks for the heads-up & link to that article on insulin. Question: some things really jumped out at me & made me wonder if these VLC people are inducing some form of diabetes in themselves by creating an insulin deficiency. Also, is the Jaminets' glucose deficiency actually an insulin deficiency - its just that they promote eating enough starch with a minimum of side effects (I'm afraid to use the word "safe" in & "starches" in the same sentence, lest I get tarred & feathered by angry crickets) in order to avoid an insulin deficiency?

in the article, they write: " states of relative insulin lack such as prolonged fasting, insulin concentrations fall low enough to allow release of sufficient gluconeogenic amino acids to maintain blood glucose in the normal range. The price for this is a gradual but progressive loss of structural protein." Q: Is this saying that when insulin is really really low, muscle tissue gets sacrificed?

"The magnitude of the hyperglycaemia is determined by the absolute rate of hepatic glucose production (Fig. 3) and this in turn is determined by the extent of, on one hand, the insulin deficiency and, on the other hand, the magnitude of the glucagon rise in response to insulin deficiency." Q: So these VLC people, by keeping their insulin levels artificially low, are actually artificially inducing conditions of hyperglycemia??

"...insulin deficiency itself leads to over‐secretion of the ‘anti‐insulin’ hormones glucagon, cortisol, growth hormone and catecholamines. This in turn aggravates the metabolic effects of insulin lack." Q: Wouldn't creating an "insulin lack" then lead to things like your hair falling out & feelings of being really burned out & lethargic?

"Once insulin deficiency develops this control is lost, and energy substrates are over‐produced and flood the system. The metabolic consequences result from the excess of substrates not (as is often misconceived) by a lack of energy substrate getting to the tissues." Q: If energy substrate can't get where it needs to be, would this mean you're tired all the time?

"As a result of lack of insulin in adipose tissue, lipolysis proceeds at an accelerated rate and this is further enhanced by over‐secretion of growth hormone and catecholamines." Q: Are they saying here that not having enough insulin in fat tissue leads to more of it being made?

Sanjeev said…
> Q: Is this saying that when insulin is really really low, muscle tissue gets sacrificed?
the insulin need not be "really, really low" - protein breakdown happens all the time and regularly gets higher between meals, after the insulin is mostly gone.

This is one reason bodybuilders take "anti-catabolic" drugs in addition to anabolics.
Sanjeev said…
> after the insulin is mostly gone.

but it definitely does not need to be "exceptionally gone", just the "normal low" between meals is enough.

Also, when one is exercising even in the presence of high insulin one is catabolizing muscle/mitochondrial/connective tissue protein.

You see muscle loss for example, with pro bike racers who can stuff themselves with thousands of calories of fat and starch and probably have high insulin for most of the race. Thousands means a lot in this context because most of those guys are light (to pedal up several mountains in a day one must be light).

If you read much of the sports nutrition research you see studies claiming "eating a lot of xxx during the effort reduced muscle damager markers over controls that consumed yyy"

... but nothing eliminates the markers completely

The simple act of using glycogen increases the activity of some protein-catabolizing enzymes in muscle tissue.
CarbSane said…
Glad you liked that ... I linked to that study a few times before ... perhaps I'll bump the general post from time to time b/c it's an important read IMO.

Sanjeev already answered a few Q's but here goes anyway:

(1) Yes, although I think it has to do with low glucose b/c your body must get precursors for gluconeogenesis from somewhere.

(2) Yes, again. Many LC'ers see their fasting BG's creep up. They also report that when they do eat carbs their BG's go disproportionately through the roof and take a long time to come down. It is standard lore to "carb up" for several days before taking an OGTT if one is a low carber.

(3) Stuff like that and less severe things as well. It's tough ... after a few years of eating a certain way, it gets ingrained (and top that with a big dollop of fatty dogma ...) and as health deteriorates you keep looking to something else. Lots have reported hair graying, lack of libido, lethargy, even -- gasp! -- hunger, etc. Of course it can't be the diet? Perhaps not ... but perhaps!

(4) I think the lethargy comes from energy excess forcing fat burning (the obese are quite good "fat burners", having lower RQ than lean -- lower means more fat less carb). So carb doesn't get used properly and the signaling to energy output is perhaps all outta whack.

(5) I don't think so. It's more that it will lead to fatty acids stored in non-adipose tissue.
Sanjeev said…
> despite pegging the HOMA-IR meter, the fat and muscle tissue of this mouse retain insulin action

I had to argue this point just last week.

Apparently there's a generalized idea that (the notion that high hormone levels lead to a reduction in receptors) is some kind of a law, not something one must establish on a per - hormone per- context- basis.
Galina L. said…
Sorry, guys, I am reading that blog in order not to be locked in a bubble of same opinions, but sometimes it is too much for me read that I suppose to be tired all the time with hair falling out, hungry and miserable because of ketosis, while opposite is going on. Probably, I need a break .
ProudDaddy said…
I'm hoping Evelyn (or you) will offer more insight into what is really happening in resistance phenomena. So, too, with the idea of "worn out" beta cells. Has anyone actually measured the number of insulin receptors in an IR cell or determined how many of same have already been clamped onto (my layman's word) and by what actual molecule (mimetic?)?

As you have already deduced, I've never read a textbook about such matters, and I would suspect most of Evelyn's readers haven't either. So, thank you for your contributions.
ProudDaddy said…
Evelyn: As you may note, I am re-reading this to prepare for your continuation of the IR series. (Sometimes I'm a good student.) To keep my misunderstandings to a minimum, would you comment on any parts of the Sonksen article that you might not agree with?

I found Fig 4 to be fascinating, both due to the small deviations (measurement?) and to the implications. How much insulin would a T1 need if they had no alpha cells?