Insulin Resistance II ~ The Complexity of "Hormone Resistance" Phenomena
It's been a while since Part I of this series ... too many irons in too many fires and all that jazz. But one research track I went down recently reminded me of this lingering series and I thought I'd finish up this second installment. We hear all the time truisms such as that the acute effects of a hormone differ from the chronic effects, and whenever a hormone is present in excess of normal levels, the term "fill in hormone here resistance" is sure to be close behind. Now there is no doubt that hormone resistance is a very real phenomenon, but what does it mean, specifically?
The concept of insulin resistance, IR, is highly complicated by the fact that insulin has varying actions in various tissues and organs. I do intend to discuss tissue-specific IR in more depth as this series unfolds. But for today, I am going to limit the discussion to insulin and the muscle cell. After all, when general IR is discussed, it is usually systemic or skeletal muscle insulin resistance.
In my opinion, a good, simple, definition for IR is when the dose/response relationship for any action of insulin is impaired. In even simpler terms, it takes more insulin to accomplish some action than is normally required. Or, at the risk of complicating things, another way of stating this is IR is when a normal dose of insulin is unable to elicit the appropriate response.
Skeletal muscle insulin resistance is almost universally measured in terms of glucose uptake rate. Skeletal muscle plays a significant role in "clearing" dietary glucose from the blood stream, so your standard oral glucose tolerance test, OGTT, is the usual test for muscle IR (hereafter just IR). An OGTT involves ingesting a 50-75g dose of liquid glucose and measuring BG levels for 2 or more hours following the test. Lingering elevated glucose levels are indicative of IR (although I plan to address other reasons in future installments). But this is already complicated by other contributing factors from the get-go.
Focusing on the muscle cell, however, we have quite a list of actions of insulin to further muddy the waters. In the muscle cell insulin:
- stimulates GLUT4 mediated transport
- stimulates glycogen formation (non-oxidative disposal)
- stimulates glycolysis (oxidative disposal)
- inhibits glycogenolysis
- suppresses lipid oxidation
- (stimulates de novo lipogenesis?)
IR can be a diminished response to insulin of any one of the 5 or 6 (the last one in parentheses is likely for significant overfeeding) actions above, several, or all of them. For example:
- are the insulin receptors "clogged" or otherwise indifferent to the insulin molecule?
- does insulin bind but not properly activate/stimulate transport?
- is transport slowed by impaired insulin action inside the muscle cell to dispose of the glucose?
- does insulin fail to act inside the cell to stimulate/suppress enzymes?
When one thinks of "resistance" they tend to equate this with some sort of built up tolerance. Indeed this is the general description of the phenomenon by various LC proponents. That chronically spiking insulin causes the cells to lose their sensitivity to the call ... sound familiar? This particular argument appeals to intuitive or "common" sense. Unfortunately, intuition can often fool us which is why the term "counterintuitive" is part of our vocabulary! Just because it sounds plausible, doesn't make it so.
In this regard the LIRKO mouse is the TWICHOOB's worst nightmare. LIRKO mice are missing insulin receptors in the liver only. Early on in life these mice become profoundly hyperglycemic and hyperinsulinemic, but they become neither obese nor classically diabetic (beta cell decline/insulin deficient). Later in life the hyperglycemia subsides as their livers "poop out" but the pancreas continues to pump out insulin. But here's how this relates to the topic at hand here:
Since we have previously demonstrated that mice with tissue-specific knockout of the insulin receptor in muscle still showed normal insulin tolerance, it is unlikely that the modest downregulation of insulin receptors in muscle could account for this finding. To test this proposal directly, we analyzed glucose transport in vitro in isolated soleus muscles from control and LIRKO mice. Basal glucose transport was not different between control and LIRKO mice (1.07 ± 0.14 μmol/g/hr in controls versus 0.98 ± 0.11 μmol/g/hr in LIRKO). Furthermore, stimulation of glucose transport by incubating the muscles in the presence of 33 nM insulin resulted in a 3.4-fold increase in glucose transport in muscles from both the controls and the LIRKO mice (3.64 ± 0.47 μmol/g/hr in controls versus 3.26 ± 0.36 μmol/g/hr in LIRKO). Taken together, these data suggest that a considerable portion of the decrease in blood glucose following intraperitoneal administration of insulin in mice is due to suppression of hepatic glucose output rather than an increase in muscle glucose disposal.
So while these same authors describe the LIRKO as exhibiting "dramatic insulin resistance, [and] severe glucose intolerance", what has just been described in the above paragraph indicates that these mice are not IR in the sense that IR is most commonly assessed. That is they don't exhibit any significant defect in either glucose transport rates or insulin's ability to stimulate glucose uptake.
What's my point here? Well mostly to point out the madness of it all! More specifically, how do we define insulin resistance (or "resistance" phenomena for other hormones like leptin)? Currently, hyperinsulinemia (or elevated hormone levels is the most "direct" clinical measure, although often FBG and/or OGTT glucose levels are substituted as surrogate. Clearly just looking at glucose levels for the LIRKO would misdiagnose muscle IR. So part of my reason for bringing this up is in preface to hopefully getting to teasing out some different versions of IR and/or diabetes that are unfortunately studied/discussed/treated together as if they are of one etiology ... when I believe it's all far more complex and this adds confusion on top of controversy. In many cases I think this has prevented well meaning folks from talking to each other rather than past each other (and I include myself in this group). But this also provides cover to those who are just talking in sound bites based on statements such as the characterization of LIRKO as extremely IR. It has allowed a myth (and I say this with a high degree of certainty based on over two years of looking into this very topic) to perpetuate that carbohydrate consumption causes insulin resistance by virtue of postprandial insulin spiking. It is a goal of mine to turn that myth on its head for once and for all.
While "femmes importantes" are now setting their sites on the "sins" of the great Robert Lustig...because, hey, that's what happens when you have no value to add to anyone, pretending instead you offer value by tearing down value...I'm off on a different track, and will continue to do so. It was fun engaging the cunt while it lasted.... Onward.
Maybe you should consider ditching all this science stuff that's like...work...and contribute something of value like a hot dog wrapped in a corn tortilla.
I think you're absolutely right. This happens all the time. My dad has had type 2 for about 15 years and has never had his insulin measured. They just test fasting bg and A1c quarterly and adjust medication. I think it's all about cost. Trying to figure out exactly what's causing the high bg is just too expensive. The A1c is good enough for most people, and I don't know if that will ever change unfortunately.
Sadly it probably is all about the money, and I'm getting more skeptical about this -- and cynical -- that part of the hysteria over obesity is scare monger over diabetes (the threshold for pre-diabetes was lowered arbitrarily by like 20 points in the early 2000's), get more people into the system and reasons for draconian legislation.
This is why I wish the anti-establishment wing of the movement would tone it down just a bit. After a point you come off as a tinfoil hat wearing whacko and now nobody knows what to take seriously anymore.
Researchers have found several variations each whith slightly different effects. When people with MODY are diagnosed as children they are often misdiagnosed as T1.When diagnosed later in life they are often diagnosed as T2. Metformin doesn't help as it is aimed at hepatic insulin resistance, small doses of sulphonylureas that stimulate insulin production do.
Genetic tests are expensive so a lot of people who might have it don't get them. They'e treated as T1 or T2. There are some recent cases of people misdiagnosed as children coming off insulin many years later.
Jennys page on MODY is http://www.phlaunt.com/diabetes/14047009.phpn
Going back to your point, I suspect that a significant number of the 20%of people diagnosed with T2 who are not overweight are also not insulin resistant. They may be MODY or LADA (a slowly progressing form of T1 in adults)
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