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 where it is repeated 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
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.
Peter loves the FIRKO mouse. Knock out the fat insulin receptors, and mice are obesity resistant. This is all he needs to know about fat tissue regulation and insulin's role. Now LIRKO, not so much. I discussed that in LIRKO Wars. That is a rather long post, and I can't help the snark, Peter really brings it out in me with his presentation of "facts". So the Cliff Notes version is that the LIRKO mouse, one without liver insulin receptors, becomes profoundly hyperinsulinemic and hyperglycemic, though the latter outcome fades as the mice age. Remarkably, LIRKO are not obese!! Houston, there's a problem aboard the SS TWICHOO! Now Peter has given convoluted explanations for why this is the case and TWICHOO still rules, but none passes either the smell test or a modicum of scrutiny paid to the full texts of the studies he cites.
You see, the LIRKO mouse remains essentially insulin sensitive in both muscle and adipose tissue despite being described as IR. It stated so in one of the papers Peter likes to cite:
... 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 ... stimulation of glucose transport by incubating the muscles in the presence of 33 nM insulin resulted in a [similar] 3.4-fold increase in glucose transport in muscles from both the controls and the LIRKO mice.
In other words, measured directly, glucose transport and insulin action are not impaired by either elevated insulin or the hyperglycemia. Therefore, in LIRKO:
hyperinsulinemia does not cause IR, and hyperglycemia does not cause IR, and
hyperinsulinemia + hyperglycemia still does not cause IR
If it did, one would also expect this to progress with age as the cumulative effects of excess insulin and glucose did more and more damage. Not the case. Before they kick the bucket, these mice actually become more normoglycemic as their livers start to give out while their beta cells hum happily (well maybe not happily) along. These mice, while mutant, establish physiologically relevant elevated levels of glucose and insulin, endogenously produced by "natural" means. They do so far in excess of the contribution of dietary carbohydrate in a normal mouse. If anyone can explain how this is consistent with hyperinsulinemia/hyperglycemia causing IR I'm all ears.
If we put too many more nails in the coffin it might lose structural integrity.
Regardless of what else is manipulated by genetics or environment, obesity will fail to occur if fat tissue insulin receptors are knocked out. This means to say, no matter WHAT scientists do to a rodent's brain, liver, muscle, or what they feed the rodents... if insulin signalling in fat tissue is terminated via receptor knockout, obesity CAN NOT occur. Manipulations to other tissues only determine what happens in lieu of obesity, but obesity NO LONGER BECOMES AN OPTION if FIRKO condition is present.
If you answer false, I would appreciate evidence of a FIRKO rodent that was able to be made obese. Even a hypothetical scenario of how this might occur would suffice.
If you answer true, please explain how this logical conclusion is consistent with the notion that insulin signalling in fat tissue is incidental and reactive and not that important to determining body fatness? Please explain how insulin signalling in fat tissue is not a prime candidate for understanding and controlling obesity, if we have already agreed that preventing insulin signalling in fat tissue will totally prevent fat gain?
IF you don't feel like answering the second part, just a true or false to question 1 will do.
2. Because all humans save type 1 diabetics have basal insulin levels enough to via ASP store fat. Furthermore there is no way to eat which does not provoke an insulin response. And lastly low-carb would be much more effective if insulin was the main player.
I was shocked when Dr. Oz recommended a snack made with agave syrup. I had seen a previous program by America's representative of the medical industry in which he revealed the hazards of agave syrup as a new source of fructose. Now he just skipped over the use of this fructose syrup as a "natural" sweetener, even though it is even less healthy than high fructose corn syrup, HFCS. There seems to be a lot of deliberate confusion about sweeteners and since I am trained as a carbohydrate chemist, I will try to tell it as I see it.
Carbohydrates are not needed in your diet, since your liver can make all the blood sugar that you need from fats and protein. Most diabetics can benefit from a low carbohydrate diet.
Glucose, the blood sugar, is primarily responsible for turning on insulin production, so sweeteners (glucose, sucrose, HFCS, corn syrup) or dietary carbohydrates (starch, e.g. cereal, rice, pasta, potatoes, bananas) that are readily converted to glucose, cause blood insulin levels to rise.
Fructose in any form (HFCS, sucrose, agave syrup) contributes to liver damage. Fructose is the most chemically reactive sugar.
Artificial sweeteners, especially in soft drinks, do not contribute dietary calories, but they apparently increase insulin production and contribute to hunger, eating and obesity.
Insulin production removes glucose from the blood, i.e. lowers blood sugar, by increasing glucose transport into fat cells. If glucose is in your blood, but insulin is not present, e.g. type I diabetes, then you get thin. If glucose is in your blood and insulin is present, then you get fat. If you are fat and glucose is still high in the blood and insulin is present, then the fat cells will die unless they shut off the insulin response, i.e. insulin resistance. Lowering the amount of carbohydrates, sweeteners/starch, in your diet makes it easier to control blood sugar levels and avoid hunger.
Decreasing dietary carbohydrates means that calories have to be present in some other form and the answer is saturated fat. Most polyunsaturated fats, e.g. vegetable oils, except olive oil, are not healthy. The fats in meat, butter, eggs and coconut oil are the healthy choices supported by the biomedical literature, and along with vegetables, form the foundation of a healthy, anti-inflammatory diet.
I can tell you haven't been around this forum much.
"Lowering the amount of carbohydrates, sweeteners/starch, in your diet makes it easier to control blood sugar levels and avoid hunger."
Remember that quote; it is the most important aspect of low carb (and maybe the only important thing) that you need to know. Chuck the rest.
Can everyone agree that one will not put on fat if calorie intake is lower than expenditure (I don't mean just exercise here-total expenditure) no matter what macro is consumed or how much insulin is present? Take in 1000 cal of sugar and you will lose fat, not gain it, if your expenditure is 2000 cal (or 1500) even if you are a diabetic or just IR or whatever (You will get profoundly ill and die of malnutrition, but you won't get fat!) Insulin is NOT at the base of the fat loss/gain pyramid, consumption is. Why do we keep trying to rehash how insulin will make us fat when a calorie surplus must be present to do so? How in the hell does insulin make us fat when the obese and diabetics and people with IR improve and generally return to normal on a calorie restricted diet with plenty of carbohydrates? Where does insulin fit in here? It really doesn't, unless calories are too high (over expenditure), and then it still doesn't.
Remember, no matter what: cardiovascular collapse, shock and death is a result of more blood leaving the body than staying in. Injury is not the cause of death. As long as you micromanage your cardiovascular system with modern medical technology you can be a hemodynamic stability success story.
It's like dieting. If you obsessively focus on not eating and forcing your lethargic POS body to move, you will be somewhat less unsightly looking (no, not thin... just semi less fat). Therefore, CICO, and insulin is reactive to obesity. LOL.
Oh and thomas, calorie restricted diets ALWAYS lead to profound reductions in insulin, even if carbohydrate is not reduced ;)
Here's another shocking FACT!
A low carb diet might raise insulin, if you eat fourty millionty calories worth of butter. Thus jimmy moore keeps gaining weight.
1. The FIRKO mouse is like any physiological condition in humans
2. You can "FIRKO-ise" a mouse by putting it on a ketogenic diet
3. Lowering postprandial insulin response through diet has any effect on insulin receptors on adipocytes
4. Human obesity has been tied to excessive insulin receptors on adipocytes
5. Insulin receptors are the only thing you can knock out in adipocytes to prevent obesity
Building on #5, are you aware that if you knockout the precursor to ASP (C3KO -- http://carbsanity.blogspot.com/2011/09/fat-tissue-regulation-part-ii-meet-c3ko.html, http://carbsanity.blogspot.com/2011/09/fat-tissue-regulation-part-iii-c3ko.html) or the ASP adipocyte receptor (http://carbsanity.blogspot.com/2011/10/fat-tissue-regulation-part-v-c5l2ko.html) you produce mice with fat tissue comparable to that of FIRKO? (http://carbsanity.blogspot.com/2012/04/fat-tissue-regulation-part-viii-c5l2ko.html)
Nobody, but NOBODY, denies that insulin plays a role in fat tissue metabolism. But postprandial insulin levels, for the purpose of regulating circulating metabolic substrate levels, are not dominant in the 24 hour period. The very fact that most obese have both elevated basal insulin levels AND elevated circulating free fatty acids AND elevated triglyceride stores in muscle cells, should be enough to put this notion that insulin is the be all and end all.
Would you agree that proper insulin signaling should be the goal? From what I've read from you, it would appear not. You seem to believe that the less insulin signaling the better ... or am I reading you wrong?
Blaming insulin for doing what it's supposed to do is like blaming the fire service for making your house wet.
The next time your house is on fire, don't phone the fire service and see what happens. You won't get a wet house.......
Insufficient insulin => Skinny.......corpse.
If only our internal environment were as concerned about weight gain as it is about weight loss; I'm not convinced. The mechanisms that help prevent weight gain (including leptin signalling) are weak in the presence of continuous calorie intake (which is far more common these days than it has ever been), much stronger in the presence of a starvation environment; just look at how often people eat out vs. the not too distant past. Continuous huge calorie overloads! I believe our body fat regulation mechanisms (particularly leptin signalling)are more for slowing the consequences of lack of food, not preventing the consequences of over-consumption.
So, in today's environment, to be a "metabodynamic stability success story", our volition comes in to play (at least for most) big time. It sucks, but it could be worse.
over @ chez Stephan our good friend "john", aka "magic metabolism cue ball" just claimed that many do deny it ... I wonder who he could mean?
I had a response all typed up but decided not to hit "post" because it was just SOooo argumentatively over the top. I always feel so bad putting that type of comment on Mr. G's forum, considering his own unflappability
Most of us who utilize and promote low carb diets view it as a method of managing postprandial insulinemia, and promoting body fat oxidation rates that are consistent with healthy body fat level... without necessitating white knuckle hunger through hypoglycemic / low FFA episodes and fatigue. IT is a therapy for specific people who might benefit.
Low carb is very effective for many truly obese people. I pretty much cured my obesity with it. Not everyone benefits. Find me one person who can say the same thing about a calorie restricted diet - that as soon as they restricted calories something clicked and their body worked properly? Or fat or protein?
1 - A lack of excessive fat tissue signalling is rather like normal obesity resistant humans, and very much unlike humans prone to unstable blood sugar often associated with obesity (where there is periodic excessive insulin signalling, and symptomatic rapid drops in blood sugar/FFA).
2 - I agree, but ketogenic diets can be effective therapies to manage a tendency to postprandial hyperinsulinism, associated with obesity/ reactive hypoglycemia. It can also manage hyperglycemia of IR by not requiring suppression of hepatic glucose as much/often.
3 - True. There is some evidence hyperinsulinemia promotes insulin resistance. Insulinoma patients are profoundly IR for example, which is a direct effect of hyperinsulinemia. They sometimes develop diabetes and almost always gain a lot of weight. This in spite of the fact no metabolic disorder existed prior to the neoplastic hyperinsulinemia.
Insulin excess is just frankly bad. Insulin is a sympathetic stimulant that can lead to hypertension and sodium retention, which is why high blood pressure is a ubiquitous sign of metabolic syndrome and one of the first things to improve on carb restriction (sudden decline of insulin -> low BP and sodium/fluid wasting). There is some evidence it may accelerate aging. The lowest healthy insulin measurements are probably best. Insulin deficiency is bad. Similar to low weight being a sign of health, but being sickly and emaciated is bad.
4 - No, but skeletal muscle insulin resistance will result in hyperinsulinemia, with (sometimes) a net effect of greater partitioning of energy to fat tissue / increased appetite just to supply other tissues with minimal energy substrate. My appetite follows my energy level, no exceptions; high energy = low appetite and low appetite = high appetite. ENERGY is the most important arbiter of caloric intake, in my extensive experience as a fatso in remission.
A greater partitioning of consumed nutrition to fat tissue is typically the result of insulin resistance, because of chronic hyperinsulinemia required to achieve glucose oxidation. An obese person has insulin resistant fat tissue relative to a lean person, but it is less resistant than other tissues, with the net effect of less energy produced (fidgeting, movement) and greater body fatness/appetite.
Keep in mind not all obesity is the same, I don't think I am particularly insulin resistant but rather have a hair trigger insulin production which can be excessive and promote easy hypoglycemia. I have no signs of IR and all signs of a tendency to hyperinsulinism. It is possible to have one w/o the other.
That an untreated type 1 diabetes still results in uncontrolled lipolysis/ketogenesis in spite of ASP being dandy, ought to suggest ASP is ultimately insulin's prison punk. So then we arrive at a situation where, again, the fatness problem is ultimately insulin signalling in fat tissue. This is the only condition that can produce uncontrolled fat loss - NO MATTER WHAT ELSE is changed. More ASP, less ASP, doesn't matter if you don't have insulin.
Again, we need to separate the insulin hypothesis from the CIH. They are not the same. Lots and lots and lots of things affect insulin other than carbs. Eating a lot of dietary fat promotes glucose intolerance and higher insulin and weight gain. Duh.
Another example: Taking sympathetic stimulant drugs leads to greater fat oxidation, with loss of weight lower appetite but higher blood sugar often being observed (not to mention the more pertinent risk of cardiovascular complications sometimes fatal). The higher blood sugar of sympathetic stimulant drugs is a direct result of ramping up fat oxidation and lipolysis. Fat tissue is basically saying to insulin: "F*CK OFF INSULIN, I have fat to liberate and oxidize now with all this CAFFEINE in my body! hahahaaa". End result, a higher glucose, but crazy loss of weight and energy.
OTOH, suppressing sympathetic nervous system activity to fat tissue leads to greater weight gain. Beta blockers for arrhythmia and high blood pressure lead to weight gain metabolic syndrome depression fatigue and hypothyroid-like symptoms. This is all related to the SNS gimping. You have made the SNS now impotent; it is the polar opposite of taking ephedra or caffeine or any diet drug. These beta blocking drugs are noted to be shitty to take, and can cause an opposite health risk problem of bradycardia (sort of the opposite of the kid who drank 2 redbulls and has heart pounding out of their chest).
This being true of SNS drugs does NOT mean the SNS Is superior to insulin, or equally important to insulin, or somehow DISTINCT from insulin. It just means it is important, contributing factor to body fatness, another thing that modulates fat tissue insulin signalling. However, ultimately, these divergent effects of sympathetic modulating drugs are only so by modulating insulin activity in fat tissue. The crazy high sympathetic action in fat tissue makes the fat tissue tell insulin to "talk to the hand". Fat is oxidized at a higher rate leading to glucose elevation. Fat tissue IR + generalized suppressed glucose oxidation is the result.
Regarding insulin signalling, yes, proper insulin signalling is the goal. No resistance in muscle, with greater sensitivity in fat. No crazy high levels after eating paleo friendly potatoes leading to a 160 -> 60 in a hot minute sort of situation.
For almost all of us with fatness and blood sugar problems, "less insulin signalling" is pretty much redundant with "proper insulin signalling".
You don't seem to understand insulin problems are more complex than eating too much/not moving enough. You seem to have bought, hook and line, the dogma that insulin is always neutral and reactive to expanding adipocytes and overnutrition. Sad.
For some reason you become upset when I say you believe in gluttony/sloth hypothesis, even though everything you say is the same old gluttony/sloth CICO bullshit. I guess it's kind of like when a racist says racist crap, but gets upset if you call him a racist, because he simulataneously wants to feel progressive and socially acceptable while believing "the other" is inferior?
In so far as metabolic disease and obesity is concerned, a better analogy would be a very corrupt police/fire department that harrasses citizens, commits crimes against them, and sprays water all over your property for no reason, for fun and entertainment at your expense. A disregulation of social order.
This is how insulin acts when your blood sugar zig zags after perfect paleo potatoes.
You seem to be unaware or in denial of the medical fact that postprandial hyperinsulinism is real, promotes abnormal hunger/lethargy for many fatties out there, including myself? GOt the blood sugar tests to prove it, but oh, don't forget, champion of knowledge and light Stephan Guyenet will inform you that having your blood sugar go from 140 -> 60 in a few minutes won't make you hungry.
"post-prandial hyperinsulinism is real" "got the the blood sugar tests to prove it"
I'm confused, surely one needs the post-prandial insulin tests to demonstrate it. I know I would.
While diabetic doctors claim that BS tests are a surrogate for insulin response, I would require concomitant blood-insulins with blood-sugars in an OGTT.
1. "Like" in some nebulous fashion is not "is". There is no physiological condition in humans analogous to FIRKO or the opposite FIROO (O = overexpression).
2. Postprandial hyperinsulinemia is most often the result of obesity not the cause. Too many people associate ppHI with glucose spikes and have never had it measured. If low carb works for you to manage blood glucose levels that's great, but it's not FIRKO-ising you.
3. Yes, insulinoma and hypothalamic lesions lead to HI that can lead to IR which appears to be related to reduced non-oxidative disposal of glucose due to perpetually topped-off glycogen stores. However the development of IR cannot be separated from being caused by weight gain. It's Lustig's experiment without a syringe. Overload an otherwise normal person with inappropriate amounts of insulin -> hypoglycemia = hunger = eats a lot -> gains fat. LIRKO has unchecked gluconeogenesis, so no hypo = no hunger/hyperphasia = normal weight.
Excess insulin is not a good thing, but in certain situations, without it, you'd be in far worse condition. Indeed part of the reason many obese are HI is because their body is trying to keep fat stored where it should be. Low insulin + obesity = ectopic fat + lipotoxicity. Are you aware of the body of evidence out there that insulin is both a vasodilator and anti-inflammatory?
4. Are you aware that GLUT4's are downregulated in adipose of systemically IR individuals?
"Keep in mind not all obesity is the same." Really? You could have fooled me, because you use your own outlier experience as proof of everything about obesity. You are probably genetically predisposed to obesity from an inherent endocrine disorder. About 2-3% of all humans seem to be. I don't see the benefit of trying to convince the 30% or so that now find them obese that they, too, are.
However you are correct, you can be HI w/o being IR and vice versa, and I should be more cautious with comments composed in a rush to avoid absolutisms at the expense of wordiness.
5. This is an example of why constructive dialog is so difficult with you. If you want me to read and thoughtfully respond to your lengthy comments, the least you could do is read the links I have provided. I'm routinely bombarded in my Inbox by emails saying "have you seen what Wooo said you wrote lately", and 9 out of 10 times it demonstrates you didn't actually read what you're ranting against. The third link demonstrates that you get the SAME phenotype if you knock out just the insulin receptors, or just the ASP receptors. ASP stimulates insulin, insulin stimulates ASP. Neither is the other's bitch it would appear. You cannot seriously discuss fat tissue metabolism and regulation by only discussing insulin. That is the fatal flaw of Taubes' version of Adiposity 101.
Not all roads go through insulin. There is no FFA deficiency in the obese.
"It is also worth mentioning a lot of things that lead to CRAZAY weight loss/gain resistance in mice don't translate to humans. "
Ahhh yes ... FIRKO is relevant because there's no such analogous condition in humans. But ASP is probably just a rodent thing despite the fact that there's a wealth of peer review literature on its action in humans. Again, you're surmising and guessing when most of this has been studied and the results known.
Not all people with fatness have blood sugar problems. You are describing reactive hypoglycemia. Were you ever diagnosed with it? Ever have an OGTT where they measure blood sugars and insulin levels? As part of the leptin trials perhaps?
I doubt any further responses from me will change things, so I probably won't respond unless there's something new under the sun.
They are also more complex than you seem to be willing to acknowledge.
Exercise improves insulin sensitivity, carbohydrate improves insulin sensitivity, over nutrition is involved in hyperglycemia, dietary fat can negatively impact insulin sensitivity, most people who consume appropriate volumes of unrefined carbohydrate do not experience hyperglycemia [even if they are overweight], etc ad so on into the distant horizon.
You seem unwilling to acknowledge any evidence contrary to your weight loss experience as valid and you seem unwilling to concede that two years of trade school provides only a very rudimentary grasp of biology. Is that class warfare? If it's irrelevant how extensively someone has studied any given subject then why continue to bring your own training and clinical experience into the equation as evidence of your own credibility and refer to the ignorance of others when they disagree? You can't have it both ways.
I'm willing to consider the role of insulin [or glucose sensitivity] but it's got to be in way that respects the big picture and is congruent with at least most of the evidence at hand. High carb raw vegans are notoriously crazy lean. Leaner in general than I personally think is healthy or attractive. This includes people who were previously very obese. Low carbers are notoriously overweight in general, the exceptions are exceptions. An easy reference would be any social gathering specific to that dietary philosophy so low carb cruise compared with whatever the 30 BAD crowd calls their "go team" meet ups.
If you were trying to decide which diet had a better rate of success purely in regard to fat loss with LC cruise on one side of the room and 30 BAD on the other it would be a no brainer. That's about the time LCers start to evade and obfuscate and bring other health concerns into the picture because when it comes to fat loss they are behind the power curve in a big way and they know it.
This is not an argument for high carb raw vegan btw, just using the example for the purpose of perspective. If the insulin relationship was so cut and dry there would be no still obese low carbers. Their hyperphagia would disappear but for a lot of people it doesn't. If the sensitivity to glucose or insulin was so simple then people would not be able to improve their markers by eating high carb *yet they do* while low carbers see their glucose sensitivity/insulin resistance deteriorate.
There are more moving parts [and obviously so] than you seem willing to acknowledge so it's a little like trying to have a dialogue with the borg. Things are the way you say they are even if there is clinical evidence stacked up to the ceiling that disagrees, resistance is futile.
I'd love to hear your take on the broader picture, it'd be entertaining at the very least, but more interesting to me is how those biological responses might line up with your observations [as I've mentioned before I agree with a fair number of them]. If you ever decide to go poking around that data and interacting with people who were in fact very obese with depression etc until they went on a fruit based diet [or whatever] and they now have a success story that rivals yours in every regard..be sure to mention it so I can frequent your blog.
Nothing upsets me (I laugh when people on the internet call me a c*nt), but nice projection....yet again.
In your mind, CICO = gluttony/sloth bullshit. It isn't, but trying to convince an insane person that they're insane is equally futile. Did you see what I did, there?
bentleyj74 has given a thorough reply, so I don't need to. Also, what LeonRover said.
When someone's blood sugar goes very high, and then very low, after taking dextrose or glucose, do you really suppose an abnormal insulin reaction is not behind it? Maybe reward did it! LOL.
@Nigel You're fond of contradicting yourself semi-regularly and seem to mostly enjoy arguing whereever you might be found, so I am not surprised to learn you are simultaneously arguing FOR and AGAINST the same position. This comment from you clearly argues that insulin is a reaction to calories/inactivity (the fire = excessive food and insufficient movement). When I tell you this position is wrong, your response is to say you don't believe that position (even though MINUTES ago you wrote the post).
LOL. This is an exercise in futility, at least I know I'm getting my futility exercise quota in.
"do you really suppose" ?
I make no suppositions without observations.
I expect someone who professionally bases treatment on observations to do no less when discussing their own.
"futility exercise" ?
Perchance "futile cycling" - very NEAT.
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