October 5, 2015

ITIS -- It's the Insulin, Stupid (Pt 3/8)





If you made it through the encyclopedic posts that were part 1 and part 2 of this series on insulin, and you’ve come back for more, thank you! It is one of my biggest flaws as a writer: brevity is not my strong suit. (But at least I admit I have a problem. That’s the first step, right?) This post is no exception. In fact, it's probably longer than the first 2. So go grab a cuppa joe, or tea, or whatever you like, and hunker down for a nice, long read.

Okay. So I left off last time pointing out that, in covering the effects of elevated insulin and glucose on the cardiovascular system, reproductive function, the brain, kidneys, eyes, and inner ear & balance mechanisms, I had not said one word about obesity. I hope we’re all on the same page and can agree that insulin resistance is not something limited to people who are carrying around a few—or a couple hundred—extra pounds. Obviously, there are millions of non-overweight people who are infertile, have heart disease, kidney disease, vision problems, dementia, and more. (I have written about this before. One of my personal favorite posts on this entire blog is the one where I explained that obesity is simply one more effect of metabolic derangement, rather than its cause. I also wrote about this topic for Designs for Health.)

Nevertheless, we’d be missing a substantial piece of the insulin puzzle if we didn’t talk about the role of insulin in regulating body weight. Before we get to that, however, we first need to look at the actual functions of insulin, as well as the pancreas. It is an unfortunate byproduct of our epidemic of “diabesity” that we automatically think of blood glucose when we hear the word insulin. And there’s no doubt insulin does have an important role in regulating—or, more specifically, lowering—blood glucose (BG). But that’s not insulin’s only function. In fact, I would argue it’s not even the primary function. We will get to weight, I promise. But just like we did in the cancer series, we’ve got to trudge through a lot of biochemical weeds before we get to the good stuff. So here goes.

Time for a brief extremely verbose endocrinology lesson.



Physiological Actions of Insulin & 
Insulin-Counter-regulatory Hormones


Chart courtesy of Charles Saladino, PhD, Misericordia University

As you can see, there are three hormones—three—whose job is to raise blood glucose (BG), and just one—one—whose job is to lower it. Right off the bat, this hints at something: the human body may have been conditioned in an environment in which there was likely a frequent and/or immediate & crucial need to raise BG, and much less of a need to lower it. This suggests that our BG wasn’t running super-high all that often, considering there is a triplicate redundancy in mechanisms for raising it, but only a single point of failure for lowering it. (Hormonally speaking, that is. I’m not forgetting about non-insulin-mediated glucose disposal, which is a nice benefit of intense exercise.)

I’m not claiming that the evolutionary/ancestral health perspective is correct 100% of the time, nor that it is the only thing we should consider when trying to make sense of things. I do believe, though, that it provides a handy framework to guide us in assessing things logically and intelligently, and that we can look to the anthropological record to try and find answers for some of our modern ills. For example: our ancestral diets were likely far less insulinogenic than our modern, grain-heavy one is. Even if Paleolithic man—or whoever you want to look back to as your individual ethno-geographic dietary ancestors—ate some small amount of grain in addition to a generous supply of tubers and seasonal fruit, overall, the glycemic load and insulin-raising effects of the total diet were probably very small. And these hominid ancestors may have had a need—not constantly, but often enough—to run away from predators or to chase prey, which would have necessitated an immediate way to raise blood glucose. And because the raising of BG at a critical moment would have literally been a matter of life or death, it makes sense that the triple redundancy is there. It is only in the modern world, where cortisol and adrenaline (epinephrine) are high all the time in some people, where this constant flooding of the blood with glucose gets us in trouble—particularly when combined with a high-carbohydrate diet. Back in the day, getting BG up at the appropriate time was lifesaving. Today, however, keeping BG (and insulin) up all the time is quite literally killing us.

Okay, so there are three hormones that raise BG, while insulin lowers it. And the blood glucose lowering effect of insulin is quite important. Ask a type 1 diabetic if insulin is “toxic,” and you’ll probably get a very different answer than if you ask a nutritionist in the LCHF/keto camp. Insulin is not toxic. It is a damn handy hormone to have—when your body responds to it properly. In fact, insulin, itself, is a lifesaving hormone. The development of synthetic insulin to help type 1 diabetics was nothing short of a miracle. People who were at death’s door could now lead long, healthy, productive lives. There is most definitely a role for a low-carb diet for type 1 diabetics, but even those following a LCHF diet will still require some insulin. (Just far, far lower doses than they typically need on a high-CHO diet.)

Because insulin injections were nothing short of lifesaving for T1 diabetics, we can forgive the early pioneers of treating diabetes for assuming they would be equally beneficial for T2 diabetics. After all, if insulin lowers blood glucose in T1 diabetics, and T2 diabetics have high BG, then it stands to reason that insulin will help T2 diabetics as much as it does T1s. Problem solved, illness cured, right?!

Unfortunately, as we now know, the therapeutic use of insulin for type 1 diabetes does not translate to type 2 diabetes.

What mainstream endocrinologists don’t seem to realize is that BG is elevated in T1 diabetics and T2 diabetics for completely different reasons. In T1Ds, it’s because they produce little to no insulin. In contrast, T2Ds produce plenty of insulin. They’re awash in it. Their cells are practically drowning in it. The problem is, their cells have stopped responding properly. It’s like the story of the boy who cried wolf: do it over and over and over again, and eventually the villagers stop paying attention. In T2D, insulin is knocking, but no one’s home. T1 is insulin deficiency, while T2 is insulin resistance in the face of insulin excess. (There may come a time, when someone has very advanced, very longstanding T2D, that their pancreatic beta-cells actually call it quits and they don’t produce much insulin. This is called “beta cell burnout.” Obviously, that’s not the scenario we’re focusing on here. I just want to acknowledge that it can happen. Also, it is as yet undetermined whether chronic hyperinsulinemia causes insulin resistance, or if cells become insulin resistant first, resulting in hyperinsulinemia. Which is the cart, and which is the horse?)

Another clue that T1D and T2D are different pathologies is that an untreated T1 diabetic will have sky-high blood glucose along with sky-high ketones. (Sky-high ketones are the result of the uncontrolled catabolism of their adipose tissue. This is ketoacidosis, which is a completely different state from diet-induced nutritional ketosis.) T2 diabetics, on the other hand, will have sky-high blood glucose without sky-high ketones. Why? Because they produce tons of insulin, and insulin inhibits lipolysis. Let’s say that again: Insulin inhibits lipolysis. (With lipolysis being the primary source of ketones.) We’ll come back to this next time, when we talk about body fat regulation. T2 diabetics can experience ketoacidosis, but it's far more common in T1s.

Giving insulin to a type 2 diabetic who already secretes too much insulin is like the misguided prescribing of antacids to individuals who have low stomach acid. If doctors would measure the HCl activity of patients who complain of GERD, heartburn, and general indigestion, they would see that the majority of these folks don’t have excess stomach acid; they actually have too little!  And if doctors would measure a T2 diabetic’s insulin levels, the way Dr. Kraft did with so many patients, they would see that they have too much. And, in following the anointed standard of care, they would have to reconcile the wisdom of giving these people even more insulin. Maybe making the insulin assay a part of a regular checkup would finally wake modern medicine up to the idea that type 2 diabetes is not an insulin deficiency.

The Pancreas:
Endo-, Exo-, and Paracrine


Okay. Now that we’ve entered the territory of lipolysis and ketosis, it’s time to dive a little deeper into the physiological mechanisms of insulin and other blood glucose regulating hormones, as well as take a closer look at the pancreas.

With all this blood glucose talk, it would be easy to think that your pancreas has one job, and one job only: to secrete insulin. On the contrary, this is just one of many functions this precious organ performs. The pancreas is an endocrine, exocrine, and paracrine organ. As an endocrine organ, it secretes hormones into the blood. As an exocrine organ, it secretes substances into a duct. As a paracrine organ, it secretes substances that act on itself. (Specifically, certain cells of the pancreas secrete hormones that act locally, i.e., on other cells of the pancreas.) Here’s how this works:

(1)  Remember from way back in the series I did on digestion, that the pancreas is a major player in helping your body break down food so you can absorb all those great nutrients from your caramel pecan cheesecake grass-fed ribeye and organic asparagus. The pancreas, itself, doesn’t digest anything. What it does is secrete several enzymes into the small intestine, and it is the small intestine that actually does the work of digestion. Pancreatic digestive enzymes (which include enzymes that break down protein, carbs, and fat) make their way to the intestine via the pancreatic duct. This is the exocrine function of the pancreas.

(2) The specialized beta cells of the pancreas secrete insulin into the blood, and the alpha cells secrete glucagon into the blood. This is the endocrine function.

(3) Insulin and glucagon travel through the bloodstream to exert their effects on target cells all over the body, but they also act locally, on the pancreas itself. This is the paracrine function. This is a big deal. Bigger than big. It’s huge, in fact, and I didn’t even realize how huge until about two weeks ago. More on this at the end of the post.

The digestive/exocrine function is not relevant to the topic at hand, so we’ll leave it aside. Let’s look at the endocrine function. When a healthy, non-metabolically derailed person consumes carbohydrates, their blood glucose goes up a little bit, and insulin is secreted to bring it back down. On the other hand, if it’s been a while since this person has eaten anything, the pancreas secretes glucagon. Recall from the hormone chart above that glucagon maintains blood glucose levels during fasting—or, really, just between meals, after insulin has returned to its low-ish baseline. Glucagon is what keeps blood glucose from plummeting to dangerously low levels if it’s been, say, 14 hours since your last meal.


Glucagon:
Totally Underappreciated


Glucagon is a fascinating hormone. It’s the Rodney Dangerfield of hormones; it gets no respect. And that is a shame. The truth is, glucagon is such a huge player in all this that, upon learning more about it, I was worried I had done you all a disservice, because I should have called this series “It’s the Glucagon, Stupid.” But then, when I learned even more, I felt reassured, because it is really about the insulin. (Shut up, Amy. No one cares. Get back on topic.)

Insulin, glucagon, and blood glucose:
the ultimate balancing act.
One of the things that stimulates glucagon is low blood sugar. This is how glucagon helps keep things on an even keel. It’s isn’t necessarily “low” BG that stimulates it—meaning, it’s not like your BG hits 35mg/dL and all of a sudden a big spike of glucagon raises it back up. Let’s say it’s falling BG that tells glucagon to keep things safe. Let’s say your BG is at a nice, cool 78. Well, your body and brain are using glucose constantly. Even on a ketogenic diet, the body and brain do need some glucose. (Recall from this post that there are some cells, such as red blood cells, that have no mitochondria, and therefore cannot metabolize fats. They must use glucose. And even our beloved ketones cannot provide 100% of the brain's fuel.) So, with cells taking glucose out of the bloodstream all the time, if there was no mechanism to put some glucose back into the bloodstream, you would pass out and die very quickly. So what glucagon does is play a kind of balancing act with blood glucose, making sure that it never gets too low.

Something else that stimulates glucagon is ingestion of protein. This is where things get interesting. The seasoned low-carbers among you know that protein stimulates insulin. (This is a good thing. This is a big part of how we build muscle mass; insulin helps escort amino acids into the cells. It’s also why you don’t absolutely need carbs post-workout. The protein will raise insulin all by itself.) Some of you low-carbers who aren’t quite as familiar with the ins and outs of all this might have heard somewhere that protein “spikes blood glucose.” You might have also heard people saying that, in terms of blood glucose regulation, for some people, a big whack of protein is as bad as chocolate cake, and for this reason, people on low-carb diets for the specific purpose of keeping blood sugar low should be careful not to overconsume protein.

I am not arguing that ingesting protein doesn’t raise blood glucose. (It does.) And I’m not arguing that certain amino acids aren’t strongly glucogenic. (They are.) BUT: let’s see how this actually works, because steak and chicken are not chocolate cake, okay?

Let’s look at this through our evolutionary lens. Let’s say your tribe has just had a good kill. And let’s say you’re somewhere down toward the middle of the tribal hierarchy. Maybe the higher ranking males and females have first dibs, and they chow down on the organs, the entrails, and some of the other prized pieces of this prey. By the time it’s your turn to lop a piece off with your handy stone tool, maybe all that’s left is a big ol’ piece of muscle meat—and a relatively lean one, at that. But this isn’t 2015 in the U.S., and there’s no baked potato, buttered roll, and soda to go with your meat, so your meal is meat, and nothing else. Lots of protein, a little bit of fat, and virtually zero carbohydrate.
If you were to eat this piece of meat, and the protein raised insulin (as it does), not only would the amino acids go from your bloodstream into your cells, but plenty of glucose would go along with them. Now, being that you are a Paleolithic “person,” let’s say your blood glucose is cruisin’ somewhere around 75. But now, thanks to your piece of meat, you have an insulin rise in the absence of dietary carbohydrate. Without a counter-regulatory hormone, your blood glucose could get too low. (Assuming you’re not overtly ketogenic, that is. You can have what would otherwise be considered freakishly low BG but feel completely fine if your ketones were high enough.) So thank goodness there is a counter-regulatory hormone, in glucagon. Sorry for this little digression; I just figured that, for some of the lay readers out there, who might not know about all this, this would be a good way to explain why dietary protein stimulates both insulin and glucagon. It’s quite nifty, how nature does this.

SO: I don’t think it’s correct to say that eating a large whack of protein “spikes blood glucose.” I think what it does is stimulate glucagon, which raises blood glucose in order to counteract the glucose lowering effect of insulin. This is totally normal, and no problem whatsoever—FOR A METABOLICALLY HEALTHY PERSON. (And it's why plenty of low-carbers don't need to deliberately limit protein intake.) But let’s see what happens in a metabolically UNhealthy person—specifically, someone who is insulin resistant.


It could be the glucagon, stupid,
but really, it’s still the insulin


Insulin resistance occurs when cells no longer respond to the presence of insulin. We know for sure that muscle cells can become insulin resistant. But you know what other kinds of cells can become insulin resistant? THE GLUCAGON-SECRETING ALPHA CELLS OF THE PANCREAS. Yes! Now we’re getting somewhere.

It’s time to examine the paracrine function of the pancreas. Recall from the hormone chart way above that glucagon mobilizes fuels. It activates gluconeogenesis, glycogenolysis, and lipolysis. We know glucagon does this. This is how it keeps blood glucose at a safe (i.e. high enough) level between meals or during a longer fast – it catabolizes existing muscle tissue to get at some glucogenic amino acids, and it stimulates the breakdown of down glycogen into individual glucose molecules. It also stimulates lipolysis—that is, the breaking down of stored body fat, the glycerol portion of which can be used to make glucose. Now that we see what glucagon does, we can have a much better understanding of type 1 diabetes. T1D is glucagon run amok in the absence (or deficiency) of insulin. Untreated, type 1 diabetics remain in a perpetual state of catabolizing their own bodies in order to be fueled. They break down their muscles, they break down their adipose tissue, and, eventually, they’ll break down their organs. You can see why, in the absence of insulin to counteract the glucagon, T1 diabetics might be emaciated.

Here is something absolutely fascinating about the paracrine pancreas. Before entering the general blood circulation, the insulin that is secreted by the beta cells works directly on the alpha cells. The alpha cells are insulin’s first stop before it travels to the rest of the body. Basically, insulin tells the alpha cells to stop churning out glucagon. BUT: the amount or concentration of insulin that hits the alpha cells is much, much greater than the concentration of insulin than the rest of the body responds to. It’s almost like, in tamping down the alpha cells, most of the insulin is siphoned off, so a much lower concentration is left for the rest of the body. This is what is supposed to happen. And this explains why it is so difficult for type 1 diabetics to manage their blood sugar. If they were to inject themselves with insulin at the strength needed to suppress glucagon, it would completely overwhelm the rest of the body and certainly induce a life-threatening “low.” In a best case scenario, the amount of insulin they inject is matched to the amount of carbohydrate (and protein) they eat. But this does not at all take into account the extremely concentrated amount the alpha cells require in order to stop secreting glucagon. So you can see now why T1s have BG that is all over the map.  

Okay, back on message. In a healthy person, glucagon’s catabolic effects only dominate when insulin is low—between meals and during a fast. For someone on a low-carb diet, glucagon will be somewhat active all the time, but in the fed state, it will be mostly overridden by the presence of insulin—yes, even just the relatively small amounts of insulin a low-carber would secrete. In a type 1 diabetic, glucagon dominates all the time. This is why they waste away without exogenous insulin, and also why they have concomitantly high glucose and ketones. In a metabolically healthy person, even small amounts of insulin are enough to limit the effects of glucagon. (This is the beauty of a low-carb diet in a healthy person: BG that is neither too high nor too low. I emphasize again: insulin is not toxic. Insulin is great, provided your body knows what to do with it.)

I said earlier that T1D is glucagon run amok, because there’s no insulin to shut off that signal. Oddly enough, for many type 2 diabetics, their condition is also glucagon run amok, but it’s obviously not because there’s no insulin. There’s a ton of insulin; many cells just don’t care anymore. And remember: among the cells that don’t care anymore are the glucagon-producing alpha cells. Because the alpha cells are insulin resistant, they function as if there is no insulin. That is, they continue to hemorrhage glucagon. So, even when blood glucose is high, such as after a high-carb meal, glucagon can raise it even higher. The carbs would have raised BG, and therefore, insulin, but because the alpha cells no longer sense the insulin there, they will continue to pump out glucagon as if a high-carb meal had not been ingested. And what will this glucagon do, but continue to raise BG even more, by breaking down existing muscle tissue to get at the glucogenic amino acids? (Remember, though, that even with sky-high glucose, hyperinsulinemic T2 diabetics might not generate lots of ketones, because, in a cruel twist of fate, the adipose tissue still seems to be sensitive to insulin, and insulin inhibits lipolysis.)

As bad as soda? Come on.
I suspect this is why some T2 diabetics occasionally have BG in the 300s and 400s, despite (because of?) being on insulin. These people’s bodies are churning out glucose almost no matter what they eat. If it doesn’t come from bagels and pasta, then yes, in a severely insulin resistant person, it can come from their own muscle tissue, as a downstream effect of unchecked glucagon release. I still think it’s misleading to say that a pork chop is no better, metabolically speaking, than a sugar-frosted jelly donut. But you can see the logic in that claim—in the specific case of the severely insulin resistant. And you can see why some of these folks do best on diets that are very low in carbohydrate and also relatively low in protein—for example, maybe 75% fat, 15% protein, and 10% carbs. See, not only do they need to control their carb intake; they also need to be mindful of not stimulating a ton of glucagon...at least, not until they become more sensitive to insulin.

And remember: protein elevates both insulin and glucagon. THIS is why people who are extremely insulin resistant are well-served not to “overconsume” protein. (Whatever that means, anyway. The threshold is an individual thing.) If they are eating “too much” of a food that raises glucagon, and, by extension, blood glucose, but they cannot clear that glucose out of the blood due to insulin resistance, this is a kind of double whammy.

I suspect these forces were at work in my own mother, who had poorly controlled T2D. (Read about her unfortunate and hapless medical care here.) She was on insulin, and her blood sugar was completely unpredictable, regardless of what she ate or her insulin dose.

It’s interesting to note that, among many overweight T2 diabetics, they are “large,” but they don’t seem to have much muscle mass. With what we just covered, we can speculate that maybe they have less muscle because their bodies are so good at breaking muscle down. As for how they end up heavier, when someone is severely insulin resistant (and remember, this goes for their alpha cells), I suspect it works like this:

Elevated glucagon --> catabolize muscle
Elevated insulin --> do NOT catabolize stored body fat

Boy, is that a horrible scenario to find one’s self in: break down your extremely valuable muscle tissue, but nope, don’t touch any of that fat! Leave it right where it is! In fact, make more!

Okay, since I’ve finally—finally—circled back to the topic of body fat, this is a good place to end for now, and we’ll start right back here next time.

In the meantime, if you’d like to learn more about all this glucagon stuff, I cannot recommend this video highly enough. I wasn’t kidding when I said I had just learned a lot of this recently, myself. Most of it came directly from this video. (Thanks again to Ivor Cummins for letting the rest of us know about it.) I am not ashamed to admit I was absolutely FASCINATED. RIVETED. Here was my reaction:      



You, too, will have your mind blown. Guaranteed. (Especially when Dr. Unger talks about the concentration of insulin as it exerts its paracrine function on the alpha cells. Seriously, WATCH IT!)








Remember: Amy Berger, M.S., NTP, is not a physician and Tuit Nutrition, LLC, is not a medical practice. The information contained on this site is not intended to diagnose, treat, cure, or prevent any medical condition.

23 comments:

  1. >>And you can see why some of these folks do best on diets that are very low in carbohydrate and also relatively low in protein—for example, maybe 75% fat, 15% protein, and 10% carbs. See, not only do they need to control their carb intake; they also need to be mindful of not stimulating a ton of glucagon...at least, not until they become more sensitive to insulin.<<

    So critics of low carb diets claim that low carb diets don't improve insulin sensitivity--in fact, they worsen insulin sensitivity. Is there anything that can reasonably be done to improve insulin sensitivity?

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    1. That's the million-dollar question, Jan. I'm going to watch this video and see what they say (https://www.youtube.com/watch?v=lYQgxjlDuQQ) -- practitioners who actually KNOW what they're doing. (Also recommend parts I and II -- very informative stuff, especially with regard to *causes* of IR other than "carbohydrate abuse," and markers to look out for that have nothing to do with body weight or fasting glucose & A1c. Really refreshing to see doctors who *get it.* (Part I: https://www.youtube.com/watch?v=uc7LoVJ4zOk and Part II: https://www.youtube.com/watch?v=wLJSNYG36aA)

      I'm not sure what can be done to improve insulin sensitivity. I think it's right that low-carb doesn't "cure" diabetes or IR, in the sense that these people cannot go back to their old dietary habits and stay in the free & clear. They have to stay low-carb for the long haul. Maybe not *ultra* LC, but certainly limited to some degree. I think regular exercise -- especially if you can lift and build some good muscle mass -- is a huge player. But not because it "burns calories!" It has much, much more to do with increasing mitochondrial number and efficiency. Getting adequate sleep, managing stress levels, and all those other factors also likely play a role. (My sleep has been TERRIBLE for a while now...my own fault...and it's definitely wreaking havoc with my weight & body composition...and, presumably, my insulin sensitivity.) Gut biome is probably also a factor, but I think so incredibly little is understood about all that gut stuff, and I'm not educated enough about it to say what the deal is.

      I think we underestimate the integrated picture: diet, sleep, stress, possibly even environmental factors that mess with cell signaling. (Part I of that video is pretty good for explaining this.)

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    2. I think the loss of muscle mass as we age is a HUGE player in why aging is a risk factor for basically *everything* -- diabetes, heart disease, decline in kidney & liver function, sexual dysfunction. The more muscle mass you have, and the more insulin sensitive you can keep it (through multiple means), the better glucose disposal/handling you will have. I think there should be far more emphasis on being *strong*, hardy, and robust, for overall health, rather than this constant harping on BMI and "weight loss." Sarcopenia and dynapenia don't get anywhere near enough attention. Jamie Scott, the guy who founded the Ancestral Health Society of New Zealand, is all over this: https://www.youtube.com/watch?v=L0Cke5kUfc8

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    3. You do not want to improve insulin sensitivity while following very low carb, BENIGN physiological insulin sensitivity prevents hypoglycemia.
      I could become insulin sensitive quickly again by eating more carbohydrate, ↓↓ketones, ↓FFA so skeletal muscle insulin resistance would reverse quickly to utilize glucose again.
      A person with very full adipocytes can not become insulin sensitive like that because of distended adipocyte FFA leakage causing downstream insulin sensitivity of skeletal muscle removing a big glucose sink.
      Said person almost certainly has a large mass of inflammatory visceral adipose and yes crappy mitochondria too.

      Extremely doubtful the majority of humans need to limit protein in any way.
      Limiting protein so you are in negative nitrogen balance is a extremely fast way to lose the wrong type of weight because muscle is only 20% ish protein compared to adipose majority fat. Lose weight and increase your relative fat % doesn't seem remotely ideal to me.

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    4. Are you familiar with Dr. Fung's work? https://intensivedietarymanagement.com/blog/

      He argues that one can cure type 2 diabetes through a combination of diet (low carb) and fasting. Whether he actually "cures" it or not, is an open question. For me, using low carb, increasing my fat content to as much as I can eat per day, and performing intermittent fasting has decreased my fasting blood glucose and fasting insulin, which are markers of insulin resistance/insulin sensitivity, eg, via HOMA-IR. See, eg, https://en.wikipedia.org/wiki/Homeostatic_model_assessment. Some say that this is an inaccurate measure of insulin resistance/insulin sensitivity, however.

      Regardless, there aren't many tests for a person like me to do to gauge whether I'm becoming insulin sensitive or not. The GTT plus insulin might be a better gauge over time, but I cannot find anywhere to get that test done. I certainly feel as if I'm becoming more insulin sensitive, as when I do splurge on carbs, I don't feel my blood sugar skyrocketing the way I used to. However, that's a "seat of the pants" experiment and not one most people will accept.

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  2. Thanks great article...someday I hope to find the right food program for my body! I was vegan for about 28 years, now doing a LCHF lacto-vegetarian food plan for the last 3 months. Before that, I was attempting LCHF vegan for 5 months! I look forward to Part 4...

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    1. And how are you DOING? That's the important thing. Are you feeling well? After 28 years as a vegan, did you switch strategies because you found your diet lacking in some way, or you felt you were having complications that may have been due to nutritional imbalances? I'm always curious when people make that kind of change. Let me know if I can offer any advice...

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  3. There are two important details to always remember:
    1. Insulin in physiological conditions (in healthy, insulin sensitive people) is not needed for cellular glucose uptake. At elevated concentrations however, it does accelerate uptake. See http://bja.oxfordjournals.org/content/85/1/69.full

    2. The blood glucose lowering effect of insulin comes from inhibiting glucose output in the liver. However, it is not a direct effect on hepatocytes, but an indirect one. It is in fact also the result of inhibiting lipolysis in white adipose tissue, thereby influencing (reducing) acetyl CoA levels in the liver. Ac-CoA determines pyruvate-carboxylase (gluconeogenesis) activity which is thereby the main regulator of glucose output. See http://www.cell.com/cell/abstract/S0092-8674(15)00014-8

    So insulin is indeed mainly chalonic (inhibitory) and its two main actions on metabolism are inhibiting glucagon secretion (reducing glycogenolysis) and inhibiting lipolysis in white adipose tissue (reducing gluconeogenesis). Now it seems that what we actually call hepatic insulin resistance is in fact happening in WAT, most likely in visceral fat.

    Just an interesting addition (and confirmation) to above from a very recent article:
    "Interestingly, improvement in insulin sensitivity was associated with changes in fat tissue rather than skeletal muscle, suggesting that fat tissue may play a larger role in insulin sensitivity than currently believed, the team wrote."
    http://ajpregu.physiology.org/content/309/5/R510

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    1. Awesome comment. Thanks for these insights. (I'll check out the papers when I have a chance.) Yes, insulin is anabolic...or, maybe more accurately, it's anti-catabolic, at least with regard to inhibiting the breakdown of adipose. Will be addressing this in part 4.

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  4. Thanks Amy, i have been so frustrated with the specialists telling my daughter that she just needs to log everything she eats and the amount of insulin she takes and make sure she doses properly and then her blood glucose won't be so high all the time. She is 16 years old, was diagnosed at 9 and things just keep getting worse, the doctors don't seems to have anything helpful to say and just make her (and me) feel like we aren't trying hard enough. The information that you have provided actually makes sense. I wish I could make the doctors read your articles and watch the video!

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    1. If she's a type 1, I recommend reading Dr. Bernstein's book. Lots of T1s have had darn near miraculous success in reducing insulin doses and managing glucose beautifully.

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  5. I definitely need to watch that video.

    Thanks for your long posts, Amy. This was a really interesting one.

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    1. I liked the video, but an increased caloric intake causes hyperinsulinemia?
      Therefore, eating too much is the real cause of T2D. Is that right?
      I don't understand why do they link insulin with calories.

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  6. I find this article very informative and I would like to add an important piece to the T2D puzzle.

    Let me start by saying that I think Insulin Resistant is a misnomer. It makes it sound like cells stop responding to Insulin because, over time, something has changed in them. I do not think that is the case. If that were the case reversing "Insulin Resistance" would have to be also a gradual process taking place in each affected cell.

    Two pieces of evidence show that immediate reversal of Insulin Resistance is in fact possible:
    1.- Experiments with diabetic rats that have had visceral fat surgically removed show Diabetes disappearing. http://goo.gl/dDzgzj
    2.- In patients that undergo bariatric surgery to remove or bypass most of the stomach "Rapid
    improvement in blood sugars and reduction or elimination of diabetic medications is often seen
    within the immediate period following bariatric surgery, even before significant weight loss." https://goo.gl/lqbAMW

    If not Insulin Resistance then what? Simply put: conflicting hormonal message resolution. When a cell receives two contradictory signals one in the form of Insulin and another of Glucagon it has to decide which is more important, lower sugar or raise sugar. Raising sugar is more important because low levels of sugar can be fatal. So Insulin is purposefully ignored. It is an intrinsic mechanism, not a defect that arises in time.

    What about the alpha cells? are they ignoring the Insulin message too? are they Insulin Resistance?
    What role do visceral fat and the stomach play in this?

    Here is my theory: the alpha cells in the pancreas have no problem receiving and complying with the insulin message. After all they sit side by side with the beta cells, the message gets to them loud and clear. The problem is the alpha cells in the stomach. They are farther away and my theory is that visceral fat somehow blocks or attenuates the insulin message which fails to reach them at the necessary levels. That would explain why both visceral fat removal and bariatric surgery both cure diabetes by two different mechanisms. The former by unblocking the passage way to the far away alpha cells and the latter by reducing the number of far away alpha cells.

    So, what could be the purpose of the alpha cells in the stomach?
    I suspect it is to raise the sugar levels in preparation of the demanding task of digestion.

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    1. Man, my readers are SMART! I'm gonna have to step up my game! I can barely keep up with all the knowledge bombs being dropped in the comments these days. :) Really good insights here. I agree -- you've got to wonder how IR can be "reversed" so quickly, when we're operating under the assumption that it doesn't develop overnight. (About the weight loss surgery, I suspect the very quick reversal there is that they simply can't eat much of anything for a while. Of course some of the metabolic/biochemical changes occur before any weight loss -- these people are consuming a mere fraction of the total food they were before surgery -- including carbohydrate.)

      The visceral fat probably has a lot more to do with it than we currently understand. But then again, there are plenty of lean people out there with whopping, raging cases of IR. (But maybe they are extremely fat in their *organs,* right? We can't see a fatty liver from the outside, and someone with a fatty liver could have a flat stomach on the outside, I suppose.)

      Either way, a big, big intervention seems to be cutting way back on CHO intake. This would go a long way toward mobilizing some of that visceral fat, wouldn't it? Fasting probably does the same thing, as does bariatric surgery. The surgery *forces* you to eat less; fasting makes it more of a deliberate choice.

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    2. Wow I agree Amy some great info all around from you and your commenters. I like TechMind's theory and was wondering if they had thoughts on how we could unblock the passage way or reduce the number of far away alpha cells in the stomach short of surgery.

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  7. Amy, thank you very much for this enlightening post. It shed some light on the question why I cannot gain any weight while I really need to. I enjoy reading your blog a lot.

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    1. Thanks for reading! :) As for wanting to *gain* weight, you are probably in the minority of people out there. Are you type-1 diabetic, or do you just have a hard time putting on healthy weight?

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  8. Being a minority does not help much. I cannot gain weight at the moment whatever I try. I don't think that I am a diabetic, but your description of a type one diabetic made me wonder. My father had diabetes later in life, probably type two. I came from GAPS to low carb high fat, then to ketogenic and then to zero carb. I will read dr Bernsteins book to see if I can find some useful ideas.

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    1. If you started with GAPS, then I assume you had reason to suspect major gut disruption. If that's the case, then it makes sense you would struggle to gain weight...if you're not *absorbing* your food, then you'd remain very thin (too thin!) no matter what you do. If you were T1 diabetic, you'd probably know it, because you'd have lots of other symptoms. I think Bernstein's book is more about blood sugar control than weight, but it's probably still a good read. Perfect Health Diet might be really informative for you, too. Some people really do a little better with some carbs, especially for weight gain.

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  9. Great blog indeed!

    Yes - I earlier watched Professor Unger's talk on diabetes a number o times and it is for sure mind-blowing.

    Dr. Göran Sjöberg

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  10. Amy,
    Just found your Site - the Glucagon explanation is for me (a poorly educated junior High School Grad 50+ years ago)
    FANTASTIC. I've been trying to make sense of what was happening to me - but couldn't. Now, your explanation and your sense of logic gives me something to work with. THANK YOU! All the Best to You.
    Luciano.

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  11. Just as the effect of dizziness can also be a cause of people falling down and breaking their hips, so also can obesity be a cause of problems. I suggest that the body's having to service excess fat cells is a drain of its resources and thus causes other problems. Most problems in the body are parts of vicious cycles of multiple causes of multiple effects.

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