October 14, 2015

ITIS -- It's the Insulin, Stupid (pt 4/8)





“Insulin is vital for lipogenesis. Its role as a lipogenic hormone is underplayed, but we know that without insulin, you can’t get fat.”
                                        --Dr. Roger Unger




Having raved about Dr. Unger’s lecture in the previous insulin post, obviously, I think he’s pretty brilliant. That being said, chronically elevated insulin isn’t the only mechanism by which people accumulate excess adipose tissue. (For the newbies out there, “accumulating excess adipose tissue” is the fancy way to say “get fat.”) I prefer to use the word adipose instead of fat, because I am trying to make a distinction between dietary fat that we consume in food, and the body fat that we all love to hate so much on our bellies, hips, thighs, and elsewhere. Even if they both occur in the form of triglycerides, I still want to keep them separate, since eating dietary fat does not automatically result in said fat depositing itself on our rear ends or forming second and third chins.

Apart from insulin, there are several other things that contribute to the regulation of body weight, and, perhaps more important, the composition of that weight. And I’m not ignoring those. Sometime in the next few weeks, I’ll be writing a post about the myriad other reasons someone might not be losing weight on a low-carb diet (unrelated to this insulin series). For our purposes right now, though, we’ll stick with insulin. Because even if there are other factors playing a role in excess adiposity, when we look at changes that have occurred to the food supply and the general dietary guidelines from various government and professional medical/health organizations during the last several decades, systemic hyperinsulinemia is probably one of the largest influences, if not the single largest.

In tackling the role of insulin on the accumulation of adipose tissue, first we need to explore just a few more things about insulin’s biochemical & physiological roles. After that, we’ll see how it all plays out in the real world—that is, in the body.


Last time, I wrote, “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.” But even if lowering BG is the primary function of insulin, then the method by which this is accomplished sheds a lot of light on what insulin does and explains the rest of insulin’s effects more satisfactorily. Time to revisit the hormone chart from last time, but with a focus on different things:



Chart courtesy of Charles Saladino, PhD, Misericordia University

Do you remember that song from Sesame Street? “One of these things is not like the others…” Well, three of these hormones—glucagon, epinephrine, and cortisol—all “stimulate fatty acid release from adipose tissue.” You know what that means, right? That’s lipolysis—the breaking down of fat—stored body fat! But now look at insulin. It is the only one—the only one—of these four hormones that “stimulates fatty acid synthesis & storage after a high-carbohydrate meal.” And you know what that means, right? The storing of fat on the body. Indeed, THIS may be the primary role of insulin: inhibition of lipolysis. (Or, anti-catabolism, in general -- the building up, rather than the breaking down, of tissue.)

Evolutionary Biology:
A Clash Between Our Genes and our Jeans


We can put this in perspective by looking at it through our ancestral/evolutionary health framework: If you were consuming lots of fruit in summertime, and plenty of squash and starchy tubers throughout autumn, your overall insulin levels might have been higher than at other times of year. But this would have served a good purpose, right? The biochemical signal of elevated insulin tells the body to store fuel. The storage of fuel (in the form of adipose tissue) would have been a crucial survival mechanism to get you through the long winter, when food was presumably less abundant. The body would see frequent and large-ish insulin spikes in summer and fall as a good thing. You would want to inhibit lipolysis for most of summer and fall. If you were breaking down a bunch of your adipose tissue during those seasons, you would be in deep trouble come the food-scarce winter. This is a perfectly good protective and survival mechanism. The problem now, as most of us recognize, is that in the modern industrialized world, the metaphorical winter never comes, but our diets and lifestyles still promote storage, storage, storage. (We will look at another way the accumulation of adipose is a protective mechanism in a future post. Just keep this overarching theme in mind: the body tends to do whatever it can in order to stay alive, all the way down to the cellular level. Seen this way, many of our modern ills and “diseases” are quite elegant, biochemically speaking, even while they wreak fatal havoc at the level of the whole organism. I addressed this in my cancer series, when I explained that cancerous changes at the cellular level can be interpreted as a survival mechanism on the part of the cells.)

Back to the hormone chart: As you can see, there are three hormones that are catabolic. That is, they break tissue down, mostly in response to falling blood sugar. In order to keep blood sugar high enough to do whatever the body needs to do—run from a tiger? Fight off a bear?—glucagon, epinephrine, and cortisol all stimulate gluconeogenesis and/or glycogenolysis. Meaning, they stimulate the breakdown of glycogen into individual glucose molecules, and/or they stimulate the catabolism of muscle tissue, in order to liberate amino acids that can be converted into glucose. They also stimulate the catabolism of adipose tissue, which releases fatty acids that can be used as fuel, as well as the glycerol portion of the stored triglycerides, which can be converted into glucose.

So we know insulin lowers blood glucose, right? How insulin does this is another story. Insulin doesn’t actually escort glucose out of the bloodstream and into cells. What insulin does is act more like a signaling agent: insulin binds to a receptor on the surface of the cell membrane, and in response to the binding of insulin, glucose transporters (GLUTs) are moved (or “translocated”) from inside the cell to span the cell membrane. It’s the GLUTs that actually suck the glucose into the cell. And, just so we know the full story here, some GLUTs require insulin to stimulate their translocation; others don’t. So insulin is not the only way glucose can get into cells. (As I mentioned last time, physical activity is a great way to induce “non-insulin mediated glucose uptake.”)

Insulin: Miracle-Gro for Adipose Tissue


We know one of insulin’s functions is to stimulate the glucose-lowering cascade. What else does insulin do? Well, whereas cortisol, epinephrine, and glucagon are catabolic, insulin is anabolic. The first three break things down; insulin builds things up. What does it build up? At the very least, it stimulates the buildup of glycogen; the synthesis of structural & skeletal protein; and the synthesis of fatty acids via the conversion of glucose into triglycerides. (Again, nerd that I am, I am being very careful with how I word things. See, insulin is a hormone, not an enzyme. Again, as a hormone, it’s more of a signaling agent than something that actually does anything, itself. Insulin stimulates or inhibits various biochemical processes by affecting enzymes, which are what actually participate in the moving & shaking that goes on at the cellular level. I am not always so careful with my phrasing, so I’m just putting this out there so you’ll know how these things work, even when I get linguistically lazy. It would be less-than-correct to say that insulin, itself, does x, y, and z. It’s more like insulin tells other players what to do.)

Two of the enzymes insulin affects are hormone sensitive lipase and lipoprotein lipase. (I talked briefly about this way back in the fuel partitioning series. In fact, that post is probably the CliffsNotes version of this one, so if you’re pressed for time, just go read that instead.) As I wrote there: “We need only to look at untreated type-1 diabetics to understand that (barring any other wacky hormonal complication) it is darn near impossible to accumulate body fat in the absence of insulin. And we need only to look at an insulin-dependent type-2 diabetic with poorly managed blood glucose to understand that sustained, elevated insulin levels make it darn near impossible not to accumulate excess body fat.”

The reason is (partly) this: Insulin stimulates an enzyme that lets fat get into adipose cells, and it inhibits an enzyme that allows fat to get out of adipose cells. Talk about a double-whammy. Insulin is like a prison guard, who helps lock triglycerides into fat cells, and then stands there in order to make sure they never get back out. Son of a…!

This requires a bit of explanation. Triglycerides—that is, three fatty acid molecules connected to a glycerol backbone—are too large to enter and leave cells freely. They can’t cross the cell membrane. Therefore, in order for triglycerides to get into the cell, they have to be broken down into individual fatty acids. The primary enzyme that does this is called lipoprotein lipase. Once inside the cell, the fatty acids reassemble themselves into triglycerides (also called triacylglycerols, or TAGs, for short). So you see the problem now, right? If TAGs are too large to cross the cell membrane and get inside, then we probably need some other enzyme to break them back down into individual fatty acids before they can be released  back out of the adipose cells. After all, that’s what we want, right? Fatty acids to be released from adipose tissue so they can be used as fuel somewhere else, such as in cardiac muscle or skeletal muscle cells—that is, we want to burn fat.

Well, the enzyme that breaks TAGs back down into fatty acids is hormone-sensitive lipase (HSL), and, as I mentioned earlier, insulin inhibits the action of this enzyme. (There are lots of other things that might influence HSL, but insulin is a biggie.)

So, you can clearly see how insulin affects both the storage and mobilization of fatty acids. Leaving other potential influencing mechanisms aside for now, you can also see why, in chronically hyperinsulinemic people, it is darn near impossible to lose body fat. The prison guard is always at the gate, never giving the inmates a chance to escape. And you can see why lowering insulin levels—be that through a low-carbohydrate intake, a moderated protein intake, intermittent fasting, physical activity, pharmaceutical drugs, nutritional supplements, or some combination of all of these—can result in fatty acids finally being able to leave the adipose cells.

Bottom line: As long as insulin levels are high, it will be extremely difficult to lose body fat. 


Whether or not your cells’ mitochondria are up to the task of using those fatty acids (i.e., “burning fat”) would be a whole separate blog series, and I think you’ll agree we’ve got our hands full enough here with insulin. So maybe I’ll tackle that can of worms some other time. I’m just planting that seed in your mind for now—that even when insulin levels are lower, some people still struggle to lose body fat on a low-carb diet, and there are lots of reasons why.

The posts in this series so far have been ridiculously long, so I’m going to end this one here. There’s quite a lot to cover with regard to insulin’s role in regulating adipose tissue, so I’m breaking it up into a few shorter posts rather than having one absolutely ginormous one that no one would want to spend time reading. The next couple of posts will explore in more detail the idea of accumulating body fat as a “protective mechanism,” and we’ll also see how dietary influences on insulin can stand in the way of fat burning, as well as lead to many of other effects of dysregulated blood glucose and insulin, such as brain fog and low energy levels.









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.

2 comments:

  1. #4 was another great chapter, very clear and informative, keep'em comin. The genes against jeans evolutionary clash was a brilliant homophone crack.... Do you scream when you see ice cream?

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  2. Sedge warblers are sparrow-sized insectivorous birds that breed in Europe. At the end of the breeding season they DOUBLE their body weight to fuel a trans-Saharan migration. They do this by eating high-carb insects - plum reed aphids which are basically little protein bags full of sugary plant sap.

    I predict that if anyone studied their physiology they would switch on insulin resistance for the food storage and then switch it off again in order to metabolise the stored fat.

    Likewise for some thrushes, blackcaps, etc. which turn from insects to berries and fruit in autumn/winter to gain fat to fuel them through food shortages and hard weather movements.

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