66: The Impact of Estrogens on Glucose Metabolism and Insulin Resistance with Dr. Ben Bikman

Hello and welcome to the Metabolic Classroom. I'm Professor Ben Bickman, a biomedical scientist and professor of cell biology. Thanks for joining me today. The topic for today's lecture is one that is not often considered when we think about estrogens, but I want to focus on some of these specific metabolic effects of estrogens, particularly estrogens and the handling of, of blood glucose and generally glucose metabolism. Now, this is a topic that's of interest to me, of course, as a metabolic scientist, because so much of what I do is focused on the hormone insulin. And insulin regulates so many metabolic processes and none no more well known than its regulation of glucose. But insulin's not alone, or to say that another way, it has other influences that in turn affect it, namely estrogens. Now, over the course of this lecture, while the first part, and indeed the majority of it, is going to be focused on estrogens, I also want to take a little time to talk about the role of progesterone because it actually ends up, I believe, providing a pretty interesting nuance and even counterpoint to the discussions with regards to estrogens. So by way of background, estrogens and progesterone are produced, are produced primarily in the gonads. Now, in the case of now, I say gonads as a generic term, I.e. ovaries in women and testes in men. And estrogens are also made by males in the testes, albeit much less relatively compared to what is made in the females. Now during menopause, which we will touch on later in the discussion. The production of the estrogens in particular is less so in the ovaries and now more so from the adrenal glands. Now that the source is less important for the sake of this discussion. In other words, where are the estrogens or progesterone coming from? What is more important is what they're doing. So that's of course, what we're focusing on. So this is not intended to be a discussion about the changes in sex hormone production and menopause. That's actually something we've discussed in previous metabolic classrooms. Okay, now briefly, I think it's worth discussing again briefly how these hormones are produced. I just mentioned where they're produced. It's important to understand all sex hormones, including estrogens and progesterone, come from cholesterol. Cholesterol is the precursor for all of the steroid hormones and I just mentioned the ones of topic hormone of interest today. So firstly, cholesterol gets converted to a molecule called pregnenolone then pregnenolone is converted into progesterone, and if so it's done, then progesterone is the hormone, and it's done. And it has its effects, some of which we'll talk about in the context of glucose metabolism. Or alternatively, pregnenolone can go into dhea, and then DHEA can be converted into an androgen, a prototypical male sex hormone called androstene dione. And then we get to a very important enzyme called aromatase. This enzyme is so important because not only do women have a much more active version or profile of aromatase, but it also is the enzyme that gets inhibited during insulin resistance, stop at the doorways of the cell and knock. That's what's happening here, where estrogen can bind to estrogen receptors on the cell surface, which ends up sort of running parallel and then converging on pi3kinase, activating pi3kinase with insulin. It's basically facilitating insulin's signal, enhancing the effect of insulin. So that's why I took the time to, to. To describe that pathway. All right, so estrogens, estradiol in particular, basically grease the skids of the insulin signaling pathway. It allows the insulin pathway to work a little better. The. The signal maintains its fidelity as it sent from protein to protein. Now, that's not all estrogens are doing here. Estrogens are also activating ampk. Ampk, short for amp or amp, which is a metabolite of ATP. ATP is the main energy molecule in the. In all cells. So ATP can, when it gets broken, will turn into amp in the course of its metabolism. And then when there's a lot of amp, it will activate ampk, AMP activated protein kinase. So AMP is the main activator. It's basically a signal within a cell where the cell says, I'm getting low on energy. I've been burning a lot of ATP. I need to start producing more energy. And so when AMPK is activated, it will stimulate glucose uptake, because that's in addition to other effects. Because AMPK is when it gets activated in a state of low energy, it wants to correct that low energy. One way it can do that is by enhancing the pulling in of energy, such as glucose, and then burning that glucose, or activating glycolysis, to be more precise, the breakdown of glucose. But it doesn't want to be wasting. It doesn't want to be making glucose. So while AMPK is activating glucose uptake, it doesn't want to be storing it. It wants. It wants the cell to use it. So estrogens once again activate ampk, and when AMPK is activated, among other things, the cell will pull in more amp, more, more glucose. So Glut4AMPK has a way of actually hijacking that same AKT pathway that I just mentioned and activating it without insulin even having to come and knock on the door. This is in fact one of the ways in which exercise can have the muscle pull in glucose without insulin being elevated during exercise, which it isn't. All right, so there are two mechanisms whereby, at least at the muscle, estrogens are facilitating maintaining ideal glucose levels or helping the body bring the glucose down. One, it enhances the efficacy of the insulin signal. And. And two, it has its own backdoor signal via ampk, which will also kind of hijack that pathway or complement or amplify that pathway. Okay, now let's kind of shift from the. A muscle focused description, which is appropriate to focus on because by mass it is, there's so much and it is the main consumer of glucose. But the liver is so important because if the liver isn't playing along with what insulin's trying to do, lowering blood glucose, it can totally break the whole thing apart because it has such a potential to release glucose into the blood even if a person's not eating it. So it is worth covering what estrogens might be doing at the liver, because, again, it's relevant. So there are estrogen receptors at the liver, just like there were at the muscle. And estrogens, when they come to the liver, estradiol in particular, will suppress hepatic glucose production. Now, the main, when a, when a liver cell is making glucose, it's through gluconeogenesis. So making it from scratch or breaking it down. Now, glycogen ends up being a bit of a separate little pathway where it can bypass some of these. But there are two enzymes. When, when you talk about gluconeogenesis, which is the liver making glucose from scratch, there are two critical enzymes. One is an enzyme, long name, the short name is, the short version is pepc, K, pck, phosphoenolpyruvate carboxy kinase. That's one essential enzyme on this. Now, I keep sort of pointing up because when we teach this in biochemistry, I, I teach glycolysis, which is the breakdown of the glucose, breaking it down all the way to lactate and then going into the mitochondria, or just being done at lactate and then getting ATP from that, or if it's gluconeogenesis, Lactate is in fact the most common source of gluconeogenesis. So it just goes back up and there are a couple points that have to be bypassed. So one of the essential points is Pepsi K that allows this reaction to start going in reverse. Except estrogens inhibit that. Estrogens don't want Pepsi K to do this. Now you would say, well, there's still the inclusion of glycogen, which comes in at the very top. The last step of, of the liver cell going back to glucose, which can then go out of the liver cell, is the activation of an enzyme called glucose 6 phosphatase. In fact, it is an enzyme that is largely unique to the liver. Why does the muscle not let glucose go out? Because it doesn't have that enzyme. Why? Why can the liver let glucose go out? Because it can take a phosphorylated glucose molecule and strip off the phosphate group and now the glucose is just alone and able to go out. So it's a unique enzyme that is critical to the liver's ability to release glucose. But once again, estrogens inhibit that. So estrogens are turning off two of the most important steps that would allow the liver to be dumping out its glucose. As a result, with these enzymes being suppressed, blood glucose levels have an easier time coming down. So not only are estrogens doing that directly, but also the estrogen receptor alpha once again will enhance insulin's effect because insulin also wants to turn those off. So here we have once again, just like we did in the muscle, estrogen's having this anti gluconeogenic effect or the suppressive effect on the liver, releasing glucose by both enhancing insulin's signaling and then having its own signaling. All right, now so far we've been talking about estrogen's ability to generally help keep blood glucose in check. And this is certainly one of the reasons why women tend to have such a lower risk of type 2 diabetes than men. Do those higher levels of estrogens, as I have said before, allow the woman to be a little bit of a metabolic superhero that she is largely immune, although less and less, it seems, these days than her male counterpart, to the consequences of or. Or to. To hyperglycemia and, and high glucose levels and thus somewhat protected from type 2 diabetes. All right, now let's flip the coin over. As much as it seems like I have described everything as a very rosy metabolically, it gets a little complicated when we include progesterone. Because as much as we want to assume progesterone and estrogen have similar effects, and in some ways they do. If we were talking about the normal, say, ovarian cycle and the activation of the proliferation of the uterus, I'm getting really technical here. So as much as estrogens and progesterone sometimes do work together when it comes to nutrient metabolism, they don't. They, they were siblings that were getting along quite nice at some time, and now other in other ways they're not. Does any parent know that is so common? All right, so let's talk about progesterone and glucose metabolism and once again highlight some specific signaling, albeit a little in a little less detail than we did. Now, in stark contrast to estrogens enhancing insulin signaling, progesterone can decrease insulin sensitivity by actually acting at that Same pathway at pi3kinase and akt, which, which converge. That's part of the same pathway. It's two dominoes, one bumping into the other. Progesterone tends to mitigate that. It activates some phosphatase enzymes that are stripping off the activation, if you will, of these enzymes, thereby blunting the GLUT4 activation. So that means not only is the obvious effect, certainly in the context of this discussion of glucose, but progesterone generally promotes a degree of insulin resistance. And this is seen not only in the muscle, but it also starts to counter insulin's signaling and insulin's desires at the liver, where in the liver progesterone will tend to increase blood glucose by enhancing gluconeogenesis. So those same enzymes that were getting turned off pepsi K and glucose 6 phosphatase with estrogens. Progesterone doesn't want that. It will start to counter that. Now, with all of this in mind, it allows us to explore the really remarkable metabolic influence of the menstrual cycle or the ovarian cycle. Those, I don't usually describe those as the same thing. Maybe let's just say the ovarian cycle, which we can break up into just two simple cycles, the follicular phase and the luteal phase. If we talk about the menstrual cycle, that someone might want to say, well, there's the shedding, the proliferative secretory phases, but let's just keep it up the simple. These all overlap. You know, ladies, any ladies listening just appreciate the fact that fertility in the female is just so much more, remark, remarkably complicated than in the male. And that shouldn't be surprising. Females have the really kind of the metabolic responsibility when it comes to fertility. Love it or hate it, but it does mean that there are more checks and balances than in the male counterpart. Okay, so let's say that this is the ovarian cycle where we have two phases. The follicular phase dominated by estrogens and the luteal phase dominated by progesterone. Because of this, there are these metabolic consequences that I mentioned earlier. So during the follicular phase, the high estrogen levels enhance insulin sensitivity and glucose uptake. So literally during the first half ish of the ovarian cycle, although it's not always exact, you know, across all the variety of differences among all women. But she will have an easier time controlling her glucose. She will be more insulin sensitive. Estrogens are upregulating glute 4, they're enhancing insulin sensitivity in the muscles and in the liver, generally promoting both greater glucose use in the muscle and then preventing that liver from dumping out glucose when, when the body doesn't want it. So again, during the follicular phase with, with this estrogen dominant period of time, the woman will have an easier time controlling her glucose and insulin sensitivity. However, during the ludal phase, where the little, the ovulation has occurred and now there's this remnant little structure where the follicle is called the corpus ludium. That's why it's called the ludal phase, this little remnant str in the ovary, whatever, whichever ovary ovulated the egg. Now this is a progesterone dominated period of time. And progesterone can induce insulin. Progesterone. There's not multiple. I shouldn't have said that. Progesterone can induce insulin resistance. It antagonizes estrogen's effects in this regard, leading to decreased glute 4 movement and reduced glucose uptake. Also, progesterone, just as a interesting aside, stimulates fat storage. This also, you know, promotes, you know, a general, a difference in the metabolic milieu because estrogens promote greater fat use. So progesterone, when it comes to metabolism, while they do have similarities at certain aspects of the body or some complementary effects, estrogens and progesterone, when it comes to insulin, glucose, even fat metabolism, which is not the topic at hand, they end up fighting against each other. So it is the difference, it is the balance of estrogen, estrogens and progesterone that is crucial for understanding the variations in glucose metabolism in the woman during a normal ovarian cycle. Now, as we wrap up or near the end of this discussion, let's just touch on menopause because I can anticipate the questions already. What happens during menopause? Of course, menopause is a state where the, the ovaries now are empty of eggs. And with the, with all the eggs having been spent, she now does not have these high changes in estrogens and progesterone. Everything starts to flatline. And so there is a marked decline in estrogens, of course, progesterone as well. But it's the estrogens that matter a little more. After all, when it comes to metabolic health, she norm, a woman normally wouldn't care for progesterone because it tends to not be overly favorable. So it's the loss of estrogens that really matter most. And it, that's the, that's what's most significant. So with menopause, we have the significant drop in estrogens, which does have a consequential effect on glucose metabolism. First and foremost, she will immediately experience a greater degree of insulin resistance. She has lost out on this favorable signal of the estrogens, as I said earlier, greasing the skids, you know, helping the insulin just work a little better. She also has a slightly lower level of AMPK activation at any given moment. And when AMPK is activated, the cell wants to use energy. As related but somewhat tangential, estrogens tell the body where to store fat by stimulating the expression of an enzyme called lipoprotein lipase. This is something I've touched on a long time ago in a metabolic classroom. But just to revisit it very briefly, why does a little girl start to look so different from her little boy friend as they start to go through puberty? It's all about sex hormones. And it's those estrogens that are stimulating the expression of an enzyme that tells the body where to store fat. Again, that enzyme is lipoprotein lipase. And as you might guess, estrogens are telling her body to express more lipoprotein lipase in the prototypical female areas, like breasts or buttocks and hips or upper arm as well. Now, of course, there's variety across all people. Whereas androgens, the male sex hormones, increase lipoprotein lipase generally in the abdominal space almost totally. Now, with the loss of her estrogens, she can also start to experience a shift in where she stores fat, storing it in these very healthy places like on the buttocks and hips. That's a very healthy place to store fat and storing it more centrally, which is a less healthy place to store fat, because those fat cells, particularly in the Visceral space tend to only grow through hypertrophy. And as you know well by now, fat, fat cells are more harmful than more abundant but smaller fat cells or skinny fat cells. So that also compounds the problem. So that then begs the question that I know you're thinking now, which is, well, what about hormone replacement therapy? That is a very polari and it's one that I don't care to heavily wade into. Those are troubled waters. I am fine with people coming to their own conclusions. There are considerations, there's evidence for and against them, and I leave that up to you to make that decision, of course, because I'm not your clinician at all. I'm just your friendly neighborhood scientist. But when it comes to the metabolic consequences, there's no question hormone replacement therapy can help mitigate a lot of the negativity that comes from losing the estrogens, including maintaining a female fat storage pattern as and helping maintain an insulin sensitivity that the estrogens were providing. Now, there are other considerations, including potential cancer concerns, etc. Which I believe are very meaningful, but that's a topic for another time. I hope these thoughts have been helpful. I hope it's helped you understand your own body and your own metabolic nuance, particularly for the women who tuned in to this. It is complicated. And while you can be a little frustrated at these changes, maybe sometimes take a step back and appreciate just how. Just how nuanced and delicate it all is. I've joked before that if male fertility is a barbershop quartet, female fertility is like a 100 piece orchestra. There are a lot of parts that play together generally very nicely. And that's. That's pretty miraculous. Now, as much as we focus on sex hormones strictly through the lens of fertility, what is fertility without metabolism to support it? And so it's no surprise that even these sex hormones, estrogens in this case being the discussion today, have a powerful effect on telling the body what to do with energy. Not only in their own right. Estrogens have their own direct signals, but by also complementing the actions of other more metabolically minded hormones, most especially insulin. Thanks for joining me. Until next time, more knowledge, Better health. With the loss of her estrogens, she can also start to experience a shift in where she stores fat. Storing it in these very healthy places like on the buttocks and hips. That's a very healthy place to store fat and storing it more centrally, which is a less healthy place to store fat, because those fat cells, particularly in the visceral space, tend to only grow through hypertrophy. And as you know well by now, fat, fat cells are more harmful than more abundant but smaller fat cells or skinny fat cells. So that also compounds the problem. So that then begs the question that I know you're thinking now, which is, well, what about hormone replacement therapy? That is a very polarizing subject and it's one that I don't care to heavily wade into. Those are troubled waters. I am fine with people coming to their own conclusions. There are considerations, there's evidence for and against them, and I leave that up to you to make that decision, of course, because I'm not your clinician at all. I'm just your friendly neighborhood scientist. But when it comes to the metabolic consequences, there's no question hormone replacement therapy can help mitigate a lot of the negativity that comes from losing the estrogens, including maintaining a female fat storage pattern as and helping maintain an insulin sensitivity that the estrogens were providing. Now, there are other considerations, including potential cancer concerns, et cetera, which I believe are very meaningful. But that's a topic for another time. I hope these thoughts have been helpful. I hope it's helped you understand your own body and your own metabolic nuance, particularly for the women who tuned in to this. It is complicated. And while you can be a little frustrated at these changes, maybe sometimes take a step back and appreciate just how, just how nuanced and delicate it all is. I've joked before that if Male Fertility is a barbershop quartet, Female fertility is like 100 piece orchestra. There are a lot of.