insulin resistance

Stress, Hormones, and Migraine

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Here you can read a small and slightly modified section from my upcoming book “Fighting the Migraine Epidemic: A Complete Guide. How to Treat & Prevent Migraines Without Medicines.” This is the 2nd edition of my book that thousands of migraineurs have used for years. The excerpt here explains what stress is in terms of the body, how it is connected to hormones, and why it may end up as a migraine for those who have what I call a migraine-brain. Migraine-brain is anatomically and physiologically very different from a non-migraine brain and this difference gives rise to the possibility of a trigger, causing a migraine.

Listing triggers is one thing; understanding them and explaining how they initiate a migraine is much more difficult—this is just a taste of the full explanation found in the book.

Stress in Biology

Stress is probably one of the most common words in our everyday use. By stress we normally mean something that makes us busy, angry, we find irritating, or we simply feel under duress, or even extremely happy for the moment. Here is well-accepted definition of stress in biology:

“…a person’s response to a stressor such as an environmental condition or a stimulus. Stress is a body’s method of reacting to a challenge… Stress typically describes a negative condition or a positive condition that can have an impact on a person’s mental and physical well-being” (quote).

The body’s reaction to the negative or positive environmental stimulus takes place by the activation of the autonomic (unconscious) nervous system via biochemical processes. This was a mouthful, so let’s take it apart: environmental stress on the body initiates internal chemical processes, these in turn activate systems in the body that are not under conscious control, such as anxiety, fight-or-flight, IBS, RLS, heartbeat, heavy breathing, nausea, vomiting, diarrhea, dizziness, etc. Stress need not be negative. Positive environmental influences can just as much affect our stress response. For example, extreme happiness about getting an A on a test in a hard subject, ending up with a sunny warm day when the forecast predicted cold and gloomy weather on vacation, getting a new job, getting engaged or married, all can bring on a euphoric high, causing a hormonal changes that results in a migraine. Such a stressor is also one of the reasons why laughing strongly we may find ourselves crying. Thus, a stressor can both come from positive and negative stimulus. Both can cause stress on the body, and change many hormones that, in the case of a migraineur, can disrupt electrolytes, and thereby, cause a migraine.

Stressors, Cakes, and Migraines

Many people respond to stress by craving sweets. Eating a piece of cake at a wedding or birthday makes one feel good because it releases dopamine in the brain (1, 2). This can cause many undesirable after-effects such as hunger, shakiness, sugar crash (reactive hypoglycemia), as well as a migraine. Thus, while eating sweets is a customary celebration of life events and a happy end to dining out or watching a favorite movie, for migraineurs it is a major stressor. The reason is that migraineurs are glucose sensitive (3-7). To show the problem, I grab a quote from my medical manual:

“…serum Na+ [sodium] falls by 1.4 mM for every 100-mg/dL increase in glucose, due to glucose-induced H2O [water] efflux [exit] from cells” (8)

While a 100-mg/dL increase in blood glucose seems unrealistic—after all the guideline is that the healthy blood glucose level is between 70 and 140 at all times, but for those who are glucose sensitive, the increase can be significantly higher. I am a migraineur (and therefore, glucose sensitive) and have tested this on myself. I don’t eat sugar so I ate 20 cherries instead. The amount of glucose in the 20 cherries is miniscule compared to a slice of cake, 21 carb grams, of which only 10 grams is glucose: 2.5 teaspoons of pure glucose. The human body’s entire blood supply only contains 1 teaspoon of sugar, by eating 20 cherries I more than tripled the amount. This showed up as a near 100-point increase in my glucose 30 minutes after I finished the cherries. Before you give a thought to insulin resistance in my case: don’t. My blood sugar returned to normal in about one hour. Glucose sensitivity is neither diabetes nor insulin resistance, but it represents a glucose regulation genetic variance. So you can see that by eating a piece of cake, a major electrolyte problem will follow (both sodium and water leave the cells), especially for those with glucose sensitivity.

In the book, I thoroughly discuss electrolyte disruption. Here, I refer you to an article in which I summarized some of the genetic variances associated with migraineurs being so sensitive to the dysregulation of their electrolytes—particularly by the loss of sodium.

Can Stress Disrupt Electrolytes?

For a very long time I’ve heard people say that stress brings on headaches, but not migraines—this is not true. Our nervous system translates external stress and transmits it to relevant internal organs, tissues, and cells via hormones. In response to this hormonal change, the affected cells change their biochemistry. This internal biochemical change is the stress response to the external stress events and conditions. Just as there are internal stressors, such as the menstrual cycle or a tummy bug, that can change the body’s chemistry, so can external stressors create biochemical imbalances and disturb hormonal processes. To help you distinguish very clearly between external and internal stressors, here are three short examples with connection to a chain-reaction of effects:

External stressor: a migraineur driver gets stressed out about the traffic-jam on the freeway. This causes her adrenaline, steroid, cortisol, and other stress hormones to increase, blood pressure to rise, and her heart to pump faster and stronger, creating a potential for heart attack or stroke. In this case, an external factor directly caused the internal stress on the vascular system.

Internal stressor: the increase in our driver’s blood pressure causes extra stress on her arteries. This alone can cause trouble for the vascular system but let’s continue to the brain. This extra stress calls on the brain and its neurotransmitter activities to use energy for satisfying the higher demands of brain regions reacting to the external situation, and being involved in the preparations for a possible response to it. This unplanned, extra physiological activity may force the neurons in the driver’s brain to work at a pace that is above what she is prepared for—her threshold—while she is simply sitting in her car. Increased energy levels are needed, but as she is fuming over the traffic jam, she is not providing any extra energy (e.g., food) to address the deficit. During this unexpected energy expenditure – this internal stress – the body must suddenly work harder without any increase in nutrition and hydration. If not mitigated, this will lead to a biochemical imbalance, i.e. electrolyte disturbance. So even if the external conditions have not directly caused a life threatening, vascular reaction, that is, she was not hit by a stroke or a heart attack, the stress may still end up giving her a migraine.

This is not a good situation for anyone; even non-migraineurs often come down with a stress headache. Furthermore, some of these hormones use insulin receptors, thereby leaving few insulin receptors free to pick up glucose, reducing the speed with which blood glucose can be delivered to cells by insulin. The longer glucose stays in the blood, the unhealthier it is. Having lots of glucose in the blood for a long time is biologically equivalent to insulin resistance. Since all insulin receptors are taken up by steroid hormones, the brain is not receiving glucose, so it requests the liver to release glucose—the liver retains a supply of glycogen for this reason. However, receiving more glucose (from the liver) into the blood when the insulin receptors are still occupied by steroid hormones just increases the level of glucose in the blood, while the brain continues to starve.

Stress on the Brain: a neuron is stimulated by the unpleasantness of the traffic. The neuron’s message is transferred to another neuron by the neurotransmitters it passes into their shared synapse. Since the migraine brain is endowed with more sensory receptor connections than normal, whatever neurotransmitters a sensory neuron releases, more receptors will pick them up with the effect of amplifying the signal. This is why migraineurs are “hyper sensitive” to odors, sounds, etc. The migraineurs’ hyper sensitive brain amplifies everything sensory.

The Migraine

How does this become a migraine? The answer is quite simple. If we stimulate a single neuron and no other neuron pays attention (as in a non-migraine brain), all the effort of that neuron is inhibited, the fire is put out, and no energy is used. When a migraine brain is stimulated, the activation of the neurons with many more receptor connections pass the signals to more neurons—the signal will be amplified. More stimulation results in alarm level reactions. The release of the extra neurotransmitters uses more energy; a migraine-brain uses much more energy than the brain of a non-migraineur. Using more energy means the brain needs to take in more energy. The kind of energy needed is for action potential generation, which requires salt (sodium chloride) and not glucose. Unfortunately, if the migraineur doesn’t recognize the need for salt, sugar cravings will follow! The more sweets are eaten, the more sodium and water is lost from the cells and the more trouble the migraineur gets into. Without eating salt, the region deficient in energy will stop producing action potential and will go off-line. Neuron regions that went offline and cannot create action potential are said to experience cortical depression, which initiates cortical spreading depression (watch the video to see how it moves), which is a wave of voltage from unaffected parts of the brain, that can reach the pain sensory nerves in the meninges. Migraine pain is on its way!

Having pain when something is not working right is an evolutionary advantage, but in the case of migraineurs, the sensitivity is in overdrive. Migraine management and prevention requires quick actions and very serious maintenance of the electrolyte homeostasis. Because of the hyper sensory sensitivity of the migraine brain, the electrolyte minerals for a migraineur need to be in different density from that of a non-migraineur. In conclusion: stress is a migraine trigger.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

Additional Sources:

  1. Rada P, Avena NM, & Hoebel BG (2005) Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience 134(3):737-744.
  2. Avena NM, Rada P, & Hoebel BG (2008) Evidence for sugar addiction: Behavioral and neurochemical effects of intermittent, excessive sugar intake. Neuroscience & Biobehavioral Reviews 32(1):20-39.
  3. Mohammad SS, Coman D, & Calvert S (2014) Glucose transporter 1 deficiency syndrome and hemiplegic migraines as a dominant presenting clinical feature. Journal of Paediatrics and Child Health 50(12):1025-1026.
  4. Gruber H-J, et al. (2010) Hyperinsulinaemia in migraineurs is associated with nitric oxide stress. Cephalalgia 30(5):593-598.
  5. Kokavec A & Crebbin SJ (2010) Sugar alters the level of serum insulin and plasma glucose and the serum cortisol:DHEAS ratio in female migraine sufferers. Appetite 55(3):582-588.
  6. Dexter JD, Roberts J, & Byer JA (1978) The Five Hour Glucose Tolerance Test and Effect of Low Sucrose Diet in Migraine. Headache: The Journal of Head and Face Pain 18(2):91-94.
  7. Shaw SW, Johnson RH, & Keogh HJ (1977) Metabolic changes during glucose tolerance tests in migraine attacks. J Neurol Sci 33(1-2):51-59.
  8. Longo DL, et al. (2013) Harrison’s Manual of Medicine 18th Edition (McGraw Hill Medical, New York).

Image by Pedro Figueras from Pixabay.

This article was published originally on July 10, 2017. 

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Hormones, Birth Control, and Insulin Resistance

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birth control insulin resistance

Little known fact. Your reproductive hormones influence how your body responds to insulin. The artificial hormones in hormonal birth control also play a huge role in how your body responds to insulin. And, your body’s response to insulin determines how well you are able to use glucose to supply your daily energy needs.

In this article, we will discuss the basics of how your body creates energy. In this first section, we will unpack:

  • How your body creates energy from glucose
  • Glucose vs. fatty acids as an energy source
  • How insulin resistance impacts the shift between glucose burning and fat burning
  • How glucose enters your cells to become fuel for energy
  • How insulin resistance interferes with the transfer of glucose into your cells

Then, we will tie in how your natural reproductive hormones, estradiol and progesterone, impact your body’s use of glucose as a fuel source and discuss how hormonal birth control disrupts this natural balance.

How the Body Creates Energy From Glucose

Many of your cell types are designed to run on glucose, a metabolic product of carbohydrates, as their main source of energy, and in fact, certain cells that don’t contain mitochondria (or contain very few mitochondria) like red blood cells and cells of certain parts of your eye (lens, retina, and cornea) rely either exclusively (as is the case for red blood cells) or primarily on glucose as an energy source.

The reason for this is that mitochondria are responsible for aerobic (oxygen required) energy creation processes within your body, and cells with no or very few mitochondria rely mostly on anaerobic (no oxygen required) energy creation by glycolysis in the cytoplasm of the cell. As we will discuss in more detail later, when your body uses fatty acids as a fuel source, this pathway is purely aerobic, so it is not possible for fatty acids to be used in anaerobic energy creation processes within your cells.

When you eat a meal containing sugar (sucrose) or carbohydrates, enzymatic processes begin breaking the sugar and carbs down into their basic structures within your digestive tract. The structure of both sugar and carbs contain glucose.

Glucose fuels the creation of ATP in a process known as glycolysis, which happens within the cell, and through oxidative phosphorylation (OXPHOS), which happens within the mitochondria (substructures within the cell). When ATP is broken down within your cells, it releases energy, which is harnessed to power your mitochondria and other important cellular functions. The by-products of that ATP creation (pyruvate and ATP) fuel additional energy production cascades within the cell.

How the Body Switches From Glucose to Fatty Acids for Energy

Even when particular cell types prefer carbs (glucose) as their energy source rather than fatty acids, most cell types are capable of using either of these macronutrients (and also, when necessary, amino acids) as a fuel in order to survive periods of fasting (including overnight fasting).

Insulin plays a key role in regulating whether your body uses glucose (glycolysis in the cell’s cytoplasm and OXPHOS in the mitochondria) or fatty acids (lipolysis in the cell’s cytoplasm and fatty acid oxidation in the mitochondria) as its preferred fuel source. This is because insulin impacts the ratio of two key enzymes (malonyl Coenzyme A and acetyl CoenzymeA) that determine which of these energy pathways is preferred (here and here). The ratio of these enzymes is dynamic, changing throughout the day in response to when and what you eat, and in response to this fluctuating ratio, your body preferentially uses carbs (glucose) or fatty acids as its fuel source.

In an insulin resistant state, your body does not easily shift between glycolysis/OXPHOS (glucose as fuel) and lipolysis/fatty acid oxidation (fatty acids as fuel) and instead remains in a state of using fatty acids as fuel. We will talk about why this is the case in the next section.

How Glucose Gets Inside Cells

The glucose released in your digestive tract from the food you eat is absorbed into your bloodstream, and when your blood glucose levels start to rise following a meal (or any drink containing carbs or sugar), it signals your pancreas to release insulin.

Insulin is the messenger that lets your cells (specifically, your skeletal muscle, fat, kidney, and liver cells) know there is glucose available in your bloodstream.  Insulin does this by binding to the cellular membrane, and this activates glucose transporters on the cellular membrane.

Once blood glucose levels start to drop, a healthy body clears insulin fairly quickly so that it can maintain adequate blood sugar levels. Insulin must be cleared so that blood sugar doesn’t drop too low.

What Is Insulin Resistance?

A number of factors influence how your cells respond to insulin. External influences (like stress, diet, and lack of sleep) along with internal factors (hormonal fluctuations) play a role in how the cells respond to insulin. And, different types of cells respond differently to insulin. Skeletal muscle cells are the most sensitive to insulin. Fat cells and liver cells are also sensitive to insulin, and so these cell types (skeletal muscle, fat, and liver) are the quickest to take up extra glucose from the bloodstream.

When your body becomes more insulin resistant, the cells are not as able to respond to insulin. My favorite analogy for this is to imagine that you are at a rock concert. You cannot easily hear the person next to you because the volume in the venue is so loud that your ears are overloaded by the background noise. In order to carry on a conversation, you must move to a quieter place. In this scenario, insulin is the background noise or the decibel level. When you are insulin resistant, your pancreas releases extra insulin to try to get your body’s cells to respond. This would be the same as somebody yelling at you in a concert hall so that you are able to hear them speak.

When you restore insulin sensitivity, it is like taking your body out of that loud concert hall and placing it somewhere quiet. Now, you are able to hear and carry on a conversation without any problems. When you restore insulin sensitivity, the cells are capable of responding to a much lower amount of insulin much more quickly and take the action of absorbing glucose from the bloodstream.

Insulin Resistance Begets Insulin Resistance

With insulin resistance, the cells are used to the high insulin environment (partially deaf to insulin), so they stop responding to insulin’s call. This prompts the pancreas to release more insulin in order to get your cells to hear the message to soak up the extra glucose circulating in the bloodstream. When insulin is unable to be heard because of the high background noise (because there is so much circulating insulin the cells are deaf to it), then glucose isn’t taken up by the cells. This then creates the false message from your cells to key organs to start releasing stored glucose (in a process called gluconeogenesis) to supply the body’s energy needs.

When we are talking about diabetes, this feedback loop often, but not in everyone with diabetes, results in a perfect storm of upward spiraling blood sugar levels.

 

insulin resistance cycle common in diabetes showing increased insulin resistance triggering gluconeogenesis resulting in higher blood sugar levels which increases insulin resistance
Figure 1. Insulin resistance begets more insulin resistance.

Even in conditions besides diabetes where blood sugar levels are dysregulated, you might have one condition (for example, insulin resistance), without the other (increased release of glucose from your body’s reserves).

With all of that in mind, let us take a look at how reproductive hormones impact insulin resistance and gluconeogenesis, the process of releasing glucose from stored reserves.

Estradiol, Synthetic Estrogens, and Insulin Resistance

Reproductive hormones play a key role in insulin resistance. Most scientific studies agree that estradiol (the endogenous estrogen produced primarily in the ovaries throughout the reproductive years) boosts the release of insulin from the pancreas. While at first glance, this looks like estradiol might contribute to insulin resistance because it prompts release of extra insulin, the opposite is actually true.

Estradiol is widely accepted as a potent compound to restore insulin sensitivity. Whether this is because of upregulation of insulin from the pancreas or whether it is also because of the influence estrogen has on the cells when it binds to estrogen receptors or a combination of both of these is not clear. What is clear, is that estradiol encourages cellular uptake of glucose and more rapid reduction of blood glucose levels after a meal. Estradiol also reduces gluconeogenesis in the liver suppressing the release of free glucose into the bloodstream from the body’s reserves, and this supports healthy blood sugar levels (here and here).

Estrogen Concentrations and Insulin Resistance

How estradiol affects insulin resistance is concentration dependent. Estradiol concentrations in the bloodstream within the normal circulating range (not more than 1 nanomolar abbreviated 1 nM) are associated with healthy insulin sensitivity and healthy blood sugar levels while concentrations higher than 1 nM are associated with insulin resistance. This may be why gestational diabetes is a common condition during pregnancy with up to 10% of pregnant women in America developing gestational diabetes. Progesterone also plays a key role in gestational diabetes as we will discuss in more detail below.

Non-bioidentical Estrogen and Insulin resistance

Ethinyl estradiol, the most common synthetic estrogen used in hormonal contraceptives here in America, also impacts insulin resistance, but like endogenous estradiol, the relationship is not straightforward. Ethinyl estradiol has been shown to impact insulin sensitivity and gluconeogenesis differently depending on:

  • its concentration in the hormonal birth control
  • what progestin (synthetic progesterone) it is paired with

Just as high concentrations of endogenous estradiol increase the chances of dysregulated blood glucose control, the synthetic estrogen, ethinyl estradiol, also increases chances of dysregulated blood glucose control. Chemical diabetes caused by hormonal birth control is also well documented in the literature. This is one of the reasons why, since the 1960s, the concentration of artificial estrogens in combined oral contraceptives has been dramatically reduced from upwards of 60 micrograms per pill to as low as 10 micrograms. Currently, most birth control options contain from 20 to 35 micrograms of ethinyl estradiol per pill.

Estrogen Binds to Insulin Receptors Affecting Insulin Resistance

Estrogens, whether synthetic or endogenous, affect blood sugar regulation differently at different concentrations because of their ability to bind to insulin receptors. This concentration-dependent effect of both endogenous estradiol and synthetic estrogens is often overlooked in the conversation regarding the impact of hormonal contraceptives on blood sugar control. Inasmuch as estrogens play a role in insulin sensitivity, insulin secretion, and in gluconeogenesis, and because estrogens are combined in hormonal contraceptives with a wide range of synthetic progestins, the effects on blood sugar regulation are quickly compounded and convoluted.

Progesterone, Progestins, and Insulin Resistance

As with estradiol, the concentration of progesterone also impacts whether progesterone improves or diminishes insulin sensitivity. It is generally accepted that higher concentrations of progesterone during pregnancy are a major contributor to gestational diabetes. Similarly, high concentrations of progesterone, even after menopause, are linked to an increased risk of developing type 2 diabetes.

The actions of progesterone on glucose metabolism is very much related to carrying a pregnancy to term, promoting glucose storage (rather than consumption of glucose for fuel) and promoting ketogenesis (fat burning) within the body. Even when not pregnant, progesterone is the dominant hormone during the luteal phase (second half of your cycle), and this effects how your body uses glucose and its sensitivity to insulin. This ties into common experiences during the second half of your cycle including carb cravings, potentially diminished appetite (if you are like me), and also weight gain.

Unlike artificial estrogens, of which there is only one used in the combined hormonal contraceptives available in the United States, for progestins, the synthetic forms of progesterone, there are four generations of progestins, with each generation containing progestins of different molecular structures. The class of molecules used in synthetic progestins are similar in structure to the endogenous progesterone molecule, but they are not the same. In other words, they are non-bioidentical.

Progestins bind differently to the progesterone receptors within the body (and also bind to a variety of other receptors), than the endogenous progesterone and their specific structure contributes to how much and whether insulin resistance increases. The molecular structure also affects how the body conserves glucose (increases glucose storage) or uses glucose (in the process of gluconeogenesis). It is generally believed that the androgenic nature of progestins determine their role in reducing insulin sensitivity (here and here).

Hormones and Body Composition

An interesting note, whether we are talking about natural reproductive hormones, estradiol and progesterone, or artificial hormones, ethinyl estradiol and the various progestins, these are all fat-soluble hormones. That means, these hormones may be stored in, and thus, impact the behavior of fat cells. One study evaluated the response of fat cells (adipocytes) in the presence or absence of treatment with artificial hormones and found that in the presence of artificial hormones, the adipocytes were more insulin resistant. This suggests that fat cells may serve as a reservoir for artificial hormones and endogenous hormones alike. They essentially soak up circulating hormones from the bloodstream, and these absorbed hormones in turn impact how the fat cells behave.

This finding means that body composition affects how you respond to hormones, whether endogenous or synthetic, and vice versa. It also suggests that, among other things, we ought to consider dosing hormonal contraceptives relative to body composition. Women with higher body fat may store more of the hormones than those with lower body fat and this may initiate or exacerbate insulin resistance.

Summary

In summary, reproductive hormones are intricately intertwined with metabolism, both with how the body creates energy and how it stores fats and carbs to meet energy demands between meals. Hormonal birth control impacts this finely choreographed dance between reproductive hormones and insulin sensitivity, and this seemingly small influence has a dramatic ripple effect. Insulin sensitivity dictates things like weight gain, oxidative stress, and even, as we will discuss in the next article, susceptibility to UTIs and UTI like symptoms.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

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Popping the Obesity Balloon

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obesity

It is well known that obesity in the United States is in epidemic proportions. It is also well known that it presents a risk for metabolic disease, the most common being diabetes. Books have been written about various diets and appetite curbing pills are legion. It is, of course, obvious that the type of diet consumed by so many people is responsible. What has not been understood is the exact mechanism.

Obesity and the Brain

Fat is stored in cells called adipocytes (from Latin adep, fat) these cells are capable of producing a hormone called leptin. This circulates in the blood until it comes to the part of the brain known as the hypothalamus. The message that leptin delivers to this organ tells it that the fat stores in the body are full and food intake should be curtailed. It is an important mechanism of appetite control. It is not generally appreciated that it is the brain, not the stomach, that is responsible for the sensations of hunger and satiety, thus controlling appetite.

As usual in basic science research, leptin was discovered in mice. By injecting it into fat mice that were made to be leptin deficient experimentally, appetite control resulted in reduction in body weight to normal proportions. It was concluded that this would be the obvious treatment for obese humans. Clinical trials with leptin treatment in obese humans failed to make any difference. It was then found that these humans already had plenty of circulating leptin but the hypothalamus was insensitive to its message. Adipocytes were doing their part but the hypothalamus was unresponsive. The question then was why the hypothalamus was insensitive and not responding to this important mechanism. The next phase of research was published in a scientific journal called Cell. This is read only by a group of scientists that are studying the properties of the cells that make up the body. It will be a long time before this research reaches clinicians and it also has the disadvantage of having been performed in mice. The message is so transparent, I undertook to report it here because we can use it now.

Of Mice and Men

When mice were fed on a high-fat diet, a mechanism was found in the hypothalamus. A “master switch” that controls inflammation in the body was turned on. This switch normally remains inactive throughout life in healthy animals. However, with it turned on, the mice gained weight and became resistant to insulin and leptin. By using genetic engineering, the researchers were able to turn off the master switch and they were then protected from becoming obese, even on a high-fat diet. It has been known for a long time that obese people develop inflammatory disease. The mechanisms involved are extremely complex but the simple message is one that is timeless “don’t overeat, particularly high calorie junk foods”. It has also been long known that calorie restriction in experimental animals is the only way to extend their longevity. Hungry animals fed this way not only live longer than those fed with enough food to give satiety, they also remain much more active into old age. We are obviously not required to remain permanently hungry, only to reach satiety with the right food. It is therefore not surprising that “junk food” eaters are always hungry.

Diet Basics: Eat Real Food

If this research is true for humans, it may be that it is actually a protective factor as long as we obey the rules of diet that have been with us for thousands of years. It is only recently that we drive a two ton machine to a store to buy food in a variety of boxes packaged by a food industry that depends entirely on their products being purchased. We would not require anti-inflammatory drugs or even a special diet. All we would need is self discipline and a full recognition that the only food we should ingest is the natural food that I used to tell all my patients is “made by God”. The high calorie man-made foods, many of which are simple carbohydrates, should be rejected completely. This is, of course, advice that is bound to be ignored by the majority because our sense of sweet taste that provides so much pleasure is perceived by our brains. Also, natural food is expensive. Taste buds on the tongue send a sensory input signal to the brain where it is interpreted. Reducing it to first principles, so much of our diet is hedonistic. As the old saying goes, we live to eat rather than eating to live.

Sugar on the Brain

Sugar extracted from its natural source is more of a drug than a food. This is because censors on the tongue send an input message to the brain where the sensation of sweet taste is perceived and interpreted. I remember that several physicians wrote letters to medical journals to state that the sweetener, aspartame, was responsible for a number of symptoms in their patients identical to those induced by sugar, including migraine headaches. The manufacturers responded by performing a study in which aspartame was given to experimental subjects in the form of capsules that they swallowed, thus bypassing the sweet taste mechanism. The study showed that there was no evidence for migraine or any other symptoms as a result of administration of this chemical sweetener by this method, suggesting that its effects are produced by the sensory input from tongue to brain. I am personally highly sensitive to sugar. The ingestion of one cookie gives me whole-night insomnia. Since I am not unique, I wonder how many people are taking sleeping pills because of chronic insomnia induced by their innocent consumption of sugar.

Artificial Sweeteners: Chemical Cocktails

Aspartame breaks down in the body to formaldehyde (used to pickle bodies), formic acid (used by bees to sting) and wood alcohol (that makes people go blind). Irrespective of the chemical content of artificial sweeteners, however, they are no substitute for sugar since they are likely to do the same thing. The only escape is to break the sweet taste craving by “cold turkey” withdrawal. I have seen many people get well by doing this. Sometimes it only takes a very small intake of sweet taste to cause relapse and reappearance of the previous symptoms. To back up my conclusion that this is a drug effect, I have seen many people that cannot resist sugar, even though they know perfectly well that they will suffer for it. In fact, animal studies have shown that sugar is more addictive than cocaine.

Doctors and Self-Discipline

Doctors therefore have the responsibility to educate patients about how their God-given health can be maintained. We know now that our genes are drastically changed by poor diet and lifestyle and we therefore can produce diseases in ourselves. The choice is ours to make.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

Image capture from a YouTube video of a water balloon popping, various attributions.

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Stop the Metformin Madness

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Chandler Marrs

I have never been a fan of Metformin. It seemed too good to be true. Many years ago I had a conversation with a researcher about all of its possible therapeutic indications. His lab was actively pursuing the anti-cancer angle. That should have been a clue that Metformin might be causing more damage than we recognized, but it wasn’t. At that point, I was still enamored with the wonders of pharmacology and hadn’t yet begun my path toward understanding medication adverse reactions. Indeed, it wasn’t until very recently, when a family member began suffering from one of these reactions, that I began my investigation in full. This is what I learned.

Type 2 Diabetes is Big Business

The global profits from Type 2 diabetes medications rested at a paltry 23 billion dollars in 2011 but are expected to grow to over $45 billion annually by 2020. The market growth is bolstered in large part by the ever-expanding demand for therapeutics like Metformin or Glucophage. Metformin is the first line of treatment and standard of care for insulin resistance across all populations of Type 2 diabetics with over 49 million Americans on Metformin in 2011-2012. It is particularly popular in women’s health with an increasing reliance on Metformin for the metabolic dysfunction observed in women with PCOS, PCOS-related infertility, and even gestational diabetes. Metformin is prescribed so frequently and considered so innocuous that it is sometimes euphemistically referred to as vitamin M.

If we quickly scan the safety research for metformin, there is little immediate evidence suggesting any side effects whatsoever. In fact, in addition to controlling blood sugar by blocking the hepatic glucose dump, this drug is suggested to promote weight loss, increase ovulation in women, (thereby helping achieve pregnancy), and prevent an array of pregnancy complications (everything from miscarriage to gestational diabetes, pre-eclampsia and preterm birth). Metformin is argued to prevent cancer and the neurocognitive declines associated with aging, even aging itself. By all accounts, Metformin is a wonder drug. Why isn’t everyone on Metformin prophylactically? Increasingly, we are.

With the increasing rates of obesity and associated metabolic disturbances, drugs that purportedly reduce those indicators are primed for growth. Like the push to expand statin prescription rates from 1 in 4 Americans to perhaps 1 in 3, millions have been spent increasing the therapeutic indications and reach for this medication. Amid all the excitement over this drug, one has to wonder if it isn’t too good to be true. In our exuberance to get something for nothing, to have cake, if you will, have we overlooked the very real risks and side effects associated with Metformin?  I think we have.

Metformin and Vitamin B12 Deficiency

As we’ve reported previously, Metformin leaches vitamin B12 and to a lesser degree B9 (folate) from the body. One study found almost 30% of Metformin users are vitamin B12 deficient. For the US alone, that’s almost 15 million people who could be vitamin B12 deficient and likely do not know that they are deficient. What happens when one is vitamin B12 deficient?

Firstly, inflammation increases, along with homocysteine concentrations, which is a very strong and independent risk factor for heart disease (the very same disease Metformin is promoted to prevent).  And that is the tip of the iceberg.

Vitamin B12 is involved with a staggering number of physiological functions including DNA, RNA, hormone, lipid, and protein synthesis. Deplete vitamin B12 and a whole host of problems emerge, mostly neurological.

Vitamin B12 is critical for the synthesis of the myelin sheaths around nerve fibers. There is a growing relationship between multiple sclerosis, which involves the disintegration of myelin and brain white matter, and vitamin B12 deficiency.  Often the first signs of B12 deficiency are nervous system-related with cognitive disturbances and peripheral neuropathy among the most common.

Additionally, many women have dysregulated hormones connected to vitamin B12 deficiency. In light of the Metformin-mediated vitamin B12 deficiency, one has to wonder if some of the chronic health issues plaguing modern culture are not simply iatrogenic or medication-induced.

Metformin, Pregnancy and Maternal and Fetal Complications

Considering that half the population is female, many of whom are on Metformin and may become pregnant, we must consider the potential effects of Metformin-induced vitamin B12 deficiency during pregnancy. As troubling as the effects of B12 deficiency are on non-pregnant individuals, during pregnancy they can be devastating. Vitamin B12 deficiency during pregnancy leads to an increased incidence of neural tube defects and anencephaly (the neural tube fails to close during gestation). Once thought to be solely related to folate deficiency (vitamin B9) which Metformin also induces, researchers are now finding that B12 has a role in neural tube defects as well.

Scan the internet for Metformin and infertility and you’ll see long lists of fertility centers boasting the benefits of this drug. During pregnancy, the exuberance for vitamin M is palpable, although entirely misplaced. Early reports suggested Metformin would reduce an array of pregnancy complications including gestational diabetes. The data supporting these practices were mixed at best. At worst, however, they were downright incorrect. Metformin, it appears, may evoke the very conditions it was promoted to prevent during pregnancy and then some. Additionally, recent research suggests Metformin alters fetal development and induces long-term metabolic changes in the offspring, likely predisposing the children to Type 2 Diabetes, an epigenetic effect perhaps.

Metformin Inhibits Exercise-Induced Insulin Sensitivity

As if those side effects were not enough to question mass Metformin prescribing practices, it appears that Metformin reduces any gains in insulin sensitivity that normally would be achieved from exercise. I cannot help but wonder if Metformin impairs insulin signaling in general. Cancer research suggests that it might.

According to one study, physical exercise can increase insulin sensitivity by up to 54% in insulin-resistant individuals, unless of course, they are taking Metformin. Metformin abolishes any increased insulin sensitivity gained by exercise. Metformin also reduces peak aerobic capacity, reducing performance and making exercise more difficult. Moreover, despite claims to the contrary, Metformin does not appear to be an especially effective tool for weight loss, netting a reduction of only 5-10 pounds over 4-8 months. Regular exercise and a healthy diet net on average a loss of 5-10 pounds per month for most people and are significantly more effective at reducing diabetes and associated health complications without the potential side effects.

Metformin and Mitochondrial Damage

Perhaps most troubling amongst the Metformin side effects is its ability to severely impair mitochondrial functioning.

Recall from high school biology, the mitochondria are those bean-shaped organelles inside cells that are responsible for cellular respiration or energy production. Through a variety of pathways, the mitochondria provide fuel for cell survival. In addition to cellular energy production, mitochondria control cell apoptosis (death), calcium, copper, and iron homeostasis, and steroidogenesis. In essence, mitochondria perform the key tasks associated with cell survival, and indeed, human survival. Damage the mitochondria and cellular dysfunction or death will occur. Damage sufficient numbers of mitochondrion and chronic, multi-symptom illness arises.

As we have come to learn, many pharmaceuticals, environmental toxicants, and even dietary deficiencies can impair mitochondrial functioning and induce disease processes that are often difficult to diagnose and treat. Metformin is no different. Metformin impairs mitochondrial functioning quite significantly by several mechanisms and, in doing so, sets off a cascading sequence of ill effects.

At the center of metformin’s mitochondrial damage is its effect on the most basic of mitochondrial functions – ATP (cellular energy) production. Metformin reduces mitochondrial ATP production in skeletal muscle by as much as 48%. Sit with that one for a moment, a 48% reduction in cell fuel. Imagine functioning at only half capacity. This would make basic activities difficult at best and exercising to lose weight a very unlikely proposition. Imagine similar reductions in ATP production were observed in the brain or the heart or the GI tract (which, when on Metformin are likely), the types of disturbances we might see become quite clear: neurocognitive decline, psychiatric instability, neuropathy, heart rate, rhythm and blood pressure abnormalities, along with gastrointestinal distress to name but a few. Underlying all of these symptoms, and indeed, all mitochondrial dysfunction is an overwhelming sense of fatigue and malaise.

Metformin Alters Immune Reactivity via the Mitochondria

As I wrote in a previous post:

Some researchers argue that the mitochondria are the danger sensors for host organisms; having evolved over two billion years to identify and communicate signs of danger to the cells within which they reside. The signaling is simple and yet highly refined, involving a series of switches that control cellular energy, and thus, cellular life or death. When danger is present, energy resources are conserved and the immune system fighters are unleashed. When danger is resolved, normal functioning can resume.

If the danger is not resolved and the immune battles must rage on, the mitochondria begin the complicated process of reallocating resources until the battle is won or the decision is made to institute what can only be described as suicide – cell death. Cell death is a normal occurrence in the cell cycle of life. Cells are born and die for all manner of reasons. But when cell death occurs from mitochondrial injury, it is messy, and evokes even broader immune responses, setting a cascade in motion that is difficult to arrest.

Metformin alters this process, first by damaging the mitochondrial ATP factory and reducing energy production capacity and then by inhibiting the signaling cascades that would normally respond to the danger signals. The double hit fundamentally alters immune function and I would suspect predisposes those who take Metformin to more infections and an array of inflammation-based disease processes. More details on this in a subsequent post.

Metformin and the Statins: Beware

The mechanisms through which Metformin derails mitochondrial functioning are complex but likely related to depletion of coQ10, an enzyme involved in what is called the electron transport chain within the mitochondria. CoQ10 also referred to as ubiquinol and ubiquinone, is critical for mitochondrial functioning. Recall from a previous post, that statins, like Lipitor, Crestor and others also deplete coQ10 and from a pharmacological perspective these mechanisms are implicated in the development of atherosclerosis and heart failure.

“statins may be causative in coronary artery calcification and can function as mitochondrial toxins that impair muscle function in the heart and blood vessels through the depletion of coenzyme Q10 and ‘heme A’, and thereby ATP generation.”

CoQ10 depletion is also implicated in the more common statin-induced side effects like muscle pain and weakness and in severe cases, rhabdomyolysis. Since Metformin and statins are regularly co-prescribed, the potential for severely depleted mitochondria and significant side effects is very high. Consider muscle pain and weakness among the first signs of problems.

My Two Cents

When we contrast the reduction in glucose mediated by Metformin with the damage this medication does to the mitochondria and immune signaling, along with its ability to leach vitamin B12, block insulin sensitivity and reduce aerobic capacity, one cannot help but wonder if we are causing more harm than good. Admittedly, obesity and hyperglycemia are growing problems in Western cultures. As we are coming to learn, however, obesity itself is not linked to the diseases processes for which many drugs like statins and Metformin are promoted to protect against – the obesity paradox. Growing evidence suggests that obesity is indicative of mitochondrial dysfunction and chemical exposures which then may provoke impaired insulin sensitivity and hyperglycemia and continued fat storage versus metabolism. If this is true, simply reducing circulating glucose concentrations, in an effort to reduce obesity and the purported health problems associated with obesity, will do nothing to treat the underlying problem.

Insulin resistance and the associated hyperglycemia are environmental and lifestyle-mediated problems that should be reversible with environmental and lifestyle changes. Having said that, those lifestyle and dietary changes will fail unless we consider the underlying mitochondrial damage initiated by dietary choices, pharmaceuticals, and other environmental exposures. For that, we must dig deeper into mitochondrial functioning and correct what we can.

I believe obesity and hyperglycemia are symptoms of damaged and dysfunctional mitochondria, partly mediated by lifestyle, partly iatrogenic (pharmaceutically induced), and likely epigenetic. If we are to solve the ‘obesity’ problem and prevent the damage mediated by hyperglycemia, we have to address these variables. Failing to do so serves no one except those who profit from our continued ill-health.

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