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Insulin Resistance, the Scourge of Our Time

What do the following diseases of modern civilization have in common?:

  • Obesity
  • Fatty Liver
  • Type 2 Diabetes
  • Coronary Artery Disease
  • Hypertension
  • Peripheral Vascular Disease
  • Cancer of certain types
  • Alzheimer's Disease

They all stem from insulin resistance.  But what causes insulin resistance?  Why does the body become less responsive to insulin?

To understand that, we need to understand what insulin is. 

Insulin is a hormone released by the beta cells of the pancreas whose job, when bound to cells' insulin receptors, is to allow glucose (also known as blood sugar) to enter from the blood stream into our body's cells.  Glucose is the fuel that the cells use to make energy and perform their functions.  We can get glucose by eating carbohydrates -- starches and sugar -- but the liver can make glucose from protein and fat, if a person consumes few or no carbohydrates.

  • "Insulin resistance means that your body has become less sensitive to the effects of insulin, a powerful hormone released after meals that tells your body what to do with the calories you eat.... If you eat too much sugar and/or starch too often, as most people do, your blood glucose will spike frequently and your body will have to release lots of insulin over and over again to deal with those glucose spikes. Eventually your cells can become so accustomed to insulin spikes that they become less responsive to insulin. If your cells become numbed to insulin's signals, they can't absorb extra glucose from the bloodstream as well, and your blood sugar could stay too high for too long after meals. In response, the body releases even more insulin to try to get cells to respond better. One result of this vicious cycle can be type 2 diabetes, a disease marked by high blood sugar and high insulin levels."

How and why does insulin resistance, the cells' "becoming numbed to insulin's signals," develop?  This is where the liver comes in, because it plays a central role in metabolizing glucose and regulating the body's response to insulin release by the pancreas. 

The liver's central role in glucose metabolism and orchestrating the effects of insulin

As mentioned above, one of insulin's functions is to enable cells to transport glucose inside the cell, where it can be used by the cell to make energy.  Most cells have insulin receptors, most notably the liver, muscle, fat, brain and pancreatic beta cells.

But more than regulating glucose metabolism and homeostasis, insulin regulates growth.  It does this by directing what the liver does in the presence of glucose under varying circumstances.  After a meal containing carbohydrates (starches or sugar), the digestive system quickly breaks down the carbohydrates into glucose and releases it into the blood stream.  The liver is the first organ that encounters this spike in blood sugar:

  • "Under the influence of insulin, your liver can do any of following things with the new glucose load [after a meal], depending on your body’s needs at the time:
  • Burn it or ferment it for energy (ATP). If liver [and the body's other] cells need energy to conduct their cellular business, glucose will be chopped in half in preparation for burning in the mitochondria (your cellular furnace)....
  • Transform it into 5-carbon building blocks (ribulose-5-phosphate) plus powerful helper molecules (NADPH) required to build components of new or growing cells, such as proteins, RNA, and DNA....
  • Store it as glycogen or fat. In a process called glycogenesis, the liver strings glucose molecules into long chains of animal starch called glycogen, which is stored in the liver. If the liver’s glycogen tank is already full, glucose can be turned into fat instead (lipogenesis). The healthy liver doesn’t store much fat; it prefers to ship it out to other cells by releasing it into the bloodstream as triglycerides."

And here we can see where problems might begin.  What happens if you consume excess amounts of carbohydrates -- in particular refined carbohydrates like white flour and sugar -- and too often, as most modern humans living in the US do?

What happens is that the liver begins to churn out a lot of triglycerides and circulate them for storage in the body's fat cells.  This happens because you are consuming more carbohydrates than are needed to be burned for energy.  This increased circulation of triglycerides and the build-up of excess fat is how eating excess carbohydrates makes you overweight and obese, and underlies the mechanism of insulin resistance.

The mechanism of insulin resistance: excess circulating triglycerides interfere with intracellular insulin signaling

These excess triglycerides and their free fatty-acid by-products circulating in the blood work their way into cells.  There they begin to disrupt the cell's insulin signaling pathway.

Normally, after a spike in blood sugar, insulin arrives on a cell's insulin receptor and signals the cell to open its glucose transport channel (GLUT) to allow glucose inside the cell to be burned for energy.

But with the cell's insulin signaling pathway interfered with by triglycerides and free fatty acids, the glucose transport channel remains closed and glucose cannot get inside the cell, but instead remains in the blood stream.

The beta cells of the pancreas detect the still-elevated blood glucose levels and release yet more insulin into the blood stream.  And thus the vicious cycle of insulin resistance begins.

This lecture by medical educator Dr. Mobeen Syed beautifully explains the mechanism underlying insulin resistance:

The result of insulin resistance: hyperglycemia, hypertriglyceridemia, glycated proteins, oxidation, and chronic inflammation

Over time, as insulin resistance becomes progressively worse, and blood sugar levels remain chronically elevated, a variety of damage occurs in the body by the following mechanisms:

  • Glycation:  "excess blood sugar can bind to vital proteins, DNA, RNA, and fats in the body and damage them, sometimes beyond repair. This process is called “glycation”. Think of it this way: sugars make proteins sticky. Proteins are supposed to be able to fold and move in special ways to perform their various special functions, but they can’t do that if sugar is gumming up the works. When sugars bind permanently to proteins, they turn the proteins into nuisance compounds called “Advanced Glycation End Products” or AGE’s. AGE’s have been linked to a wide variety of chronic diseases, including heart disease, kidney failure, diabetic retinopathy, Alzheimer’s disease, and aging."
  • Oxidation:  "Fast carbs [refined carbohydrates] are “pro-oxidants.” This means that they have the power to damage important body molecules, such as DNA, by stealing their electrons away from them. Pro-oxidants are the opposite of anti-oxidants; they fight against each other.... Oxidative damage caused by pro-oxidants such as sugars can be the first step towards serious problems, such as cancer (by damaging DNA) and heart disease (by oxidizing cholesterol)."
  • Inflammation:  "Both glycation and oxidation trigger inflammation in the body. Physicians and scientists have come to understand that most common chronic diseases are rooted in inflammation. This is not necessarily the kind of inflammation we can see or feel—it is usually on a much smaller scale that we may not be aware of. For example, the cholesterol plaques that block arteries to the heart and cause heart attacks are found to contain all the mini-markers of inflammation when you look at them under a microscope. Even diseases such as depression are associated with mini-markers of inflammation."

This lecture by Dr. Mobeen Syed reviews with wonderful clarity the damage that can accrue in various bodily systems as a result of the glycation, oxidation and inflammation that occur due to the chronically elevated blood sugar caused by insulin resistance:

The carbohydrate hypothesis of disease

Thus it seems like a good idea to limit the consumption of carbohydrates -- in particular refined carbohydrates, which cause the fastest, largest spikes in blood sugar -- in order to keep our blood sugar levels steady, and to avoid inducing insulin resistance.

Indeed, there is growing scientific and medical consensus in the past decade or so that the diseases of modern, Western civilization are caused by the over-consumption of refined carbohydrates in the modern, Western diet.

A diet limiting the intake of refined carbohydrates and regular exercise are the best way to control blood sugar levels.  The nutritional supplements below may help to control blood sugar levels and to support the liver, the organ which is centrally involved in glucose metabolism and orchestrating the body's response to insulin, but they will not allow you to be sedentary and to engorge yourself on refined carbohydrates.

Choline for liver health

Keeping the liver healthy is critical to maintaining healthy glucose metabolism, insulin signaling, and to controlling inflammation throughout the body.

As insulin resistance progresses to type 2 diabetes, fatty liver disease is a common complication; the two are highly correlated with each other (12).   As of 2016, approximately 25% of US adults were estimated to have non-alcoholic fatty liver disease (NAFLD); and of those with NAFLD, up to 20% have the more severe non-alcoholic steatohepatitis (NASH), liver inflammation due to fatty deposits. 

NASH can lead to fibrosis (scarring) of the liver and, over time, to cirrhosis (permanent scarring and damage) and liver cancer.  Liver cancer is the most common cancer in the world, and choline deficiency likely in part explains the worldwide epidemic of fatty liver disease. 

Choline is an essential nutrient for maintaining liver health, and one that must be gotten from the diet.  Choline is a key source of methyl groups, molecules consisting of one carbon and three hydrogen atoms.  Methyl groups, and the biochemical processes they take part in, called methylation and demethylation, regulate the expression of our genes.  The liver is the main organ in which methylation and demethylation reactions occur.

Additionally, without choline, the liver is unable to clear triglycerides (fats) from itself.  And as we saw, the liver's churning out of excessive trigycerides in response to over-consumption of refined carbohydrates is the trigger of insulin resistance.  A deficiency of choline is intimately involved with the liver becoming fatty as insulin resistance progresses:

  • "The two major fates for choline are to be phosphorylated and used to make phospholipids, or to be oxidized and used as a donor of methyl-groups. An especially important choline metabolite in liver is phosphatidylcholine, which is necessary for the packaging and export of triglycerides in very low density lipoprotein (VLDL) [] and for the solubilization of bile salts for secretion []. Aberrant VLDL– mediated secretion of triglycerides is a central mechanism in hepatic steatosis []."

Indeed, this 2019 study found that obese, insulin-resistant, and type 2 diabetic patients had much lower levels of choline in their blood and higher markers of impaired liver function than both lean body-mass index patients, and obese but non-insulin-resistant patients.  So choline seems to have a protective effect against insulin resistance and impaired liver function even in obese persons.

Although choline is an essential dietary nutrient, at least 75% of U.S. adults consume less than the Adequate Intake (AI) levels of 7.5 mg of choline per kg of body weight (the AI level is higher during pregnancy and lactation).  In those over the age of 71, only 4% of men and 2% of women are getting the recommended AI levels.  Note that the AI levels of choline are minimum levels that were set by the U.S. Institute of Medicine to avoid impaired liver function.  The AI levels are not optimal levels.

Silymarin (Milk Thistle extract)

Silymarin is the active extract of milk thistle (Silybum marianum), a plant that has been used for thousands of years by traditional societies to treat various ailments, in particular liver ailments:

  • "Silybum marianum has been used since the time of ancient physicians and herbalists to treat a range of liver dysfunctions and gallbladder disorders. The first records of this plant can be found in the Old Testament (Genesis 3:18). In ancient Greece, the Silybum marianum was administered to cure liver dysfunction. It has been also discovered that Indian and Chinese medicines used Silybum marianum in clinical practice for liver and gallbladder problems []. Its hepatoprotective action has been proven by many researchers [,,]. Thanks to its healthful properties, silymarin—an extract of milk thistle fruits—was classified by the WHO in the 1970s as an official medicine with hepatoprotective properties []."

In recent decades, scientific research has established that silymarin has numerous properties that may make it beneficial for the treatment of liver diseases:

  • It is a powerful antioxidant, acting as both a free radical (reactive oxyen species/ROS) scavenger, and an inhibitor of lipid peroxidation;
  • It inhibits pro-inflammatory signaling pathways, such as those derived from nuclear factor-κB (NF-κB) activation, involved in the synthesis of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6;
  • It increases sensitivity to insulin and improves glucose metabolism;
  • It inhibits accumulation of fat in the liver, other visceral fat and reduces blood triglycerides by modulating genes that trigger lipolysis (breaking down of fat);
  • It has antifibrotic (anti-scarring) activity and can induce apoptosis (cell death) in cancer cells

In clinical trials of patients with NAFLD and NASH, silymarin:

  • normalized liver enzyme levels;
  • reduced fatty liver;
  • reduced liver fibrosis and inflammation;
  • improved insulin sensitivity; 
  • reduced fasting blood glucose

One problem with taking silymarin orally is its poor solubility and absorption.  This can be improved by taking it with meal containing agents that improve its solubility:  choline, protein, fat, cholesterol or other flavonoids.

Alpha Lipoic Acid

Alpha lipoic acid (ALA) is an essential water- and fat-soluble co-factor for enzymes in the Krebs cycle, which feeds the Electron Transport Chain that produces mitochondrial energy in the form of ATP.   Without ALA our cells would not be able to produce energy. 

ALA is produced in very small amounts by the body, and can also be gotten from food in modest amounts.

ALA also functions as a powerful antioxidant, reducing oxidative stress by scavenging reactive oxygen species (ROS) and chelating heavy metal toxins.

This systematic review and meta-analysis of clinical trials found that alpha lipoic acid supplementation in patients with metabolic diseases:

  • reduces fasting blood glucose
  • reduces insulin resistance
  • reduces blood triglycerides
  • reduces hemoglobin A1c (a measure of the percentage of hemoglobin in the blood that is glycated)

Curcumin is the most prevalent active compound derived from the roots of the turmeric plant (curcuma longa), and is commonly used as a spice, food coloring and in ayurvedic medicine as a treatment for inflammatory diseases.  Curcumin has been shown in numerous studies to have potent anti-inflammatory and antioxidant properties

  • It down-regulates several transcription factors, such as nuclear factor kappa beta (NF-kB), and protein kinases, such as mitogen-activated protein kinase (MAPK), involved in pro-inflammatory pathways such as those in the production of pro-inflammatory cytokines (e.g. IL-6), tumor necrosis factor alpha (TNF-a) and signal transducer and activator of transcription (STAT) proteins;
  • Its chemical structure acts as an electron trap, preventing the formation of pro-oxidant reactive oxygen species (ROS);
  • Its chemical structure also enables it to chelate heavy metals, thus protecting against metal-induced toxicity;
  • It is ten times more powerful than vitamin E as a free-radical scavenger;
  • In addition to acting as a direct scavenger of ROS, it increases levels of gluthatione, the body's master antioxidant;
  • It is able to cross the blood-brain barrier, and is thus able to protect the brain from oxidative stress and inflammation

This systematic review and meta-analysis of randomized clinical trials of curcumin for NAFLD found that curcumin:

  • Reduced fasting blood glucose
  • Improved insulin sensitivity
  • Reduced liver enzymes (markers of liver function)
  • Reduced waist circumference
  • Reduced blood triglycerides
  • Reduced body-mass index (BMI)

However, one challenge that must be overcome with curcumin is that its bioavailability is very low, perhaps as low as 1% for unformulated curcumin.  Support Protocols Turmeric Curcumin Phytosome, however, uses Meriva®, a patented formulation of curcumin that uses phosphatidylcholine to increase its bioavailability 29-fold compared to unformulated curcumin.

Glutathione, the master antioxidant

We saw above that refined carbohydrates are pro-oxidant, and that elevated blood glucose causes oxidation, which, along with glycation, triggers the chronic inflammation that underlies the many diseases stemming from insulin resistance.

Glutathione is the body's 'master antioxidant' and detoxifying agent.  It is a tri-peptide (three amino acid) compound that is produced in the cytoplasm of every cell in the body, with a high concentration in the liver.  Although glutathione is made by the body, it is critical that our diet provide either glutathione precursors, or glutathione itself, in order to maintain adequate levels of glutathione.  Modern diets, because of the high prevalence of processed foods, provide only negligible amounts of glutathione.

Glutathione, called the body's "master antioxidant:"

  • Plays a critical role in the body's detoxification process;
  • Has a central role in maintaining the function of both the innate immune system (e.g. Natural Killer cells) and the adaptive immune system (e.g. T cells);
  • Relieves symptoms of respiratory conditions by reducing inflammation in lung tissue;
  • Increases insulin sensitivity by reducing inflammation in fat cells and insulin receptors;
  • Reduces the risk of cardiovascular disease by protecting against oxidative damage in heart tissue and by having a vasodilating effect;
  • Boosts brain health by protecting against oxidative damage in brain tissue

Supplementing with N-acetyl cysteine (NAC) as a strategy to boost glutathione levels is common.  Although NAC is commonly used because of its believed ability to boost glutathione levels, its ability to do that is not clear:

  • "Three conditionally essential amino acids, glycine, cysteine, and glutamic acid combine to form glutathione in a two-step biochemical reaction.... Cysteine is frequently identified as rate-limiting, which provides the rationale of why N-acetylcysteine (NAC) is frequently studied and suggested as a supplement for glutathione support [], yet a review of the data indicates its use may be inconclusive or equivocal.... Although NAC is promising as a supplement to both boost glutathione levels and potentially mitigate some of the issues related to oxidative stress [,], the research is not conclusive [,,,]"

Nevertheless, the reason that people supplement with glutathione precursors like NAC is because of glutathione's generally poor oral bioavailability. 

However, Kyowa Hakko, makers of the patented Setria form of oral glutathione, have shown in a clinical trial that Setria is able to survive the digestive system and to increase blood levels of glutathione. 

With the advent of Setria glutathione, it is possible to supplement glutathione levels directly, rather than having to rely on supplementation with NAC or other precursors to indirectly boost glutathione levels.

EPA and DHA Omega-3 Fatty Acids

The omega-3 fatty acids (FA) are an essential group of nutrients that must be obtained from the diet.  The liver can convert the omega-3 FA alpha-linolenic acid (ALA) -- found in seeds, nuts and vegetable oils -- into eicosapentaenoic acid (EPA), and from EPA into docosahexaenoic acid (DHA), but only very inefficiently

The best dietary sources of EPA and DHA are oily fish such as salmon, sardines and mackerel, or algae and plankton.  In the US and in many parts of the EU, however, the most prevalent dietary form of omega-3 FAs is ALA; DHA and EPA are consumed in insufficient amounts.

DHA and EPA have been and continue to be extensively studied for their ability to modulate inflammation. 

Inflammation is the innate immune system's first-line response to infection or injury, and is characterized by redness, heat, swelling and pain.  These are the result of white blood cells, in particular neutrophils, rushing to the site of injury or infection to do their job to defend the body against the injury or infection.

Omega-3 fatty acids, in particular EPA and DHA, are actively involved in the regulation of both the initiation and the resolution of inflammation. 

In the initiation phase, EPA and DHA can act in an anti-inflammatory role, by regulating pro- and anti-inflammatory signaling molecules (cytokines and chemokines), and by modulating gene activity involving nuclear factor-kappa B (NF-κB).

In the resolution, or healing, phase, it has been discovered in the past 20 years that EPA and DHA are precursors to the molecules actively involved with and necessary for the successful resolution of inflammation, known as Specialized Pro-resolving Mediators (SPM).  A number of these SPM have been identified:  resolvins, protectins and maresins.

These inflammation-resolving SPMs are relevant not only to acute infection and injury, but to many chronic diseases as well, because these have chronic inflammation as their underlying characteristic:  for example, cardiovascular diseases, metabolic syndrome, autoimmune diseases, and neuro-cognitive diseases.

Thus EPA and DHA may be beneficial both for recovering from acute infection or injury, and for healing many chronic conditions involving underlying unresolved inflammation.

Additionally, in the past couple of decades, medical research has established that EPA and DHA are effective in lowering blood triglycerides, and they are now recommended as a treatment for hypertriglyceridemia.  And we saw above that high circulating triglycerides are central to the mechanism that triggers insulin resistance.

There is also evidence that EPA and DHA reduce fatty liver in NAFLD.

Vitamin D, Magnesium and Boron: Nutritional Triumvirate

Vitamin D is among the most powerful of micronutrients, being involved in the cell signaling of nearly every system in the body, including those involved in glucose metabolism and insulin signaling.  For its active metabolite form in the body, calcitriol, it is more accurate to state that vitamin D is a hormone rather than a vitamin. 

In particular, vitamin D is relevant to insulin resistance, as pancreatic beta cells (the cells that produce insulin) are involved in converting vitamin D to its active form; and a deficiency in vitamin D has been found to increase the risk of developing type 2 diabetes:

"Over the last decade, low blood 25-hydroxyvitamin D (25[OH]D) level has emerged as a risk factor for type 2 diabetes, and vitamin D supplementation has been hypothesized as a potential intervention to lower diabetes risk (, ). Observational studies strongly support an inverse association between blood 25(OH)D level and risk of developing type 2 diabetes in diverse cohorts of variable diabetes risk, especially in persons with prediabetes (, ). Results from short-term mechanistic studies offer a biologic plausibility to the hypothesis (, )....
The hypothesis that vitamin D status may influence the risk of type 2 diabetes is biologically plausible, because both impaired pancreatic beta-cell function and insulin resistance have been reported with low blood 25(OH)D levels (). Importantly, critical tissues in the physiology of glucose homeostasis, such as the beta cell, express 1-alpha-hydroxylase (CYP27B1) and can convert inactive vitamin D to its active metabolite (). Furthermore, vitamin D deficiency in mice leads to reduced insulin secretion that can be restored by vitamin D supplementation (). Systemic inflammation is another component in the pathophysiology of type 2 diabetes, and low blood 25(OH)D levels have been associated with high levels of inflammatory markers ()."

Magnesium:  Less well-known is magnesium's role in health:  it is involved in over 600 enzymatic reactions in the body, and is critical to heart, brain and musculoskeletal health.  It is difficult to get from the diet, and 60% or more of the population is estimated to be deficient in magnesium.  Magnesium modulates cellular reactions controlling inflammation and immune responses in the body -- a deficiency of magnesium will lead to increased inflammation and an over-reaction in immune responses.

Magnesium is important for glucose metabolism and insulin signaling, as it is critical for the enzymatic reactions that take place in the pancreas and liver:

"Patients with diabetes mellitus type 2 often have low serum Mg2+ levels (36, 491, 541). These low serum levels are associated with poor disease outcome and may even increase mortality (98). Hypomagnesemia may contribute to the development of diabetes mellitus type 2 by increasing insulin resistance. Insulin receptors (IR) are part of the family of tyrosine kinase receptors, and the kinase function is dependent on the binding of two Mg2+ ions (249). Upon activation of the IR, a complex intracellular signaling cascade is activated and mediated via insulin receptor substrate proteins (505). In low Mg2+ conditions, activation of the IR may result in diminished signal transduction, contributing to insulin resistance....
[G]iven that many of the enzymatic reactions that take place in the hepatocytes [liver cells] are dependent on Mg2+, particularly in fat metabolism, the importance of Mg2+ should not be underestimated. Mg2+ supplementation has been reported to reduce alanine aminotranferase (ALT) levels in obese women with hypomagnesemia (421).... The first reports of hypomagnesemia in liver diseases such as cirrhosis and nonalcoholic fatty liver disease suggest that liver function contributes to proper intestinal Mg2+ absorption (286, 526)."

Boron helps the body to use vitamin D; aids in the absorption of magnesium; works with both vitamin D and magnesium to reduce inflammation; raises levels of antioxidants such as glutathione; and aids in wound healing.  Boron deficiency has become widespread due to modern industrial agriculture, fertilizer use, and the depletion from topsoil of minerals essential to human health.

Vitamin D, magnesium and boron should be thought of as the three co-essential members of a nutritional triumvirate, and should be taken together.

Multivitamins and Minerals

Vitamins and minerals are essential to all aspects of human health, including healthy glucose metabolism and immunological health. 

A healthy immune system involves not only the ability to fight off infections by pathogens, or to clear toxins from the body, but also to remain in immunological balance so that chronic inflammatory or autoimmune disorders do not develop.  And we saw above that the diseases of insulin resistance involve chronic inflammation.

The best way to obtain the vitamins and minerals necessary for proper immune functioning is through the diet.

However, food has become much less nutrient-dense over the past couple of generations, both because of the soil-depleted conditions under which source ingredients are grown, and the increased prevalence of highly processed foods in our diet. 

Thus it has become more difficult to rely on diet alone to support immune function, and we don't always eat as well as we should.

Quality multivitamins like Support Protocols Men's and Women's Multivitamin Softgels contain more than the US RDA of vitamin C, zinc and selenium, which are known as having immune-supporting properties

But vitamin C, zinc and selenium by themselves are not enough for healthy immune function:  all vitamins and many minerals play a key role too:  vitamin A, the B vitamins (B1, B2, B3, B5, B6, B7, B9, B12) vitamin C, vitamin D, vitamin E, vitamins K1 and K2, iron, iodine, magnesium, and copper.

Additionally, many vitamins and minerals are involved in healthy glucose metabolism:  vitamin A, vitamin B and vitamin C, for example.

A well-balanced multivitamin and multi-mineral is an insurance policy and safety net for the diet, to make sure that every day we are getting the micronutrients we need for peak immune performance, to keep inflammation in check, and for healthy glucose metabolism.